Epidemiology and Prevention of Cardiovascular Disease: A Global Challenge, Second Edition

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Epidemiology and Prevention of Cardiovascular Diseases: A Global ChaLLEnge second edition

Darwin R. Labarthe, MD, MPH, PhD


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World Headquarters Jones and Bartlett Publishers 40 Tall Pine Drive Sudbury, MA 01776 978-443-5000 [email protected] www.jbpub.com

Jones and Bartlett Publishers Canada 6339 Ormindale Way Mississauga, Ontario L5V 1J2 Canada

Jones and Bartlett Publishers International Barb House, Barb Mews London W6 7PA United Kingdom

Jones and Bartlett’s books and products are available through most bookstores and online booksellers. To contact Jones and Bartlett Publishers directly, call 800-832-0034, fax 978-443-8000, or visit our website, www.jbpub.com. Substantial discounts on bulk quantities of Jones and Bartlett’s publications are available to corporations, professional associations, and other qualified organizations. For details and specific discount information, contact the special sales department at Jones and Bartlett via the above contact information or send an email to [email protected]. Copyright © 2011 by Jones and Bartlett Publishers, LLC All rights reserved. No part of the material protected by this copyright may be reproduced or utilized in any form, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without written permission from the copyright owner. This publication is designed to provide accurate and authoritative information in regard to the Subject Matter covered. It is sold with the understanding that the publisher is not engaged in rendering legal, accounting, or other professional service. If legal advice or other expert assistance is required, the service of a competent professional person should be sought. This book was written by Darwin R. Labarthe in his private capacity. No official support or endorsement by the Centers for Disease Control and Prevention, Department of Health and Human Services is intended, nor should be inferred. Production Credits Publisher: Michael Brown Editorial Assistant: Catie Heverling Editorial Assistant: Teresa Reilly Production Manager: Tracey Chapman Senior Marketing Manager: Sophie Fleck Manufacturing and Inventory Control Supervisor: Amy Bacus Composition: Auburn Associates, Inc. Cover Design: Kristin E. Parker Cover Image: fruit: © Daniel Gilbey/Dreamstime.com; family: © Pavel Losevsky/Dreamstime.com; no smoking: © Rosengaard/Dreamstime.com Printing and Binding: Courier Stoughton Cover Printing: Courier Stoughton Library of Congress Cataloging-in-Publication Data Labarthe, Darwin. Epidemiology and prevention of cardiovascular diseases : a global challenge / Darwin Labarthe. — 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-0-7637-4689-6 (pbk.) ISBN-10: 0-7637-4689-4 (pbk.) 1. Cardiovascular system—Diseases—Prevention. 2. Cardiovascular system—Diseases—Epidemiology. 3. Cardiovascular system—Diseases—Etiology. I. Title. [DNLM: 1. Cardiovascular Diseases—epidemiology. 2. Cardiovascular Diseases—prevention & control. WG 120 L113e 2011] RA645.C34L33 2011 614.5'91—dc22 2009044199 6048 Printed in the United States of America 14 13 12 11 10 10 9 8

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Contents Foreword xi Preface xiii Dedication xv Acknowledgments

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PART I—A PUBLIC HEALTH PERSPECTIVE Chapter 1

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Cardiovascular Diseases: A Global Public Health Challenge

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Summary 3 The Epidemiology and Prevention of Cardiovascular Diseases: Definition and Scope 3 The Basis of Public Health Concern Worldwide 5 Rates of Occurrence in Selected Populations and Changes in Recent Decades 10 Current Burdens of Major Cardiovascular Diseases in the United States and the World 12 Opportunities for Prevention 15 References 17

Chapter 2

Distributions and Disparities

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Summary 19 Introduction 19 Age and Life Stages 22 Sex or Gender 26 Race or Ethnicity 27 Geography or Place 29 Person, Place, and Time 32 Conclusion 35 References 36

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CONTENTS

PART II—THE MAJOR CARDIOVASCULAR DISEASES Chapter 3

Atherosclerosis

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Summary 41 Introduction 41 Methods of Measurement––Invasive and Noninvasive 42 Manifestations––Above and Below the “Clinical Horizon” 43 Mechanisms of Atherogenesis 46 Person, Place, and Time 47 Atherosclerosis in Childhood, Youth, and Early Adulthood 49 Prevention and Treatment of Atherosclerosis 54 Current Issues 55 References 55

Chapter 4

Coronary Heart Disease

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Summary 59 Introduction 59 Background 62 Population Studies––Definition and Classification, Diagnostic Algorithms, and Criteria Rates 65 Risks 74 Trends and Explanations 79 Forecasts 83 Current Issues 83 References 83 Appendix 4-A: Key to Population Abbreviations Used by the WHO MONICA Project

Chapter 5

Stroke

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Summary 89 Introduction 89 Background 91 Population Studies––Definition, Classification, and Diagnostic Methods Rates 93 Risks 101 Trends 104 Forecasts 107 Current Issues 107 References 107

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CONTENTS

Chapter 6

Related Conditions

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Summary 111 Introduction 111 Peripheral Arterial Disease 113 Aortic Aneurysm 120 Chronic Heart Failure 123 Deep Vein Thrombosis and Pulmonary Embolism Arrhythmias 135 References 136

PART III—THE MAIN DETERMINANTS Chapter 7

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Genes and Environment

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Summary 141 Introduction 142 Concepts and Strategies of Genetic Epidemiology 144 Family History 146 Gene–Environment Interaction 150 Cardiovascular Applications of Genomic Epidemiology 152 Current Issues 155 References 156

Chapter 8

Dietary Imbalance

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Summary 159 Introduction 159 Concepts and Definitions of Dietary Patterns Measurement 165 Determinants 168 Distribution 170 Cardiovascular-Related Effects of Diet 172 Prevention and Control 180 Current Issues 185 References 186

Chapter 9

Physical Inactivity

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Summary 191 Introduction 191 Concepts and Definitions Measurement 194

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Determinants 194 Mechanisms 196 Distribution 197 Cardiovascular-Related Effects Prevention and Control 211 Current Issues 217 References 218

Chapter 10

Obesity

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Summary 223 Introduction 224 Concepts and Definitions 224 Measurement 229 Determinants 229 Mechanisms 233 Distribution 236 Rates and Risks 244 Prevention and Control 253 Current Issues 262 References 262

Chapter 11

Adverse Blood Lipid Profile Summary 269 Introduction 269 Concepts and Definitions 270 Measurement 273 Determinants 274 Mechanisms 275 Distribution 277 Relation to Rates and Risks 283 Relation to Other Factors 290 Prevention and Control 292 Current Issues 302 References 304

Chapter 12

High Blood Pressure Summary 311 Introduction 312 Concepts and Definitions Measurement 316

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Determinants 317 Mechanisms 322 Distribution 323 Relation to Rates and Risks 336 Relation to Other Factors 339 Prevention and Control 341 Current Issues 351 References 352

Chapter 13

Diabetes and the Metabolic Syndrome Summary 361 Introduction 362 Concepts and Definitions 363 Measurement 366 Determinants 367 Mechanisms 368 Relation to Other Factors 369 Distribution 369 Rates and Risks 375 Prevention and Control 382 Current Issues 387 References 389

Chapter 14

Smoking and Other Tobacco Use Summary 395 Introduction 395 Concepts and Definitions 396 Measurement 397 Determinants 398 Mechanisms 398 Distribution 400 Relation to Rates and Risks 404 Relation to Other Factors 414 Prevention and Control 414 Current Issues 424 References 425

Chapter 15

Other Personal Factors Summary 431 Alcohol Consumption

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Adverse Psychosocial Factors 447 Hemostatic Factors 464 Evolving and Emerging Factors 476 References 491

Chapter 16

Social and Physical Environment

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Summary 503 Introduction 503 Social Status 505 Changes in Social Conditions 512 Particulate Air Pollution 522 Neighborhood Characteristics 524 Current Issues 527 References 528

PART IV—CAUSATION AND PREVENTION: THEORY, PRACTICE, AND FURTHER RESEARCH Chapter 17

What Causes Cardiovascular Diseases?

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Summary 535 Introduction 535 Causal Judgment 536 Causal Constructs 540 Causation of Atherosclerotic and Hypertensive Diseases Conclusion 547 Current Issues 547 References 548

Chapter 18

Strategies of Prevention

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Summary 551 Introduction 551 Concepts and Language of Prevention 552 Strategies of Prevention 557 Intervention Approaches 560 A Developing Country Perspective 561 Current Issues 563 References 565

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CONTENTS

Chapter 19

Evidence and Decision Making

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Summary 567 Introduction 567 Nature of Evidence 569 Evidence-Based Decision Making 570 Approaches to Evaluation of Evidence 573 Current Issues 587 References 587

Chapter 20

Recommendations, Guidelines, and Policies

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Summary 591 Introduction 592 Clinical Guidelines 594 Community Guidelines 607 Public Policies 609 Current Issues 613 References 614

Chapter 21

The Case for Prevention

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Summary 619 Introduction 619 Experience with Multifactor Primary Prevention 621 The Burden of Risk 636 Economic Considerations 640 Models for Explanation and Prediction 642 Visions of Success in CVD and Chronic Disease Prevention Counter-Arguments 648 Current Issues 649 References 649

Chapter 22

Taking Action

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Summary 657 Introduction: Calls to Action 657 Overview: Goals, Strategies, and Action Plans 658 Case Study: A Public Health Action Plan to Prevent Heart Disease and Stroke Obstacles to Taking Action 669 Current Issues 673 References 675

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Chapter 23

Epidemiology and a CVD Prevention Research Agenda Summary 679 Introduction 680 Concepts of Epidemiology 681 Goals 682 Strategies of Investigation 683 Proposed Research Agendas 685 Capacity Requirements 690 Populomics: The Population Context of Research on Health Current Issues 693 References 693

INDEX

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Foreword

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ublication of this second edition of Dr. Darwin Labarthe’s invaluable book, Epidemiology and Prevention of Cardiovascular Diseases: A Global Challenge is most opportune: As Dr. Labarthe emphasizes, the CVD prevention effort at this juncture—50 years down the road—confronts both “. . . considerable challenges and immense opportunities . . . .” On the one hand, the CVD epidemic persists; on a global scale it is waxing—indeed a challenge. And the challenge holds also for countries like the United States, where epidemic CVD persists despite substantial declines in coronary/stroke death rates during the latter decades of the 20th century. The current situation in the United States is problematic— as this book documents—making the challenges considerable indeed: tapering or cessation in recent years of down trends in CVD mortality and in major CVD risk factor levels (e.g., for saturated fat and cholesterol intakes, and for diet-dependent serum cholesterol and blood pressure); epidemic obesity with its consequences, including rampant incidence of diabetes and other obesity-driven metabolic CVD risk factors; unabated high salt intake; overall dietary and physical activity patterns still generally adverse populationwide including among children and teenagers; all too many still smoking, all too many teenagers becoming smokers; even more so for lower socioeconomic strata of all ethnicities, hence paltry proportions of all strata at low CVD risk––a critical index––and little or no evidence of a sustained upward slope in this index; in the media, especially TV, an on-going flood of promotions of foods/beverages harmful for heart health; in medical practice, overwhelming reliance on a high risk strategy (reactive, not proactive) to cope with these challenges––a focus on detection of people who already have a high level of the established major CVD risk factors and their long-term treatment with medications (in 2008, 320.4 million prescriptions for antihypertensive and 139.6 million prescriptions for antihypercholesterolemic drugs, as reported by the AARP). However useful for patients already at high CVD risk, this limited one-sided strategy relying on pills as the remedy begs the basic issue: Epidemics are due to population-wide exposures to new ways of

life for which the human species has not been adapted over the 2–4 million years of hominid/hominoid evolution; their roots are mass “. . . disturbances of human culture . . .” (Rudolf Virchow)—generalizations fully applicable/valid for the CVD epidemic, as this monograph details. To end the CVD epidemic, the sine qua non is rectification of the multiple disturbances in human culture causing it—a proposition repeatedly verified as valid by the history of conquest of earlier epidemics (e.g., tuberculosis, pellagra, rickets). The opportunities to conquer the CVD epidemic are indeed immense. First and foremost, prerequisite knowledge concerning the etiology of the CVD epidemic: the data base (already substantial 50 years ago) is now vast—extensive concordant data, worldwide in scope, accumulated over decades by epidemiology and every other research methodology available to medicine. Critical detailed information on the multiple causes of epidemic CVD is in hand—and for prevention of mass disease, such information on causation, the “question of questions,” is decisive. We know in depth what needs to be done—at every level of prevention—to break links in the chain of causation, including for primary and primordial prevention, i.e., the prevention in the first place (from preconception on) of the adverse lifestyles and the lifestylerelated established major risk factors. Crucial to this effort are improved eating patterns, Mediterranean and East-Asian style cuisines updated for this century, especially as to lower salt, plus moderation in intakes of alcohol, fats, and total calories—along with regular frequent exercise and non-smoking. The update for the 21st century—derived from the research achievements of the last 50 years—gives an enhanced nutrient intake pattern: as earlier, low in saturated fats and cholesterol; reduced in total fats; enhanced in polyunsaturated fats; calorie controlled; plus free of trans fats; much lower in salt; reduced in sugars especially separated sugars (e.g., from sweetened beverages); enhanced in total protein, especially vegetable protein (lower in animal protein from meats); for those who drink, moderate (not excessive) in alcohol; enhanced in potassium/calcium/magnesium/phosphorus/ non-heme iron, the vitamins, and fiber (from whole xi


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FOREWORD

grains/beans/vegetables/fruits). As this enumeration indicates, the research findings (including from population-based observational studies and clinical trials) document the multifaceted dietary imbalances–– concurrent excesses and inadequacies––now implicated in the etiology of the CVD epidemic and its diet-related major metabolic risk factors. Consequent recommendations enable variegated approaches to modern delightful eating styles assuring avoidance/rectification of these imbalances. These eating styles, along with regular frequent exercise, offer the potential for all population strata (socioeconomic/ethnic) to prevent/check/correct the nowadays still usual development of adverse levels of major metabolic risk factors: serum total/LDL/ VLDL/HDL cholesterol; blood pressure; plasma glucose; weight; and they go beyond these merits, since adverse eating patterns produce excess CVD risk over and above their adverse influences on these metabolic risk factors. So the opportunities are truly immense, as Dr. Labarthe emphasizes. Their scope encompasses potential for realization of the critical goal: continuous progressive enhancement in the coming years/decades of the percent of the population at low risk, so that for most people—not just a small minority—CVD risk is miniscule; they are freed of the burden of epidemic CVD, with consequent enhanced longevity with health. High stakes indeed! The opportunities are immense also because on a world scale and in several regions of the world, public policy is in place at the national level (including in the United States), policy committed to the accomplishment of CVD prevention through a two-pronged strategy (population-wide and high risk) emphasizing improved lifestyles. In a few places, public policy specifically includes priority for achieving the decisive goal of progressively increasing the percentage of the population at low risk. In the United States, substantial funds have recently been allocated—specifically to the national Centers for Disease Control and Prevention (CDC)—for the CVD prevention effort. Opportunities are immense also for this effort because many countries—ranging from Finland to Japan to the United Kingdom and the United States— have already over decades accrued extensive positive experiences with sustained public health efforts to improve lifestyles, thereby control lifestyle-related major CVD risk factors, and contribute to CVD

prevention/control. Repeatedly, the public has been responsive and substantial progress (albeit incomplete) has been achieved, despite opposition from special interests (including sectors of the food and beverage industries, the big tobacco companies)––e.g., in the United States, sizable declines in intakes of saturated and trans fats, total fats, cholesterol; the related decrease in adult population average serum cholesterol from about 240 mg/dl 50 years ago to about 200 mg/dl by the year 2000, achieving a national public health goal; marked falls in the prevalence of cigarette smoking; associated declines––in the order of 50% or more—in mortality from CHD and stroke, with consequent addition of years to life expectancy for young, middle-aged, and older adults. And, in several countries, as well as internationally, there are significant social movements in place, supporting/encouraging the effort, bringing together health professionals and lay leaders in effective alliances. As Dr. Labarthe notes, this too is an important component for a successful prevention effort—important today for CVD, as it was in the 19th century for TB control. All these are indeed solid bases for accomplishment of next key tasks. As noted repeatedly, this book is replete with many-sided up-to-date information invaluable for every person concerned with the CVD prevention effort. It is a fitting product of Dr. Labarthe’s extraordinary capacities and experiences over decades— as a colleague, teacher, researcher, public health leader—in academia, at the CDC, at local/national/ international learning venues, including the seminal US and International Ten Day Teaching Seminars on CVD Epidemiology and Prevention he has effectively led for years. On a personal note, over 40 years ago when I authored an early monograph on this same subject, it was my privilege for it to have a Foreword by Paul Dudley White, MD––distinguished cardiologist, statesman, world leader, humanist/humanitarian. Its opening sentence read, “Dr. Jeremiah Stamler has written the book on Preventive Cardiology that I would liked to have written.” Today these words are mine in regard to this volume by Darwin Labarthe. Jeremiah Stamler, MD Professor Emeritus Feinberg School of Medicine Northwestern University Chicago, Illinois


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Preface The central messages of this second edition are these:

change on the context and content of the book is substantial; however, it is necessary to underscore the disclaimer that the views expressed throughout are personal and are not intended to represent the official position of the US Centers for Disease Control and Prevention (CDC) or the US Department of Health and Human Services (DHHS). The book has changed principally in presenting greater emphasis on public health in cardiovascular disease prevention while retaining its epidemiologic content. The intent has been to increase the book’s value for both epidemiologists and public health professionals by bringing the original content up to date in Parts I–III and expanding discussion of how epidemiology is translated into policy and practice in Part IV. Currency has been achieved by including more than 1600 citations and nearly 400 tables and figures, many from recent sources; rewriting the chapters on the major cardiovascular diseases and their determinants; introducing a chapter on genomic epidemiology; and expanding discussion of the global dimensions of CVD. For many sources, URLs are included to permit continuing access for interested readers. New chapters in Part IV address strategies of prevention as part of a recently developed action framework; the nature of evidence for prevention, and methods for its evaluation as practiced by several leading authoritative bodies; current national, regional, and global recommendations, guidelines, and policies for prevention of CVD and other major chronic diseases; the case for CVD prevention at individual and population levels; and action plans adopted for implementation in the United States, Europe, South Asia, and worldwide. Expansion in these areas had one regrettable cost—lack of updates on rheumatic heart disease, Chagas’ disease, congenital heart disease, and Kawasaki disease—which are treated only in the first edition. Features retained in the second edition include the basic structure in which the public health perspective is introduced in Part I; the major atherosclerotic and hypertensive diseases are discussed in Part II;

(1) Cardiovascular diseases remain the foremost causes of preventable death globally and continue to grow in prominence, because of their attendant burden, disparities, and costs. (2) Epidemiology has contributed immeasurably to a vast body of knowledge about the causes and means of prevention of these and related conditions, but this knowledge has yet to be applied on a sufficient scale to confer its potential societal benefit. (3) Public health is accountable for putting this knowledge more fully to work by setting goals, devising strategic plans and policies, implementing targeted actions, and documenting their impact in improving the health of populations. These messages are consistent with the content of the first edition but have gained force from developments in the intervening decade: increased awareness of the global burden of cardiovascular diseases, with their immense social and economic consequences; a growing sense of need to integrate approaches to cardiovascular diseases with prevention of other chronic or noncommunicable diseases, with transformation of health systems to address them coherently; and the ever more urgent goal to reduce the mounting burden, disparities, and costs of these diseases. Epidemiology, through its applications in development, adoption, and implementation of health policy and in public health practice, is fundamental to achieving this goal. It is the author’s hope that this new edition will contribute to this effort. The difference of a decade is due importantly to advances in science and practice that better inform our understanding of the need and opportunity for effective action. From the start of this past decade, the perspective of the author, too, has advanced—from that of the academic epidemiologist to that of the public health practitioner. This was a result of undertaking a US governmental role at the federal level and the greatly enhanced public health experience afforded by this opportunity. The influence of this xiii


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PREFACE

their main determinants are reviewed sequentially in Part III; and implications of this evidence for theory, practice, and research are discussed in Part IV, which concludes with a chapter on CVD epidemiology of the future—the rich and varied research opportunities presented and the place of epidemiology as the core discipline of “populomics,” the scientific foundation of population health. A historic perspective is also retained, although this is not meant to recount the history of the field, which is being done in a far more effective way elsewhere. The purpose instead is to illustrate wherever appropriate the key studies that, from early in the development of CVD epidemiology, have made fundamental and lasting contributions to our current knowledge. Throughout the book, the unifying approach of a single author has the advantage of a consistent presentation and coherent interpretation across the many topics addressed. There is room for differing opinion and further exploration of many topics raised. The content reflects one person’s perspective and in no

case represents an exhaustive systematic review, although those of others are cited extensively. Closing each chapter is a more or less speculative suggestion of current issues most important for further discussion. In these ways the text is intended to stimulate thinking and debate. The author welcomes comments, queries, and criticisms from readers. A Chinese proverb says, “Teachers open the door but you must enter by yourself.”1 It is hoped that the material that follows will open many doors for students and practitioners of CVD prevention and public health, revealing a world of opportunity for fulfilling our highest obligation: to assure conditions in which people can be healthy.

Reference 1. Schiller D. The Little Zen Companion. New York: Workman Publishing; 1994.


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Dedication This book is dedicated to all whose work is reflected here and to all who will contribute to advances in the understanding of cardiovascular diseases and reduction of the public health burden they represent throughout the world.

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Acknowledgments George Howard, William Kannel, Thomas Kottke, Ian MacMahon, Henry McGill, Kenneth Pelletier, Douglas Schocken, Richie Sharrett, Jeremiah Stamler, Elaine Stone, Jack Strong, and Thomas Thom. Several peer reviewers provided valuable comment and suggestions. Although their anonymity precludes personal recognition, it is hoped that they will see their input reflected in the final product. Merrily Labarthe deserves boundless gratitude for her support and forbearance throughout this project.

Technical assistance in bibliographic work was provided with diligence and skill by T. Christopher Bond; the permissions process was supported by Tiffany Lynn Williams and by Anthony Omokheowa Anani and Elohor Anani. Contributions of critical points of information were made by Patty Borhani, Ross Brownson, Michele Casper, Elizabeth Barrett-Connor, Rory Collins, Leonard Cook, Jeffrey Cutler, Jack Farquhar, Lawrence Green, Nancy Haase, Millicent and Ian Higgins,

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A Public Health Perspective

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P A R T

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C H A P T E R

1 Cardiovascular Diseases: A Global Public Health Challenge vention of cardiovascular diseases define a significant public health challenge.

SUMMARY Cardiovascular diseases comprise especially the major disorders of the heart and the arterial circulation supplying the heart, brain, and peripheral tissues. Their common occurrence in most populations and the great attendant mortality, loss of independence, impaired quality of life, and social and economic costs are compelling reasons for public health concern. The epidemiology and prevention of these diseases involve the understanding of their causes, identification of means of prevention, and monitoring of populations to assess the changing burden of these diseases and the measurable impact of interventions to control them. Together, the cardiovascular or circulatory diseases have figured prominently in the large shifts among causes of death, especially in industrial societies, during the 20th century. During this period they have become the predominant cause of death in many countries and in the world as a whole. The “theory of epidemiologic transition” offers an interpretation of these shifts. It may have special implications for developing countries, as increasing proportions of these populations attain older ages, social changes unfold, and disease patterns change. Evidence indicates that cardiovascular diseases are already epidemic in low- and middle-income as well as high-income regions of the world and have become deep-rooted in most societies in recent decades. Cardiovascular epidemiology has documented the nature and extent of the major atherosclerotic and hypertensive diseases as global phenomena. It has contributed substantially to establishing their underlying causal factors. It has also identified the potential for prevention on a population-wide scale, including prevention of the risk factors themselves. Together, the global burden and immense opportunities for pre-

THE EPIDEMIOLOGY AND PREVENTION OF CARDIOVASCULAR DISEASES: DEFINITION AND SCOPE The cardiovascular diseases, or diseases of the heart and blood vessels, comprise many conditions that vary widely in manifestations and in public health importance. The present focus is chiefly on the atherosclerotic and hypertensive diseases. These are the cardiovascular conditions that develop on the basis of longstanding disease of the walls of arteries, especially in the heart, brain, and lower extremities, or of the aorta or as a consequence of persistently high blood pressure. In many but not all populations, these underlying processes—both atherosclerosis and hypertension—coexist. Heart attacks and strokes are very common manifestations of these conditions and are the chief contributors to their major public health importance. Also of public health concern are certain conditions affecting the venous circulation as well as disturbances of cardiac rhythm. After the presentation of a public health perspective on the atherosclerotic and hypertensive diseases in Part I, these and several related conditions will be described in detail in Part II. Their main determinants have become scientifically established over a half century or more through research in populations as well as clinical and laboratory studies. This population research is the main subject of Part III. The contribution of cardiovascular epidemiology to strategies of prevention of these conditions, the evidence and rationale for public health approaches to prevention, and plans of action regarding public health 3

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policy, practice, and research are addressed in Part IV, the concluding section. Preceding a broad overview that addresses some historical and global dimensions of the atherosclerotic and hypertensive diseases, two notes may be useful for clarification. First, terminology varies widely as the conditions of concern are defined and discussed throughout the extensive literature of this field. For example, “CVD” may refer to cardiovascular disease, meaning specifically disease of the heart or its blood supply, or to cerebrovascular disease, affecting the circulation of the brain. A major condition of the heart, coronary heart disease, may be abbreviated as “CHD,” “IHD” (ischemic heart disease), or “CAD” (coronary artery disease). Throughout the book, terminology of original sources is used in presentation of tables, figures, and sometimes text. It is hoped that fidelity to the source will not result in confusion for the reader. In general, the expressions “cardiovascular disease or diseases” or “heart disease and stroke” are used here as equivalent terms and refer to the full spectrum of the atherosclerotic and hypertensive diseases. Second, an underlying view of epidemiology in general and of cardiovascular epidemiology in particular doubtless gives shape to the organization and presentation of what follows. One premise is that the utility of epidemiology, and a great part of its societal value, depends on application of its findings toward improvement of the public’s health. Translated into cardiovascular epidemiology, the premise of this book is that the work of a half-century or more to understand the causes and discover the means of prevention of cardiovascular diseases on a national and global scale establishes not only the possibility but also the public health responsibility to seek effective action based on this science.

Table 1-1

An overview follows that addresses issues of classification; the nature and magnitude of the public health challenge; rates and burdens of cardiovascular diseases past, present, and future; and concepts of cardiovascular disease development and prevention. The Cardiovascular Diseases—An International Classification What is the scope of cardiovascular diseases? Definition and classification of the cardiovascular diseases, as with other conditions, have evolved with changing concepts of disease and take many forms, in part because of different purposes. In epidemiology, special value attaches to a classification that is standardized and in common use in many or most hospitals, medical practices, states, countries, and regions of the world. In this way, some confidence is justified that reference to the same condition in different information sources corresponds to the same reality. The leading source of such a classification for use throughout the world is the World Health Organization publication, now in its 10th revision, the International Statistical Classification of Diseases and Related Health Problems (ICD 10).1 Published in 1992, ICD 10 presents the category of Diseases of the Circulatory System as shown in Table 1-1. Each three-character code in this classification has an alphabetic initial followed by two digits. The alpha code for this category is the letter I, with blocks of digits from 00-02 to 90-95 that distinguish 10 classes. Within a block, each two-digit code corresponds to a distinct subset of that class. Greater detail can be provided by use of an additional decimal place. For example, for “ischemic heart diseases” (I20-I25) the code I21 identifies acute myocardial in-

Diseases of the Circulatory System (I00–I99)

I00–I02

Acute rheumatic fever

I05–I09

Chronic rheumatic heart diseases

I10–I15

Hypertensive diseases

I20–I25

Ischemic heart diseases

I26–I28

Pulmonary heart disease and diseases of pulmonary circulation

I30–I52

Other forms of heart disease

I60–I69

Cerebrovascular diseases

I70–I79

Diseases of arteries, arterioles, and capillaries

I80–I89

Diseases of veins, lymphatic vessels, and lymph nodes, not elsewhere classified

I90–I95

Other and unspecified disorders of the circulatory system

Note: Classification excludes congenital malformations, transient cerebral ischemic attacks and related syndromes, and certain others.

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pertensive diseases and selected venous system disorders (essentially I10-I15, I20-I25, I26, I60-I69, and parts of I70-I79, I80-I89, and G45) are discussed. In the chapters specific to a given condition, further detail of the ICD 10 codes will be noted, and earlier ICD codes will be referenced as needed. This is because ICD 10 has been widely implemented only recently; the data currently available on the conditions of interest therefore represent largely one or another of the previous versions, each of which was current for about a decade.

farction, or heart attack; codes I21.1 through I21.4 represent the anatomic location of the damage within the heart; and I21.9 is used for cases where location is not specified. Thus a case record, whether in the form of a death certificate or a hospital discharge summary, can potentially be coded in a consistent way, and cases with the same code can be collected and treated statistically as representing the same kind of circulatory event. The validity of such analyses depends, of course, on the quality of information available and the nosologic coding procedures applied. The conditions listed in Table 1-1 are those judged by the writers of ICD 10 to be classified best as diseases of the circulatory system. The conditions addressed in the following chapters are mainly I20-I25, I60-I69, and I10-I15. One additional category not shown in Table 1-1 also receives attention— transient cerebral ischemic attacks (TIA) or “light strokes.” For present purposes, these events are considered to belong with the cerebrovascular diseases or circulatory conditions affecting the brain. More detailed classification of these conditions is addressed in Chapters 3–6, in which the atherosclerotic and hy-

THE BASIS OF PUBLIC HEALTH CONCERN WORLDWIDE The Magnitude of the Problem Why do the cardiovascular diseases, taken together, warrant epidemiologic attention? The answer lies in part in the very large proportion of deaths, throughout the world, attributed to cardiovascular conditions. Figure 1-1 presents the percentages of deaths

World Total Perinatal diseases Accidents 6% 5% Cancer 9%

All other diseases 24%

Infectious and parasitic diseases 14%

CVD 23% Respiratory diseases (including TB) 18%

Industrial Countries

Developing Countries

Accidents 5% Cancer 6% Perinatal diseases 7%

Respiratory diseases (including TB) 7.5% Accidents 7%

All other diseases 27%

All other diseases 18.5%

Cancer 19%

CVD 16% Respiratory diseases (including TB) 21%

Infectious and parasitic diseases 18%

5

CVD 48%

Note: CVD, cardiovascular disease; TB, tuberculosis. Of the total deaths 78% are in developing countries.

Figure 1-1 Relative Contributions of Cardiovascular Death to Total Mortality in Developing and Industrial Countries and the World, 1980. Source: From Disease Control Priorities in Developing Countries, edited by DT Jamison et al., © 1993 by World Bank. Reproduced with permission of World Bank in the format Textbook via Copyright Clearance Center.

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due to cardiovascular diseases (“CVD” in the figure) in the world as a whole (23%) and separately in developing countries (16%) and industrial countries (48%) as already recognized in 1980.2 (This inclusive category comprises all cardiovascular deaths, which is heavily dominated by ischemic and hypertensive heart diseases and cerebrovascular disease.) Such estimates are subject to reservations, especially for the developing countries, as to the completeness of death registration and accuracy of cause-of-death assignment. Even allowing for these concerns, there is substantial support for the view that cardiovascular diseases have been increasing in frequency for some decades to constitute a rising public health problem of developing countries. In fact, the proportion of all deaths worldwide occurring in these populations is so great that the majority of cardiovascular deaths worldwide occur in developing countries.

the 20th century, as shown for the United States, over the period 1900–1970 in Figure 1-2.3 The importance of this early analysis of mortality in the United States is its contribution to a theory of populationwide changes in patterns of disease formulated in the 1970s, discussed below. The figure serves well even now to illustrate the changes in death rates, or the numbers of deaths per 100,000 population per year, due to multiple categories of causes over several decades. The relative shift for heart disease resulted from both an absolute increase in the rate of heart disease deaths (from a little more than 100 deaths to about 400 deaths per 100,000 population) and concurrent major decreases in other causes of death, especially in tuberculosis and other infectious diseases. Even before the 1920s, heart disease and stroke together exhibited mortality greater than that from any other category. In 2004 (the most recent year for which final mortality data were available at the time of writing), they still accounted for more than 35% of all deaths in the United States, as described in subsequent chapters.4

Changing Patterns of Mortality in the United States In industrialized countries, the prominence of heart disease among causes of death rose sharply during 2000 1000 INFECTIOUS DISEASES 500

Deaths per 100,000 Population

HEART DISEASE

CANCER STROKE

100

VIOLENT/ACCIDENTAL DISEASES OF EARLY INFANCY

50

10 TUBERCULOSIS 5

UNITED STATES 1900–1970 1

1900

1910

1920

1930

1940

1950

1960

1970

Years

Figure 1-2 Secular Trends for Cardiovascular Disease and Other Cause-Specific Death Rates in the United States, 1900–1970. Source: From the Population Bulletin. © 1977, Courtesy of the Population Reference Bureau, Inc., Washington, DC.

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Such vast shifts in causes of death stimulate strong epidemiologic interest because they must reflect profound changes in the factors that influence health and disease. Factors identified or confirmed through their association with such trends may constitute clues to causation or point to potential interventions. As will be seen, major increases or decreases in disease occurrence have until recently proven to be difficult to explain in retrospect. Methods of data analysis that incorporate information on factors related to prevention and treatment are currently used to sort out the contributions of these influences (see Chapter 4). But the experience of the United States indicated in Figure 1-2 is not unique, and such changes in patterns of mortality may be in progress in many countries. This creates the possibility of observing these changes—to the extent they may escape effective control measures—as they actually unfold in some populations. The likelihood of this is suggested both by epidemiologic theory and by a number of observations illustrated in the following section. The “Theory of Epidemiologic Transition” The theoretical basis for this view is that of “epidemiologic transition,” formulated by Omran in an analysis of long-term patterns of mortality in human societies and first published in 1971.5 According to Omran, “Conceptually, the theory of epidemiologic transition focuses on the complex change in patterns of health and disease and on the interactions between

these patterns and their demographic, economic, and sociologic determinants and consequences …”5, p 509 Omran distinguished three stages of progression, historically over centuries, in the dominant patterns of mortality: the “age of pestilence and famine,” the “age of receding pandemics,” and the “age of degenerative and man-made diseases.” In a later extension of the theory, Olshansky and Ault have proposed a fourth stage, the “age of delayed degenerative diseases.”6 These four stages of the epidemiologic transition are indicated in a representation by Gaziano and others published in the second edition of a major World Bank publication, Disease Control Priorities in Developing Countries, in 2006 (Table 1-2).7 These authors elaborate on an earlier version presented by Pearson and others2 by expanding the description of each stage and adding information on life expectancy, the percentage of the world’s population in each stage, and the regions affected. In addition, they note “CHF”—chronic heart failure—among dominant forms of cardiovascular diseases present in the fourth phase (see Chapter 6). One point of particular interest in this and the previous version of the table is the “percentage of deaths attributable to CVD.” These estimates of proportionate mortality due to cardiovascular diseases in each stage were introduced by Pearson and colleagues as approximations based on their judgment (T.A. Pearson, personal communication, 2004). The shift from very low to much higher frequencies of circulatory diseases

Table 1-2

The Epidemiologic Transition Phase of Deaths from Epidemiologic Circulatory Transition Disease (%) Age of pestilence 5–10 and famine

7

Circulatory Problems Rheumatic heart disease; infectious and deficiencyinduced cardiomyopathies

Risk Factors Uncontrolled infection; deficiency conditions

Age of receding pandemics

10–35

As above, plus hypertensive heart disease and hemorrhagic stroke

High-salt diet leading to hypertension; increased smoking

Age of degenerative and man-made diseases

35–55

All forms of stroke; ischemic heart disease

Atherosclerosis from fatty diets; sedentary lifestyle; smoking

Age of delayed degenerative diseases

Probably under 50

Stroke and ischemic heart diseasea

Education and behavioral changes leading to lower levels of risk factors

Note: Omran introduced the concept of epidemiologic transition with discussion of phase 1, 2, and 3. Olshansky and Ault added the concept of a fourth phase. a

At older ages. Represents a smaller proportion of deaths.

Source: From Disease Control Priorities in Developing Countries, edited by DT Jamison et al. Copyright © 1993 The International Bank for Reconstruction and Development/The World Bank. Used by permission of Oxford University Press, Inc.

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as causes of death is much like that demonstrated in Figure 1-2. As shown in Table 1-1, under this theory circulatory diseases increase from a minor proportion of all deaths in the first stage to become the predominant cause of death in the third stage; finally, they may decrease slightly in relative importance, though still perhaps representing the largest single category of deaths. Characteristic shifts also occur in the predominance of particular forms of circulatory disease over the successive phases: first, solely rheumatic heart disease and cardiomyopathies; second, these and also hypertensive heart disease and hemorrhagic stroke; third, all forms of stroke plus ischemic heart disease; and fourth, the latter causes persisting but occurring at older ages and as a somewhat reduced proportion of all deaths. In the United States and other countries undergoing industrialization in the 19th and 20th centuries, this epidemiologic transition is already far advanced into the third or fourth stage. Developing countries, however, have widely been thought to remain in the

first or second stage because proportionate mortality from circulatory conditions remained low; but absolute rates reached levels of concern even while dominance of communicable diseases persisted. Two decades and more ago, demographic changes already under way were thought capable of producing more rapid transition in these countries than was experienced by the already-industrialized countries. Dodu, of the World Health Organization Cardiovascular Diseases Unit in Geneva, wrote in 1988 of the emergence of cardiovascular diseases in developing countries.8 He presented data (Figure 1-3), based on Omran’s work, to show that the percentage of deaths due to cardiovascular diseases (and cancer) in a population increases as life expectancy at birth increases. This would be anticipated because cardiovascular disease death rates are very much higher for successively older age groups in adulthood. As shown by Dodu, when the average person attains age 61 or 62 years, cardiovascular diseases are expected to predominate over infectious diseases as a cause of death.

Figure 1-3 Percentages of Deaths Due to Cardiovascular Diseases (CVD), Cancer (CAN), and Infections, in Relation to Life Expectancy at Birth. Source: From Cardiology, Vol 75, Emergence of Cardiovascular Diseases in Developing Countries, SRA Dodu, © 1988 S Karger AG, Basel. Reproduced with permission from United Nations Secretariat, p 58.

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Dodu further demonstrated, as shown in Figure 1-4, that life expectancy at birth increased sharply in developing regions of the world in the third quarter of the 20th century. Further, this increase was projected to continue, so that by the year 2000 even Africa would attain an average life expectancy at birth of nearly 60 years. This value would be exceeded slightly by that for the population of South Asia but by far for East Asia and Latin America. This changing demographic picture alone, influenced partly by recession of infectious diseases as a cause of neonatal and infant mortality, leads to an expectation of an increasing proportion of deaths from circulatory diseases, in accordance with the theory of epidemio-

9

logic transition. As a concrete example, Dodu cited the experience of Singapore, where in 30 years (1948–1979) life expectancy increased from about 40 years to 70 years, and cardiovascular diseases shifted from only 5% to more than 30% of all deaths. Economic Considerations Worldwide public health concern about cardiovascular diseases is partly because of the high frequency of occurrence of these diseases as a cause of death. This reality continues in industrialized countries and is increasingly recognized in developing countries. In addition, among the personal and social costs of cardiovascular diseases, both fatal and nonfatal, are their

Figure 1-4 Life Expectancy in Relation to Calendar Time, by Region of the World, 1950–2030. Source: From Cardiology, Vol 75, Emergence of Cardiovascular Diseases in Developing Countries, SRA Dodu, © 1988 S Karger AG, Basel. Reproduced with permission from United Nations Secretariat, p 62.

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economic costs, which are increasingly important. In the United States in the year 2009, for example, the cost of medical care alone for cardiovascular diseases is projected to be $313.8 billion, with additional indirect costs due to disability and death in working years of $161.5 billion, making the total one-year economic burden $475.3 billion.4 The World Health Organization estimated the economic burden of lost income (analogous to the indirect costs above) due to heart disease, stroke, and diabetes for nine countries across a spectrum of income levels, over the years 2005–2015.9 For China, such losses were projected to reach 18.3 billion international dollars for 2005 and 131.8 billion dollars in 2015. These macroeconomic dimensions of cardiovascular diseases lend importance to intensified efforts to prevent these diseases in populations throughout the world, in both industrialized and developing countries.

RATES OF OCCURRENCE IN SELECTED POPULATIONS AND CHANGES IN RECENT DECADES World Bank Regions, 1985 The status of the major regions of the world with respect to mortality from circulatory system diseases toward the end of the 20th century is summarized in Table 1-3.2 For the total world population and for each geographic/economic area distinguished by the World Bank, Table 1-3 indicates for 1985 the total numbers of deaths (in thousands), the percentages of the total due to circulatory diseases (as discussed

above), and the death rate (per 100,000 population, adjusted for differences between regions in age composition) for all circulatory diseases and for two of the component categories, ischemic heart disease and cerebrovascular disease. The percentages of deaths from circulatory diseases were highest for the industrial economies, both market economies such as the United States (46%) and nonmarket ones such as the countries of the former Soviet Union (47%). They were only one-half to one-quarter as high for the remaining four regions (10–22%). The total death rate was highest for the industrial nonmarket economies (357 per 100,000). This group of countries experienced a 60% higher death rate from “ischemic disease” and a 65% higher death rate from cerebrovascular disease than did the industrial market economies. Scrutiny of Table 1-3 reveals something of a paradox. The lower percentages of deaths due to circulatory diseases in all of the nonindustrial regions might be taken as consistent with the epidemiologic transition and give the impression that circulatory diseases are not yet important in these regions. However, this interpretation is refuted by the actual death rates for ischemic disease and cerebrovascular disease. These rates were nearly as high or higher for nonindustrial as for industrial market economies—such as the United States. Asia was again exceptional, in this instance by having the lowest mortality for “ischemic disease” of any region (46 per 100,000) and the highest for cerebrovascular disease (91 per 100,000) outside the industrial nonmarket region. Clearly, both categories of circulatory disease were as well established in the nonindustrial regions of the world as in the industrial market economies as measured by mortality experience as

Table 1-3

Estimated Mortality from Circulatory System Diseases, World Bank, 1985 Age-Standardized Death Rate (per 100,000 Population)a Region Deaths Total Ischemic Cerebrovascular (Thousands) Deaths (%) Total Disease Disease Industrial market economies 3355 46 235 99 59 Industrial nonmarket economies 2220 47 357 164 106 Latin America and the Caribbean 691 22 222 69 57 Sub-Saharan Africa 756 10 273 85 74 Middle East and North Africa 602 14 250 82 68 Asia 3841 17 195 46 91 Total 11,465 23 243 84 81 a

Rates are standardized using the 1985 world age structure.

Source: From Disease Control Priorities in Developing Countries, edited by DT Jamison et al. Copyright © 1993 The International Bank for Reconstruction and Development/The World Bank. Used by permission of Oxford University Press, Inc.

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RATES OF OCCURRENCE IN SELECTED POPULATIONS AND CHANGES IN RECENT DECADES

early as 1985, more than two decades ago. These rates were simply dominated in these regions by persistent high mortality from noncirculatory causes, resulting in low proportionate mortality despite substantial circulatory death rates. The epidemiologic transition had evidently taken a different course in these regions than in the industrialized parts of the world. Change from 1988–1998 in 15 Countries As of the late 20th century, marked differences—2- to 3-fold in Table 1-2—in mortality from specific cardiovascular causes were demonstrable in populations comprising major economic and geographic regions of the world. The mortality pattern of a single country such as the United States was seen to have evolved throughout much of the last century. But a country may experience striking change in ischemic heart disease mortality within a decade or less, as shown in Figure 1-5.7 In this figure, data on ischemic heart disease mortality are presented as the percentage change in death rates among people aged 35–74 years at death,

from 1988 to 1998 for 15 selected countries. The changes in rates are shown for both males and females in each country. The resulting picture is one of a continuous gradient of change that ranges from ⫹62% to ⫺49% for males in Croatia and Denmark, respectively, and from ⫹61% to ⫺52% for females in Croatia and Australia, respectively. That the adverse, upward changes were clustered in Eastern European countries of the former Soviet Union is noteworthy, as is the exceptional situation of Hungary with virtually no change. Also noteworthy is the similarity in patterns of change—in both direction and magnitude—for males and females in the same countries. These differences over time in changes in mortality are of great epidemiologic interest because of the between-population dimension of variation that they represent and resulting possibilities for comparative investigation. Deeper insight into the causes of these large population changes and the potential for prevention or control of the underlying epidemic processes would be anticipated as a result.

62%

Croatia

61%

Kazakhstan

56%

Belarus

53%

30%

Ukraine

49%

38%

Romania

26% 26% 210%

Japan

22%

Hungary 215%

Greece

229%

Portugal

28% 2% 211% 219%

229% 239%

Netherlands

Luxembourg

36%

229% 230%

United States

Sweden

11

240% 220%

243% 243%

Australia

252%

246%

Denmark

246%

249%

Males Females

Figure 1-5 Percentage Change in Ischemic Heart Disease Death Rates in People Age 35–74, 1988–1998, Selected Countries. Source: Reproduced with permission from Disease Control Priorities in Developing Countries, 2nd edition, edited by DT Jamison et al., © 2006 by World Bank. Courtesy of the International Bank for Reconstruction and Development/The World Bank.

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CURRENT BURDENS OF MAJOR CARDIOVASCULAR DISEASES IN THE UNITED STATES AND THE WORLD US Mortality and Morbidity Among Adults, Children, and Youth at Mid-Decade, 2000–2010 In the United States, not only vital statistics but also extensive survey data from several sources contribute to an ongoing assessment of the cardiovascular disease burden. The Centers for Disease Control and Prevention (CDC) operate multiple surveillance systems, including those of the National Center for Health Statistics. The National Health and Nutrition Examination Survey (NHANES) began with periodic surveys first conducted in 1960–1962 and has now become a continuous data collection process with a complete new probability sample of the civilian, noninstitutionalized population of the nation as a whole every 2 years. The Behavioral Risk Factor Surveillance System (BRFSS) is a telephone interview survey conducted annually in a probability sample of each of the 50 states and the District of Columbia. Numerous other systems collect data on specific behaviors, hospital and ambulatory medical care, and other related topics. The National Heart, Lung and Blood Institute conducts continuing multicenter population studies across the adult age range—most renowned being the Framingham Heart Study—and including the Coronary Artery Risk Development in Young Adults Study (CARDIA), the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and others. Each year the American Heart Association, through the work of a committee representing these

agencies and the broader cardiovascular epidemiology community, compiles data from these and other sources into an extensive update published online (www.americanheart.org) as well as in the journal Circulation. The 2008 update concluded with summary tables illustrated by Table 1-4a, for adults, and Table 1-4b, for children and youth.4 The estimated numbers and percentages of persons in the United States as a whole and numbers or percentages by sex within categories of race/ethnicity are indicated. With few exceptions these data represent the years 2006 or 2007. To appreciate these summary data fully requires familiarity with the design and methods of each source, for which references are provided in the publication. It is important to note certain limitations, however. Not all population groups of interest are represented, such as American Indian/Alaska Natives or Asians, for whom limited available data are provided in the body of the report. Prevalence estimates are based on sample surveys and projected to the population as a whole, with whatever limitations of sampling error and bias from nonparticipation may apply. Reference to “new and recurrent” CHD and strokes reflects inability from available data to distinguish between first events and recurrences, and numbers of events could include multiple events in the same individual. Among persons age 20 or older, more than 80 million are estimated to have some form of cardiovascular disease (Table 1-4a). Included in this total are CHD, stroke, high blood pressure (HBP), and heart failure (HF), as well as other conditions. Coronary heart disease is by far the dominant condition with respect to reported deaths (more than 450,000), with

Prevalence of Selected Cardiovascular Conditions in Adults,a by Sex and Race/Ethnicity, United States, 2006 High Blood Heart Total CVDb CHDc Stroke Pressure Failure 80.0 16.8 6.5 73.6 5.7 All Adults (⫻106) Females (%) Whites 33.3 6.6 3.2 30.3 1.8 Blacks 45.9 9.0 4.1 43.9 4.2 Mexican Americans 32.5 6.3 3.8 30.4 1.4 Males (%) Whites 37.8 8.8 2.3 34.1 3.1 Blacks 45.9 9.6 3.9 44.4 4.2 Mexican Americans 26.1 5.4 2.1 23.1 2.1 a Ages ⱖ 20 years. Table 1-4a

b

CVD, cardiovascular diseases.

c

CHD, coronary heart disease.

Source: Data from Heart Disease and Stroke Statistics—2009 Update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Committee. D Lloyd-Jones et al., © 2008. Courtesy of the American Heart Association/American Stroke Association.

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CURRENT BURDENS OF MAJOR CARDIOVASCULAR DISEASES IN THE UNITED STATES AND THE WORLD

Table 1-4b

13

Prevalence of Selected Cardiovascular Risk Factors in Children and Youth, by Sex and Race/Ethnicity, United States, 2007a Mean Total Meet Current Current Cholesterol Physical Activity Cigarette Concentration Recommendations Smoking (%) (mg/dl) (%) Overweight (%) (Grades 9–12)b (Ages 12–19 Years)c (Grades 9–12)b (Ages 2–19 Years)c

Females White Black Hispanicb or Mexican Americanc Males White Black Hispanicb or Mexican Americanc

22.5 8.4 14.6

165.0 162.8 163.1

27.9 21.0 21.9

29.5 39.2 35.0

23.8 14.9 18.7

154.5 161.7 158.2

46.1 41.3 38.6

31.9 30.8 40.8

a

Mean total cholesterol concentration from the National Health and Nutrition Examination Survey, 2005–2006; overweight from the National Health and Nutrition Examination Survey, 2006. bData for Hispanics. cData for Mexican Americans. Source: Data from Heart Disease and Stroke Statistics—2009 Update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Committee. D Lloyd-Jones et al., © 2008. Courtesy of the American Heart Association/American Stroke Association.

stroke deaths occurring about one-third as frequently (150,000). More than one-half of the total cardiovascular disease deaths are due to coronary heart disease. Because the total prevalence for the four specified conditions would be 100.1 million, it is evident that some persons are affected by multiple conditions. High blood pressure predominates in the prevalence estimates overall and in each sex-race/ethnicity group and differs notably in prevalence among groups— from 23.1% in persons identified as Mexican American males to 43.9% in Black females. Differences between Blacks and Whites in prevalence of total CVD and several components parallel their differences in high blood pressure. The importance of these prevalence figures is that they represent the numbers of persons who continue to live with each condition, perhaps having disability or incurring substantial medical care costs, as well as high risk of recurring cardiovascular events. They also underscore the fact that mortality data, which have been considered alone up to this point in the discussion, do not provide a complete picture of the cardiovascular diseases. Information of other kinds is needed for adequate assessment of their importance in the population. It is striking that large proportions of the population—children and youth as well as adults (Tables 1-4a and 1-4b)—are affected by the indicated risk factors: tobacco use, high blood cholesterol, physical inactivity, being overweight or obesity, and diabetes. Each of these and several other factors are examined in detail in Part III.

World Income Groups and Regions, 2001 To update the global experience of cardiovascular mortality from the previous pictures of 1980 and 1985 (Figure 1-1 and Table 1-3), the recent World Bank publication, Global Burden of Disease and Risk Factors, provides estimated ischemic heart disease and cerebrovascular disease mortality as numbers of deaths and percentages of all deaths in 2001 for economic (highand low- and middle-income) and geographic regions of the world (Table 1-5).10 It is important to recall discussion of proportionate mortality in the context of the theory of epidemiologic transition, above. Here, a portion of circulatory mortality is represented by the sum of percentages of death in the two major categories shown: among low- and middle-income countries, from 47.9% in Europe and Central Asia to 6.5% in subSaharan Africa, versus 27.2% in the aggregate of highincome countries. Europe and Central Asia include the nonmarket industrial economies, in which death rates from these causes were highest among world regions in the 1985 World Bank data (Table 1-2). Together, these two components of circulatory mortality in 2001 accounted for 2,714,000 deaths in the region. But even in sub-Saharan Africa, 698,000 deaths were attributed to these two causes. They also represented more than 10 million deaths in low- and middle-income countries overall, and just over 2 million in high-income countries. These estimates indicate a substantial public health burden from ischemic heart disease and cerebrovascular disease in the developing world by the year 2001; other estimates date the establishment of these conditions in developing countries earlier.

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Table 1-5

Percentages and Numbers of Deaths Attributed to Ischemic Heart Disease and Cerebrovascular Disease, by Broad Income Group and by Region Among Low- and Middle-Income Countries, 2001 Income Group and Ischemic Heart Cerebrovascular Region Disease Disease (%) N (ⴛ1000) (%) N (ⴛ1000) Low- and Middle-Income - East Asia and Pacific 8.8 1151 14.6 1902 - Europe and Central Asia 29.7 1685 18.2 1029 - Latin America and the Caribbean 10.9 358 8.2 267 - Middle East and North Africa 16.9 323 6.8 130 - South Asia 13.6 1838 6.8 923 - Sub-Saharan Africa 3.2 343 3.3 355 All 11.8 5699 9.5 4608 High-Income 17.3 1364 9.9 781 Source: Data from Global Burden of Diseases Study, edited by AD Lopez. © 2006. The International Bank for Reconstruction and Development/ The World Bank.

Projected Cardiovascular Contributions to the Global Burden of Disease Early assessments of the global burden of cardiovascular diseases focused on available mortality data, which are often the most readily found health indicator albeit with important and sometimes severe limitations. Two significant new approaches were undertaken with a major initiative under leadership of C.J.L. Murray and A.D. Lopez, the Global Burden of Disease and Injury Series that began in 1988.11 First, it represented a major new investment in making country-level estimates for the world population both for a baseline year, 1990, and projected to 2020, thus providing insight for health policy that might reduce or avert the anticipated burdens of specific diseases. Second, the project went beyond mortality data to estimate burdens due to disability and to deaths within the working years. Extensive discussion of methods and detailed presentation of country- and regionspecific data occupy several volumes of published material from this study, including the 2006 publication that provided the data for Table 1-5. Deaths, Years Lost, and Disability Three aspects of the projections for ischemic heart disease and stroke, from 1990 to 2020, are presented

here (Table 1-6). First is the relative position of these two conditions among all major causes of death worldwide, as estimated for each of these years. Ischemic heart disease and cerebrovascular disease were found to be the first and second leading causes of death worldwide as of 1990 and were projected to remain in this rank 30 years later, in 2020. Second, years of life lost (YLL) were estimated, taking into account predicted ages at death in relation to an assumed life expectancy of 82.5 years. In these computations, ischemic heart disease was projected to advance from fourth to first rank and cerebrovascular disease from seventh to third rank between 1990 and 2020. Not only the fact of death but also the age at death is taken into account in estimating the burden. Third, in addition to years of life lost, years lived with disability of given severity is combined to yield the measure of disability-adjusted life years (DALYs). When attributed to specific causes, these can then similarly be ranked as to their contribution to disease burden for a given population. The results for ischemic heart disease and stroke were, respectively, increases from fifth to first rank and from sixth to fourth rank from 1990 to 2020. It is noteworthy that both conditions contribute importantly to disease burden in terms

Table 1-6

Rank Order of Ischemic Heart Disease and Cerebrovascular Disease as Causes of Death, Years of Life Lost (YLL), and Disability-Adjusted Life Years (DALYs), 1990 and 2020 Death YLLs DALYs Condition 1990 2020 1990 2020 1990 2020 Ischemic heart disease 1 1 4 1 5 1 Cerebrovascular disease 2 2 7 3 6 4 Source: Data from Global Burden of Diseases Study, edited by CJL Murray and AD Lopez, © 1996. Harvard School of Public Health.

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OPPORTUNITIES FOR PREVENTION

not only of death but also of reduced life expectancy and disability. Ischemic heart disease ranks first among all health conditions in all three measures by 2020 scarcely more than a decade from now. The World Health Organization has developed maps of the global distribution of DALYs lost to coronary heart disease and to stroke that are accessible at: http://www.who.int/cardiovascular_diseases/resources/ atlas/en/index.html. Productive Years of Life Lost In a further approach to gauging the population impact of death and disability attributable to cardiovascular diseases, Leeder and colleagues reported a subsequent analysis, A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries.12 The study was undertaken in an effort to put cardiovascular diseases on the world map after it was neglected, as were the chronic diseases overall, in a major report on macroeconomics and global health. Its message was that death and disability from cardiovascular diseases will strike working age populations with a devastating impact on economic development of low- and middle-income countries unless effective public health action is taken urgently. The strategy of A Race Against Time was to examine “productive years of life lost” by focusing on the projected cardiovascular disease mortality occurring in the workforce at ages from 35 to 64 years. The impact was estimated for the year 2000 and projected to 2030, in five countries—Brazil, South Africa, Russia, China, and India. The United States and Portugal were assessed as comparison countries, the former with markedly declining cardiovascular mortality and the latter with the lowest rates among the high-income countries of Europe. Details of the methods are presented in the report, and the central findings are summarized in Table 1-7. Table 1-7

Country Brazil S. Africa Russia China India US Portugal

15

The specific age group of interest, with sufficiently high cardiovascular disease mortality to be significantly affected, was persons from 35 to 64 years of age. The 30-year projections indicate a major increase in years of life lost from 2000 to 2030 for India and China and a similar relative (though much lesser absolute) increase for Brazil. The 2030 rate for the United States of 1661 years of life lost/100,000 population is not markedly less than that for China, 1863/100,000—but the relative population sizes of the countries contribute to a five-fold greater impact in China. Among 10-year age groups within the workforce, the 45–54 year age group generally experiences the heaviest burden. Among the authors’ conclusions is this central point: “that without concerted, ongoing intervention to prevent the precursors and reverse the negative effects of CVD in developing countries, a global health crisis in the current workforces (and later among the elderly) of those countries will occur––and sooner, rather than later.”12, p 84

OPPORTUNITIES FOR PREVENTION An overview of the major cardiovascular diseases as a public health challenge would be incomplete without recognizing opportunities for prevention. It is the potential impact of effective public health action that makes the challenge more than an academic interest and a matter of urgent national and global health policy. In Part IV, concepts and strategies of prevention, supporting evidence and the case for prevention, and finally a plan of public health action to prevent cardiovascular diseases on a population level are discussed in some detail. But briefly, here, before the major conditions themselves and their determinants are addressed in Parts II and III, a closing note on prevention is included for perspective.

Productive Years of Life Lost (Thousands) Due to Cardiovascular Diseases by Decade of Age and Overall, 35–64 Years, in Selected Countries, Years 2000 and 2030

Age 35–44 2000 358 112 976 1551 2260 481 13

2030 487 125 740 1768 3691 443 12

Age 45–54 2000 457 123 1427 3070 3959 714 16

2030 740 157 1420 3695 7790 741 22

Age 55–64 2000 246 67 911 2046 3002 437 12

2030 514 110 1012 4998 6456 789 19

Age 35–64 2000 1061 302 3314 6667 9221 1631 41

a

Rate/100,000 population at age 35–64.

Source: Data from A Race Against Time, © 2004, The Trustees of Columbia University in the City of New York.

2030 1742 392 3208 10460 17937 1,972 53

Ratea in 2030 1957 2667 5887 1863 3707 1661 1317

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The past half-century, in which cardiovascular epidemiology came into being, saw not only extensive documentation of the occurrence of cardiovascular diseases throughout the world but also successful investigation of its underlying causes and means of prevention. Strategies of prevention were derived from the concept of risk factors, introduced in 1961 by Dawber and colleagues in the Framingham Heart Study.13 Rose articulated most clearly, in 1981 and after, the idea of two complementary approaches to shifting adverse population distributions of risk factors toward more favorable ones, by a “high-risk” strategy of intensive intervention targeting those at the extreme of risk and a “mass“ or “population-wide” strategy to shift the whole distribution toward lower risk.14 Strasser, meanwhile, had proposed in 1978 what he termed “primordial prevention.”15 This was conceived as a means of preventing, on a worldwide front, the epidemics of risk factors themselves that Rose’s strategies were devised to reverse. In 2004, Stamler and colleagues reviewed the history of research that established the major risk factors—serum total cholesterol, blood pressure, cigarette smoking, body mass index, diabetes, and, the “pivotal” factor, adverse diet. He emphasized the concept of maintaining low risk, or absence of risk factors, in increasing proportions of the population through “safe improvements in population lifestyles, especially dietary habits from childhood on.”16,17 The concept of primordial prevention is clearly embedded in the idea of maintaining low risk, on a population-wide basis and beginning in childhood. Growing recognition of the global dimensions of the cardiovascular disease epidemic, evidenced for example in the attention paid by the World Bank, has stimulated efforts to place cardiovascular diseases and, more broadly, chronic diseases on national and global health agendas. This effort has itself been a challenge. In the United States, for example, a report in the mid-1990s on this nation’s investment in chronic disease prevention indicated that less than 3% of the aggregate budgets of state health departments, where constitutional responsibility for public health resides, and a similarly small proportion of public health personnel were dedicated to chronic disease prevention.18 A Race Against Time, published in 2004, was a rejoinder to the World Health Organization Commission on Macroeconomics and Health that failed to acknowledge the role of chronic diseases among major health-related impediments to economic development.12 The editor of The Lancet in 2005 addressed “The neglected epidemic of chronic disease” in introducing a set of reports exhorting

health policy-makers throughout the world, and especially in India and China, to take meaningful action in this area.19–23 It is significant that the recently expanded report Global Burden of Disease and Risk Factors incorporates a detailed assessment of risk factors, as well as diseases on a national, regional, and global scale.24 Among the extensive data presented are estimates of the contributions of selected risk factors to the burden (in DALYs) and mortality due to ischemic heart disease and stroke, both worldwide and separately for high- and low- and middle-income regions (Table 1-8). The population attributable fraction (PAF) for each risk factor and outcome represents the percentage of “burden” (in DALYs) or mortality that would be avoided if the lowest population risk, or “theoretical-minimum-risk exposure distribution,” rather than the actual or assumed distribution were present for the population in question. Each factor is considered separately, although factors frequently overlap in their occurrence. As a result, the cumulative percentages for multiple risk factors may exceed 100%. Mazzati and coauthors present details of methods for estimating joint effects of multiple risk factors (Joint PAF). For the risk factors considered individually, high blood pressure stands out as the leading factor for stroke and is nearly equivalent to high cholesterol for ischemic heart disease. For example, if the blood pressure distribution of the high-income region were reduced to the theoretical-minimum-risk exposure (estimated to be 115 mm Hg with a standard deviation of 6 mm Hg), the burden of stroke in DALYs would be expected to be 56% lower for the region. Attributable fractions for blood pressure and cholesterol, as well as for smoking and alcohol use, are higher in high-income than in low- and middleincome regions, although the differences in PAF for high blood pressure are negligible. Low fruit and vegetable intake and physical inactivity contribute more strongly to risk of ischemic heart disease than to stroke. Urban air pollution, though minor in relation to other factors, does contribute to both outcomes, to a greater degree in the low- and middle-income than the high-income region. Importantly, the joint contribution of these risk factors accounts for the great majority (80%) of ischemic heart disease as well as the majority (60–70%) of stroke, with only minor differences between economic regions. This glimpse of evidence based on epidemiologic observations suggests a vast potential for prevention, if public health strategies can be devised, implemented, and sustained to preserve low risk or restore

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Table 1-8

Individual and Joint Contributions of Risk Factors to Ischemic Heart Disease and Stroke, World Total and by Broad Income Group Ischemic Heart Disease Stroke Factor PAF for individual factor (%) PAF for individual factor (%) HighLow- and Middle- World HighLow- and Middle- World Income Income Income Income High blood pressure 48 44 45 56 54 54 High cholesterol 57 46 48 25 15 16 Overweight and obesity 27 16 18 20 10 12 Low fruit and vegetable intake 19 30 28 9 11 11 Physical inactivity 21 21 21 8 6 7 Smoking 23 15 17 21 12 13 Alcohol use 13 4 2 11 5 3 Urban air pollution 1 2 2 1 4 3 -------------------------------------------------------------------------------------------------------------------Joint PAF—burden (%) 84 80 80 68 64 65 Joint PAF—mortality (%) 80 78 79 54 61 60 Source: Data from Global Burden of Diseases Study, edited by AD Lopez. © 2006. The International Bank for Reconstruction and Development/ The World Bank.

the more favorable distributions of risk that can be presumed to have existed historically. Here, then, is the global challenge, to be addressed country by country: to recognize and acknowledge the immense burden of chronic diseases, and of cardiovascular diseases in particular, and the need for concerted public health action to achieve the demonstrated potential for major reductions in risk. REFERENCES 1. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th rev. Geneva (Switzerland): World Health Organization; 1992. 2. Pearson TA, Jamison DT, Trejo-Gutierrez J. Cardiovascular disease. In: Jamison DT, Mosley WH, Measham AR, Bobadilla JL, eds. Disease Control Priorities in Developing Countries. Oxford (England): Oxford University Press; 1993:577–594. 3. Omran AR. Epidemiologic transition in the United States: the health factor in population change. Population Bulletin. 1977;32:1–42. 4. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e1–e161.

5. Omran AR. The epidemiological transition: a theory of the epidemiology of population change. Milbank Q. 1971;49:509–538. 6. Olshansky SJ, Ault AB. The fourth stage of the epidemiologic transition: the age of delayed degenerative diseases. Milbank Q. 1986;64: 355–391. 7. Gaziano TA, Reddy KS, Paccaud F, Horton S, Chaturvedi V. Cardiovascular disease. In: Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006:645–662. 8. Dodu SRA. Emergence of cardiovascular diseases in developing countries. Cardiol. 1988; 75:56–64. 9. World Health Organization. Preventing Chronic Diseases: A Vital Investment. Geneva (Switzerland): World Health Organization; 2005. 10. Mathers CD, Lopez AD, Murray CJL. The burden of disease and mortality by condition: data, methods, and results for 2001. In: Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, eds. Global Burden of Disease and Risk Factors. Washington, DC: The

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International Bank for Reconstruction and Development/The World Bank; 2006:45–240. 11. Murray CJL, Lopez AD. Alternative visions of the future: projecting mortality and disability, 1990–2020. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston, MA: The Harvard School of Public Health; 1996. 12. Leeder S, Raymond S, Greenberg H. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries. New York: The Trustees of Columbia University in the City of New York; 2004. 13. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes III, J. Factors of risk in the development of coronary heart disease—six-year follow-up experience: the Framingham Study. Ann Intern Med. 1961;55:33–50. 14. Rose G. Strategy of prevention: lessons from cardiovascular disease. Br Med J. 1981;282: 1847–1851. 15. Strasser T. Reflections on cardiovascular diseases. Interdisc Sci Rev. 1978;3:225–230. 16. Stamler J. Established major coronary risk factors: historical overview. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology: From Aetiology to Public Health. 2nd ed. Oxford (England): Oxford University Press; 2005:18–31. 17. Stamler J, Neaton JD, Garside DB, Daviglus ML. Current status: six established major risk factors—and low risk. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology:

From Aetiology to Public Health. 2nd ed. Oxford (England): Oxford University Press; 2005:32–70. 18. National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention. Unrealized Prevention Opportunities: Reducing the Health and Economic Burden of Chronic Disease. Bethesda, MD: Public Health Service, US Dept of Health and Human Services; 1997. 19. Horton R. The neglected epidemic of chronic disease. Lancet. 2005;366(9496):1514. 20. Strong K, Mathers C, Leeder S, Beaglehole R. Preventing chronic diseases: how many lives can we save? Lancet. 2005;366(9496): 1578–1582. 21. Epping-Jordan JE, Galea G, Tukuitonga C, Beaglehole R. Preventing chronic disease: taking stepwise action. Lancet. 2005;366(9497): 1667–1671. 22. Reddy KS, Shah B, Varghese C, Ramadoss A. Responding to the threat of chronic diseases in India. Lancet. 2005;366(9498):1744–1749. 23. Wang L, Kong L, Bai Y, Burton R. Preventing chronic disease in China. Lancet. 2005;366 (9499):1821–1824. 24. Mazzati E, Vander Hoorn S, Lopez AD, et al. Comparative quantification of mortality and burden of disease attributable to selected risk factors. In: Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, eds. Global Burden of Disease and Risk Factors. Washington, DC: The International Bank for Reconstruction and Development/The World Bank; 2006:241–396.

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C H A P T E R

2 Distributions and Disparities mension to the picture of a far-reaching epidemic at local, national, and global levels. Data shown in Chapter 1 illustrate variation in cardiovascular disease burden among the World Bank regions. Such distributions are widely regarded as indicating global disparities in health, disfavoring low- and middle-income countries. Several aspects of place and time are considered as background for topics that follow.

SUMMARY Age, sex, and race are three personal characteristics used in describing the epidemiology of virtually every disease and condition. They are part of the epidemiology of atherosclerotic and hypertensive diseases and each of their underlying determinants. From an epidemiologic perspective, distributions by age, sex, and race demonstrate variation or patterns of interest in occurrence of diseases or determinants within or between populations. These patterns are regarded as “clues to causation” or signs of potential for prevention. From a public health perspective, such variation often represents something more: disparities, or inequities, in health and disease. Here the perception is that one or more groups within a society— elderly, women, or racial/ethnic minorities, for example—may bear a disproportionate, and intrinsically unfair, burden. Each of these perspectives contributes to shaping public health approaches to prevention, in cardiovascular disease as elsewhere. Although age, sex, and race are commonplace in epidemiology, each of them still deserves attention from the start as to points of definition, ascertainment, and interpretation. The triad of person, place, and time (where “person” is represented by age, sex, race, and other personal characteristics) is also an epidemiologic convention. Adding place, or geography, to the picture of cardiovascular diseases reveals further patterns that convey local, regional, or global variations of both epidemiologic and public health importance. Why is one region, such as the southeastern United States, more heavily afflicted by stroke than elsewhere in the same country? Mapping occurrence of cardiovascular diseases over time adds another important di-

INTRODUCTION Epidemiology and Public Health Knowing the distribution of a disease within or between populations is basic to its epidemiologic understanding. Epidemiology is frequently characterized as study of the distribution of disease in relation to person, place, and time. One tenet of epidemiology is that patterns in the distribution of a disease may suggest “clues to causation” and possibilities for prevention. Epidemiology documents the occurrence of cardiovascular diseases in relation to personal characteristics, beginning with age, sex, and race (each to be defined later). Taking into account other personal characteristics as well as place and time extends the picture of disease distribution and deepens understanding of its occurrence. Some examples follow. Death rates for coronary heart disease in the United States in 2004 are shown in Figure 2-1.1 They present a striking pattern of variation in rates with age. A several-fold increase is apparent across age categories, from youngest (ages 35–44 years) to oldest (ages 75–84 years). Clear patterns are also evident by sex: The rates are greater for males than for females in each age category. By race, the rates are

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2,000 Black Male

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Figure 2-1 Death Rates for Coronary Heart Disease by Age, Race, and Sex, U.S., 2004. Source: Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

greater for Blacks than for Whites in each age category and for both sexes. On careful inspection, the picture reveals another significant feature: any given death rate, for example 500 or 1000 deaths/100,000 population, is reached by men at an age level roughly 10 years younger than the age at which women reach the same rate. This “lag in CHD death rates” for women is a commonly observed pattern that remains to be adequately explained. A geographic pattern is also apparent when death rates are compared among the states. In Figure 2-2, categories of death rates for cardiovascular diseases (here including coronary heart disease, stroke, and other cardiovascular causes of death, excepting congenital heart disease) are represented by states for the combined years 2001–2003.1 The map reveals a concentration of highest cardiovascular mortality mainly in southeastern states but extending into the north, a picture that might stimulate a number of speculations about the cause. In these and many other examples to follow, the influences of age, sex, race, and place, or geography, are described. Variation over time, the third aspect of the triad, was illustrated in Chapter 1 by decadeslong trends in cardiovascular mortality. Each of these dimensions of “distributions” will be discussed below from an epidemiologic perspective, as background for addressing the major cardiovascular diseases and their determinants.

From a public health perspective, distributions of disease have a further implication. Some groups within a population, or some populations, experience a greater disease burden than do others. Such differences in disease burden are often considered to represent “disparities,” in a sense beyond the simple fact of variation in disease frequency. According to Braveman, “Health disparities/inequalities are potentially avoidable differences in health (or in health risks that policy can influence) between groups of people who are more and less advantaged socially; these differences systematically place socially disadvantaged groups at further disadvantage on [sic] health.”2, p 180 This sense of “disparities” has a particular meaning in public health. It goes beyond mere variation in disease frequency, or the epidemiologic concept of distribution, as expressed by the National Institutes of Health: “Health disparities are differences in the incidence, prevalence, mortality, and burden of diseases and other adverse health conditions that exist among specific population groups in the United States.”3 Explicit attention to who is affected most, and the special concern when—as is very often the case—it is “socially disadvantaged” groups, leads to consideration of “health equity,” or justice, in the arena of health and society. When addressed in British or European literature, social or socioeconomic position is often understood as the measure of relative disadvantage.2

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Age-Adjusted Death Rates for Cardiovascular Diseases* by State, U.S., 2001⫺2003

Deaths /100,000 Population 336⫺425 (14) 300⫺335 (12) 280⫺299 (13) 235⫺279 (11)

* Excludes congenital malformations of the circulatory system.

Figure 2-2 Age-Adjusted Death Rates for Cardiovascular Diseases by State, US, 2001–2003. Source: Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

In the United States, health objectives for the nation are presented for each decade in successive Healthy People reports. Eliminating health disparities has become an overarching goal, second only to increasing life expectancy and quality of life for all. Disparities are defined in relation to several population characteristics: “The second goal of Healthy People 2010 is to eliminate health disparities among segments of the population, including differences that occur by gender, race or ethnicity, education or income, disability, geographic location, or sexual orientation.”4, p 11 In addition to this broad goal, in each of several areas such as heart disease and stroke (Focus Area 12), disparities are addressed in relation to specific objectives for the decade. The 2010 objectives include targets to be achieved for each demographic group, usually as defined by age, sex, and race. The more stringent targets are often set for one or more of the racial/ethnic minorities. Special efforts to achieve the targets for these groups are implied, above and beyond those required to improve health for the population as a whole.

This public health perspective can be developed further, as reviewed by Kumanyika and Morssink.5 They argue against defining health disparities chiefly in terms of excess deaths from any particular cause, as is often done. They suggest that this approach is inadequate to address the wide-ranging public health consequences of social disadvantage. In part this leads to an undue focus on healthcare services and individual-level approaches, whereas a broader concept of health of the population would hold greater promise. The focus on cause-specific excess deaths is represented as limited in scope in contrast with a population health focus that invokes a wide range of community attributes in their social and environmental context. The public health perspective on disparities and its implications are raised here alongside the epidemiologic perspective on distributions because these fundamental characteristics—age, sex, and race, and person, place, and time—are important from both points of view. They provide the basic frame of reference for understanding the distribution, determinants,

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and means of prevention of the atherosclerotic and hypertensive diseases, and they point to issues regarding public health action. Dimensions of Population Diversity Two additional points warrant comment before each of these basic characteristics is discussed in greater detail. The first is population diversity with respect to age, sex, and race. More adequate epidemiologic data are needed on cardiovascular diseases for population groups underrepresented in health surveys and other data sources. If data are not sufficient to describe the health status of specific groups, the nature and extent of variation and disparities remain unknown, with consequent limitations on both epidemiology and public health response. Validity of generalizing results of intervention studies from one population group to others is another concern. Whether results for White men of middle age are applicable to women, non-Whites, or older or younger persons is often a matter of judgment without directly relevant data. Broader representation of women as well as men and minorities as well as Whites in future studies can address this issue in the long run, but in the interim a dilemma remains regarding whether a particular intervention should be applied generally on the presumption of universal benefit and safety or whether this should await direct evidence within each specific group of concern. For both reasons, each of these aspects of population diversity has received increasing emphasis in connection with health research in general, including both clinical and population studies of cardiovascular diseases. Specifically in cardiovascular epidemiology, many of the early population studies focused on middle-aged White men. There are important counterexamples, such as the Framingham Heart Study of men and women, the Tecumseh Study of a whole community at all ages, and the Evans County Study in Black adults. But a landmark report in 1978 on the associations of cigarette smoking, blood pressure, and cholesterol concentrations with coronary heart disease event rates, from the US National Pooling Project, was necessarily based on data exclusively for White men aged 40–59 years at entry to the respective studies.6 This was the only age-sexrace stratum among contributing studies with sufficient numbers of events for detailed analysis. Although based on rational design considerations of the time, the insufficiency of corresponding data for women became a prominent issue in more recent years. The need for much more extensive data for

older and younger persons, for women, and for nonWhite groups became much more fully appreciated in the late 1980s and since. This recognition, reinforced by social and political influences, has led to explicit emphasis in policies of the US National Institutes of Health, for example, on inclusion of women and minorities in clinical and population research.7 Modifiability of These Factors One further aspect of age, sex, and race is a common presumption that each of these is “unmodifiable,” contrasting in principle with such factors as dietary patterns or physical activity. But differences in disease distribution by any of these characteristics could reflect underlying social or environmental factors— social conditions, behavioral patterns, specific exposures, or others. To this extent, health patterns by age, sex, or race may in fact point to modifiable characteristics. For example, a rise in population mean levels of blood pressure was long regarded as a natural or inevitable concomitant of aging. But epidemiologic studies have repeatedly shown that populations differ widely in degree of rise in blood pressure with age, a pattern that is altogether absent from some populations. Thus age, as it predicts blood pressure levels, is not strictly “unmodifiable.” It is instead a marker for other factors whose modification can counter a tendency for blood pressure to rise with age. Similar relationships for sex and race suggest the value of identifying “cofactors” that may permit mitigating apparent effects of age, sex, or race. It may be useful to bear in mind these concepts of population diversity and modifiability of the “unmodifiable” factors, as age, sex, and race are examined more closely.

AGE AND LIFE STAGES Definition and Classification A few considerations suggest that “age” is not always so simple an attribute as it might appear. The range of ages relevant to cardiovascular diseases extends throughout the life span, from conception to the oldest attained ages: from determination of genetic makeup and the course of fetal development to the oldest ages with the greatest risks of coronary events, strokes, and other major cardiovascular conditions. Quantitative measures of gestational age are usually expressed in weeks from the mother’s last menstrual period to a specified date; in the early postnatal period

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in days, weeks, or months since birth; and thereafter in completed years, that is, age in years at the most recent birthday. Categories of age are expressed either in class intervals of the quantitative measures or in any of several qualitative terms, including the preadult categories of fetus, newborn, infant, child, adolescent, or youth (with some overlap) and young, middle-aged, older, or elderly adults. Often these terms are used without definition, so their actual age correspondence is unclear. Other terms related to physiological or social aspects of age include developmental age (as assessed by secondary sexual characteristics or skeletal age), age at menarche or menopause, age at majority or attainment of legal responsibility, reproductive age, retirement age, and others. Ascertainment Age is generally ascertained by determining from available records or by questionnaire the age of the subject or respondent, in years, as of the last birthday. A few special considerations sometimes arise. Ascertainment of gestational age is subject to uncertainty in the timing of the last menstrual period. Date of birth by day, month, and year is usually known and can often be confirmed from a birth certificate or other official record (although there are populations for which documentation is unavailable). Knowledge of the actual birth date is obviously more precise than age at last birthday, given that exact age as of any given date can then be calculated and expressed in decimal years (e.g., 10.3 years). This level of accuracy can be important in studies in childhood and adolescence. In this period, change in characteristics of interest can be so rapid that age at last birthday is too imprecise for sound interpretation of the results. In some circumstances, such as death or incapacity, knowledge of an individual’s age may depend on the report of a relative or other surrogate informant, whose reliability may be unknown. In general, however, accuracy of classification by age is expected to be satisfactory absent intentional misrepresentation. Age Adjustment and Standardization Most health-related phenomena are strongly age dependent. Therefore, groups with dissimilar age composition typically exhibit different patterns of these conditions. Accordingly, any differences in such patterns between populations might merely reflect underlying dissimilarities in age distributions and offer only spurious hints of more meaningful differences. In most populations, to use a now familiar example,

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blood pressure does increase with age in adulthood; if the prevalence of high blood pressure were compared between two populations with different proportions of older members, a finding of a higher prevalence in the population with the greater proportion of older adults would be expected and uninformative. For this reason, comparisons within specific age groups are more informative than “crude” comparisons that do not take age into account. Comparison of prevalence of high blood pressure between two populations is preferably based on rates for age strata of 10 years or less, such as ages 30–39, 40–49, and so on. A summary measure of overall population prevalence is often useful for comparing two or more populations. In that case, these age-specific data can be used to adjust for differences in the age distribution of each population, resulting in a single “ageadjusted” or “age-standardized” value for each population to be compared. This value, for example, for prevalence of high blood pressure, is not likely to be the true prevalence in any of the populations, but it can be compared with values calculated for other populations with the same standard population, with knowledge that the comparison is not distorted by differences in age composition among the populations. Ahlbom and Novell present a simple demonstration of this important principle, which can be applied to other characteristics as well as age.8 This is the implied underpinning of data presentations identified as “agestandardized” or “age-adjusted,” as already seen for the example in Figure 2-2. Another example of different representations of age and the meanings they convey is shown in Figure 2-3.1 Deaths for major cardiovascular diseases each year from 1979–2004 are represented in two ways: The bar graph or histogram shows the number of deaths each year (in 1000s) in relation to the scale on the left; the curve represents the age-adjusted death rate each year (per 100,000 population), in relation to the scale on the right. The numbers of deaths were roughly constant, nearly 1 million per year, from 1979 to 2004. The death rate declined substantially, from more than 500 to just under 300 deaths/100,000 per year. Did cardiovascular deaths decline or not? The answers are yes for the rates, calculated as though the age composition of the population were constant over these years, and no for the actual numbers of deaths because the increasing proportion of older persons in the population (with their very high cardiovascular mortality—see Figure 2-1) offset the decline in age-adjusted rates.

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1,200

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Figure 2-3 Deaths and Age-Adjusted Death Rates for Cardiovascular Diseases, US, 1979–2004. Source: Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

Interpretation of Health Patterns by Age The Fetal and Neonatal Period The fetal and neonatal periods have been the focus of research suggesting that conditions of life in this period may be critical for future risks of adult cardiovascular diseases.9 For example, in a cohort of British men born in the early 1900s, associations were demonstrated between low birth weight, or limited weight gain to age 1 year, and adult cardiovascular mortality. This and related observations have been interpreted as reflecting adverse social conditions that influence fetal and neonatal growth and development. Under this theory, the developing metabolic and physiologic systems of the fetus become “programmed” in response to these conditions in a manner that unfavorably affects risk factor development in later life. This theory is addressed further in the context of social and environmental conditions (Chapter 16). Childhood and Youth Childhood, adolescence, and “youth” (defined by the World Health Organization as spanning the ages from birth to 24 years10) are conventional categories of preadult ages. For this period of life, chronologic age is only an approximate indicator of biological age

because of wide variation between individuals in growth tempo, or rates of growth and maturation.11 Much attention has been devoted to cardiovascular risk factors in these age groups in the past three decades or more. As a result, the view is increasingly accepted that prevention of the risk factors and early manifestations of atherosclerotic and hypertensive cardiovascular diseases requires intervention before adulthood. The basis of this view includes several links between factors measured in youth and observations in adults, as follows: familial aggregation—the greater similarity of risk factor levels of parents and offspring within families than between them; familial concordance—the relatively adverse risk factor levels of offspring of parents with cardiovascular disease when compared with those of unaffected parents; tracking—the tendency for risk factor levels in an individual at a given age in childhood or adolescence to be predictive of levels at later ages; correlations with vascular pathology—associations between risk factor levels and the extent of atherosclerosis in the aorta and coronary arteries, in childhood, adolescence, and youth. The current view of the potential for preventive measures in this period of life is illustrated by exten-

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sive reviews and recommendations from the World Health Organization (WHO) and the American Heart Association, among others.10,12 Young and Middle Adulthood Studies of the atherosclerotic and hypertensive diseases have most often focused on middle adulthood. This emphasis was based primarily on a sufficient frequency of detectable disease events in initially healthy subjects, the feasibility of long-term followup from first observation through a period of years at moderately high risk, and other design considerations. Older people experience much higher event rates but competing risks of other diseases and death may confuse the picture; younger people offer the greatest potential for true prevention of advanced atherosclerosis but experience few clinically detectable events. Methods for detection of subclinical disease are especially applicable in youth and early adulthood and include, for example, measures of endothelial function, arterial stiffness and calcification, and echocardiography. These methods provide intermediate measures that can be useful both as outcomes of earlier influences and as predictors of later clinical disease. The period of young and middle adulthood remains important for continued study, although ideally in continuity with observations and development of preventive strategies throughout life. The Elderly The view that chronological age is only a surrogate for modifiable underlying characteristics implies that many characteristics of older persons are not inevitable concomitants of aging. Consistent with this view, current concepts of aging focus not on an inexorable progression of disease but on the potential for preserving maximum functional capacity, independence of living, and quality of life.13 Greatly increasing numbers of persons in the United States and many other countries survive myocardial infarction or stroke only then to experience chronic ischemic heart disease, congestive heart failure, or vascular dementia, with significant disability and dependence. A major question is the extent to which these common occurrences can be prevented, resulting in better health and quality of life in the later years. Better understanding of how to preserve low risk throughout life is therefore important. In many populations, life expectancy is increasing and proportions of persons attaining advanced ages are growing, with profound impacts on society and on health and disease. Recognizing this, the World

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Health Organization convened a Study Group on Epidemiology and Prevention of Cardiovascular Diseases in Elderly People.14 The Study Group Report is a valuable resource for assessing the cardiovascular disease situation of the “elderly” (those aged 65 years and older) with respect to the occurrence of cardiovascular diseases and their prevention, rehabilitation, and related health policy. In addition, the report demonstrates the projected growth of older age groups as proportions of the population of each World Health Organization Region (Table 2-1). The projected aging of Europe is striking, with more than 20% of the population over age 65 by 2025. North America is not far behind. Substantial increases are projected everywhere but in sub-Saharan Africa. The health of the elderly, not least their cardiovascular health, becomes an ever greater concern. It should also be noted that, in addition to usually higher rates, morbidity and mortality data in the elderly differ from those for younger adult age groups in two other respects. First, data on specific diagnoses and causes of death may be less reliable owing to multiple coexisting health conditions in the elderly. Second, the high prevalence of many cardiovascular disease risk factors in older persons tends to result in reduced estimates of relative risk, or the apparent force of a factor such as blood pressure on the risk of an event. This is because even those who remain clinically free of these events have, on average, higher risk than younger persons. The absolute risks attributable to a given factor, on the contrary, are greater than in younger persons owing to the much higher disease rates at older ages. Interpretation of measures of risk among older adults therefore requires special caution. This will be illustrated subsequently in connection with the relation of blood pressure to risk of stroke in different age groups (Chapter 5). A recurring issue regarding the progression from earliest onset to latest outcomes of the atherosclerotic and hypertensive diseases is the inability to study the full process in one population continuously through the life span. For example, only a few studies have followed this process from childhood into early adulthood. The exceptions are highly informative; but at the same time, the factors in childhood and adolescence that were influential for a particular adult population may have changed over time and may have limited relevance to a subsequent generation. Such potential “cohort effects” must be considered in interpreting long-term trends across age groups.

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Table 2-1 Region

Projected Proportion of the Population Aged 65 Years and Over, 1990–2025 Percentage of the Population Year ⬎ 65 Years ⬎ 75 Years ⬎ 80 Years

Europea

1990 2010 2025

13.7 17.5 22.4

6.1 8.4 10.8

3.2 4.9 6.4

North America

1990 2010 2025

12.6 14.0 20.1

5.3 6.5 8.5

2.8 4.0 4.6

Oceania

1990 2010 2025

9.3 11.0 15.0

3.6 4.8 6.6

1.8 2.8 3.6

Asiaa

1990 2010 2025

4.8 6.8 10.0

1.5 2.5 3.6

0.6 1.2 1.8

Latin America/Caribbean

1990 2010 2025

4.6 6.4 9.4

1.6 2.4 3.6

0.8 1.2 1.8

Eastern Mediterranean/North Africa

1990 2010 2025

3.8 4.6 6.4

1.2 1.6 2.2

0.5 0.8 1.1

Sub-Saharan Africa

1990 2010 2025

2.7 2.9 3.4

0.7 0.8 1.0

0.3 0.3 0.4

a

Data exclude countries of the former USSR.

Source: Kinsella K, Tauber CM. An aging world II. Washington, DC, US Government Printing Office, 1992 (US Bureau of the Census, International Population Reports, P-95, No. 79).

Finally, it is important to note a set of populationbased studies in the United States, supported by the National Heart, Lung and Blood Institute, spanning the adult years—in sequence by age, the Coronary Artery Risk Development in Young Adults Study (CARDIA), the Atherosclerosis Risk in Communities Study (ARIC) of middle-aged adults, and the Cardiovascular Health Study (CHS) in the elderly— all discussed in subsequent chapters.

SEX OR GENDER Definition, Classification, and Ascertainment In the cardiovascular arena, there is little ambiguity about classification as male or female, and both the terms “sex” and “gender” are used. “Gender,” the grammatical term, and “sex,” the biological term,

are used here interchangeably, although “sex” is more frequently found in presentations of epidemiologic data. Sex-Specific Observations Epidemiologic observations are nearly always reported on a sex-specific basis, when data for both males and females are available. However, when the numbers of observations are insufficient for sexspecific analysis, combined rates may be presented instead. In such instances, comparisons between populations or groups that differ in composition by sex may, like those for age, be distorted unless adjustment is made for this difference. Interpretation of Differences in Health by Sex A widely recognized example of sex differences in the occurrence of cardiovascular disease is the “lag” of 10 years or more in coronary mortality by age in women

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relative to men. This lag was noted, for example, in describing Figure 2-1. Such sex differences are interpreted variously as evidence of biological, social, cultural, or behavioral effects. Plausible bases for such effects could include chromosomal, hormonal, or reproductive factors; sex-specific social roles leading to different patterns of activity, occupation, and interpersonal relationships, and therefore different exposures; or sex-related perceptions or practices that determine access to education, health information, or health services. These factors can be viewed as either protective for women or hazardous for men. Sex differences in distributions of blood lipids and blood pressure as well as body fatness are apparent beginning in adolescence, and these and other risk factors progress differently between women and men throughout adulthood. The relative lack of information about several aspects of cardiovascular diseases in women—including evaluations of preventive strategies, diagnostic test performance, and responses to medical and surgical treatments—has been addressed with increasing frequency. Reviews include the report of the National Heart, Lung and Blood Institute conference, Cardiovascular Health and Disease in Women,15 a text of the same title,16 and the American Heart Association’s Report of the Special Writing Group on Cardiovascular Disease in Women and guidelines for cardiovascular disease prevention in women, first published in 2002 and updated in 2007.17,18 An essay by Barrett-Connor is particularly thought-provoking in bringing attention to long-held and untested theories of sex differences in coronary heart disease.19 This emphasis reflects in large part a sense of relative neglect of the problem of coronary heart disease in women. The cumulative lifelong coronary mortality of women is actually no less than that for men in the United States and several other populations. Misapprehension of this fact results from a longstanding failure to recognize that the greater life expectancy of women than men places more women than men at the highest risks of coronary heart disease death. A critical review of sex differences in coronary heart disease posed the question of what role sex hormones—either exogenous or endogenous—could actually be playing, especially at older ages where coronary heart disease incidence and mortality are greatest.20 Gradients in coronary mortality across countries are closely parallel for women and men, and rates are higher among women in the highestrate countries than among men in the lowest-rate countries (see, for example, Figure 2-6, as follows, for the 45- to 64-year age stratum). Thus, coronary mor-

27

tality for women is not universally low but varies widely in different environments. This view suggests that environmental factors are paramount determinants of these population differences and that intrinsic hormonal differences between the sexes may have a lesser role than has often been presumed. The continuing uncertainties about the meaning of these and other sex differences in atherosclerotic and hypertensive diseases add to the importance of further study of women as a population of special concern. Risks and Rates in Successive Periods of Life Sex differences in risk factors are recognized in the first months of life but become clearer with adolescence and the many changes associated with puberty. Age-specific mean values for systolic and diastolic blood pressure and for each component of the blood lipid profile differ by sex from puberty onward reflecting distinct time patterns of development. Tobacco use progresses rapidly in this period and tends to remain somewhat less prevalent among females than among males at successive ages. In the age interval from 15 to 34 years, atherosclerosis of the coronary arteries at the fatty streak stage is about equally frequent between females and males, but raised lesions are notably less frequent among females.21 Through early and middle adulthood, women tend to have lower age-specific mean values for blood pressure and total cholesterol concentration, but greater prevalence of physical inactivity and being overweight.16 In middle age, although rates for coronary heart disease events increase for women more gradually than for men, rates of stroke for women closely parallel those for men. In later adulthood, both total cholesterol concentration and blood pressure (especially systolic pressure) increase to values greater than those for men of the same age. Rates of coronary heart disease and stroke both increase sharply among women and men with further increase in age, as do rates of other complications of advanced atherosclerosis and hypertension.

RACE OR ETHNICITY Definition and Classification If “race” once denoted a specific biologic concept and “ethnicity” a cultural/anthropological one, the earlier distinction between terms has become less clear. A common convention, “race/ethnicity” or “race and ethnicity,” is generally used here. Because isolated populations with very limited genetic admixture and

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little contact with other cultures are rare, the concept of genetically or culturally homogeneous groups may no longer be meaningful. It is nonetheless true that when groups of persons identify themselves or are classified by others as members of particular racial or ethnic groups, they often differ in disease rates or risk factor distributions. In the United States, classifications of racial or ethnic minority populations have changed in recent practice. One such system distinguishes Black Americans, Hispanics, Native Americans, and Asians/ Pacific Islanders.22 Other classifications include “color,” which differentiates among non-Hispanic Blacks, non-Hispanic Whites, and Mexican Americans. “Underprivileged minorities” is intended to distinguish some racial/ethnic groups, characterized as being of low socioeconomic status by income, education, or occupation, from others. Country by country, and from one situation to another, group distinctions may be made on various bases, such as religion, national origin, or others. Group membership defined by race/ethnicity may indicate genetic, cultural, socioeconomic, or other differences, and interpretation of related differences in health and disease may require some depth of investigation. Ascertainment In routine recording of health data or in population studies, assignment of race or ethnicity is often based on individual self-report. Classification by simple observation may be unsatisfactory and unreliable, given that parental origins, language preference, and other considerations are difficult to take into account in this approach. In studies of children, the reported race or ethnicity of parents may be used to classify offspring. Inconsistencies in methods between data sources can introduce potential error. For example, when the numerator of a rate is based on one data system, such as death certificates, and the denominator is based on another, such as census data, distortions in the resulting rates may occur. For example, this is at issue in interpreting mortality data for Mexican Americans, for whom individuals may be “Mexican American” by self-identification in census data but simply “White” as often described on death certificates. Mortality for Mexican Americans would be underestimated in this case. State-level mortality statistics have been cited as indicating comparatively low coronary mortality among Mexican Americans (largest of the Hispanic subgroups). However, results of community surveillance for coronary heart disease “on the ground” in Corpus Christi/Nueces County, Texas, have shown higher rates of hospitalization, higher

case-fatality, and higher long-term mortality for coronary disease among Mexican Americans than among non-Hispanic Whites in the same community.23 The discrepancy may result from distortion of the vital statistics data in this way. Interpretation of Differences in Health by Race or Ethnicity If such classifications identify groups at special risk, it is desirable from a public health perspective that this information be obtained and applied appropriately. This implies looking beyond a genetic or cultural basis for the observed differences. Just as age and sex may be markers for any of a variety of group differences, so may race and ethnicity have underlying bases—some known, others unknown. Potentially important cofactors of race or ethnicity may remain to be recognized. Others that are presumed may not be valid for a particular group in one specific time or place. There is some risk of misinterpreting group differences when potential confounding factors are not considered. For example, if a study finds higher blood pressure in Black American adolescents than in Whites, this could be due to earlier occurrence, on average, of the adolescent skeletal growth spurt in Blacks. Because blood pressure levels are strongly correlated with height in adolescence, Blacks should be expected to exhibit higher age-specific levels of systolic blood pressure at these ages. This underlying variation in growth tempo suggests the explanation that, in Black as in White adolescents, “growth” in blood pressure parallels skeletal growth.11 Data for Specific Population Groups in the United States Data for multiple racial/ethnic minority groups in the United States are increasingly available, although many gaps remain. Data from the National Health Interview Survey of 2004, reported in a special issue of Health Affairs, illustrated the groups often represented in such data and the marked variation—or disparities— among them.24 The proportions of survey participants who reported having had a stroke, other heart disease, coronary heart disease (CHD), and hypertension were demonstrated for groups identified as White, non-Hispanic; Black, non-Hispanic; Hispanic or Latino; Asian; Native Hawaiian or Pacific Islander; and American Indian or Alaska Native. Several observations stood out, including marked dominance of hypertension for all groups and its striking excess among non-Hispanic Blacks; relatively high prevalence of both coronary heart disease and stroke among Native Hawaiians or other Pacific Islanders; and ex-

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ceptionally low frequency of all four conditions among Asians. These patterns are important from both epidemiologic and public health perspectives. Concerning cardiovascular diseases and other aspects of the health of Blacks and other minority groups in the United States, there remains a relative lack of data for these groups. As a result, special reviews of available data, identification of priorities for acquiring needed health data, and adoption of policies for participation in research by certain minorities have taken place. Similar developments address concerns about women and the elderly. Cardiovascular diseases have been a prominent part of this concern. These were addressed, for example, in the 1985 Report of the Secretary’s Task Force on Black and Minority Health of the US Secretary of Health and Human Services,22 and in a subsequent special report from the American Heart Association, “Cardiovascular Diseases and Stroke in African-Americans and Other Racial Minorities in the United States, A Statement for Health Professionals.”25 Corresponding reports on cardiovascular diseases in women were noted earlier. The first of these reports provided summary information on cardiovascular diseases for Black Americans, Hispanics, Native Americans, and Asian/ Pacific Islanders.22 The paucity of information for all but Black Americans was emphasized. Data for other groups were considered less reliable because, for example, of underreporting of race on death certificates. Data on morbidity are even more limited. Heterogeneity within groups is a further consideration. “Hispanic,” for example, includes Mexican Americans, Puerto Ricans, Cuban Hispanics, and Central American immigrants to the United States, or subsequent generations. These considerations emphasize the importance both socially and scientifically of increased representation of diverse groups within the US population in both official health surveillance activities and in research on patterns in cardiovascular disease risks, morbidity, and mortality by race/ethnicity. Whether such expanded information will reveal new insights into causation or point to distinct requirements for intervention remains to be seen. It is often recommended that community- or individual-level interventions be tailored in culturally sensitive ways to meet the needs of specific groups. This is to acknowledge that interventions that are effective in one group may not be so in others. However, it is also important to recognize interventions that are effective across multiple population groups, so that their benefits are not withheld inappropriately.

29

Other Populations Migrants to the United States illustrate a special type of population comparison involving race and ethnicity. Kelleher and others examined the effect of chiefly Northern European immigration to the United States from 1850 to 1930 on coronary heart disease mortality in this country from 1900 to 1980.26 They concluded that this immigration contributed to both the rise and fall of coronary heart disease mortality rates in the United States. They estimated that between the time of immigration and rise of the epidemic, there were lags of about 50 years for men and 38 years for women. They attributed the experience of the immigrant population to deprived socioeconomic conditions on arrival in the United States and to changes in behavior that followed. Another analysis of migrant populations used the National Longitudinal Mortality Study, 1979–1989, to evaluate the mortality experience of native-born compared with foreign-born Americans.27 It was necessary first to adjust for differences between groups in distributions of age, sex, marital status, rural/urban residence, education, and family income. Several groups, including foreign-born minorities, were found to have experienced lower mortality than their USborn counterparts. Foreign-born non-Hispanic Whites, Blacks, Asian and Pacific Islanders, or Hispanics experienced significantly lower cardiovascular disease mortality than those of the same racial/ethnic group who were born in the United States. As an explanation, the authors noted that immigration policy has resulted generally in selection of “a much healthier, more driven, physically-fitter group than those who remain in their countries of origin.”27, p 103 These two studies of migration show the potential error in assumptions about group characteristics. US immigrants of many decades ago are thought to explain part of the mid-20th century peak of coronary mortality, on the basis of poorer general health. Persons able to immigrate to the United States more recently may enjoy relatively good health. Interpreting group identity requires some depth of knowledge beyond the group classification itself.

GEOGRAPHY OR PLACE Cartography of Cardiovascular Diseases The idea of place raises images of maps, such as those shown in Figure 2-1. Such geographic distributions of mortality typically represent officially defined reporting areas—especially cities, counties, states, or

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the nation as a whole. Mapping of this kind requires sufficient population size in a reporting unit to provide enough events, on an annual basis or aggregated over several years, for reliable estimation of rates. Accordingly, mapping of annual data on cardiovascular mortality by state in the United States or by country on a regional or global basis is convenient and commonplace. More detailed and refined mapping can be done for more local areas, with smaller units requiring multiyear aggregation of events. Techniques of geographic information systems (GIS) are now widely available that permit incorporation of other data of interest for public health, such as social or environmental characteristics or healthcare resources, thereby stimulating a renewed interest in cartography of disease.28 Using current mapping and graphics techniques, Mackay and Mensah produced a world atlas of heart disease and stroke.29 The atlas, with a multicolor layout and multiple text overlays, effectively communicates information about cardiovascular diseases, risk factors, and related social and economic conditions on a regional and global scale. It presents visually what is imagined in studying the tabular data from the Global Burden of Disease Study, discussed in Chapter 1.30 (Unfortunately it is not feasible to reproduce it here.) For nearly 200 countries, the atlas presents tabular data on mortality and disability from heart disease and stroke; rheumatic heart disease deaths; smoking prevalence, policies, and legislation; and prevalence of diabetes among adults. Place can mean something other than geographic location. An organizational or institutional entity whose membership constitutes a population of employees, military personnel, students, or other social groupings can also be seen as a “place” of sorts. Places of these kinds constitute settings in which customs, behaviors, and exposures may contribute to risk or promote good health. Such settings— workplaces, schools, religious institutions, or community centers—can also offer opportunities for interventions such as improving food service, providing health information, screening to detect risk factors or cardiovascular conditions, or providing health services. The United States and Appalachia Racial and Ethnic Disparities in Heart Disease among Women is one of several recently published atlases from a team led by Casper at the Centers for Disease Control and Prevention (CDC). These atlases present GIS mapping of heart disease and stroke mortality for

the United States at a much finer level than the statelevel map in Figure 2-2.31–34 This can be compared with Figure 2-4, in which smoothed county-level heart disease death rates for the period 1991–1995 have been mapped for women dying at ages 35 years and older.31 The publication and corresponding Web site present county-level data for the nation and state by state. The concentration of cardiovascular mortality in the southeastern United States seen in Figure 2-2 is seen here in greater detail. Person (age, sex, and race) and place are taken into account jointly. National maps are shown for all women and for American Indians and Alaska Natives, Asian and Pacific Islanders, Blacks, Hispanics, and Whites; state maps are provided for each group having sufficient data. Corresponding data on local economic resources, indicators of social isolation among elderly women, and medical care resources add dimensions that are potentially valuable in understanding the underlying determinants of the geographic patterns that are revealed. (The data for this series of atlases are publicly available and permit interactive analysis and mapping for selected counties—see http://www.cdc.gov/ dhdsp.) Within the area of especially high coronary mortality in the southeast, 399 counties define the Appalachian region. GIS mapping of cardiovascular mortality in this region was reported in 1998 and updated in 2004.35,36 The whole of West Virginia and parts of 12 other states from Mississippi to New York comprise the region, as shown in Figure 2-5. Ageadjusted coronary heart disease death rates for African American men aged 35–64 are represented for the period 1980–1993. Similar displays are given for four sex-race groups, male/female and African American/ White, and for two age strata, 35–64 years and 65 years and older. Among counties within the region with sufficient data, a wide range of rates was observed. As described in the 2004 report, “Many Appalachian counties with the most adverse health outcomes correlate geographically with socioeconomic characteristics, behavioral risk profiles, and available medical care resources. However, it appears that reasons for disparities in health outcomes are highly variable and localized. Identifying the causes of inconsistencies may help in developing interventions and policy at the local level.”36, p iii “Eight Americas” Another approach has made use of county-level characteristics to “map” disparities in cardiovascular and other causes of death, in accordance with geogra-

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GEOGRAPHY OR PLACE

Smoothed County Heart Disease Death Rates 1991–1995

31

All Women Ages 35 Years and Older

New York City

Washington, D.C.

Age-Adjusted Average Annual (Number of Deaths per 100,000 Counties) 212–337 338–379 380–415 416–449 450–670 Insufficient Data

(620) (626) (612) (624) (618) (3)

Figure 2-4 Smoothed County Heart Disease Death Rates, All Women Ages 35 Years and Older, 1991–1995. Source: From Women and Heart Disease: An Atlas of Racial and Ethnic Disparities in Mortality, 2nd Edition. © 2000. 1999 Office for Social Environment and Health Research, West Virginia University.

phy coupled with racial/ethnic and socioeconomic indicators. In this way, Murray and others described “eight Americas,” defined in Table 2-2.37,38 The characteristics used to distinguish these groups included location, population density, race-specific countylevel per capita income, and cumulative homicide rate. The total of 3141 counties in 1980 was condensed into 2072 county-based units aggregated to have stable boundaries through 2001. The populations of the eight Americas ranged in size from 1 million to 214 million; median per capita income varied twofold; percentage completing high school ranged from 84% to 61%; and each group constituted a relatively homogeneous cluster by race, location, and income. In general, the mortality gradient greatly favored “America 1” over “America 8” for cardiovascular

as well as other causes. Each of the “Americas” was compared with several other countries or regions with wide-ranging mortality. Relative to the experience of other countries as disparate in health as Japan and the highest-mortality regions of Africa, “America 1” had 3 years greater life expectancy than the population of Japan. For some other “Americas,” however, mortality was as great as in low- and middle-income countries. Murray and coauthors concluded: “The biggest problem is young and middle-aged male and female mortality from chronic diseases. The challenge to reduce disparities in these groups will require a major re-orientation of US public health over the coming years. While the challenge is great, opportunities exist to tackle the major risks such as tobacco, blood pressure, cholesterol, obesity, and alcohol with innovative strategies.”37, pp 9–10

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Age-Adjusted Rate per 100,000 Insufficient Data Low Outliers (152–161) First Quartile (152–278) Second Quartile (279–310) Third Quartile (311–356) Fourth Quartile (357–567) High Outliers (473–567)

Figure 2-5 Coronary Heart Disease Deaths: African American Men Aged 35–64, 1980–1993. Source: From Heart Disease in Appalachia: An Atlas of County Economic Conditions, Mortality and Medical Care Resources. © 1998. West Virginia University Prevention Research Center.

PERSON, PLACE, AND TIME Scales of Time The theory of epidemiologic transition (Chapter 1) raised the concept of decades- or century-long processes of change in disease patterns of populations. Cardiovascular epidemiology can encompass such widely ranging temporal aspects as changes in human nutrition on an evolutionary scale; fluctuation in mortality rates over only a few years; and momentary alterations in physiology or behavior that trigger acute cardiovascular events. Intermediate-term variations in mortality for coronary heart disease and stroke demonstrate linkage of time (nearly four decades, from 1950 through 1987) with person (both men and women at specified ages) and place (27 countries).39

Twenty-Seven Countries Secular trends in coronary heart disease mortality over four decades differed strikingly by country (Figure 2-6).39 The figure was compiled from data reported to the World Health Organization by each country throughout this period. This figure represents the average annual mortality for coronary heart disease at ages 45–64 years in each of eight time periods, from 1950–1954 to 1984–1987, for each of 27 countries. The countries are ordered from left to right in descending rank for male coronary heart disease mortality in 1950–1954. The initial rates for males differed widely, about sixfold, among these populations, from about 600/100,000 per year in the United States (USA) to less than 100/100,000 in France (FRA), with the remaining 25 countries arrayed continuously between them. The rates for fe-

Northland low-income rural white

Middle America

Low-income whites in Appalachia and the Mississippi Valley

Western Native American

Black middle America

Southern low-income rural black

High-risk urban black

2

3

4

5

6

7

8

7.5

5.8

23.4

1.0

16.6

$14,800

$10,463

$15,412

$10,029

$16,390

$24,640

$17,758

$21,566

Definition

Urban populations of more than 150,000 blacks living in counties with cumulative probability of homicide death between 15 and 74 y greater than 1.0%

Blacks living in counties in the Mississippi Valley and the Deep South with population density below 100 persons/km2, 1990 county level per capita income below $7,500, and total population size above 1000 persons (to avoid small numbers)

All other black populations living in countries not included in Americas 7 and 8

Native American populations in the mountain and plains areas, predominantly on reservations

Whites in Appalachia and the Mississippi Valley with 1990 county-level per capita income below $11,775

All other whites not included in Americas 2 and 4. Asians not in America 1, and Native Americans not in America 5

Whites in northern plains and Dakotas with 1990 county-level per capita income below $11,775 and population density less than 100 persons/km2

Asians living in counties where Pacific Islanders make up less than 40% of total Asian population

Source: From Eight Americas: Investigating Mortality Disparities Across Races, Counties and Race-Counties in the United States. PLoS Medicine. © 2006, Murray et al.

DOI: 10.1371/journal.pmed.0030260.t001

72%

61%

75%

69%

72%

84%

83%

80%

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214.0

3.6

10.4

2/25/10

Population, income per capita, and education were calculated for race-county combinations from the 2000 US census.

Asian

Definitions and Basic Sociodemographic Characteristics of the Eight Americas Percent Population Average Income Completing General Description (Millions) per Capita High School

1

America

Table 2-2

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USA FIN CAN SCO AUL NZE NIR ISR EW IRE CZE AUS SWI SWE FRG DEN HUN BEL ITA

NET NOR YU POL POR SPA JA

FRA

800

Rate per 100,000 Population at Ages 45–64 Years (Age Adjusted)

700

600

500

400

300

200

100

0 Men Women

Figure 2-6 Secular Trend of Mortality from Coronary Heart Disease in 27 Countries, Age 45–64 Years, by Sex, 1950–1987. Source: From TJ Thom, FH Epstein, JJ Feldman, PE Leaverton, and M Wolz, 1992, National Institutes of Health, Pub No 92-3088.

males in every country were typically half or less the rates for males, the only exception being Japan (JA) with its very low rates for both sex groups. The relative gradient in initial rates for females was similar to that for males, about sixfold from highest (Ireland [IRE]) to lowest (France). Over the eight time periods, dramatic changes in coronary heart disease mortality occurred in most of these countries for both males and females. Most striking for males are the marked decreases in countries such as the United States, Canada (CAN), and Australia (AUL) and the increases in Czechoslovakia (CZE), Hungary (HUN), Norway (NOR), and Poland (POL). Intermediate are several countries whose rates for males peaked near the midpoint and later declined toward the initial levels. Also notable is the consistently downward trend for Japan, whose clustering generally with Spain (SPA), Portugal (POR), and France evokes imaginative interpretation. By contrast, however, Japan attained the lowest coronary heart disease mortality rate of any of these countries by the early- to mid-1960s and has since remained in

that rank. Trends for females were in general parallel to those for males, except in those countries where they changed little despite sharp increases in rates for males—Czechoslovakia, Hungary, Norway, and Poland. These data indicate that marked variation in coronary heart disease mortality can occur within populations over short historical intervals. The fact that changes in population genetics require periods of generations, indicates that only environmental factors, including social and behavioral changes, can explain these marked short-term variations. The corresponding picture for stroke is strikingly different from that for coronary heart disease. For example, the United States ranked at midrange instead of first, and Japan had the highest rates rather than the lowest. Stroke mortality in the United States continued to decline through the late 1980s, as shown in the context of such changes in 26 other countries in Figure 2-7, which is analogous to that for secular trends in coronary heart disease above.39 Here, data for deaths at ages 65–74 years are presented because of the typically later ages of stroke deaths in com-

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CONCLUSION

JA

35

SCO ITA POR FRG HUN FIN ISR EW NIR AUS SPA FRA AUL SWI USA SWE DEN CZE CAN NZE YU NOR NET IRE BEL POL

1,800

1,600

Rate per 100,000 Population

1,400

1,200

1,000

800

600

400

200

0 Men Women

Figure 2-7 Secular Trend of Mortality from Stroke in 27 Countries, Age 65–74 Years, by Sex, 1950–1987. Source: From TJ Thom, FH Epstein, JJ Feldman, PE Leaverton, and M Wolz, 1992, National Institutes of Health, Pub No 92-3088.

parison with coronary heart disease deaths. The trend for the United States (the 16th in descending rank of stroke mortality in 1950–1954) reflects a decrease through the 1950s and a sharp decline through 1984–1987. In this age group, stroke mortality for the United States declined for men from 600 to about 200 and for women from about 500 to 150 deaths per 100,000 population per year. In the other countries, by far the dominant trend was declining stroke mortality as in the United States, with very close parallels for men and women. Striking for their exceptional patterns of increasing stroke mortality were Czechoslovakia, Hungary, Portugal, and Yugoslavia (YU), which had higher rates at the end of this four-decade period than at the beginning. In Poland, rates were also exceptional in increasing over the latest intervals. A Race Against Time Finally, the projections of future burdens of coronary heart disease, stroke, and other cardiovascular conditions presented in Chapter 1 approach time from yet another perspective. The forecasts represented by the Global Burden of Disease Study40 and A Race Against Time41 forecast a growing disparity in mortality and

disability from cardiovascular and other chronic diseases between the high-income and the low-andmiddle-income regions of the world. Serious consequences were predicted for economic and social development. From this global perspective, Braveman’s concept of disparities, health equity, and social justice arise. Following discussion of the epidemiology of atherosclerotic and hypertensive diseases and their determinants in Parts II and III, these considerations are addressed further in connection with strategies of prevention and planning of public health action.

CONCLUSION The simple concepts of age, sex, and race are fundamental to epidemiologic characterization of individuals and are useful dimensions for examining distributions of disease. Together with place and time, these personal traits provide a basic description of variation in disease occurrence that gives rise to ideas about causation and prevention. Age, sex, and race have further meaning with respect to relative advantage or disadvantage of individuals or groups in terms of social and economic position, education, employment, access to

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the benefits of society, and potential victimization as by racism or other injustice. It is these considerations that give certain distributions of epidemiologic interest added importance as measures of disparities, or indications of inequities in health that are also of public health concern. Each specific cardiovascular condition and each of their determinants has its own epidemiology, population distributions, and potential disparities. It is useful to bear in mind the rudiments of definition, ascertainment, and interpretation of age, sex, and race. Adding place and time to the picture of cardiovascular diseases underscores the global reach they have assumed in very recent history and may suggest alternative visions for the future. REFERENCES 1. National Heart, Lung and Blood Institute. Morbidity & Mortality: 2007 Chartbook on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: US Department of Health and Human Services. Public Health Service, National Institutes of Health; June, 2007. 2. Braveman P. Health disparities and health equity: concepts and measurement. Ann Rev Public Health. 2006;27:167–194. 3. Addressing health disparities: the NIH Program of Action. What are health disparities? http:// healthdisparities.nih.gov/whatare.html. Accessed May 15, 2007. 4. US Department of Health and Human Services. Healthy People 2010. 2nd ed. With Understanding and Improving Health and Objectives for Improving Health. 2 vols. Washington, DC: US Government Printing Office; 2000. 5. Kumanyika SK, Morssink CB. Bridging domains in efforts to reduce disparities in health and health care. Health Education & Behavior. 2006;33:440–458. 6. Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the pooling project. J Chronic Dis. 1978;31: 201–306. 7. Bennet JC, Board of Health Sciences Policy, Organization of the Institute of Medicine. Inclusion of women in clinical trials—policies

for population subgroups. N Engl J Med. 1993; 329:288–292. 8. Ahlbom A, Novell S. Introduction to Modern Epidemiology. Chestnut Hill, MA: Epidemiology Resources, Inc; 1990. 9. Barker DJP. The developmental origins of cardiovascular disease. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology: From Aetiology to Public Health. 2nd ed. Oxford (England): Oxford University Press; 2005:547–567. 10. World Health Organization Study Group. Prevention in Childhood and Youth of Adult Cardiovascular Diseases: Time for Action. WHO Technical Report Series 792. Geneva (Switzerland): World Health Organization; 1990. 11. Tanner JM. Fetus into Man: Physical Growth from Conception to Maturity. 2nd ed. Ware (England): Castlemead Publication; 1989. 12. Williams CL, Hayman LL, Daniels SR, et al. Cardiovascular health in childhood. A statement for health professionals from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 2002;106:143–160. 13. Harlan WR, Manolio TA. Coronary heart disease in the elderly. In: Marmot M, Elliott P, eds. Coronary heart disease epidemiology: from aetiology to public health. Oxford (England): Oxford University Press; 1992:114–126. 14. World Health Organization Study Group. Epidemiology and Prevention of Cardiovascular Diseases in Elderly People. WHO Technical Report Series 853. Geneva (Switzerland): World Health Organization; 1995. 15. Wenger NK, Speroff L, Packard B. Cardiovascular health and disease in women. N Eng J Med. 1993;329:247–256. 16 . Douglas PS. Cardiovascular health and disease in women. Philadelphia, PA: WB Saunders Co; 1993.

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17. Mosca L, Appel, LJ, Benjamin EJ, et al. American Heart Association. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109: 672–692. 18. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481–1501. 19. Barrett-Connor E. Sex differences in coronary heart disease: why are women so superior? The 1995 Ancel Keys Lecture. Circulation. 1997;95:252–264. 20. Khaw K-T, Barrett-Connor E. Sex differences, hormones, and coronary heart disease. In: Marmot M, Elliott P, eds. Coronary heart disease epidemiology: from aetiology to public health. Oxford (England): Oxford University Press; 1992:274–286. 21. Strong JP, Oalmann MC, Malcolm GT. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Atherosclerosis in youth: relationships of risk factors to arterial lesions. In: Filer LJ Jr, Lauer RM, Luepker RV, eds. Prevention of Atherosclerosis and Hypertension Beginning in Youth. Philadelphia, PA: Lea & Febiger; 1994: 13–20. 22. US Department of Health and Human Services. Report of the Secretary’s Task Force on Black and Minority Health, 1: Executive Summary. Bethesda, MD: US Department of Health and Human Services; 1985. 23. Goff DC Jr, Varas C, Ramsey DJ, Wear ML, Labarthe DR, Nichaman MZ. Mortality after hospitalization for myocardial infarction among Mexican-Americans and non-Hispanic Whites: the Corpus Christi Heart Project. Ethnicity Dis. 1993; 3:55–63. 24. Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Affairs. 2007;26:38–48. 25. Cardiovascular diseases and stroke in AfricanAmericans and other racial minorities in the United States: a statement for health professionals. Circulation. 1991;83:1463–1480.

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26. Kelleher CC, Lynch JW, Daly L, et al. The “Americanisation” of migrants: evidence for the contribution of ethnicity, social deprivation, lifestyle and life-course processes to the mid-20th century coronary heart disease epidemic in the US. Social Science & Medicine 2006;63:465–484. 27. Singh G, Siahpush M. Ethnic-immigrant differentials in health behaviors, morbidity, and cause-specific mortality in the United States: an analysis of two national databases. Human Biology. 2002;74:83–109. 28. Koch T. Cartographies of Disease: Maps, Mapping, and Medicine. Redlands, CA: ESRI Press; 2005. 29. Mackay J, Mensah GA. The Atlas of Heart Disease and Stroke. Geneva (Switzerland): World Health Organization; 2004. 30. Mazzati E, Vander Hoorn S, Lopez AD, et al. Comparative quantification of mortality and burden of disease attributable to selected risk factors. In: Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, eds. Global Burden of Disease and Risk Factors. Washington, DC: The International Bank for Reconstruction and Development/The World Bank; 2006:241–396. 31. Casper ML, Barnett E, Halverson JA, et al. Women and Heart Disease: An Atlas of Racial and Ethnic Disparities in Mortality. 2nd ed. Morgantown, WV: Office for Social Environment and Health Research, West Virginia University; 2000. 32. Barnett E, Casper ML, Halverson JA, et al. Men and Heart Disease: An Atlas of Racial and Ethnic Disparities in Mortality. 1st ed. Morgantown, WV: Office for Social Environment and Health Research, West Virginia University; 2001. 33. Casper ML, Barnett E, Williams GI Jr, Halverson JA, Braham VE, Greenlund KJ. Atlas of Stroke Mortality: Racial, Ethnic, and Geographic Disparities in the United States. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention; 2003.

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34. Casper ML, Denny CH, Coolidge JN, et al. Atlas of Heart Disease and Stroke Among American Indians and Alaska Natives. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention and Indian Health Service; 2005. 35. Barnett E, Elmes GA, Braham VE, Halverson JA, Lee JY, Loftus S. Heart Disease in Appalachia: An Atlas of County Economic Conditions, Mortality, and Medical Care Resources. Morgantown, WV: Prevention Research Center, West Virginia University; 1998. 36. Halverson JA, Ma L, Harner EJ. An Analysis of Disparities in Health Status and Access to Health Care in the Appalachian Region. Executive Summary. Prepared for the Appalachian Regional Commission, Washington, DC: West Virginia University; 2004. 37. Murray CJL, Kulkarni S, Ezzati M. Eight Americas: new perspectives on U.S. health disparities. Am J Prev Med. 2005;29:4–10. 38. Murray CJL, Kulkarni SC, Michaud C, et al. Eight Americas: investigating mortality disparities across races, counties, and race-counties in the United States. PLoS Med. 2006;3: 1513–1524.

39. Thom TJ, Epstein FH, Feldman JJ, Leaverton PE, Wolz M. Total Mortality and Mortality from Heart Disease, Cancer and Stroke from 1950 to 1987 in 27 Countries: Highlights of Trends and Their Interrelationships Among Causes of Death. NIH publication 92-3088. Bethesda, MD: National Heart, Lung and Blood Institute, National Institutes of Health; 1992. 40. Murray CJL, Lopez AD. Alternative visions of the future: projecting mortality and disability, 1990–2020. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston, MA: The Harvard School of Public Health; 1996: 325–395. 41. Leeder S, Raymond S, Greenberg H. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries. New York: The Trustees of Columbia University in the City of New York; 2004.

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The Major Cardiovascular Diseases

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P A R T

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3 Atherosclerosis with behavioral interventions, drugs, or surgery to lower cholesterol concentrations has been shown by serial angiography to delay progression and even produce regression of atherosclerotic lesions. How is the epidemiology of atherosclerosis changing on a national and global scale? Continuing development of noninvasive examination methods and wider application of existing standardized protocols for pathological examination of coronary arteries of young decedents could contribute to answering this question.

SUMMARY Atherosclerosis is a pathological condition that occurs in medium and large arteries throughout the body. Its clinical manifestations appear especially in the heart, brain, lower extremities, and aorta. It is the underlying condition in the occurrence of myocardial infarction (heart attack), ischemic cerebrovascular accident (occlusive stroke), peripheral arterial disease of the lower extremities, and aortic aneurysm. Postmortem study of tissues obtained at autopsy has been a major component of atherosclerosis research since long before the 20th century. Recent technology has permitted study of patients and populations through invasive and noninvasive methods, respectively—for example, by angiographic examination of patients and by ultrasonography to measure carotid artery lesions in large population studies. Through autopsy studies, atherosclerosis has been found in populations throughout the world. Early-stage lesions occur ubiquitously, beginning in childhood. Autopsies of US military casualties dying from combat-related or other injuries in Korea and Vietnam indicated unexpectedly severe coronary atherosclerosis in some young soldiers with no known symptoms of coronary heart disease. Recent evidence indicates strong correlations between the extent and severity of atherosclerosis in adolescents and young adults and such characteristics as adverse blood lipid profile, high blood pressure, and cigarette smoking. Singly or in combination, these factors, measured in childhood and adolescence, predict the extent and severity of coronary atherosclerosis not only in early adulthood but at least to the mid-50s. Public health recommendations promote desirable behavior patterns beginning in childhood to prevent development and progression of atherosclerosis. Treatment of adults

INTRODUCTION “Atherosclerosis” refers to the consistency of material typically found on the inner, or luminal, surface and in the wall of large- to medium-diameter arteries throughout the body. The areas of the circulation, or vascular beds, where this development is most critical are those supplying the heart and brain. Atherosclerosis is a descriptive term for the pathological mushy areas (atheromata), often encrusted or hardened (sclerosed) by deposition of calcium, which weaken the arterial wall and intrude into the lumen or channel of the vessel, restricting or obstructing blood flow. The atherosclerotic plaque, whether fully matured or in intermediate stages of development, is now regarded as the key to precipitating blood clot formation (thrombosis) with sudden interruption of blood flow. A variety of outcomes may follow, depending on the location, severity, and duration of the interruption. Most important among these are heart attack, stroke, and related conditions. Figure 3-1 presents a microscopic cross section of a coronary artery from a fatal case of myocardial infarction.1 The clear area at the upper right within the

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Figure 3-1 Light Micrograph of a Histological Section of a Complicated Atherosclerotic Plaque from Human Coronary Artery with Attached Mural Thrombus. Source: Reproduced with Permission from RW St. Clair, Biology of Atherosclerosis, in TA Pearson et al., Primer in Preventive Cardiology, © 1994, American Heart Association.

artery (from 12 to 3 o’clock) is all that remains of its lumen or channel of blood flow. This area has been greatly reduced by the dark-staining thrombus that shares this quadrant of the artery and rests on top of a large accumulation of material that occupies three quarters of the vessel area, from 3 to 12 o’clock. This latter region of the wall contains not only dead tissue but also crystals of cholesterol, often described as “shale-like” in microscopic appearance, which are an essential component of the classical atherosclerotic plaque. Details of classification of atherosclerotic lesions as observed at the histologic, or tissue, level by light microscopy are found in two successive reports from the Committee on Vascular Lesions of the Council on Arteriosclerosis of the American Heart Association.2,3 The first category of abnormality, not yet an atherosclerotic condition, is adaptive thickening of the coronary artery. Grades 1 and 2 apply to low-grade lesions, grossly visible yellow fatty streaks in the innermost, or intimal, layer of the artery wall. Grade 3 lesions are intermediate in their development. Grades 4 and 5 apply to advanced lesions, potentially most significant for development of clinical manifestations. These latter lesions include the “vulnerable plaques,” which are most susceptible to rupture and

initiation of a process leading to thrombosis, with obstruction of blood flow as seen in Figure 3-1. Chronic inflammation, which tends to soften the material within the fibrous cap of the plaque, predisposes to rupture or cracking (fissuring) of the plaque covering.4 The resulting thrombosis may heal, adding to growth of the plaque, or it may expand to obstruct blood flow. Whether the inflammatory process within the plaque depends on systemic infection or another chronic inflammatory condition is unresolved. It has recently been proposed that the vulnerable plaque should include three types of conditions: plaque rupture, as described above, with a preceding stage called a “thin-cap fibroatheroma”; plaque erosion, not associated with inflammation; and calcified nodules.5 These differ in their patterns of occurrence in specific clinical situations. The concept of progression from the lowest- to highest-grade lesions is basic to understanding development of atherosclerosis beginning in childhood and adolescence.

METHODS OF MEASUREMENT— INVASIVE AND NONINVASIVE The foregoing perspective on atherosclerosis is the pathologist’s view, based mainly on examination of

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material obtained at autopsy. Study of atherosclerosis in living persons utilizes measurement methods broadly categorized as “invasive” and “noninvasive.” Location and extent of atherosclerotic lesions can be investigated clinically, in patients suspected of having atherosclerosis, by injection of radiopaque dye into specific regions of the arterial circulation, as in coronary angiography. This technique permits repeated measurement in individual patients to detect change in size of atherosclerotic lesions—such as reduced rates of progression or actual regression of lesions in response to treatment.2,6 By reason of risk, feasibility, and cost, less direct, or “noninvasive,” methods of examination are needed for populationbased studies of atherosclerosis in living persons. Two methods for rendering images of atherosclerosis are ultrasound examination of the carotid artery, which supplies blood flow in the neck to connect the thoracic aorta with the cerebral circulation, and computed tomography of the coronary arteries, which supply the heart muscle or myocardium. Ultrasound reflectance by B-mode ultrasonography has been validated for estimating carotid arterial wall thickness as an indicator of underlying atherosclerosis. The carotid artery is readily accessible, is relatively immobile, is relevant to circulation to the brain and implicated in risk of stroke, and correlates well with pathology in the coronary arteries. The measure obtained is the intimal-medial thickness (IMT), sometimes referred to as the carotid IMT (CIMT). This technique uses an ultrasound transducer and sensor applied over the carotid artery and measures variations in wall thickness or lumen diameter to the scale of tenths of a millimeter. By this means, epidemiologic assessment of atherosclerosis is no longer limited to postmortem samples or highly selected cases of known or clinically suspected arterial disease but can be extended to the general, living population. This technique is being used, for example, in a population study of some 15,800 healthy American adults in the Atherosclerosis Risk in Communities (ARIC) Study. A recent review provides details of the technique, representative images in normal and diseased arteries, findings of the ARIC Study linking CIMT with other characteristics of participants, and summary results from a number of clinical trials showing reduction in CIMT after blood lipid-lowering therapy.7 A second noninvasive method now being investigated in a number of studies, most prominently the Multi-Ethnic Study of Atherosclerosis (MESA) Study, is ultra-fast computed tomography (UFCT), or CT scanning.8 As applied to examination of the heart, UFCT detects and quantifies calcified atherosclerotic

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lesions by measuring the intensity of the coronary artery image due to calcium deposits in plaques. “Ultrafast” refers to rapid imaging that permits examining coronary arteries even though they are in constant motion throughout the cardiac cycle. The resulting measure is the coronary artery calcium (CAC) score. The primary purpose of the MESA Study, a major multicenter prospective epidemiologic study, is to determine the value of the CAC score in estimating the risk of future coronary events and its potential role in clinical risk assessment. Parallel development of CT angiography offers another mode of examination for assessing the diameter of the arterial lumen. However, it is important to recognize that these techniques involve exposure to ionizing radiation, a concern when mass screening for coronary artery calcium, for example, is contemplated. Discussion of the CAC as a screening tool has stimulated development of a scientific consensus statement reviewing available evidence and providing recommendations on its role.9 Current judgment, as reflected in this review, is that neither high- nor lowrisk individuals stand to benefit from this examination, but persons at intermediate risk might be reclassified to a higher-risk category on the basis of the CAC score. Among several reservations expressed about utility of the score, the report notes that presently available data are largely limited to nonHispanic Caucasian men and cautions against extrapolation to women and ethnic minorities. (The issues of sex and race/ethnicity raised in Chapter 2 have clearly not yet been resolved in this area but are being addressed in the MESA Study.) Other approaches to assessing atherosclerosis without clinical angiography or autopsy include several clinical or subclinical examinations that can provide indirect evidence of disease. Magnetic resonance imaging (MRI) may become applicable for population use in the future, to assess plaque characteristics and as a form of angiography, avoiding radiation exposure.

MANIFESTATIONS—ABOVE AND BELOW THE “CLINICAL HORIZON” Atherosclerosis is a systemic disorder, in that it occurs in large- and medium-diameter vessels throughout the arterial tree. For this reason its manifestations above the “clinical horizon,” as termed by McGill and others and illustrated in Figure 3-2, may relate to any of several different regions of the circulation, for example, the heart, brain, lower extremities, or aorta.10 This schematic view of the development of atherosclerosis from below to above the clinical horizon has

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Figure 3-2 Schematic View of the Development of Atherosclerosis. Source: Reprinted with Permission from HC McGill Jr., JC Geer, and JP Strong. The Natural History of Human Atherosclerotic Lesions, in Atherosclerosis and Its Origin, M Sandler and G Bourne, eds, p 42, © 1963, Academic Press.

been published in several versions since the 1950s. In the intervening years, atherosclerotic lesions at several stages of development below the clinical horizon have become detectable, for example, by CIMT and UFCT. There are two especially important implications of this schematic representation. First is that the earliestappearing lesions, fatty streaks, are truly precursors of fibrous plaques, and they in turn lead to complicated lesions. Today, refinements in categorization of lesion types and the concept of the vulnerable plaque would be added to the scheme. Second is that the atherosclerosis begins in the first decades of life even though its clinical manifestations most often occur in the fifth decade and beyond. Today, the occurrence of clinical manifestations in the 30s would be noted. With respect to clinical manifestations, no single cardiovascular condition, such as coronary heart disease alone, reflects the full contribution of atherosclerosis to disease, disability, and death in a population. Accordingly, among the conditions identified in Table 1-1 by ICD 10 codes, all those from I10 through I79 and some in the category I95 through I99

are potential consequences of atherosclerosis. The epidemiology of atherosclerosis has been approached mainly in studies of coronary heart disease and stroke. A more complete assessment includes peripheral arterial disease and aortic atherosclerosis. The epidemiology of these latter conditions is based on their occurrence either as causes of death or as conditions detectable in life through clinical data sources or special ascertainment in epidemiologic studies. These conditions are discussed separately in Chapters 4–6. The extent to which atherosclerotic conditions occur below the clinical horizon, and with what manifestations, is a question addressed, for example, in the Cardiovascular Health Study (CHS) involving adults aged 65 years and older.11 CHS investigated a composite index of subclinical atherosclerosis through carotid ultrasound, echocardiography, electrocardiography, the ankle-brachial index (ABI, a measure of blood pressure differences between arm and ankle reflecting obstruction in lower extremity arterial supply), and responses to questionnaires about symptoms of impaired coronary or lower extremity arterial blood flow, also known as ischemia. More than onethird of participants had subclinical (i.e., clinically inapparent) signs or symptoms of atherosclerosis. In the same study, only one-quarter to one-third of men and women had clinical disease. Detection of subclinical disease among the rest of the population showed atherosclerosis to be more than twice as prevalent as indicated by clinical evidence alone. In a further report on the findings of CHS, presence of several indicators of subclinical disease was described for Black and White men (Figure 3-3a) and women (Figure 3-3b).12 The two pictures appear generally consistent. They show somewhat higher prevalence of these conditions for men than for women, more frequent occurrence among Blacks than Whites for most conditions for both men and women, and— taking all conditions together—more than two-thirds of men and more than one-half of women being affected by one or more conditions. Additional data in this report indicate the importance of these observations in relation to major clinical events. Among those with subclinical disease, compared with those without, total mortality was more than twice as frequent (5.5% versus 1.9%); total coronary heart disease was nearly twice as frequent (8.2% versus 4.3%); and incident myocardial infarction was 1.2 times as frequent (3.1% versus 2.6%). CHS demonstrates the high frequency of subclinical disease that can be identified when sought by special-purpose examination among Black and White men and women in this age group.

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MANIFESTATIONS—ABOVE AND BELOW THE “CLINICAL HORIZON”

70

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Figure 3-3b Prevalence of Subclinical Disease Among Black (Shaded Bar) and White (Open Bar) Men with at Least One Subclinical Disease at Their Baseline Examination in the Cardiovascular Health Study. Source: Reprinted with permission from Cardiology Clinics, Vol 17, Kuller L, Sutton-Tyrrell K, Aging and cardiovascular disease. Use of subclinical measurements, pp 51–65, © Elsevier 1999.

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MECHANISMS OF ATHEROGENESIS The question of how atherosclerosis develops has been investigated at least since the mid-19th century. An overview by Stamler is the basis for the following highlights of the early research.13 The work by Virchow in the latter half of the 19th century established atherosclerosis as a distinct pathological entity in which the “mush” was identified as fatty (lipid) material, specifically including cholesterol. Clinical research that followed showed that diseases characterized by prolonged high blood cholesterol concentrations produced severe premature atherosclerosis, establishing a link between atherosclerosis and blood lipid concentrations. Early in the 20th century, the accidental discovery was made that experimental manipulation of rabbits’ diets by feeding them animal products produced atherosclerosis. Subsequent animal experiments indicated that even small cholesterol supplements as part of long-term dietary changes would also produce this condition. Further animal studies suggested cellular processes in which migrating cells especially high in cholesterol content invaded the arterial wall. The laboratory research data on diet were reinforced in the mid-1930s on an altogether different scale by reports on “geographical pathology.” These were studies that linked differences among populations in frequency of occurrence of atherosclerosis with differences in their typical diets. In the period immediately following the Great Depression and Second World War, laboratory and clinical research on atherosclerosis expanded rapidly and included biochemistry, biophysics, pathology, and cell biology. Mechanisms of lipid metabolism and transport were investigated intensively. By the mid-1970s, studies in vascular biology led to refined concepts of atherogenesis. Three complementary mechanisms were outlined by Ross in the “response-to-injury” hypothesis, attributed in its original formulation to Virchow.14 An early step in atherogenesis appeared to be adhesion of blood monocytes to the arterial endothelium, followed by migration of these cells into the intimal layer, and subsequent concentration of lipid in these cells. This process was facilitated by the oxidation of lipids carried by lowdensity lipoproteins. In a second phase of development, fatty streaks beneath the endothelium may be altered by migration of smooth muscle cells from the medial into the intimal layer of the arterial wall. Here, factors that stimulate cellular proliferation may produce a marked multiplication of these cells to produce raised lesions. Then, in later progression of these lesions, a long-hypothesized step of endothelial cell

dysfunction and damage may occur from elevated blood lipid concentrations, viral infection, or other plausible causes. Platelet adherence to damaged endothelial cells then leads to local thrombosis, with occlusion of the artery and the resulting signs and symptoms of impaired or obstructed blood flow to the tissues beyond.1 Further laboratory studies continued to elaborate on this concept of atherogenesis, some aspects of which still require confirmation, including the relation of this process to clinical manifestations of atherosclerosis. By the late 1990s, Ross declared that the fundamental process underlying the response-to-injury hypothesis was inflammation, a series of specific cellular and molecular changes in the arterial wall:15, p 115 The most recent version of this hypothesis emphasizes endothelial dysfunction . . . each characteristic lesion of atherosclerosis represents a different stage in a chronic inflammatory process in the artery; if unabated and excessive, this process will result in an advanced, complicated lesion. Possible causes of endothelial dysfunction leading to atherosclerosis include elevated and modified LDL [low-density lipoprotein cholesterol— see Chapter 11]; free radicals caused by cigarette smoking, hypertension, and diabetes mellitus; genetic alterations; elevated plasma homocysteine concentrations; infectious microorganisms such as herpesviruses or Chlamydia pneumoniae; and combinations of these or other factors. A separate and more limited line of investigation lends some support to the concept that atherosclerosis originates with viral infection.16 Members of the herpesvirus group (herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and herpes zoster virus) have been of particular interest on the basis of both animal and human studies. It has been suggested that coronary reocclusion after angioplastic surgery to relieve stenosis may be associated with viral infection.17 Widespread occurrence of these viruses and high incidence of infection early in life add to epidemiologic interest in this concept, which also deserves further investigation. How this might be linked with evidence for other processes involved in atherosclerosis remains to be established. Bacterial infection has also been invoked as a factor in the progression of atherosclerosis, with growing interest in apparent associations between infection with Chlamydia pneumoniae or Helicobacter pylori, for example, and presence of coronary heart disease.17,18 Weighing against this hypothesis is failure of many trials of antibiotic therapy

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and some prospective epidemiologic studies to provide supporting evidence.

PERSON, PLACE, AND TIME Published accounts indicate the presence of atherosclerosis even in antiquity. Well-preserved human remains from ancient China and Egypt have revealed atherosclerosis in the coronary arteries.19,20 As to how widespread its occurrence may have been in early times, it can be presumed that those whose remains were so carefully prepared for burial were persons of exceptional affluence and not typical of their societies. In more recent times, occurrence of atherosclerosis has been well recognized since the mid-19th century. A detailed account of work in the pathology of atherosclerosis up to the mid-1950s was presented by Holman and colleagues in 1958, the source of the original version of Figure 3-2.21 The concept advanced at that time was based on a large series of autopsies in persons 1–40 years of age, at Charity Hospital of Louisiana in New Orleans, as well as previous reports from as early as 1911. The essential observation was that the earliest lesions of atherosclerosis, the fatty streaks, appear commonly in the first decade of life. These can progress with age to fibrous plaques and more advanced lesions. Rates of progression with age differ among population groups, being more gradual in Blacks than in Whites in New Orleans, for example, according to Holman’s review. Holman suggested that factors initiating fatty streaks differ from the factors leading to their gradual conversion, over 15 years or more, to advanced lesions. In addition, a rapid increase during puberty in the percentage of aortic surface involved with fatty streaks was taken by Holman as evidence that hormonal changes, rather than diet, were the major determinant of progressive atherogenesis. In 1953, a report of postmortem examinations among US military casualties in Korea revealed atherosclerosis of the coronary arteries in the majority of young men examined, typically in their early 20s.22 Lesions were visible at autopsy in the coronary arteries of 77.3% of the 300 cases studied; complete occlusion of one or more coronary arteries was found in 3.0% of cases. Presumably, these occlusive lesions had evolved very gradually, and therefore from much earlier ages, with concurrent development of collateral circulation to protect against symptoms (usually acute chest pain) of myocardial ischemia. An analogous investigation was conducted 18 years later among US military casualties in Vietnam,

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on the basis of postmortem coronary angiography to detect atherosclerosis.23 The resulting estimate of the frequency of “some degree” of coronary atherosclerosis was 45% among the 105 examinations performed and of “apparently severe atherosclerosis” was 5%. This was thought to represent a decrease in prevalence relative to the observations in Korea two decades earlier, but subsequent reinvestigation of materials from the Korean War casualties indicated that the two results were consistent, at least in the frequency of severe lesions.24 These studies reinforce the view presented in Figure 3-2 that atherosclerosis has already progressed before age 20 in a substantial proportion of US population groups, as found in young military personnel and both Black and White residents of New Orleans. Further studies of atherosclerosis in populations living under widely varying conditions were undertaken more than four decades ago, after development of carefully standardized techniques for postmortem collection and examination of specimens of the aorta and coronary arteries. A landmark investigation in the epidemiology of atherosclerosis was the International Atherosclerosis Project (IAP) in which 23,207 sets of coronary arteries and aortas were collected in 14 countries, from 1960 to 1965.25 The materials were from autopsy examinations of males and females from 10 to 69 years of age at death from conditions unrelated to atherosclerosis. Dissected and prepared under a common protocol locally, the materials were examined grossly and microscopically by teams of pathologists in a central laboratory. One measure of the extent of atherosclerosis was the percentage of the intimal surface of the artery covered by raised atherosclerotic lesions, that is, by fibrous plaques and complicated or calcified lesions. This measure of the extent of atherosclerosis in the aorta (abdominal and thoracic aorta combined) and coronary arteries (three coronary arteries combined) was presented for each of 19 race-location groups in the IAP. Subjects in these comparisons died at 25 to 64 years of age. For New Orleans Whites, for example, the percentage surface involvement of the coronary arteries was greatest for males (more than 20%), more than twice the percentage for females. For Bantus in Durban, South Africa, by contrast, the corresponding percentages of surface involvement for both males and females were much less, only about 8%. In general, the IAP showed that atherosclerosis in the aorta was not consistently more extensive among males than among females; for the coronary arteries, the extent was almost without exception greater among males. Large population differences can thus occur in the extent of atherosclerosis. It

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differs in different regions of the circulation, such as aorta versus coronary arteries, even between males and females in the same population. In addition, when nine populations of men aged 45–54 and 55–64 years were ranked by extent of raised lesions in the coronary arteries, there was close correspondence with their ranks by mortality rates for coronary heart disease. Marked progression of atherosclerotic plaques by age is indicated by selected results from the IAP and several populations studied under a protocol of the World Health Organization (WHO).26 A composite

curve for Malmo, Sweden, and four Eastern European cities studied under the WHO protocol shows increases in the proportion of persons with atherosclerotic plaques from less than 15% at age 20 to 100% at ages 50 and older (vessel and lesion type not specified) (Figure 3-4). From selected sites in the IAP, percentages of males and females combined with fibrous plaques in the left anterior descending coronary artery are indicated by age. Wide variation in the extent of such lesions even as early as age 20 is remarkable, as is the steep increase in all populations to peaks from

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Figure 3-4 The Extent of Atherosclerosis by Age, from the WHO Project and the International Atherosclerosis Project. Derived from autopsy studies; prevalence rates at age 20 (X). Source: Reprinted with permission from TRS 678, p 35, World Health Organization.

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50% to nearly 100% of persons being affected. That 25% of the New Orleans population is affected by age 20 indicates that atherosclerosis has commonly begun well before the earliest adult years. By inference, whatever factors determine the rate of progression of atherosclerosis must operate well before age 20 in some populations.

ATHEROSCLEROSIS IN CHILDHOOD, YOUTH, AND EARLY ADULTHOOD Methods and Findings The preceding work provided a strong impetus to further investigation of the onset and progression of atherosclerosis from childhood through early adulthood. In particular, interest developed in determining whether factors predictive of the later clinical manifestations of atherosclerosis are related to its early progression. A challenge for epidemiologic study of this question was to obtain information for the same individuals about both the presence and extent of atherosclerosis, on the basis of postmortem examination, and the presence of factors before death that might be predictive of the nature and extent of the disease. Two distinct approaches have been used. First, a study in childhood of factors related to atherosclerotic and hypertensive diseases was conducted by Berenson and others in Bogalusa, Louisiana, beginning in the 1970s. Ultimately, several thousand school-age children were examined. In 1986, the investigators first reported that 35 study participants had died and undergone autopsy examinations including standardized examination of the heart, coronary arteries, and aorta.27 Updates in 1992 and 1998 included totals of 62 and 93 decedents, respectively, from ages 3 to 38 years.28,29 A second epidemiologic approach was to begin by identifying large numbers of individuals dying young from noncardiovascular causes. At the time of death it would be possible to obtain information about relevant characteristics and conduct highly standardized and detailed postmortem examination of coronary arteries and the aorta. This was the approach of a large, 15-center study in the United States, the Pathobiological Determinants of Atherosclerosis (PDAY) Study. A publication from 2002 reported on more than 3000 subjects dying at ages 15–34 years between 1987 and 1994.30 Methods and many of the findings are presented in that report. In the PDAY Study, the extent of atherosclerosis was measured by the percentage of surface area of the intimal lining of the vessel involved with fatty streaks

49

or raised lesions. Such data, separately by sex and 5-year age groups, are represented in Figure 3-5, taken from a 1997 report.31 The upper panels show the extent of surface area involved with fatty streaks in the abdominal aorta (A) and right coronary artery (C), for men (open bars) and women (solid bars). The lower panels (B and D) refer to raised lesions in the corresponding vessels. Relative to males, females had less extensive raised lesions in the coronary artery, at every age. They also had more extensive fatty streaks but a similar extent of raised lesions in the aorta and a similar extent of fatty streaks in the coronary artery. Sex differences in development of coronary atherosclerosis, favoring females, were apparent among these teens and young adults. Precursors and Predictors Beyond these observations on atherosclerosis itself between the mid-teens and mid-thirties, both studies addressed the possible association between factors thought to be relevant to development of atherosclerosis and the extent of pathology in the coronary artery, aorta, or both. Because the decedents in the Bogalusa Heart Study had been examined in previous school-based surveys, the earlier measurements of blood lipids, blood pressure, and body mass index (BMI, weight/height2 measured in kg and m) could be analyzed in relation to the extent of atherosclerosis present at autopsy (Table 3-1).29 Separately for Black and White males and females, correlations were calculated between various combinations of these measurements (systolic blood pressure and BMI with different blood lipid measures) and the extent of aortic and coronary artery lesions. Although nearly all of the correlations were statistically significant in the total pool of 93 cases, the sex-race-specific groups showed some variation. For example, for White females (only 19 in number) correlations with fibrous plaques in the coronary artery were exceptionally weak. For Black females, too, these correlations were weaker than among males though stronger than among females. These and other observations hint at some degree of relative protection of females, especially Whites, from the effects of blood pressure, BMI, and blood lipids. This is consistent with the impression from Figure 3-5 of young women being favored over young men in extent of coronary atherosclerosis. An early report of the PDAY Study presented results for 390 males with postmortem examinations at ages from 15 to 34 years.32 In addition to tissue samples, the study obtained extensive information at the time of death regarding blood lipid concentrations, blood thiocyanate levels (to indicate exposure

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Figure 3-5 Extent of Fatty Streaks and Raised Lesions in the Abdominal Aorta (A and B) and Right Coronary Artery (C and D) in Men (white) and Women (black) Aged 15–34 Years from the PDAY Study. Source: Reprinted with permission from HC McGill Jr. et al., Atherosclerosis, Thrombosis and Vascular Biology, Vol 17, p 98, © 1997, American Heart Association.

to cigarette smoke), weight and height (for calculating BMI), and other characteristics. Figure 3-6, taken from that report, demonstrates the relation of percentage surface area of the abdominal aorta involved with any lesions to blood lipid concentrations and to smoking status. Taking these data into account allowed derivation of a statistical prediction of the extent of abdominal aortic atherosclerosis for males at each year of age in relation to these factors. For the group with unfavorable blood lipids who were smokers, the surface involvement was above 30% at age 15 and 50% or greater at age 34; by contrast, for the group with favorable blood lipids who were not smokers, the corresponding percentages of surface involvement were about 10% at age 15 and less than 25% at age 34. A close link was apparent between these factors and the extent of early aortic atherosclerosis.

It was of interest to investigate these relationships further, by assessing the ability to predict the extent of atherosclerosis in the coronary artery from composite scores reflecting multiple factors. By 2002, the Bogalusa Heart Study could report on examination of 517 individuals at ages 20 to 38 years with use of CIMT to indicate subclinical atherosclerosis.33 The combinations of measures considered in the analysis included up to three or more of the following: total cholesterol to high-density lipoprotein (HDL) cholesterol ratio, waist circumference, systolic blood pressure, insulin concentration, and smoking. For each of three anatomical locations in the carotid artery, IMT was consistently associated with increasing numbers of these factors. CIMT was recommended as a marker of the cumulative effects of these factors at early ages and as a stimulus to preventive measures.

0.47 0.09 0.50 0.16

Source: Am J Cardiol © 1998, Excerpta Medica, Inc.

Calculated as sum of the study-, age-, race-, and sex-specific z-scores of risk factor variable combinations shown in the table. Sample size varies based on variables used. BP = blood pressure; BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoprotein. *p 0.001. † p 0.01. ‡ p 0.0001. § p 0.05.

0.56§ 0.56§ 0.53§ 0.63†

0.93† 0.51 0.99‡ 0.35

0.53‡ 0.26§ 0.54‡ 0.49‡

0.61* 0.26 0.67‡ 0.65*

Systolic BP, BMI, triglycerides, and total/HDL-cholesterol combination Fatty streak, aorta Fibrous plaque, aorta Fatty streak, coronary Fibrous plaque, coronary

0.61 0.68 0.99‡ 0.35

0.41* 0.27§ 0.58‡ 0.51‡

0.53 0.09 0.51 0.17

0.53† 0.26 0.76‡ 0.66*

Systolic BP, BMI, and triglycerides combination Fatty streak, aorta Fibrous plaque, aorta Fatty streak, coronary Fibrous plaque, coronary

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0.35 0.40 0.37 0.58†

0.57‡ 0.23 0.54‡ 0.44*

Total (N ⴝ 93)

Spearman Correlation Coefficients Between Extent of Aortic and Coronary Artery Lesions and Multiple Risk Factor Indices White Black White Black Males Males Females Females (n ⴝ 41) (n ⴝ 23) (n ⴝ 19) (n ⴝ 10) Systolic BP, BMI, and LDL-cholesterol combination Fatty streak, aorta 0.61* 0.67† 0.43 0.52 Fibrous plaque, aorta 0.18 0.60§ 0.07 0.68 Fatty streak, coronary 0.63* 0.45 0.61§ 0.90 Fibrous plaque, coronary 0.56† 0.59§ 0.09 0.35

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Figure 3-6 Prevalence of AHA Lesion Grades by Category of PDAY Coronary Artery Risk Score Computed from the Modifiable Risk Factors for Men (Left) and Women (Right) and 10-Year Age Group. Source: From Pediatrics Vol 118, p 1450, © 2006, American Academy of Pediatrics.

The PDAY Study took the approach of deriving a risk score to predict the earliest and the most advanced atherosclerotic lesions.34 The score was based on non-HDL-cholesterol, HDL-cholesterol, smoking (present or absent), high blood pressure (present or absent, from anatomical indicators), BMI, and hyperglycemia. All were considered “modifiable” factors, distinguished from age and sex, which were regarded as “immutable” factors. Specifically for younger and older subjects and for men and women, prevalence especially of intermediate and more advanced lesions increased significantly with increasing risk score (Figure 3-6). Notably, women in the highest risk stratum were too few for separate analysis and were therefore combined into the third level of risk; also, prevalence of lesions at each level of severity was less in women than in men at every level of the risk score. The PDAY investigators took one further step. They applied the score derived from their 15- to 34year-old subjects to earlier data from the Community Pathology Study (CPS) in Orleans Parish, LA, to which many of the same investigators had contributed in the 1970s and 1980s.35 The PDAY score was used in two separate age strata from CPS: 15 to 34-year-olds and 35 to 54-year-olds. The overall result was strong association of the PDAY risk score with extent of coro-

nary atherosclerosis in both the same age range as PDAY and the later ages observed in CPS alone. This is depicted in Figure 3-7, by sex, for each of three coronary arteries (right, left circumflex, left anterior descending; see Figure 4-1). Deaths in the CPS data are categorized as “basal” (external, noncardiovascular causes), “related” (deaths with cardiovascular conditions present but not as cause of death), or “CHD” (death thought to be due to coronary heart disease). The extent of surface area involved was substantially greater for “CHD” or “related” than for “basal” deaths, greater for men than for women in each category, and greater in every instance for cases scored above the median than at or below the median value. The authors concluded that “The results from combined PDAY and CPS data suggest a seamless progression of the effects of the modifiable risk factors on atherosclerosis from 15 to 54 years of age.”35, p 371 A previous comparative study of the pathology of atherosclerosis in the United States and Japan showed substantially less extensive involvement of the aorta and coronary arteries in men in Tokyo than Black or White men in New Orleans, all autopsied at ages 25 to 44 years.36 Notably, the differences between New Orleans Whites and Japanese men was not in fatty streaks but in raised lesions as a percentage of the surface area of either aorta or coronary arteries. This

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Right Coronary Surface Area Involved (%)

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Figure 3-7 Mean Extent of Intimal Surface Area Involved with Raised Lesions in CPS Cases 35–43 Years of Age in the Right (Upper Panels) and Left Circumflex (Middle Panels), and Left Anterior Descending (Lower Panels) Coronary Arteries for Men (Left Panels) and Women (Right Panels) by That Part of the PDAY Risk Score Computed from the Modifiable Risk Factors (gray bars 4 [median]; black bars 5) and Cause of Death Category, Adjusted for Age. Source: From Atherosclerosis Vol 190, p 374, © 2006, Elsevier Ireland Ltd.

finding accords with long-recognized differences in coronary heart disease death rates in Japan relative to those in the United States and other industrialized countries. When a study of pathology of the aorta and coronary and cerebral arteries in relation to premortem factors such as blood lipids and blood pressure was undertaken in Japan, medical records were used as the source of information on these factors.37 The extent of more advanced atherosclerotic lesions was quite limited in the aorta, but in the coronary and

especially the cerebral arteries, fibrous plaques constituted a much-increased proportion of the lesions found. The extent of lesions in the aorta was primarily related to the age at death; in the coronary arteries, age, cholesterol, and blood pressure were all significantly related; and in the cerebral arteries, blood pressure was strongly and singularly related to a statistically significant degree. This report adds to the other insights to the epidemiology of atherosclerosis, especially the contrasting appearance of this

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disease in different regions of the circulation. Further, it indicates that factors thought to accelerate the development of atherosclerosis even in its early stages relate differently to the disease in these different anatomic locations. A further observation on the relation between factors measured in childhood and the development of atherosclerosis is based on the long-term follow-up of children examined in school and recontacted as young adults in their early 30s in the Muscatine Study organized by Lauer and colleagues.38 This project in Iowa began in the 1970s and later included examination by UFCT scan of the coronary arteries to detect calcified coronary lesions. The results supported those described above, indicating that factors such as weight/height index, blood lipids, and blood pressure, all measured in the school years, predict the finding of these lesions at ages as early as the 30s. More recently, prehypertension (intermediate ranges of both systolic and diastolic pressure) before age 35 years was found to predict degrees of coronary calcium at a mean age of 44 years during follow-up in the CARDIA Study.39

PREVENTION AND TREATMENT OF ATHEROSCLEROSIS Occurrence of atherosclerosis in childhood, youth, and early adulthood and its relation to multiple modifiable factors has been emphasized in this discussion in part because these are the life stages when it first appears and because this period of life is not directly germane to coronary heart disease, stroke, and related conditions, as described in Chapters 4–6. Rather, the present discussion sets the stage for appearance of those conditions later, especially in middle and older adult years. Demonstration through the Bogalusa Heart Study, PDAY, and others that identifiable and modifiable factors are strongly and consistently associated with even the earliest lesions of atherosclerosis supports the view that preventive measures applicable from childhood could in principle be effective in reducing or eliminating the risks due to atherosclerosis. Despite the lack of direct evidence of effects on early development of atherosclerosis, preventive recommendations have been made with the expectation that their implementation in childhood would have the benefit of avoiding or delaying progressive change in atherosclerotic lesions that is the basis for later clinical manifestations. In an expert committee report from the World Health Organization in 1990, for example, encouragement was given to development of national policies in support of improvements in

diet and physical activity, as well as elimination of tobacco use, in childhood and youth.40 These and other such recommendations have to date undergone limited evaluations for their effect on blood lipids, blood pressure, and weight/height indices but none with respect to atherosclerosis itself. Much could be gained in prevention of atherosclerosis if increasingly practical methods for its early detection were applied to assess and monitor changes over time, whether as natural history or in response to interventions. Treatment of atherosclerosis is essentially treatment of its presenting manifestations in a particular patient at a given stage in its development and progression. Atherosclerosis in any individual patient is regarded mainly as a localized disease where it first appears clinically—chiefly in the coronary, cerebral, or peripheral arteries or the aorta. The question of whether treatment reduces the risk of complications, recurrence, or death due to atherosclerosis becomes a question related to one or another of these specific conditions. During late stages of the disease, however, regression of lesions has been clearly demonstrated in clinical trials of behavioral, medical, or surgical intervention. By 1992, for example, 10 studies of the effect of cholesterol reduction with one or another method of angiographic evaluation had already indicated that reducing cholesterol concentrations by approximately 40% resulted in significant benefit in terms of reduced progression, or even regression, of atherosclerotic lesions.41 More recent trials have shown similar outcomes.7 Treatment of the specific conditions is addressed to only a limited extent, in Chapters 4–6, in which the primary emphasis is on their prevention. Treatment guidelines that include these conditions are discussed further in Chapter 20. It should be noted that the “hypertensive” component of the atherosclerotic and hypertensive diseases is discussed not here in Part II but in Part III, Chapter 12, among determinants of cardiovascular diseases rather than the major conditions. This is because it occupies a different place in the cardiovascular disease spectrum than does atherosclerosis. The term “high blood pressure” is often used in place of “hypertension” to recognize that these terms refer not to a discrete disease state but to the upper levels in a continuous distribution of the physiologic trait, blood pressure. As discussed later, high blood pressure is both a significant public health problem in its own right—posing challenges for prevention and control— and a major factor in occurrence of coronary heart disease, stroke, and heart failure. Its impact is largely independent of atherosclerosis (as in causing hemorrhagic stroke) or superimposed on atherosclerosis (as in coronary heart disease), as will be discussed.

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CURRENT ISSUES Among issues in atherosclerosis today, one is the potential for prevention of the progressive advance from earliest (levels 1–2) to intermediate (level 3) to advanced (levels 4–5) atherosclerotic lesions. Given the ubiquitous occurrence of the earliest lesions, preventing the condition altogether may be impractical, whereas slowing or preventing progression—at least to the threatening advanced stages—may be feasible. How to detect intermediate or early-advanced lesions by noninvasive means with sufficient sensitivity remains a challenge, but technological advances may make this possible. A second issue is to deepen understanding of the relative advantage of females over males in early development of atherosclerosis—an advantage that extends well into the adult years. Is this a universal circumstance? If there are exceptions, where and why do they occur? Can the explanation be applied to increase early protection for males as well? Third, what is the global distribution of atherosclerosis at the earliest stage detectable by noninvasive measures? Can populations be monitored, and if so, at how early an age, to assess whether the determinants of its progression are operating in the preadult years to produce a continuing, or accelerating, epidemic of atherosclerosis in one or another region of the world? Implementing existing standardized pathology protocols may make postmortem examination of samples of decedents the method of choice for monitoring the status of epidemic atherosclerosis in population samples around the world. REFERENCES 1. St. Clair RW. Biology of atherosclerosis. In: Pearson TA, Criqui MH, Luepker RV, Oberman A, Winston M, eds. Primer in Preventive Cardiology. Dallas, TX: American Heart Association; 1994:11–24. 2. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1994;89:2462–2478. 3. Stary HC, Chandler AB, Dinsmore RE, Fuster V, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association.

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Arteriosclerosis Thromb Vasc Biol. 1995;15: 1512–1531. 4. Moreno PR, Shah PK, Falk E. Determinants of rupture of atherosclerotic coronary lesions. In: Willich SN, Muller JE, eds. Triggering of Acute Coronary Syndromes: Implications for Prevention. Dordrecht (The Netherlands): Kluwer Academic Publishers; 1996:267–283. 5. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque. J Am Coll Cardiol. 2006;47:C13–C18. 6. Blankenhorn DH. Prevention or reversal of atherosclerosis: review of current evidence. Am J Cardiol. 1989;63:38H–41H. 7. Mukherjee M, Yadav JS. Carotid artery intimalmedial thickness: indicator of atherosclerotic burden and response to risk factor modification. Am Heart J. 2002;144:753–759. 8. Bild DE, Detrano R, Peterson D, et al. Ethnic differences in coronary calcification: the MultiEthnic Study of Atherosclerosis (MESA). Circulation. 2005;111:1313–1320. 9. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography. J Am Coll Cardiol. 2007;49(3):378–402. 10. Strong JP. The natural history of atherosclerosis in childhood. In: Williams CL, Wynder EL, eds. Hyperlipidemia in Childhood and the Development of Atherosclerosis. New York: Annals of the New York Academy of Sciences; 1991:9–15. 11. Kuller L, Borhani N, Furberg C, et al. Prevalence of subclinical atherosclerosis and cardiovascular disease and association with

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risk factors in the Cardiovascular Health Study. Am J Epidemiol. 1994;139:1164–1179. 12. Kuller LH, Sutton-Tyrrell K. Aging and cardiovascular disease: use of subclinical measurements. Cardiol Clinics. 1999;17:51–65. 13. Stamler J. Established major coronary risk factors. In: Marmot M, Elliott P, eds. Coronary Heart Disease: From Aetiology to Public Health. Oxford (England): Oxford Medical Press; 1992:35–66. 14. Ross R, Glomset JA. The pathogenesis of atherosclerosis. Second of two parts. N Engl J Med. 1976;295:420–425. 15. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–126. 16. Benditt EP, Barrett T, McDougall JK. Viruses in the etiology of atherosclerosis. Proc Natl Acad Sci. 1983;80:6386–6389. 17. Epstein SE, Speir E, Zhou YF, et al. The role of infection in restenosis and atherosclerosis: focus on cytomegalovirus. Lancet. 1996;348: S13–S17. 18. Patel P, Mendall MA, Carrington D, et al. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risk factors. Br Med J. 1995;311:711–714. 19. Hall AJ. A lady from China’s past. National Geographic. 1974;45:661–681. 20. Sandison AT. Degenerative vascular disease in the Egyptian mummy. Med Hist. 1962;6:77–81. 21. Holman RL, McGill HC, Strong JP, Geer JC. The natural history of atherosclerosis. Am J Pathol. 1958;34:209–235. 22. Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea. JAMA. 1953;152:1090–1093. 23. McNamara JJ, Molot MA, Stremple JF, Cutting RT. Coronary artery disease in combat casualties in Vietnam. JAMA. 1971;216: 1185–1187.

24. Virmani R, Robinowitz M, Geer JC, et al. Coronary artery atherosclerosis revisited in Korean War combat casualties. Arch Pathol Lab Med. 1987;111:972–976. 25. Tejada C, Strong JP, Montenegro MR, et al. Distribution of coronary and aortic atherosclerosis by geographic location, race, and sex. Lab Invest. 1968;18:509–526. 26. Report of a WHO Expert Committee. Prevention of Coronary Heart Disease. WHO Technical Report Series 678. Geneva (Switzerland): World Health Organization; 1982. 27. Newman WP III, Freedman DS, Voors AW, et al. Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. N Engl J Med. 1986;314:138–144. 28. Berenson GS, Wattigney WA, Tracy RE, et al. Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons ages 6 to 30 years and studied at necropsy (the Bogalusa Heart Study). Am J Cardiol. 1992;70:851–858. 29. Berenson GS, Srinivasan SR, Nicklas TA. Atherosclerosis: a nutritional disease of childhood. Am J Cardiol. 1998;82:22T–29T. 30. Zieske AW, Malcom GT, Strong JP. Natural history and risk factors of atherosclerosis in children and youth: the PDAY study. Pediatr Pathol Mol Med. 2002;21(2):213–237. 31. McGill HC Jr, McMahan CA, Malcom GT, Oalmann MC, Strong JP. PDAY Research Group. Effects of serum lipoproteins and smoking on atherosclerosis in young men and women. Pathobiological Determinants of Atherosclerosis in Youth. Throm Vasc Biol. 1997;17:95–106. 32. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. JAMA. 1990;264:3018–3024. 33. Berenson GS for the Bogalusa Heart Study Research Group. Childhood risk factors predict adult risk associated with subclinical car-

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diovascular disease: the Bogalusa Heart Study. Am J Cardiol. 2002;90(suppl):3L–7L. 34. McMahan CA, Gidding SS, Malcom GT, Tracy RE, Strong JP, McGill HC, Jr. Pathobiological determinants of atherosclerosis in youth risk scores are associated with early and advanced atherosclerosis. Pediatrics. 2006;118(4): 1447–1455. 35. McMahan CA, McGill HC, Gidding SS, et al. PDAY risk score predicts advanced coronary artery atherosclerosis in middle-aged persons as well as youth. Atherosclerosis. 2007;190(2): 370–377. 36. Ishii T, Newman WP III, Guzman MA, et al. Coronary and aortic atherosclerosis in young men from Tokyo and New Orleans. Lab Invest. 1986;54:561–565. 37. Tanaka K, Masuda J, Imamura T, et al. A nation-wide study of atherosclerosis in infants, children and young adults in Japan. Atherosclerosis. 1988;72:143–156.

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38. Mahoney LT, Burns TL, Stanford W, et al. Coronary risk factors measured in childhood and young adult life are associated with coronary artery calcification in young adults: the Muscatine Study. J Am Coll Cardiol. 1996; 27:277–284. 39. Pletcher MJ, Bibbins-Domingo K, Lewis CE, et al. Prehypertension during young adulthood and coronary calcium later in life. Ann Intern Med. 2008;149:91–99. 40. WHO Expert Committee on Prevention in Childhood and Youth of Adult Cardiovascular Diseases. Prevention in Childhood and Youth of Adult Cardiovascular Diseases: Time for Action. Technical Report Series 792. Geneva (Switzerland): World Health Organization; 1990. 41. Blankenhorn DH. Lipoproteins and the progression and regression of atherosclerosis. Cardiovasc Rev Rep. 1992;13:52–56.

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4 Coronary Heart Disease nization (WHO) MONICA Project is the largest undertaking to date in cardiovascular epidemiology and has investigated determinants of changes in incidence, case-fatality, and overall mortality from coronary heart disease in 38 populations in 21 countries. From both the knowledge gained to date and the remaining gaps in that knowledge, major issues in coronary heart disease have been identified that require attention from public health professionals if further progress toward prevention of epidemic coronary heart disease is to be achieved.

SUMMARY Coronary heart disease has been the major component of cardiovascular morbidity and mortality in much of the western industrialized world in recent decades and now matches this distinction globally. Because the initial coronary event is often rapidly fatal, and because risks of recurrence and death among survivors are high, prevention of first coronary events through interventions at both the individual and the population-wide level is a high priority in the overall approach to cardiovascular disease prevention. Several long-term epidemiologic studies undertaken in the United States and other countries beginning in the late 1950s stimulated development of standard methods for diagnosis and classification of cases. These studies, including the Seven Countries Study, documented differences in population-level measures of coronary heart disease occurrence between populations whereas others, such as the Framingham Heart Study, focused on differences in risks among individuals within a population. Long-term trends based on vital statistics demonstrate the rise and fall of the vast epidemic curve of coronary heart disease mortality in the United States throughout the 20th century. Although the declining death rates from coronary heart disease represent important progress, the total burden and disparities due to this condition are little changed and remain of paramount public health concern. In addition, chronic heart failure, a late complication of coronary heart disease, has risen sharply in prevalence in consequence of improved survival after acute coronary events. Shorter-term but also striking trends in coronary mortality—with some increasing rates—have occurred in recent decades in many countries. The World Health Orga-

INTRODUCTION The Coronary Arteries “Coronary heart disease” is one of several terms referring to atherosclerosis of the arteries supplying the myocardium, or muscle of the heart. These arteries are illustrated in Figure 4-1.1 The arteries are named descriptively after their typical anatomic configuration. At the lower right of the figure (corresponding to the lower left of the subject’s chest) is the apex of the heart. At the top and left side of the figure is the base of the heart. From the base, the principal arteries extend distally toward the apex and can be imagined to form a crown (corona) around the main muscle mass comprising the left and right ventricles, the pumps to the systemic arterial circulation and to the lungs, respectively. Reduction of blood flow through one or more of these coronary arteries or their branches can result in insufficiency of myocardial blood supply (ischemia). Myocardial cells are dependent on a continuous or, during exertion, increased supply of oxygen and nutrients and removal of metabolic products through

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CHAPTER 4 CORONARY HEART DISEASE

Left Coronary Artery

Circumflex Artery

Right Coronary Artery

Marginal Branch

First Septal Perforator Branch AV Nodal Artery

Posterior Left Ventricular Branch Posterior Septal Branches Posterior Descending Artery

Left Anterior Descending Artery

Diagonal Branch

Anterior Septal Branches

Figure 4-1 The Coronary Arteries—A Schematic View. Source: Hutter A, Scientific American Medicine, Dale DC, Federman DD, eds. 5 Cardiovascular Medicine, Subsection IX, © 1996 Scientific American, Inc. All rights reserved.

the coronary circulation. Consequently, they undergo injury and death if blood flow is interrupted and not restored within minutes. Unless emergency treatment is instituted to minimize it, the extent of the injury often widens, with increased risk of complications or death. Typical symptoms experienced by the victim include pain described as pressing, stabbing, or crushing and located especially beneath the sternum or breastbone or in the jaw, arms, or midback, often accompanied by sweating, faintness, and a sense of impending death. It is now recognized that these classic symptoms may be absent among women experiencing myocardial ischemia. This makes diagnosis in women more difficult and more easily overlooked than in men. Portions of the electrophysiologic conducting system that controls the rate and rhythm of cardiac contraction pass through the septum or wall between the right and left atria and ventricles.

Especially if the area of ischemia includes the septum, an abrupt disturbance of cardiac rhythm may result with loss of effective pumping action of the heart, resulting in immediate collapse and sudden death unless resuscitation is successfully applied. Course of the Individual Case Some common features of the course of the individual case of an acute coronary event are shown schematically in Figure 4-2. Four phases of the process are depicted from the perspective of its biological and clinical progression. For each phase the status of disease and time frame are noted. First, against a background of progressive atherogenesis over many years or several decades, described in the preceding chapter, advanced atherosclerotic lesions develop in the coronary arteries. Second, under the current concept of the acute coronary event, one or more of several po-

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Figure 4-2 Common Features of the Course of Coronary Heart Disease.

tential precipitating factors leads to disruption of an advanced atherosclerotic lesion or plaque, either at its endothelial surface or by fissuring into deeper levels of the lesion.2 Stimuli to thrombosis at the site of the plaque may produce only minor aggregation of blood platelets, with spontaneous resolution of the resulting small clot and some enlargement of the plaque. But alternatively, a large occlusive clot (thrombus) may form and persist for several hours or longer, producing acute symptoms (unstable angina), heart attack (myocardial infarction), or sudden death. If the acute event is not rapidly fatal, any of several short- or long-term outcomes is possible: recovery, with or without symptoms or residual cardiac dysfunction; short-term fatality (often defined as occurring within 28 days of clinical onset); later recurrence as a new episode (defined as symptoms present after a 28-day period from onset of an earlier event); or late coronary death, occurring more than 28 days (and up to many years) following the onset of the first event. Asymptomatic disease, or “silent” infarction, is another late outcome shown in Figure 4-2. This represents a circumstance in which evidence of myocardial infarction may be found on electrocardiographic (ECG) or echocardiographic examination and, for reasons not well understood, no history of chest pain can be elicited. Characteristics of the “vulnerable plaque” that predispose it to disruption, the precipitating factors triggering this process, and the consequent “acute coronary syndromes” including “sudden cardiac

death” are discussed extensively in published reports.2–8 Although sudden cardiac death is a common outcome of this process, definition has been controversial. One example is the following: “a natural death due to cardiac causes, heralded by the abrupt loss of consciousness within 1 hour of the onset of acute symptoms. Preexisting heart disease may or may not have been known to be present, but the time and mode of death are unexpected.”5, p 742 Previously, a 24-hour criterion was often used, and evidence of prior cardiac disease was sometimes taken to exclude cases. As currently defined, sudden cardiac death may represent 50% of all cardiovascular deaths in the United States. The other acute manifestations include additional deaths occurring within 28 days of onset (conventionally the limit for inclusion in casefatality), later-occurring deaths, or long-term nonfatal outcomes. Especially for unstable angina, there is a need for standardized definition and criteria to render reports of this condition comparable. Several aspects of the acute-stage process are particularly noteworthy from an epidemiologic perspective. First, this phase of the disease, which evolves in a time frame of seconds to hours, is a very late development in relation to the long-standing process of atherogenesis. Prevention of atherosclerosis may be opportune throughout much of the life span, whereas effective intervention within seconds, minutes, or even hours of the onset of an acute coronary event poses often insurmountable obstacles. Prevention of either irreversible myocardial damage or sudden death

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requires effective action long in advance for those who are at risk. Second, investigation of precipitating or triggering factors is in progress at multiple levels, including both extrinsic factors (e.g., physical activity, psychological factors and emotional states, and physiological aspects of circadian variation) and intrinsic factors (especially physical and biochemical aspects of the plaque, blood coagulation, and blood vessel contractility or spasm). Third, in order for acute-phase interventions to be useful, they must be rapidly accessible. Studies and well-evaluated programs are needed to improve recognition of symptoms at their onset, quick action to initiate emergency care and transport, and rapid access to a qualified hospital emergency department for diagnosis and treatment.

BACKGROUND In a detailed historical account of coronary heart disease, Liebowitz traced to Egyptian and Greek antiquity reference to apparent cases of this disease.9 (Chapter 3 also includes references to cases in Chinese and Egyptian mummies.) Only gradual progress was made in understanding the clinical and pathological characteristics of coronary heart disease until the 19th century. Publication in 1896 of Osler’s Lectures on Angina Pectoris and Allied States provided numerous case descriptions and a wide spectrum of manifestations of coronary ischemia, including accounts of cases in persons of note from the 18th century and others compiled from his own practice.10 Osler commented on the rarity of this condition in hospital practice but noted that it was much more commonly observed in private consultation and especially in wealthy patients. As of 1900, accumulated knowledge of coronary atherosclerosis and angina pectoris did not yet include full recognition of the link between the acute thrombosis of a coronary artery and the occurrence of myocardial infarction. This understanding awaited Herrick, whose publications in 1912 and 1919 are classic descriptions of pathologic and electrocardiographic findings in acute myocardial infarction.9 The first half of the 20th century saw developments enabling later emergence of epidemiologic studies: clear recognition of the clinical and pathological entity and commonly applicable diagnostic procedures, which included electrocardiography. “Geographical pathology,” comprising somewhat fortuitous observations in populations around the world, pointed to variations in dietary patterns in relation to the frequency of coronary atherosclerosis. Keys’s account of

the genesis of the Seven Countries Study (discussed as follows) indicates the contribution of such observations from China, Java, the Netherlands, and wartime Scandinavia and Germany.11 By the 1950s and early 1960s, a remarkable series of epidemiologic studies had begun, of which some continue to the present. Examples include the Seven Countries Study, in which 16 groups of men, more than 12,000 in all, were examined in one of the seven participating countries under the leadership of Keys and his local colleagues;12 the Framingham Study and other community- or employment-based studies of more than 8000 men, collectively;13 the Ni-Hon-San Study of three cohorts of men of Japanese ancestry in Japan, Hawaii, and the San Francisco Bay Area, organized after discovery of striking gradients across the three populations in mortality from coronary heart disease and (oppositely) stroke;14,15 and other studies in the United States and elsewhere. The goal of these studies was to identify factors that could explain differences in rates of coronary heart disease between populations or in risks of coronary events among individual members of a particular population. Accounts of the organization and implementation of these early studies are rich sources of insight into the formative period of modern cardiovascular epidemiology. For example, in 1951 Dawber, Meadors, and Moore described the background of the Framingham Study.16 Sample size estimation was a necessarily inventive exercise. The authors’ concern about the potential for successful follow-up of participants for as long as 20 years was revolutionary but underestimated the study’s longevity by more than 45 years (thus far). The history of the Framingham Heart Study has recently been recounted in the context of the coronary epidemic.17 Three reports, from anecdotes of the key field study organizer (Blackburn) to a scientific update after 35 years’ experience, offer unique perspectives on the Seven Countries Study, a pioneering study of international contrasts in coronary heart disease rates and their determinants.18–20 Results of these early studies led to clinical trials and community interventions to test the ability to modify one or more of the factors identified and thereby to control or prevent coronary heart disease. Some major examples, addressed in subsequent chapters, are studies of diet (e.g., the Diet-Heart Feasibility Study), high blood pressure (Hypertension Detection and Follow-Up Program), blood cholesterol concentrations (Lipid Research Clinics—Coronary Primary Prevention Trial), or multiple factors in individual participants (World Health Organization European Collaborative Trial of Multifactorial Prevention of

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POPULATION STUDIES: DEFINITION AND CLASSIFICATION, DIAGNOSTIC ALGORITHMS, AND CRITERIA

Coronary Heart Disease and Multiple Risk Factor Intervention Trial). Whole communities became subjects of intervention to modify risk-related behavior (diet, physical activity, cigarette smoking, and others) in North Karelia, Finland; in California, Minnesota, and Rhode Island; and in numerous studies elsewhere (see Chapter 21). Trials on prevention of coronary heart disease and observational studies, all in adult populations, continued. Meanwhile, other investigations were undertaken as early as the 1970s to clarify factors in the early onset and progression of atherosclerosis. As reviewed in Chapter 3, these studies reconfirmed evidence for extensive atherosclerosis in the coronary arteries of some individuals in adolescence and early adulthood. Factors related to atherosclerosis and coronary heart disease in adults (e.g., adverse blood lipid profile, high blood pressure, and smoking) were also shown to predict the extent and severity of atherosclerosis in childhood and adolescence. This research has been progressive, developing from the earliest observational to the most recent experimental studies. Multicenter trials and demonstration programs are needed to continue this development. But observational epidemiology remains essential to investigate new questions, in new populations, and under circumstances changed dramatically from those studied earlier in this halfcentury of investigation.

POPULATION STUDIES: DEFINITION AND CLASSIFICATION, DIAGNOSTIC ALGORITHMS, AND CRITERIA Undertaking population studies of coronary heart disease in the 1950s and 1960s pointed to the need to standardize definitions and classification for improved comparability of data across studies. For determining the presence or absence of coronary heart disease among participants in general population surveys, information about participants’ personal health history was needed. In addition, electrocardiographic examination was needed both to supplement the history and, because myocardial infarction can occur without symptoms, to detect previous silent infarction in cases where abnormalities persisted. Methods were developed for standardized history taking by interview or questionnaire (the London School of Hygiene or Rose questionnaire), and an objective procedure was devised for coding and classifying electrocardiographic findings (the Minnesota code). These essential tools for epidemiologic studies were incorporated

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in a more comprehensive guide, Cardiovascular Survey Methods, first published in 1968 through the auspices of the Cardiovascular Disease Unit of the World Health Organization.21 These methods were suitable for discriminating between already-established (and surviving) cases and noncases of coronary heart disease. They served for estimating its prevalence (i.e., the affected proportion of the population at large) and identifying those free of the disease. The latter would constitute a “population at risk” or cohort of persons to follow long-term and identify predictors of first coronary events. Diagnostic standardization was needed for hospital-based myocardial infarction case registers, community surveillance of newly occurring cases, and trials with new events as end points for evaluating the benefits of interventions. Acute changes in the electrocardiogram and abrupt appearance in the blood of increasing concentrations of myocardial cell enzymes were added to the diagnostic criteria for an evolving, or ongoing, myocardial infarction. In addition, a more detailed classification was developed to recognize particular characteristics of the acute event and distinguish among levels of confidence in the diagnosis. An algorithm for diagnosis and classification of acute coronary heart disease was formulated by Gillum and colleagues, under the auspices of the Criteria and Methods Committee of the Council on Epidemiology and Prevention of the American Heart Association.22 It was adopted by the WHO MONICA (MONItoring Trends and Determinants in CArdiovascular Disease) Project, in which 38 centers in 21 countries conducted a decade-long study of coronary events. The diagnostic elements for coronary heart disease in MONICA are summarized in Table 4-1.23 Both fatal and nonfatal events are classified as “definite” or “possible” on the basis of completeness of the findings; the possibility of a case representing successful resuscitation from cardiac arrest is recognized; and provision is made for the fatal case in which the rapid time course or other factors preclude the collection of the data needed to classify the event as definite or possible infarction.24 Recent development of study methods in cardiovascular epidemiology is reflected in the updated Cardiovascular Survey Methods published by the World Health Organization in 2004.25 In addition, detailed consideration of changing diagnostic criteria and classification of coronary events has led to a report on case definitions for acute coronary events with special attention to needs and opportunities for investigation in epidemiologic and clinical research.26

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Table 4-1

Summary of Diagnostic Elements and Classification Scheme for Fatal and Nonfatal Coronary Heart Disease Events in Population Studies

Diagnostic elements • electrocardiogram (up to four per acute attack) • myocardial enzymes • history of chest pain (including time of onset) • necropsy evidence Classification of events • definite infarction • possible infarction • ischemic cardiac arrest (resuscitated) • fatal cases with insufficient data • no myocardial infarction Source: Data from World Health Organization MONICA Project Investigators, The World Health Organization MONICA Project (Monitoring Trends and Determinants in Cardiovascular Disease): A Major International Collaboration, Journal of Clinical Epidemiology, Vol 41, pp 105–114, © 1988.

Anticipated use of diagnostic imaging techniques and wider application of new indicators of myocardial cell damage, such as cardiac troponins, increase diagnostic sensitivity and greatly complicate standardization of disease estimates over time or between areas with differential uptake of these newer methods. As that report notes, citing an earlier contribution on this issue from Yusuf and colleagues: “The combination of new diagnostic tests, changing disease presentation, increasing numbers of survivors, and the predicted incidence increases in developing countries all argue for better surveillance to establish valid rates and trends. Such improvement depends on consistent, reliable, and valid case definitions.”26, p 2544 The case is made by investigators in the Minnesota Heart Survey for reliance on Minnesota coding of electrocardiograms as the most consistent diagnostic tool for monitoring trends that include previous years’ experience as in the first 25-year period of that program, 1970–1995.27 Clinical categories are also changing, as summarized for example in reports from the American College of Cardiology and American Heart Association.28 Within the broader classification of coronary heart disease, a category of “acute coronary syndrome,” or ACS, is now recognized that includes acute myocardial infarction and unstable angina, a condition with unexpected onset of anginal chest pain, usually at rest. Depending on the presence at initial examination of particular electrocardiographic findings (ST-segment elevation) and presence of abnormal levels of myocardial biomarkers (such as tro-

ponins), cases of ACS may be classified as ST-elevation MI (STEMI), non-STEMI, or unstable angina. Perhaps 20 or 30% of cases with ACS have STEMI, but changing practices make this estimate uncertain for the reasons noted previously. Already, however, these changes in case identification have led to new management guidelines recognizing the revised classification.29 Comparison of coronary heart disease experience between populations and over extended periods has mainly been based on mortality data from national vital statistics. These data are collected under the system of the International Classification of Diseases (ICD) codes. Currently, the classification of coronary heart disease events and conditions is organized in the Tenth Revision (ICD 10) as indicated in Table 4-2.30 Angina pectoris (I20) is further subclassified under the ICD code into four categories: unstable angina, angina pectoris with documented spasm of the coronary arteries, other forms, and unspecified. Acute myocardial infarction (I21) is subclassified in accordance with the site of infarction and its extent, whether transmural (affecting the full thickness of the myocardial wall) or only subendocardial (limited to a few millimeters from the interior surface of the heart chamber). Subsequent myocardial infarction (I22) refers to recurrent events and is subclassified only by site. Certain current complications (I23) are conditions such as cardiac rupture or development of a defect in the interatrial or interventricular septum—not concurrent with the acute infarction but developing as a late complication. Other acute ischemic heart disease (I24) includes conditions such as coronary insufficiency or coronary thrombosis not developing into myocardial infarction. Chronic ischemic heart disease (I25) refers not only to healed or past myocardial infarction (without current symptoms) but also to coronary events with survival beyond 28 days. Widespread use of these methods has greatly facilitated collection and reporting of comparable data from population studies. Nevertheless, issues of com-

Table 4-2 I20 I21 I22 I23

Categories of Coronary Heart Disease (Ischemic Heart Disease)

Angina pectoris Acute myocardial infarction Subsequent myocardial infarction Certain current complications following acute myocardial infarction I24 Other acute ischemic heart disease I25 Chronic ischemic heart disease

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parability still require consideration in interpreting data from different populations or time periods.

RATES Occurrence of coronary heart disease in populations is measured in several ways, each contributing some insight into the epidemic process. Mortality data, usually expressed as the number of coronary heart disease deaths per 100,000 population per year, are readily available in the vital statistics for many countries and other geopolitical units, often for population subgroups by age, race, and sex, and in some cases over periods of several decades. These data are ordinarily based on the cause of death as recorded by the party completing the death certificate and subsequently coded by a nosologist in accordance with the current ICD procedures. Cause-specific mortality is the measure of the rate of loss of life due to the disease as coded. Limitations of death registration and assignment of cause of death are widespread in much of the developing world and are discussed extensively in the Global Burden of Disease Study documents.31 Incidence data indicate the number of newly occurring cases within a given period. Incidence of coronary heart disease is usually expressed per 1000 to 100,000 population per year (the smaller value of the denominator being used for groups with very high rates, such as those at older ages), or per 1000 personyears, and includes both fatal and nonfatal cases. Due to the special requirements for diagnosis and classification of first events, availability of incidence data is limited. The methods used are principally two. In one instance, community surveillance, or long-term monitoring of defined populations, is undertaken to detect the occurrence of new coronary events, for example, through hospital admissions or death notices. The other is cohort studies, in which members of a population have been examined individually and those free of coronary disease at the starting point (baseline) are followed up by surveillance methods, periodic reexamination, or both to detect new coronary events. Both methods can also provide mortality data, distinct from ordinary vital statistics in having the potential for diagnostic validation through methods specific to the individual study. It is especially difficult, except in a cohort study, to determine whether a particular event was in fact the first occurrence of coronary heart disease in that individual and therefore strictly an incident, not a recurrent, event. Incidence rates, so defined, are taken to reflect the operation of factors that are causally related to the

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occurrence of disease; inclusion of recurrent cases would cloud the interpretation due to factors influencing survival from previous events. Case-fatality is another useful measure. It indicates the proportion of all cases in the population, new and recurrent unless otherwise specified, that are fatal in outcome. Its determination requires knowledge of both the occurrence and the outcome of the event, obtained through surveillance or cohort studies. Case-fatality data are also therefore limited in availability. As already noted, the arbitrary interval of 28 days or less from the onset of symptoms is the convention used to attribute death to a given coronary event. A special subset of case-fatality is sudden death, variously defined. Case-fatality (i.e., within 28 days) is often interpreted as a measure of effectiveness (more properly, ineffectiveness) of medical treatment of acute coronary events. Sudden death has been considered distinct in being less amenable to medical care and is a particularly forceful indicator of the need to prevent acute coronary events altogether because a large proportion of these events are rapidly fatal. Prevalence, or the proportion of the population surviving with recognized coronary heart disease, is typically expressed in cases per 1000 population, usually for specific age groups, by sex, and often by race. Estimates of prevalence depend on knowledge of individual histories obtained through interview and examination surveys, as described previously. Surveys typically provide for only a single contact with participants and are much more readily conducted than surveillance or cohort studies. They are commonly undertaken as a first step in study of the coronary heart disease situation of a population. Prevalence does not include those who have died and may reflect factors influencing survival, so its interpretation warrants some caution. Nevertheless, it indicates something of the magnitude of risk and is often useful in estimating healthcare needs in a population. These several measures of disease occurrence in the population are interrelated in ways that bear on their interpretation. For example, incidence and casefatality can be considered as components of mortality because they indicate, respectively, the rate at which new cases occur and the proportion of cases with fatal outcomes. However, a death rate is usually calculated for the events in a 12-month interval, and case-fatality is restricted by definition to 28 days from the date of symptom onset. Therefore, the overall coronary death rate cannot be calculated from incidence and case-fatality alone, which does not account for all coronary deaths in 12 months among incident

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cases and excludes recurrent cases. Also, prevalence is related to incidence and mortality because it identifies previously incident cases that were nonfatal. But differences in prevalence between populations, or changes in prevalence over time, cannot be attributed simply to differences in incidence or to differences in mortality without additional information. With this understanding of measures of disease occurrence, it is useful to examine data on coronary heart disease from these several perspectives, in the United States and elsewhere. Mortality The United States Statistical information on cardiovascular diseases in the United States is provided by the National Center for Health Statistics, on the basis of vital records and sample surveys of the US population, by other components of the Centers for Disease Control and Prevention (CDC), for example, from the Behavioral Risk Factor Surveillance System, and by special studies in selected communities such as the multicenter epidemiologic studies supported by the National Heart, Lung and Blood Institute—the Framingham Heart Study and others. Data from these sources are compiled and published by the American Heart Association in its encyclopedic annual statistical update28 (accessible at http://www.americanheart.org). Detailed tabulations of health data for the US population are also published annually by the National Center for Health Statistics. The most recent tabulation of mortality specific to ischemic heart disease was Health, United States, 2006, with mortality data current through 200332 (accessible at http://

www.cdc.gov/nchs/hus/htm). From Health, United States, 2006, the overall age-adjusted death rate per 100,000 population of all ages from ischemic heart disease in 2003 was 162.9–209.9 for men, 127.2 for women, 195.0 for all Blacks or African Americans, 114.1 for all American Indians or Alaska Natives, 92.8 for Asians and Pacific Islanders, 130.0 for Hispanics or Latinos, and 164.3 for non-Hispanic Whites. These values can be compared with the national objective for coronary heart disease mortality for the year 2010, 162/100,000, a level that had very nearly been reached early in the decade.33 However, wide disparities remain, as, for example, among Blacks or African Americans whose coronary mortality exceeds that of Whites by nearly 20%. Further insight to the burden of coronary heart disease in the United States, as of 2004, is presented in Table 4-3, based on data compiled in the AHA statistical update for 2009.28 Numbers of deaths are indicated for coronary heart disease (CHD) and specifically for myocardial infarction (MI), for ages 20 years. Of the nearly half-million CHD deaths, only slightly more occurred among men than women; onethird of these deaths were due to MI, and these too were only slightly more frequent among men. Numbers of deaths from these causes are shown for non-Hispanic Whites and Blacks but not for other population groups. The geographic distribution of CHD deaths by county throughout the United States was illustrated for all women aged 35 years and older in Figure 2-6. Corresponding county-level data and United States and state maps of CHD mortality for 1991–1995 for women and men by race/ethnicity are published and internet accessible34–36 (accessible at http://www.cdc.gov/cvh/maps).

Deaths from Coronary Heart Disease and Myocardial Infarction, Age 20 Years, United States, 2005 Coronary Heart Disease Myocardial Infarction Total 445,687 151,004 All males 232,115 80,079 % of total 52.1 53.0 All females 213,572 70,925 % of total 47.9 47.0 Non-Hispanic white males 203,924 70,791 % of subgroup 52.2 53.5 Non-Hispanic white females 186,497 61,573 % of subgroup 47.8 46.5 Non-Hispanic black males 22,933 7527 % of subgroup 49.8 48.4 Non-Hispanic black females 23,094 8009 % of subgroup 50.2 51.6 Table 4-3

Source: Data from Heart Disease and Stroke Statistics—2009 Update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Committee. D Lloyd-Jones et al. © 2009, Courtesy of the American Heart Association/American Stroke Association.

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Europe and Elsewhere A major source of data on CHD morbidity and mortality in Europe is the WHO MONICA Project.23 The goal was to resolve the question of the 1978 Decline Conference of whether trends in coronary heart disease mortality were explained by changes in risk factors or treatment of cases. This would require data on key aspects of the coronary epidemic, including incidence, case-fatality, and overall coronary mortality. Participating countries were primarily in Europe, but populations in Australia and New Zealand, China, and the United States (the Stanford Five-City Study) were also included. The basic design called for monitoring of coronary heart disease events, related personal characteristics of population samples, and medical care practices over the 10-year period from the mid-1980s to the mid-1990s. At the start of the MONICA Project, coronary event registration under the Project protocol was reported in comparison with official coronary heart disease mortality for 38 populations in 21 countries, as shown in Figure 4-3.24 The figure lists study populations alphabetically by country and center and gives age-standardized annual coronary heart disease mortality for men and women, respectively. (See Appendix 4-A for site codes in MONICA.) The heavy horizontal bars represent the combined definite and possible coronary deaths according to MONICA registration, and the extended lines show the additional, nonclassifiable deaths. Official coronary heart disease mortality is represented by the short crossing vertical lines. Rates based on registered definite and possible coronary events and the official rates generally corresponded closely, although in some exceptional cases (e.g., Canada-Halifax, for men) the differences were quite large. (The scale for mortality rates is logarithmic and not arithmetic; this means that equal distances along the scale are equal multiples of the rate.) For example, the official rate for men in Finland-North Karelia (first entry in the left panel) was nearly 500/100,000, or about 10 times that of men in ChinaBeijing at 50/100,000. Similarly, a greater than 10fold range characterized the difference in rates between women in United Kingdom-Glasgow (approximately 110/100,000) and in Spain-Catalonia (11/100,000). Clearly, the United States has not been unique in its 20th-century experience with coronary heart disease mortality and did not rank highest in rates in the mid1980s; Finland, the United Kingdom, and the former Soviet Union were at or near the head of the list for both men and women. Global dimensions of ischemic heart disease are indicated in Chapter 1 as measured by estimated per-

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centages of deaths from this cause in 2001 by income group and region (Table 1-5). Table 1-6 shows the rank order of ischemic heart disease among causes of death, years of life lost, and DALYs, worldwide. Here, the estimated number of ischemic heart disease deaths for each region and mortality stratum for 2002 is presented in Table 4-4, based on data from the World Health Report, 2004.34 The 7.2 million deaths from ischemic heart disease in 2002 constituted nearly half of all 16.7 million cardiovascular deaths and 12.6% of all 57 million deaths worldwide. Variation in numbers of deaths by region reflects both death rates and population size. Sudden Death Sudden death is a large component of CHD deaths. Figure 4-4 is based on a 1993 report that combines information on sudden death from studies collected from a 20-year period.35 “Overall incidence” (in this case a measure of mortality because the incident events are all fatal) is reported to be 0.1 to 0.2% of the population or about 300,000 events per year. In subgroups of the population defined by various predictors (left panel), much higher proportions become victims of sudden death: approximately 2% of those with high CHD risk; 5% of those with a prior coronary event; 20% of those with heart failure; 25% of survivors of a previous out-of-hospital cardiac arrest; and more than 30% of those with specific disturbances of heart rhythm during recuperation from a myocardial infarction. Conversely, of the total number of sudden deaths each year (right panel), successively smaller numbers of events come from these very-high-risk groups, each of which comprises only a very small part of the population. Incidence The United States First-time instances of myocardial infarction, true incident cases, can only be distinguished from recurrent events with reliable information about prior history of cardiovascular disease. This requires special studies designed to identify those with a history of prior CHD. Accordingly, Table 4-3, which illustrates several recent measures of CHD for the United States, refers to undifferentiated numbers of “New and Recurrent MI and Fatal CHD” and “New and Recurrent MI” among persons aged 35 years and older.28 These data indicate the numbers of persons potentially requiring emergency medical services, transport, and hospital care for acute coronary events, given that

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Men

Women

FIN-NKA UNK-GLA FIN-KUO RUS-MOC

UNK-GLA UNK-BEL AUS-NEW RUS-MOI

LTU-KAU RUS-MOI UNK-BEL FIN-TUL CZE-CZE YUG-NOS SWE-NSW NEZ-AUC AUS-NEW CAN-HAL DEN-GLO POL-TAR USA-STA ICE-ICE POL-WAR SWE-GOT GER-AUU BEL-CHA GER-BRE AUS-PER BEL-LUX GER-AUR GER-RHN GER-EGE ITA-FRI ITA-BRI SWI-TIC BEL-GHE

RUS-MOC FIN-NKA NEZ-AUC LTU-KAU

CZE-CZE USA-STA YUG-NOS POL-WAR FIN-KUO FIN-TUL

GER-AUU BEL-CHA AUS-PER SWE-GOT DEN-GLO CAN-HAL GER-RHN GER-EGE

SWE-NSW ICE-ICE POL-TAR BEL-GHE CHN-BEI ITA-FRI GER-BRE

ITA-BRI GER-AUR FRA-STR

SWI-VAF FRA-LIL FRA-STR FRA-TOU

BEL-LUX FRA-LIL

SPA-CAT CHN-BEI

FRA-TOU SPA-CAT 200

100

50

20

MONICA Project: Definite and possible coronary deaths

10

Official CHD mortality

5

500

200

100

50

20

10

5

Mortality rate per 100,000 men age 35–64 years (log. scale)

Mortality rate per 100,000 women age 35–64 years (log. scale)

Official CHD mortality

MONICA Project: Additional unclassifiable deaths

MONICA Project: Definite and possible coronary deaths

MONICA Project: Additional unclassifiable deaths

Figure 4-3 Coronary Heart Disease (CHD) Mortality in 38 Populations in 21 Countries, According to the WHO MONICA Project and Official Rates. See key for MONICA abbreviations in Appendix 4–A. Source: Reprinted with permission from Circulation, Special Report, Vol 90, No 1, p 599, © 1994, American Heart Association.

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Table 4-4 Africa 1 160 1. 2. 3. 4. 5. 6.

2 172

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Numbers of Deaths (ⴛ1000) Due to Ischemic Heart Disease by Mortality Strata in Each WHO Region, 2002 South-East Eastern Western The Americas Asia Europe Mediterranean Pacific Total 3 574

4 319

5 28

4 265

5 1774

3 672

4 464

6 1237

4 142

5 396

3 129

4 864

7208

high child, high adult mortality high child, very high adult mortality very low child, very low adult mortality low child, low adult mortality high child, high adult mortality low child, high adult mortality

Source: Data from World Health Report 2004, Statistical Annex, Table 2, pp 122–123.

these needs do not differ between first and recurrent events. But they do not measure the separate impact of efforts to prevent first events (“primary prevention”) or subsequent ones among survivors (“secondary prevention”). These are important questions for evaluating preventive strategies, a topic of later discussion. Incidence of coronary heart disease can be estimated most reliably through one of two types of studies. One type is study of a cohort of persons determined initially to be free of coronary heart disease at the start of several years’ follow-up and judged to have developed coronary heart disease or not on the basis of examination at a subsequent time. The second type of study is community surveillance, by which a defined population is monitored for the occurrence of events chiefly through

review of hospital admissions and out-of-hospital deaths, in contrast to periodic examination of all members of a cohort. This was the design of the WHO MONICA Project, illustrated above. Six current studies in the United States involving a total of 23 communities are described in detail in Incidence & Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases, prepared by the National Heart, Lung and Blood Institute.36 These are the Atherosclerosis Risk in Communities (ARIC) Study, the Cardiovascular Health Study (CHS), the Coronary Artery Risk Development in Young Adults (CARDIA) Study, the Framingham Heart Study (FRS), the MultiEthnic Study of Atherosclerosis (MESA), and the Strong Heart Study (SHS). (The SHS is noteworthy as a unique source of data for the American Indian/ Alaska Native population.)

Overall Incidence in Adult Population High-Coronary-Risk Subgroup Any Previous Coronary Event Ejection Fraction ,30%; Heart Failure Out-of-Hospital Cardiac-Arrest Survivors Convalescent Phase VT/VF after Myocardial Infarction 0

1

2

5 10 20 30

Percent/Year

0

100

200

300

(⫻ 1000) Events/Year

Figure 4-4 Sudden Cardiac Deaths Among Population Subgroups. Source: Reprinted with permission from Annals of Internal Medicine, Vol 119, p 1188, © 1993, American College of Physicians.

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One of the six studies, the Atherosclerosis Risk in Communities (ARIC) Study, conducted both cohort and surveillance studies and contributed data from both methods to the Chart Book. Data from the two methods are generally in good agreement. The six studies differ in the age range and race/ethnicity of their study populations, as well as in geographic location. Some differences among studies are noted in diagnostic methods or criteria and the specific cardiovascular conditions addressed. Results are not strictly comparable among studies by reason of these differences, but agreement is generally close. The data presented are estimated mainly from the overall period of the 1990s. Age-, sex-, and race/ethnic-specific incidence rates per 1000 person-years of observation are presented separately for each study in graphic and tabular format. No information on trends in incidence is given in this report. The ARIC Study, for example, indicated incidence of CHD (MI or CHD death) per 1000 person-years in cohort follow-up, for the specific age group 55–64 years, to be 7.0 for White men, 7.7 for Black men, 2.7 for White women, and 4.7 for Black women. Rates were higher for men than women and higher for Blacks than Whites. Rates were higher for each sex-race group at age 65–74 than at age 55–64 years, and the relative increase was greater for Blacks than for Whites. Sex and race/ethnic patterns of age-standardized results

Table 4-5

Cohort Dalmatia Slavonia Tanushimaru East Finland West Finland Crevalcore Montegiorgio Zutphen Ushibuka Crete Corfu Rome railroad Velika Krsna Zrenjanin Belgrade Total

for ages 45–84 years were similar in relative rates to those described, for both CHD and MI. For angina pectoris, however, incidence was equal (about 11 per 1000 person-years) for Whites and for Black men but notably greater (about 18 per 1000 person-years) for Black women. Data based on the ARIC Study were also presented in the American Heart Association statistical update for 2009, shown in Table 4-3.28 Extrapolated to the US population, they provided estimates of 700,000 first coronary events and 500,000 recurrent events annually in the United States. Of a total of 1.2 million acute coronary events in one year in the United States, about 60% were projected as incident events and 40% as recurrences. Other Countries The cohort follow-up approach has also been used as a study design for comparing multiple populations. Incidence data from the Seven Countries Study at 10year follow-up are shown in Table 4-5.10 A familiar distinction is made in these data between “hard” and “any” coronary heart disease. The former category includes coronary heart disease death and definite myocardial infarction only, whereas the latter also includes angina pectoris and other less reliably documented conditions. Incidence of newly occurring

Ten-Year Incidence of Coronary Heart Disease (CHD) Among Men Free of Cardiovascular Disease at Entry (Age-Standardized Rate per 10,000), Seven Countries Study, 1958–1964 to 1968–1974 Hard CHD Any CHD Total N N Rate SE N Rate SE 662 13 185 52 40 629 94 680 18 253 60 40 561 88 504 8 148 54 20 354 82 728 71 1074 115 201 2868 168 806 45 539 80 129 1582 129 956 43 450 67 105 1080 100 708 22 353 69 64 966 111 845 45 513 76 91 1066 106 496 11 204 63 23 458 94 655 2 26 20 13 210 56 525 17 337 79 37 686 110 736 25 357 68 57 786 99 487 6 132 52 21 452 94 476 12 239 70 37 715 118 516 13 317 77 35 794 119 9780 351 369.9a 19.1 913 943.8a 29.6

Note: SE, standard error. a Mean of the cohort rates weighted by the number at risk in each cohort. Source: Reprinted with permission of the publisher from Seven Countries by A Keys, Cambridge Mass; Harvard University Press, © 1980 by the President and Fellows of Harvard College.

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hard coronary heart disease events over the full 10year period ranged from 1074 per 10,000 in East Finland to 26 per 10,000 in Crete, a 40-fold difference. When all coronary heart disease events were included, the range was from 2868 per 10,000 in East Finland to 210 per 10,000 in Crete, more than a 10-fold difference. The proportions of events classified as hard coronary heart disease were compared in regional groupings of these cohorts and varied rather little, from 36.6% to 54.1%. This observation lends credence to the range of incidence rates reported, whereas wide variation in the proportion of hard coronary heart disease might suggest a systematic difference, or bias, in the identification or classification of cases between populations. The relation of baseline measures of factors thought to affect the risk of coronary events (e.g., diet, blood lipids, blood pressure, smoking) to event rates was analyzed at the population level. That is, for each of the 16 cohorts, an average value was estimated for each characteristic (e.g., baseline blood cholesterol concentration) and linked with the event rate for that population. For example, by regression analysis, the question of whether differences in average cholesterol concentration were related to differences in event rates was evaluated. With this ap-

71

proach, the contribution of these and other factors to population differences in event rates was assessed. Results of these analyses are addressed in subsequent chapters where the respective factors are discussed. More recent data for populations studied beyond the United States are provided by the WHO MONICA Project.24 Table 4-6 presents selected data on CHD events reported in MONICA, including event rates and 28-day case-fatality under each of two case definitions, as well as the proportion of fatal cases for which history of prior MI was unknown. Selected from the detailed report on all MONICA populations are the data for those with the highest and lowest event rates, the highest and lowest case-fatality rates, and the overall mean rates, all under definition 1, separately for men and women. Events were enumerated for this tabulation in four classifications that included different combinations of the following subsets: F1 definite fatal event; F2 possible fatal event; F9 unclassifiable fatal event; NF1 definite nonfatal event; and NF2 possible nonfatal event. “1st event” refers to those cases meeting definition 1 for which there was a known negative history of prior myocardial infarction. The final column indicates the percentage of participants

Table 4-6

Age-Standardized Annual Event Rates per 100,000 Population, 28-Day Case-Fatality, and Confidence Intervals for Different Definitions of Events in Men and Women Age 35 to 64 in Selected Study Populations, WHO MONICA Project Population—Men Definition 1 First Event Fatal Where F1F2F9NF1 Definition 1, History of MI No Previous MI Not Known, % Event Rate, Case-Fatality Event Rate Case-Fatality 95% CI 95% CI CHN-BEI 76 9 53 6 58 51 3 FIN-NKA 915 62 48 3 586 44 1 ICE-ICE 540 45 37 4 395 33 4 POL-TAR 465 26 81 2 45 12 93 Average (excludes 465 49 281 37 22 2 populations) Population—Women

CAN-HAL FRA-LIL SPA-CAT UNK-GLA Average

Definition 1 F1F2F9NF1 Event Rate, 95% CI 138 20 67 7 30 4 256 20 101

Case-Fatality 95% CI 31 6 68 5 46 8 49 4 54

First Event Definition 1, No Previous MI Event Rate

Fatal Where History of MI Not Known, % Case-Fatality

46 46 21 187 65

9 58 34 49 43

Source: Adapted from Circulation, Special Report, Vol 90, No 1, pp 598–599, © 1994, American Heart Association.

69 31 32 4 22

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for whom history of myocardial infarction was unknown. Event rates were dependent, of course, on the inclusiveness of the definition. Definition 1 gave the largest numbers of events except when “possible nonfatal events” were added (not shown). First events were far fewer in number, especially when the percentage with unknown history was large. This striking demonstration of the dependence of rates on their definition underscores the need for explicit criteria when comparisons are made across studies. Population differences are apparent. For example, in reference to definition 1, rates ranged for men from 915/100,000 in Finland-North Karelia to 76/100,000 in China-Beijing, and for women from 256/100,000 in United Kingdom-Glasgow to 30/100,000 in Spain-Catalonia. Summary rates are given for comparison of overall male and female rates. Because two centers did not include women, they were excluded from the average values for men. Event rates were four to five times as great among men as among women. Case-Fatality On a national basis, case-fatality for acute myocardial infarction in the United States is unknown, although data are available from some of the community-based studies cited above. Data from the one US center in the WHO MONICA Project, the Stanford Five-City Study, gave the following estimates in parallel with those shown in Table 4-6: for definition 1 events, a rate of 508/100,000 and case-fatality of 50%; for first events under definition 1, a rate of 299/100,000 with case-fatality of 41% (history of MI unknown for 18% of fatal events). Again, the MONICA experience provides a unique source of information on this aspect of coronary heart disease in many populations, as seen in Table 4-6.24 Case-fatality differs in accordance with definitions as do event rates, for example, between the more inclusive definition 1 and first events with no previous MI, from 49% to 37% for men and from 54% to 43% for women. Under definition 1, overall case-fatality was 48–49% for men and 54% for women, with most centers reporting 40–55% casefatality for men and 45–70% for women. Overall, regardless of definition, case fatality was about 1.1 times as great for women as for men, after adjustment for differences in age at death. Prevalence Survivors beyond 28 days from onset of an acute coronary event constitute the known nonfatal cases. Survivors together with persons with silent infarc-

tion (detectable only through screening by electrocardiography, as conducted in surveys of the general population) constitute the true population alive with previous myocardial infarction. Surveys dependent on self-reported history necessarily underestimate this true total by missing the unknown cases. (See Table 4-3.28) Studies represented in the Incidence & Prevalence Chart Book overcome this limitation by direct examination that can reveal unrecognized CHD.36 Prevalence, like incidence, is reported for each of the six population studies by age, sex, and race/ethnicity as availability of data permits. Time periods vary among the studies, and trends in prevalence are not reported here. Prevalence was estimated in 2004 as 7.3% of the total US population aged 20 years or older, or 15.8 million persons (Table 4-3). Prevalence varies by sex and race/ethnicity, from 4.2% among Asians (18 years or older) to 9.4% among non-Hispanic White males. Between 1994 and 1995, the estimated prevalence of coronary heart disease in the United States nearly doubled, from 6.3 to 11.2 million. This abrupt increase was due to a change in classification that has since included persons with a self-reported history of angina pectoris (chest pain indicative of ischemic heart disease), or other evidence of coronary heart disease. Prevalent cases of CHD that are due to prior MI are at relatively high risk of cardiovascular events, including recurrent MI, sudden death, angina pectoris, heart failure, and stroke. Within 5 years after a first MI at age 40–69, 15% of White men, 22% of White women, 27% of Black men, and 32% of Black women will die; 16% of men and 22% of women will have a recurrent MI or fatal CHD; 7% of men and 22% of women will develop heart failure; 4% of men and 6% of women will have a stroke.28 Field surveys to estimate prevalence of coronary heart disease have been conducted in many populations since the 1950s. These surveys have usually been independent investigations without formal standardization, especially in many developing countries. One contrasting application of standardized methods for such surveys is illustrated in Table 4-7, which presents the electrocardiographic findings in surveys primarily of Pacific and Indian Ocean populations.37 When classified according to the strictest electrocardiographic criteria (Q-wave codes 1.1–1.2) by Minnesota code, “probable coronary heart disease” was found in 0–5.7% of men aged 35–59 years and in 0–2.8% of women; “possible coronary heart disease” was several times more common in most populations for both sexes but especially for women. Taking both probable and possible coronary heart disease into account, the combined prevalence was estimated to range from

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Table 4-7

Prevalence of Probable and Possible Coronary Heart Disease (CHD) in Developing Countries in Men and Women Aged 35 to 59 Years. By Ethnic Group, 1978–1987 Men Women Q and ST-T Q and ST-T Population Groups Qa ST-Tb Together Q ST-T Together Chinese Beijing—Chinese Mauritius—Chinese

0 2.5

1.5 15.0

1.5 (0–3.8) 16.6 (10.6–22.6)

0.2 0

4.1 27.5

3.6 (0.8–6.5) 27.2 (21.2–33.2)

Polynesian Cook Islands—Rarotonga Niue Western Samoa

3.5 0.9 1.1

3.1 2.6 2.2

6.3 (2.2–10.3) 3.3 (0–7.6) 2.9 (0–6.9)

0.7 0.7 0.3

18.2 9.9 12.0

19.3 (15.3–23.1) 10.8 (6.9–14.7) 11.9 (8.3–15.5)

Asian Indian Fiji Mauritius—Hindu Mauritius—Muslim

3.5 1.3 1.8

13.7 11.1 8.4

17.3 (13.2–21.4) 12.8 (10.2–15.3) 10.9 (5.8–15.9)

0.9 0.6 0.6

23.6 27.6 28.5

24.4 (20.7–28.2) 28.7 (26.1–31.2) 29.6 (24.7–34.5)

0 5.7 2.6

1.0 5.7 5.1

0.8 (0–7.2) 9.8 (0–20.9) 8.0 (4.7–11.4)

0 0 2.8

12.1 15.5 11.4

11.9 (5.3–18.4) 14.4 (5.8–23.0) 14.8 (11.1–18.4)

Melanesian—Fiji

2.5

6.4

8.7 (4.8–12.6)

1.0

17.5

18.7 (14.9–22.4)

Micronesian Kiribati Nauru

0 1.8

6.2 5.9

6.7 (4.0–9.3) 7.3 (2.9–11.7)

0.2 0.8

25.6 5.1

26.3 (23.6–28.9) 5.5 (1.3–9.5)

Creole—Mauritius

1.4

14.5

15.5 (11.7–19.3)

0.5

34.1

34.3 (30.9–37.6)

Melanesian/Polynesian Fiji (Lakeba) New Caledonia (Loyalty) New Caledonia (areas of Touho, Oundjo, Noumea, and Wallis Island)

a

Q: Probable CHD; Minnesota codes 1.1, 1.2. b ST-T: Possible CHD; Minnesota codes 1.3, 4.1, 5.1, 5.3, and 7.1.1. Source: Reprinted from Journal of Clinical Epidemiology, Vol 47, p 602. Copyright 1994 by Elsevier Science, Inc.

1.5% to 17.3% for men and from 4.1% to 34.1% for women. These estimates do not include selfreported angina pectoris, unlike the most recent data for the United States cited previously. Disability Among the consequences of CHD is substantial disability, leading to loss of employment and economic productivity, estimated to cost the US economy $10.6 billion in 2009 of $39.1 billion for all cardiovascular diseases. (This is additional to $62.0 billion in losses due to death and $92.8 billion in healthcare expenditures, from CHD alone.28) Quality of life among the population surviving with CHD is an additional concern. Beginning in 2000, the Medical Expenditure Panel Survey (MEPS) of the Agency for Healthcare Research and Quality (AHRQ) (accessible at http://www.meps.ahrq.gov/ mepsweb) has included a self-administered house-

hold questionnaire to assess health-related quality of life (HRQoL) among respondents, a national probability sample of noninstitutionalized adults 18 years of age or older.38 Four rating scales were used and addressed mental health, physical health, health utility, and self-rating of health. On every scale, persons with CHD reported reduced quality of life relative to those without CHD. Blacks were affected more than Whites on the majority of scores, and Hispanics were especially affected on the mental health score. Globally, the impact of ischemic heart disease on health-related disability has been estimated in terms of DALYs (disability-adjusted life years), as shown in Table 1-6. Ischemic heart disease was ranked fifth in contributions to total disability in 1990 and projected to rank first among all causes of disability by 2020.39 Further, the expected burden in terms of years of productive life lost due to ischemic heart disease in 2030 was projected for Brazil, South Africa, Russia,

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China, and India, compared with Portugal and the United States, shown in Table 1-7.40 This measure included both death and disability. These measures underscore the personal and societal costs of CHD and aid in appreciating its full impact on health and well-being, beyond the more common reliance on more readily available but in some respects less informative death rates alone. Disparities Disparities in CHD add further to understanding its social impact, as discussed in detail in Chapter 2. Figures 2-1, 2-2, 2-6, and 2-7 illustrate differences in CHD mortality by age, sex, race/ethnicity, and geography in the United States. Figure 2-5 shows variation in prevalence of major cardiovascular conditions by race/ ethnicity among US adults, and Table 2-2 describes the “Eight Americas” that define race/ethnic subgroups of the US population with striking differences in mortality.41 Regional variation in magnitude of CHD mortality throughout the world is shown in Table 4-4. A fundamental issue regarding racial/ethnic variation in CHD and other health conditions concerns the concept of race itself and understanding the underlying characteristics that may distinguish one group, on average—or one individual—from another. The complexity of this issue, touched on in Chapter 2, is well illustrated in the case of persons of African origin, discussed with particular insight by Cooper, who suggests that molecular genetics may introduce, and implicitly better answer, questions of variation in health and disease within and between populations.42 Examination of distributions of determinants of atherosclerotic and cardiovascular diseases in the chapters that follow includes discussion of variation in their patterns by age, sex, race/ethnicity, and other factors as available data permit. That discussion will offer some insight into the observed disparities in CHD and the other major cardiovascular conditions.

RISKS Risk Factors Variation in individual risks of coronary heart disease events within a population indicates operation of factors at the personal level. A focus on individuals or subgroups with characteristics of special interest, in relation to other members of the same population, is the approach taken in several large cohort studies since the early 1950s. Although in design each such study is analogous to study of any one cohort in the Seven Countries Study, the objective was fundamentally different, that is, not to derive estimates of event

rates and relevant exposures for comparison between whole cohorts but to compare individual subjects as the units of observation and analysis. The conceptualization and implementation of the Framingham Heart Study in the United States at midcentury are addressed in detail by Dawber and coworkers.16 Similar investigations in other community or employment settings were undertaken at about the same time in the United States. Although the Framingham Heart Study has continued longest and is widely recognized on the basis of its exceptionally extensive collection and reporting of data, other studies of its type have also contributed importantly to current knowledge of the epidemiology of coronary heart disease. For example, it became apparent early in the course of these US studies that more definitive analysis of individual differences in risks of coronary heart disease might be achieved by combining data from those studies most alike in design and examination methods. Under the aegis of the Committee on Epidemiological Studies (now the Scientific Council on Epidemiology and Prevention) of the American Heart Association, and its Subcommittee on Criteria and Methods, discussions began in 1961 that culminated in formation of the US National Cooperative Pooling Project. With support from the American Heart Association and both the Heart Disease Control Program and the (then) National Heart Institute of the US Public Health Service, this project was the major source of data for research planning and study design in the area of cardiovascular disease epidemiology and prevention for many years subsequent to its initiation in 1964. In 1978, its landmark Final Report was published as a comprehensive presentation of the pooled analyses relating characteristics of 8422 men aged 40–64 years who were free of coronary heart disease at entry to each study to the subsequent occurrence of an initial coronary heart disease event.13 The five participating studies (Albany Civil Servants, Chicago Gas Company, Chicago Western Electric Company, Framingham, and Tecumseh) provided information based on 72,011 person-years of experience and the occurrence of 658 first major coronary events prior to age 65. Table 4-8 is reproduced from the Final Report and presents the results of multivariate analysis in which baseline diastolic blood pressure, serum cholesterol concentration, smoking status, and age were taken into account. This analysis was to assess the contribution of each of these characteristics to the probability of occurrence of a first major coronary event during the 8.6 years of observation for each man. The multivariate equation derived from the pooled experience yielded significant coefficients for all four factors. When the distribution of “expected risk” based on these results was

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Table 4-8

Parameters SE t Standard No. of Men: 6875

75

Factors Related to the Incidence of Coronary Heart Disease, the US National Pooling Project, 1978 Diastolic Blood Serum Age Pressure Cholesterol Smoking 10.328022 0.068467* 0.030365* 0.006138* 0.304628* 0.008315 0.003584 0.000887 0.038270 6.234 8.473 6.920 10.050 0.349599 0.361013 0.293662 0.428591 No. of Events

Quintile of Expected Risk All I II III IV V Ratio: V/I % of events in V % of events in VI V Difference: V I

Risk/1,000 Men/ 8.6 Year

41.7 41.7–62.0 62.0–87.3 87.3–129.0 129.0

Expected 623.1 41.3 71.2 101.1 145.5 264.0 6.4 42.4 65.7 222.7

Observed 621 29 71 106 164 251 8.7 40.4 66.8 222

Rate/1,000 Men/8.6 Year Expected 90.6 30.0 51.8 73.5 105.8 192.0 6.4

Observed 90.3 21.1 51.6 77.1 119.3 182.5 8.7

162.0

161.4

*p 0.01 Source: Reprinted with permission from Journal of Chronic Diseases, Final Report of the Pooling Project, p 253, © 1978 Elsevier Science, Inc.

categorized into quintile groups (each comprising onefifth of the pooled study population), the expected and observed numbers of events and event rates could be examined in relation to the gradation of multivariate risk based on these four characteristics. Incidence of first major coronary events was 8.7 times as great in quintile V as in quintile I, and more than 40% of all events occurred in the group of men whose risk made up the highest 20% of the pooled population. This indicated the strength of the predictive relation between these four factors and risks of coronary heart disease for individuals. Notably, if the minimum risk in the pooled population were given by that of quintile I, the incidence of coronary heart disease was more than two times as great for the second quintile of risk (rate 51.6 versus 21.1), more than three times as great for the third quintile (rate 77.1 versus 21.1), nearly six times as great for the fourth quintile (119.3 versus 21.1), and nearly nine times as great for the fifth quintile (182.5 versus 21.1). These results for quintiles II–IV indicate that substantial excess risk occurred well below the highest-risk category. This indicates further that preventive measures limited to the highest-risk group could not effectively address all of the increased risk in the population. This principle is reinforced by studies of other populations. (See Chapter 18, Strategies of

Prevention.) It was clearly demonstrated 30 years ago by the Pooling Project. An example of more recent data for estimating risks of coronary events for individuals within a population is the exceptionally large cohort of men, also middle-aged Americans, who underwent risk-factor screening in the mid-1970s as potential candidates for entry to the Multiple Risk Factor Intervention Trial (MRFIT).43 Represented in Table 4-9 are the 342,815 men free of known prior heart attack or diabetes at the screening examination, which included measurements of blood pressure and serum cholesterol concentration and a questionnaire history of cigarette smoking. Death due to coronary heart disease over an average follow-up period of 11.6 years was ascertained through vital statistics sources. Because of the very large numbers of observations, it was possible to cross-classify the population according to quintile groups of systolic blood pressure (from 118 to 142 mm Hg), quintile groups of serum cholesterol concentration ( 182 to 245 mg/dl), and two smoking categories (nonsmokers versus smokers). For each of the resulting 50 groups, the death rate from coronary heart disease is presented. This follow-up experience through the 1980s indicates the same general relation of risk to these fac-

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Table 4-9

Factors Related to the Incidence of Coronary Heart Disease Among Men Screened as Candidates for the Multiple Risk Factor Intervention Trial, 1992 Systolic Pressure (mm Hg)

Serum Total Cholesterol (mg/dl)

118

118–24

125–31

132–41

142

Q5/Q1

Nonsmokers 182 182–202 203–220 221–244 245 Q5/Q1

3.09 4.39 5.20 6.34 12.36 4.00

3.72 5.79 6.08 9.37 12.68 3.41

5.13 8.35 8.56 8.66 16.31 3.18

5.35 7.66 10.72 12.21 20.68 3.87

13.00 15.80 17.75 22.69 33.40 2.45

4.42 3.60 3.41 3.58 2.70 —

Smokers 182 182–202 203–220 221–244 245 Q5/Q1

10.37 10.03 14.90 19.83 25.24 2.43

10.69 11.76 16.09 22.69 30.50 2.85

13.21 19.05 21.07 23.61 35.26 2.67

13.99 20.67 28.87 31.98 41.47 2.96

21.04 33.69 42.91 55.50 62.11 2.30

2.61 3.36 2.88 2.80 2.46 —

Source: Reprinted with permission from J Stamler, Coronary Heart Disease Epidemiology: From Aetiology to Public Health, p 49, © 1992, by permission of Oxford University Press.

tors as found in the Pooling Project and other reports. In addition it provides data indicating a much greater relative risk between categories than is possible in studies that are on the order of one-hundredth the size of this one: The highest risk, that of smokers in the top quintile of both systolic blood pressure and serum cholesterol concentration (62.11 deaths per 10,000 person-years) is more than 20 times that of the lowest-risk stratum, the nonsmokers in the lowest quintile groups of both systolic blood pressure and serum cholesterol concentration. (This observation points to the relativity of relative risk: The lower the risk of the reference category, the greater the relative risk of the highest category. MRFIT is exceptional in defining 50 strata of risk.) Demonstration of the gradient of increasing risk beginning from the lowest levels of these characteristics is also important. Even among nonsmokers in the lowest quintile for systolic blood pressure, a marked gradient of increased risk is observed with increased cholesterol concentration; the same is true for those in the lowest quintile for cholesterol as systolic pressure increases. In the lowest quintile class for both of these factors, smoking alone increases the risk more than threefold, that is, from 3.09 to 10.37 per 10,000 person-years. The INTERHEART Study was an international collaboration involving 15,152 cases of acute myocardial infarction and 14,820 controls in 52 countries representing all inhabited continents.44 Yusuf and

colleagues reported on the association of nine risk factors—current smoking, diabetes, hypertension, abdominal obesity, psychosocial factors, fruit and vegetable consumption, exercise, alcohol, and ApoB/ ApoA1 ratio (a measure of blood lipid profile)—with the occurrence of acute MI. Figure 4-5 summarizes results for each risk factor, by sex, in the overall study population, indicating each odds ratio and population attributable risk (PAR) with its 99% confidence interval. Table 4-10 demonstrates, for men and women together, the results by region and overall. The four “lifestyle factors” and five “other risk factors” are distinguished, and a cumulative total PAR is shown first for the lifestyle factors and second for all factors together. The lifestyle factors—smoking, fruits and vegetables, exercise, and alcohol—accounted for the greater part of the PAR in nearly every region, from 47.6% in the Middle East to 69.9% in Southeast Asia and Japan. All nine risk factors together yielded an estimated PAR of 90.4%, ranging from 72.5% in central and eastern Europe to 98.7% in North America. Consistent with previous studies conducted mainly in Western industrialized countries, recognized risk factors for acute MI appear to account to a very large extent for the occurrence of this condition within diverse populations throughout the world. A more recent concept relates to the continuously graded relation between such factors as blood lipids and blood pressure and risk of cardiovascular dis-

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Risk Factor Current Smoking

Diabetes

Hypertension

Abdominal Obesity Psychosocial Index Fruits/Veg

Exercise

Alcohol

ApoB/ApoA1 Ratio

Sex

Control (%) Case (%) Odds Ratio (99% CI)

77

PAR (99% CI)

F

9.3

20.1

2.86 (2.36 – 3.48)

15.8% (12.9 – 19.3)

M

33.0

53.1

3.05 (2.78 – 3.33)

44.0% (40.9 – 47.2)

F

7.9

25.5

4.26 (3.51 – 5.18)

19.1% (16.8 – 21.7)

M

7.4

16.2

2.67 (2.36 – 3.02)

10.1% (8.9 – 11.4)

F

28.3

53.0

2.95 (2.57 – 3.39)

35.8% (32.1 – 39.6)

M

19.7

34.6

2.32 (2.12 – 2.53)

19.5% (17.7 – 21.5)

F

33.3

45.6

2.26 (1.90 – 2.68)

35.9% (28.9 – 43.6)

M

33.3

46.5

2.24 (2.03 – 2.47)

32.1% (28.0 – 36.5)

F

–

–

3.49 (2.41 – 5.04)

40.0% (28.6 – 52.6)

M

–

–

2.58 (2.11 – 3.14)

25.3% (18.2 – 34.0)

F

50.3

39.4

0.58 (0.48 – 0.71)

17.8% (12.9 – 24.1)

M

39.6

34.7

0.74 (0.66 – 0.83)

10.3% (6.9 – 15.2)

F

16.5

9.3

0.48 (0.39 – 0.59)

37.3% (26.1 – 50.0)

M

20.3

15.8

0.77 (0.69 – 0.85)

22.9% (16.9 – 30.2)

F

11.2

6.3

0.41 (0.32 – 0.53)

46.9% (34.3 – 60.0)

M

29.1

29.6

0.88 (0.81 – 0.96)

10.5% (6.1 – 17.5)

F

14.1

27.0

4.42 (3.43 – 5.70)

52.1% (44.0 – 60.2)

M

21.9

35.5

3.76 (3.23 – 4.38)

53.8% (48.3 – 59.2) 0.25

0.5

1

2

4

8

16

Odds Ratio (99% CI)

Figure 4-5 Association of Risk Factors with Acute Myocardial Infarction in Men and Women After Adjustment for Age, Sex, and Geographic Region. Source: Reprinted with permission from The Lancet, Vol 364, p 944, © 2004.

eases. Rather than referring to the extreme category in the distribution of one or another factor, risk is becoming defined in relation to multiple factors, any or all of which may be only “borderline” and not “elevated” in value.45 On this basis, several factors may now be included in a “global risk assessment” to estimate the probability that an individual will experience a coronary event in some defined period, typically 10 years. From the Framingham Heart Study, Figure 4-6 shows the frequency distributions of less than 10%, 10–20%, and greater than 20% risk of “hard” coronary events in 10 years, separately for men and women, by age. These frequencies are derived from Framingham risk predictions and risk factor distributions in the US population determined in the Third National Health and Nutrition Examination Survey (NHANES III). On the basis of projected prevalence of optimal, borderline, and elevated values for five risk factors—blood pressure, serum LDL- and HDL-cholesterol concentrations, glucose tolerance, and smoking—less than 10% risk predominates for younger men and for every age level of women from 35–44 to 65–74 years. The upward shift in prevalence of higher risk is striking for men and notably less for women. For men older than age 45, risk of 10% or greater required at least one elevated risk

factor, with others at the borderline level, or two or more elevated factors. For women, 10% or greater risk occurred only at age 55 or older and required at least three elevated risk factors. Borderline risk factors alone were judged to account for only a small proportion of these events, which would occur within the next 10 years. Below “borderline” is “optimal” risk or, as discussed elsewhere in recent literature, “low risk.” Building on the data presented in Table 4-9 from the MRFIT screenees, Stamler and colleagues added the experience of nearly 40,000 employed persons who participated in the Chicago Heart Association Detection Project in Industry Study to determine the impact of “low risk” on CHD-CVD outcomes and allcause mortality.46 Low risk was defined in an early report on this work as serum cholesterol less than 200 mg/dl, systolic/diastolic blood pressure below 120/80 mm Hg without drugs, absence of cigarette smoking, no history of diabetes or myocardial infarction, and (in some but not all groups) absence of electrocardiographic abnormalities. Markedly reduced coronary, cardiovascular, and all-cause mortality was observed in low-risk men and women at all ages. Details of this topic and the concept of maintaining lifetime low risk are discussed in Chapter 21.

Region

7.3 4.8 18.3 18.0 11.2 11.1 6.6 19.8 12.9 13.7

45.5 38.9 37.4 35.9 36.2 44.8 38.3 26.1 36.4 35.7

27.6 25.6 25.5 12.2

4.2 10.1 27.1 20.3 31.4 23.8

38.4 11.3

67.6 49.6 47.6 63.4 56.6 62.3 69.9 66.0 56.6 59.9 62.9 54.6

1.0 26.6 5.5 5.7 27.9 18.6 3.7 25.5 13.9 6.7

All Lifestyles (%)

18.7 12.9

Alcohol (%)

32.7 19.0 23.4 17.9

9.2 29.6 19.3 22.1 38.4 22.6

21.9 24.5

12.7 8.0 12.3 9.9

15.5 16.7 11.8 10.0 21.0 7.2

15.0 9.1

Other Risk Factors Hypertension Diabetes (%) (%)

45.5 59.5 33.7 20.1

25.9 58.4 37.7 5.5 58.0 61.3

63.4 28.0

Abdominal Obesity (%)

35.6 51.4 28.8 32.5

41.6 40.0 15.9 35.4 26.7 28.9

38.9 4.9

All Psychosocial (%)

47.6 50.5 54.1 49.2

70.5 74.31 58.7 43.8 67.7 43.4

44.6 35.0

Lipids (%)

89.4 98.7 90.4* 90.4*

95.0 97.4 89.4 89.9 93.7 89.5

93.9 72.5

All Nine Risk Factors (%)

Source: Adapted from Yusuf S et al. Lancet Vol. 364, p. 945 © 2004.

PAR estimates in women in some countries are based on small numbers and so they are less reliable. Overall 1 adjusted for age, sex, and smoking; Overall 2 adjusted for risk factors. An extended version of this table with 99% Cls is shown in webtable 3 (http://image.thelancet.comm/extras/04art8001webtable3.pdf). *Saturated model, no difference between adjusted and unadjusted models. † Non-estimatable.

12.4 10.2

29.3 30.2

Exercise (%)

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Men and Women West Europe Central and eastern Europe Middle East Africa South Asia China Southeast Asia and Japan Australia and New Zealand South America North America Overall 1 Overall 2

Lifestyle Factors Smoking Fruits and (%) Vegetables (%)

Population Attributable Factors (PARs) Associated with Nine Risk Factors in Men and Women by Geographic Region

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TRENDS AND EXPLANATIONS

10% 2 20%

99.6%

88.8%

,10%

.20%

10

93.5%

62.3%

12

75.2%

1.5%

23.3% 1.5%

5.0%

55–64 y

65–74 y

0.4%

45.2%

52.6% 26.8%

20.6%

2

19.0%

4

6.9%

6

35.8%

30.8%

8

11.2%

At-Risk Persons in Millions, n

14

100%

10-Year Absolute Event Rates

18 16

79

0 35–44 y

45–54 y

55–64 y

65–74 y

Men

35–44 y

45–54 y

Women

Figure 4-6 Estimated Numbers of US Individuals at Risk for Hard Coronary Heart Disease Events, According to Estimated 10-Year Absolute Risk. Source: Reprinted with permission from Annals of Internal Medicine, Vol 142, p 400, © 2005, American College of Physicians.

“Triggers” Factors that have immediate effects on risks of acute coronary events, usually within 1–2 hours before the onset of symptoms, are distinguished as “precipitating factors” (as in Figure 4-2) or “triggers.” Areas of interest noted in a recent review include behavioral and emotional factors such as anger, hostility, depression, physical exertion, and sexual activity; coffee and tea consumption; marijuana use; and exposure to particulate air pollution or environmental tobacco smoke.47 Study of these factors is made difficult by the time relation between exposure and effect. The “casecrossover” design permits characterizing exposures immediately prior to the event for cases and a matching time period for controls as well as a historical point of reference for each subject, such as six months or one year earlier. Differences in exposure histories for cases and controls permit calculation of an odds ratio as a measure of association between the potential trigger and events. Specific examples of these precipitating factors are discussed in subsequent chapters.

TRENDS AND EXPLANATIONS Marked changes in coronary mortality by country were shown in Figure 2-8. Understanding these changes in the United States and elsewhere would be aided

greatly by availability of data on incidence and casefatality, such as those collected by the WHO MONICA Project. However, in the United States no such data are available on a continuous basis nationally. This is due mainly to the special requirements noted above for ascertainment and standardized diagnostic validation of acute fatal and nonfatal coronary events in the conduct of both long-term surveillance and cohort studies. The few studies that have been carried out indicate the value of this approach. The United States At the time when the population studies described above were initiated, coronary mortality in the United States had been increasing every year for several decades. Unexpectedly, a decline in national coronary mortality began in the 1960s (although a sentinel report by Borhani and Hechter indicated a downturn in California in the late 1950s48). This major change was first doubted, then debated, and finally examined extensively in a conference of the National Heart, Lung and Blood Institute in 1978 (subsequently referred to as “the Decline Conference”).49 Two leading explanations were offered, either of which could in principle have reduced the death rate: first, that medical care, especially coronary intensive care units, had reduced inhospital mortality; second, that preventive efforts had resulted in more favorable risk-factor distributions and

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thereby reduced the incidence of coronary events. Data were lacking to substantiate either explanation—an unwelcome admission of ignorance about the foremost cause of death in the United States. One response to the Decline Conference was an effort to reconstruct the history of the epidemic throughout the 20th century by compiling mortality data from published vital statistics. Stallones undertook this analysis, beginning from the premise that “whatever comes down must have gone up,” and sought a unified explanation of the rise and fall of the epidemic.50 The result is illustrated in Figure 4-7, in which each point represents the rate of death due to “diseases of the heart” in a given year from 1900 to 1978. This category is broader than “coronary heart disease” because this term was not in use early in the last century. Each year’s rate was adjusted to the age distribution of the US population in 1940, the midpoint of the period. This calculation removed any effect of increasing overall rates due to the upward shift in age composition of

the population. (This is in contrast to Figure 1-2, which shows the “crude” or absolute death rates for each category of disease each year, causing heart disease rates to appear to increase across the entire time period indicated.) The epidemic curve rises beginning in the 1920s, peaks at 1950, and declines through the 1970s. Stallones found no compelling unified explanation for both the rise and fall of the curve. However, the 20thcentury epidemic curve of coronary mortality in the United States was clearly demonstrated. Figure 2-3, from Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases, updates the course of the epidemic in the United States from 1979 to 2004.51 Age-adjusted coronary heart disease mortality for the United States declined by approximately 50%, from 350/100,000 to about 150/100,000. Numbers of deaths also declined, but by only about 20%. Efforts to explain the continuing decline in US coronary mortality have relied in part on analyses of

Figure 4-7 Heart Disease Mortality in the United States, 1900–1980. (The vertical scale is logarithmic.) Source: From The Rise and Fall of Ischemic Heart Disease, by RA Stallones, © 1980 by Scientific American Inc. All rights reserved.

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trends in incidence in local communities, such as in Framingham, MA; Rochester, MN; Minneapolis/St. Paul, MN; and the four ARIC Study communities (Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; and Washington County, MD).52–55 The Framingham Heart Study reported that both sudden death and nonsudden death due to CHD had declined from the 1950s through the 1990s, as shown in Figure 4-8. Framingham data indicate that both first and recurrent-event-related deaths declined as a consequence of improvement in both primary and secondary prevention. The differential decrease in types of CHD death left sudden cardiac deaths equal in frequency to nonsudden deaths, or 50% of the total.52 In Rochester, declining incidence of coronary heart disease—despite increasing proportions of cases being identified through angiography—was attributed to more effective primary prevention.53 In Minneapolis/ St. Paul, incidence, case-fatality, and recurrent MI all decreased. Primary and secondary prevention were credited, as well as acute care during coronary attacks.54 The ARIC communities experienced declines overall in hospitalized recurrent MI, but the rate increased among Blacks; sudden deaths and post-MI survival both improved.55 Another approach was to determine outcomes in two cohorts of participants in the NHANES I and II surveys, one followed from 1971 to 1982 and the other from 1982 to 1992.56 From the first to the sec-

81

ond cohort, there were reductions in age-, sex-, and race-adjusted cardiovascular disease mortality (31%), incidence (21%), and 28-day case-fatality (28%). Both incidence and case-fatality contributed to the decline in mortality, leading again to the interpretation that primary and secondary prevention and treatment were responsible. Among other recently developed methods for estimating contributions of change in risk-factor distributions and in treatment practices, the IMPACT model developed by Capewell and colleagues has been applied to the US experience from 1980 to 2000 by Ford and others.57 The analysis incorporates available data on risk-factor trends in the population, efficacy and utilization of treatments for cases, and the observed difference in CHD mortality rates between the base and ending years. The difference between numbers of deaths actually observed in 2000 and expected deaths had the rates of 1980 still applied is then apportioned to the several contributing factors. Between ages 25 through 84 years, 341,745 fewer CHD deaths than expected occurred in 2000. Overall, 44% of the reduction appeared to be due to risk-factor change and 47% to improvement in use of effective treatments. The benefit from reduction in risk factors (24% for cholesterol, 20% for blood pressure, 12% for smoking, and 5% for physical activity) totaled 61% but was offset by an 18% negative effect of increased prevalence of body mass index (8%) and diabetes (10%).

600

Rate/100,000 Person-Years

CHD Death Nonsudden CHD Death

500

SCD

400 300 200 100 0 Referent

1970s

1980s

1990s

Trends in age- and gender-adjusted incidence rate per 100,000 person-years for overall CHD mortality, nonsudden CHD death, and SCD from 1950–1969 to 1990–1999. Bars represent upper and lower 95% Cls.

Figure 4-8 Trends in Age- and Gender-Adjusted Rate per 100,000 Person-Years for Overall CHD Mortality, Nonsudden CHD Death, and SCD from 1950–1969 to 1990–1999. Source: From Fox CS et al., Circulation, Vol 110, p 523, © 2004, American Heart Association, Inc.

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Results from the IMPACT model in England and Wales, Scotland, Finland, and New Zealand and analyses by other methods and time periods in the United States, New Zealand, Holland, and Finland are remarkably consistent in showing 50% or more of the reduction in CHD mortality as due to risk-factor improvement. Finland indicated the greatest proportionate effect of risk-factor reduction, 76% during the early period from 1972 to 1992, reduced to 53% for the period from 1982 to 1997.57 This trend may reflect less frequent use of effective treatments in the 1970s in contrast to the latter period that includes the 1990s.

Three reports address specifically the contributions to the changing picture of coronary heart disease across MONICA Project populations to trends in coronary event rates and survival, classic risk factors, and coronary care.58–60 The observed trends for event rates and case-fatality are presented in Figure 4-9. MONICA CHD mortality declined by 2.7% in men and 2.1% in women during 371 “population-years” with 166,000 registered events. Overall event rates declined 2.1% in men and 0.8% in women; casefatality declined 0.6% and 0.8%, respectively. Main conclusions were: (1) the major determinant of the decline in CHD mortality was the change in event rates, although the declines in case-fatality were substantial; (2) the classic risk factors were mixed in direction of change—improving for blood pressure and cholesterol but opposite for body mass index—and, although a 4-year lag in the model improved the fit of risk factor and event rate trends, imprecision and ho-

Europe and Elsewhere The WHO MONICA Project aimed not only to monitor the components of change—event rates, incidence, case-fatality, and death rates—but also by identifying their major determinants to address the unanswered question from the Decline Conference.

5

0

0

25

25

210

210

FIN-NKA FIN-KUO SWE-NSW AUS-NEW NEZ-AUC ICE-ICE CAN-HAL UNK-BEL USA-STA FIN-TUL DEN-GLO SWE-GOT FRA-STR SWI-VAF GER-BRE GER-AUG BEL-GHE AUS-PER SWI-TIC ITA-BRI FRA-TOU UNK-GLA FRA-LIL RUS-NOC ITA-FRI GER-EGE CZE-CZE RUS-MOI BEL-CHA YUG-NOS POL-WAR RUS-NOC POL-TAR LTU-KAU SPA-CAT CHN-BEI RUS-NOI

5

Trend for Case Fatality in Men

RUS-MOC FRA-STR AUS-NEW FIN-NKA FIN-TUL FIN-KUO ICE-ICE SWE-GOT ITA-BRIA NEZ-AUC BEL-GHE RUS-MOI DEN-GLO USA-STA UNK-BEL SWE-NSW AUS-PER FRA-TOU FRA-LIL ITA-FRI CHN-BEI POL-TAR UNK-GLA CAN-HAL GER-BRE GER-AUG POL-WAR BEL-CHA RUS-NOI SPA-CAT CZE-CZE RUS-NOC GER-EGE LTU-KAU YUG-NOS

Trend for Coronary Events in Women 10

Trend for Case Fatality in Women

10

10

5

5

0

0

25

25

210

210

SWI-TIC FRA-TOU SWI-VAF SWE-NSW AUS-NEW ICE-ICE ITA-FRI BEL-CHA FRA-STR SPA-CAT USA-STA BEL-GHE AUS-PER CAN-HAL UNK-BEL UNK-GLA GER-BRE ITA-BRI NEZ-AUC FIN-NKA POL-WAR YUG-NOS FRA-LIL FIN-TUL RUS-NOC SWE-GOT CZE-CZE FIN-KUO LTU-KAU CHN-BEI POL-TAR GER-AUG RUS-NOC DEN-GLO GER-EGE RUS-MOC RUS-NOI

Average Annual Relative Trend (%)

Trend for Coronary Events in Men 10

ITA-BRI CAN-HAL FRA-TOU AUS-NEW GER-BRE AUS-PER FRA-STR GER-EGE UNK-GLA POL-WAR ITA-FRI FIN-TUL BEL-CHA BEL-GHE UNK-BEL LTU-KAU CZE-CZE ICE-ICE POL-TAR USA-STA GER-AUG FIN-NKA RUS-NOC SWE-NSW YUG-NOS NEZ-AUC FRA-LIL FIN-KUO SWE-GOT CHN-BEI RUS-MOC SPA-CAT RUS-MOI DEN-GLO RUS-NOI

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Population

Figure 4-9 Population rankings, by sex, of trends in coronary-event rates and case fatality with 95% CIs. Source: Reprinted with permission from The Lancet, Vol. 353, p. 1554, copyright 1999 The Lancet.

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REFERENCES

mogeneity of trends across populations limited the explanatory power of the analyses; and (3) changes in coronary care and secondary prevention were closely associated with trends in event rates, casefatality, and CHD mortality, much more so than riskfactor changes. The authors speculate that treatment changes being greater in magnitude and more easily measured than risk-factor changes might explain the apparent dominance of treatment effects. On the basis of national vital statistics for 18 industrialized countries, declining coronary heart disease mortality was found for men and women in several Eastern European countries from 1999–2004, including the Czech Republic, Poland, Hungary, and Romania.51

FORECASTS Although trends in CHD mortality over the most recent two to three decades have been favorable in many Western countries, the actual burden as measured by numbers of events and survivors has diminished little if at all for cardiovascular diseases as a whole in the United States and perhaps elsewhere. Lower rates at all ages have been offset to a large degree by growing numbers of people attaining ages where the rates are still highest, despite their decrease. Coupled with increasing prevalence of obesity and diabetes, as in the United States, improvements in some risk-factor distributions are offset as well by rates that could increase once again. Global projections were discussed in Chapters 1 and 2 and are also unfavorable, especially in low- and middle-income countries. Worldwide projections indicate ischemic heart disease retaining the lead among all causes of death and taking the lead in years of life lost and disability-adjusted life years, by 2020. There is a wide gap between these forecasts and the present national and international efforts to monitor and favorably influence the course of change. Approaches to closing the gap will be discussed in Part IV.

CURRENT ISSUES Among many issues in the epidemiology and prevention of coronary heart disease, three are most central to its occurrence as a global public health problem: 1. Can the predicted increases in population rates of coronary heart disease occurrence— whether measured by mortality, incidence and case-fatality, prevalence of clinical or sub-

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clinical disease, or extent of coronary atherosclerosis at autopsy of young decedents—be averted? 2. Can population differences in coronary heart disease occurrence and epidemic occurrence of coronary heart disease be eliminated, so that all populations share the most favorable experience? 3. Can coronary heart disease surveillance be maintained and expanded to monitor future changes in disease rates and the impact of preventive strategies effectively? REFERENCES 1. Hutter AM, IX. Ischemic heart disease: angina pectoris. In: Rubenstein E, Federman DD, eds. Scientific American Medicine. New York: Scientific American Inc.; 1995:1–19. 2. Fuster V, Fallon JT, Nemerson Y. Coronary thrombosis. Lancet. 1996;348:S7–S10. 3. Antman EM, Braunwald E. Acute myocardial infarction. In: Braunwald E, ed. Heart Disease. A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia, PA: WB Saunders Co; 1997: 1184–1288. 4. Myerburg RJ, Castellanos A. Cardiac arrest and sudden death. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia, PA: WB Saunders Co; 1997:742–779. 5. Willich SN, Muller JE. Triggering of Acute Coronary Syndromes: Implications for Prevention. Dutrecht (The Netherlands): Kluwer Academic Publishers; 1996. 6. Report of a WHO Scientific Group. Sudden Cardiac Death. Technical Report Series 726. Geneva (Switzerland): World Health Organization; 1985. 7. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque: part I: evolving concepts. J Am Coll Cardiol. 2005;46(6):937–954. 8. Fuster V, Fayad ZA, Moreno PR, Poon M, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque: part II: approaches by noninvasive computed tomographic/magnetic

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35. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med. 1993;119(12):1187–1197. 36. National Heart, Lung and Blood Institute. Incidence & Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases. Washington, DC: US Department of Health and Human Services, Public Health Service, National Institutes of Health; 2006. 37. Li N, Tuomilehto J, Dowse G, Virtala E, et al. Prevalence of coronary heart disease indicated by electrocardiogram abnormalities and risk factors in developing countries. J Clin Epidemiol. 1994;47:599–611. 38. Xie J, Wu EQ, Zheng ZJ, Sullivan PW, Zhan L, Labarthe DR. Patient-reported health status in coronary heart disease in the United States. Age, sex, racial, and ethnic differences. Circulation. 2008;118(5):491–497. 39. Murray CJL, Lopez AD. Alternative visions of the future: projecting mortality and disability, 1990–2020. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston, MA: The Harvard School of Public Health; 1996. 40. Leeder S, Raymond S, Greenberg H. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries. New York: The Trustees of Columbia University in the City of New York; 2004. 41. Murray CJL, Kulkarni SC, Michaud C, et al. Eight Americas: investigating mortality disparities across races, counties, and racecounties in the United States. PLoS Med. 2006;3:1513–1524. 42. Cooper RS. Coronary heart disease burden among persons of African origin. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology: From Aetiology to Public Health. 2nd ed. Oxford (England): Oxford University Press; 2005:118–132. 43. Stamler J. Established major coronary risk factors. In: Marmot M, Elliott P, eds. Coronary

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Heart Disease Epidemiology: From Aetiology to Public Health. Oxford (England): Oxford University Press; 1992:35–66. 44. Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937–952. 45. Vasan RS, Sullivan LM, Wilson PWF, et al. Relative importance of borderline and elevated levels of coronary heart disease risk factors. Ann Intern Med. 2005;142:393–402. 46. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy. Findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012–2018. 47. Siscovick DS. Triggers of clinical coronary heart disease. Epidemiology. 2006;17(5): 495–497. 48. Borhani NO, Hechter HH. Recent changes in CVR disease mortality in California. Pub Health Rep. 1964;79:147–160. 49. Havlik RJ, Feinleib M, eds. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. NIH publication 79-1610. Bethesda, MD: National Heart, Lung and Blood Institute, National Institutes of Health; 1978. 50. Stallones, RA. The rise and fall of ischemic heart disease. Scientific American. 1980;243: 53–59. 51. National Heart, Lung and Blood Institute. Morbidity & Mortality: 2007 Chartbook on Cardiovascular, Lung, and Blood Diseases. Bethesda MD: US Department of Health and Human Services. Public Health Service, National Institutes of Health; June 2007. 52. Fox CS, Evans JC, Larson MG, Kannel WB, Levy D. Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999. The Framingham Heart Study. Circulation. 2004;110:522–527.

53. Arciero TJ, Jacobsen SJ, Reeder GS, et al. Temporal trends in the incidence of coronary disease. Am J Med. 2002;117:228–233. 54. McGovern PG, Jacobs DR Jr, Shahar E, et al. Trends in acute coronary heart disease mortality, morbidity, and medical care from 1985 through 1997: the Minnesota heart survey. Circulation. 2001;104(1):19–24. 55. Rosamond WD, Folson AR, Chambless LE, Wang C-H for the ARIC Investigators. Coronary heart disease trends in four United States communities. The Atherosclerosis Risk in Communities (ARIC) Study 1987–1996. Int J Epid. 2001;30:S17–S22. 56. Ergin A, Muntner P, Sherwin R, He J. Secular trends in cardiovascular disease mortality, incidence, and case fatality rates in adults in the United States. Am J Med. 2004;117:219–227. 57. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med. 2007;356: 33–43. 58. Tunstall-Pedoe H, Kuulasmaa K, Mahonen M, Tolonen H, Ruokokoski E, Amouyel P. Contribution of trends in survival and coronaryevent rates to changes in coronary heart disease mortality: 10-year results from 37 WHO MONICA project populations. Monitoring trends and determinants in cardiovascular disease. Lancet. 1999;353(9164): 1547–1557. 59. Kuulasmaa K, Tunstall-Pedoe H, Dobson A, et al. Estimation of contribution of changes in classic risk factors to trends in coronary-event rates across the WHO MONICA Project populations. Lancet. 2000;355(9205):675–687. 60. Tunstall-Pedoe H, Vanuzzo D, Hobbs M, et al. Estimation of contribution of changes in coronary care to improving survival, event rates, and coronary heart disease mortality across the WHO MONICA Project populations. Lancet. 2000;355(9205):688–700.

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APPENDIX 4-A Key to Population Abbreviations Used by the WHO MONICA Project Population Abbreviation AUS-NEW AUS-PER BEL-CHA BEL-GHE BEL-LUX CAN-HAL CHN-BEI CZE-CZE DEN-GLO FIN-KUO FIN-NKA FIN-TUL FRA-LIL FRA-STR FRA-TOU GER-AUR

Population

Australia

Newcastle Perth Charleroi Ghent Luxembourg Halifax County Beijing Czech Republica Glostrup Kuopio Province North Karelia Turku/Loimaa Lille Strasbourg Toulouse Augsburg Rural

SPA-CAT SWE-GOT SWE-NSW

Spain Sweden

Augsburg Urban Bremen East Germanyb Rhein-Neckar Regionc Budapest

SWI-TIC SWI-VAF UNK-BEL UNK-GLA USA-STA YUG-NOS

Switzerland

Belgium

Canada China Czech Republic Denmark Finland

France

Germany

GER-AUU GER-BRE GER-EGE GER-RHN HUN-BUD

Population Abbreviation

Country

Hungary

HUN-PEC ICE-ICE ITA-BRI ITA-FRI LTU-KAU NEZ-AUC POL-TAR POL-WAR RUS-MOC

Country Iceland Italy Lithuania New Zealand Poland

Russia

RUS-MOI RUS-NOC RUS-NOI

UK USA Yugoslavia

a

Disagreement between local and national authorities on numbers of coronary deaths. Data for this center were incomplete as of 1994. c This register no longer exists. Data queries were answered up to January 1992. b

Source: Reprinted with permission from Circulation, Special Report, Vol 90, No 1, p 599, © 1994, American Heart Association.

Population Pecs Iceland Area Brianza Friuli Kaunas Auckland Tarnobrzeg Volvodship Warsaw Moscow Control Moscow Intervention Novosibirsk Control Novosibirsk Intervention Catalonia Gothenburg Northern Sweden Ticino Vaud/Fribourg Belfast Glasgow Stanford Novi-Sad

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5 Stroke pressure. However, population differences in the effectiveness of public health interventions for high blood pressure control cannot wholly explain population differences in trends of stroke mortality. Considerations of the burden and disparities associated with stroke pose public health challenges for the United States that are shared with many other countries. There is a need for broad international collaboration in meeting this challenge if the greatest potential impact of stroke prevention is to be achieved for many diverse populations. Common approaches to population surveillance of stroke are advocated on a multinational basis to strengthen the potential for prevention through effective national policies and practices.

SUMMARY Stroke, or cerebrovascular accident (CVA)—also now termed “brain attack” by analogy to “heart attack”— is a second major class of “end-organ” outcomes of atherosclerotic and hypertensive diseases. Just as the heart is damaged by disturbance of flow in the coronary circulation, the brain is damaged by disturbance of flow in the cerebral circulation. From transient episodes of less than 24 hours to permanent brain dysfunction, disability, or death, stroke has a wide range of clinical expressions. It constitutes a large proportion of overall cardiovascular morbidity and mortality globally. In some regions, stroke predominates substantially over coronary heart disease in its frequency. In the United States, it is about one-fourth to one-third as common as coronary heart disease as measured by both death rate and prevalence. Stroke mortality ranges widely among different populations and has been observed to change significantly within only a few years. Stroke mortality has been decreasing in many countries in recent years, although several eastern European countries have experienced sharp increases over the same period. Environmental factors have unquestionably played a major role in the long-term trends, given that they antedated by many years any widespread effective treatments. Among stroke survivors, disability and dependency are common, as is risk of recurrent strokes. In the United States, racial differences in stroke deaths persist, with relative excesses over non-Hispanic Whites long recognized in Blacks and more recently among American Indians/Alaska Natives and Native Hawaiians/Pacific Islanders. Although particular factors contribute to different types of stroke, the most prominent controllable factor common to all types is high blood

INTRODUCTION The Cerebral Arteries Figure 5-1 illustrates the anatomical relations of the main intracranial arteries to the cerebral hemispheres.1 Like the coronary arteries for the heart, these vessels are the principal suppliers of blood to the brain. However, analogy to the coronary circulation is limited by several factors. First, intermediate vessels— the external carotid arteries on the right and left sides of the neck extend into the cranium as internal carotid arteries to feed the vessels pictured here. Their potential involvement with atherosclerosis poses risks of transient disturbance of circulation to the brain independent of the intracranial vessels themselves. Second, these arteries can convey to the brain small blood clots, or thrombi, that are formed within the heart and travel through vessels of diminishing diameter until becoming lodged in an artery and blocking circulation beyond. (A thrombus sent from one site

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Parietal Lobe LATERAL SURFACE Posterior Cerebral Artery

Anterior Cerebral Artery

Frontal Lobe

Middle Cerebral Artery

Occipital Lobe

Temporal Lobe

MEDIAL SURFACE Posterior Cerebral Artery Anterior Cerebral Artery

Figure 5-1 A Schematic View of the Posterior, Middle, and Anterior Cerebral Arteries, from the Outer (Lateral) and Inner (Medial) Aspects of the Right Hemisphere of the Brain. Source: Albers GP, Cutler RWP, “Cerebrovascular Diseases” from Scientific American Medicine, Dale DC, Federman DD, Eds., © 119. Scientific American, Inc. All rights reserved.

to another in this way is termed an “embolus.”) Third, there are smaller vertebrobasilar arteries reaching the posterior part of the brain whose obstruction can also cause disturbance of brain function. Fourth, another type of process disrupting brain circulation results from a diseased and dilated segment of an artery, an aneurysm, that may rupture causing hemorrhage into the brain. Fifth, either spontaneous rupture or traumatic head injury can produce hemorrhage beneath the surface lining of the brain, the arachnoid membrane, producing a subarachnoid hemorrhage. Finally, a thrombus may form within the venous circulation of the brain, thereby disturbing normal blood flow. These multiple pathways and processes present numerous possibilities for interruption of brain circulation. Compounded by the different effects depending on the area of the brain affected, a very wide range of manifestations can occur. “Stroke” can therefore mean many things. Clinical Course of the Individual Case The hallmark of a typical severe stroke is its abrupt onset, with sudden and dramatic loss of consciousness and motor and sensory function on one side of the

body. Warning signs of a stroke are described as sudden numbness or weakness of the face, arm, or leg; sudden confusion, trouble speaking, or trouble understanding; sudden trouble walking, dizziness, or loss of balance or coordination; sudden trouble seeing in one or both eyes; and sudden severe headache with no known cause. These are the chief clinical manifestations of acute interruption of arterial blood supply to one or more areas of the brain. In Western countries, the interruption is due most often to obstruction of a major artery by thrombosis (formation of a blood clot locally) and less often to hemorrhage or embolism. Figure 5-2 illustrates the time course and potential outcomes of the typical acute cerebrovascular event. Stroke occurs most often against a background of advanced atherosclerotic lesions in the cerebral arteries or longstanding high blood pressure, or both. Although it is plausible that precipitating factors may trigger plaque disruption and its consequences just as in the coronary arteries (see Chapter 4), this process has received less attention in connection with stroke. Whether due to occlusion or hemorrhage, suddenness of onset is a defining characteristic of stroke. Signs and symptoms may diminish and disappear in

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Figure 5-2 Common Features of the Course of Stroke.

minutes or hours without residual clinical abnormalities. Alternatively, they may persist and progress, ending in death or permanent disability. An episode that resolves completely within 24 hours (an arbitrary but widely adopted criterion) is designated a “transient ischemic attack” (TIA). One that persists longer than 24 hours is termed a “completed stroke.” A completed stroke that is followed by death within 28 days from the onset of the episode is called a “fatal stroke” and is included in enumeration of case-fatality. Many variations can occur in the time course, location, and clinical features of acute disturbances in cerebral circulation, for the reasons outlined above. In addition, cumulative effects of multiple unnoticed ischemic events, blocking blood flow to small areas of the brain, can culminate over a period of years in a condition described as “multi-infarct dementia,” or impairment of cognitive function. Among these many potential manifestations, fatal or nonfatal completed strokes are the most widely recognized form of stroke and the main public health concern to date. These events currently constitute the third most frequent cause of death in the United States, with agestandardized mortality of 46.6 per 100,000 per year, just under one-third the rate for ischemic heart disease (data for the total population, 2005).2

BACKGROUND Only in the late 1950s and early 1960s were geographic comparisons of stroke mortality first reported, and Stallones remarked in a 1965 review that little epidemiologic study had been undertaken of stroke, unlike ischemic heart disease and hypertension.3 He

noted several methodologic problems: In death certificate studies, it was difficult or impossible to distinguish between major types of stroke—mainly thrombotic or embolic occlusion, intracerebral hemorrhagic, and subarachnoid hemorrhage. There was believed to be considerable variation in death certification practices in different countries. In early studies of incidence or prevalence of stroke, study populations were often too young to generate sufficient numbers of cases for reliable estimation of rates. Despite these limitations, it was possible to discern in international comparative studies, based on death certificates, a threefold or greater range in mortality (from more than 150 to less than 50 per 100,000 population per year) from all classes of vascular lesions of the central nervous system. Finland and Japan had the highest rates. Especially noteworthy was the pioneering work of Gordon, who described mortality data among three groups of men of Japanese ancestry situated in Japan, Hawaii, or California. He found a sharp gradient of decreasing stroke mortality from Japan to Hawaii to California among these men of common genetic background who, through differences in migration histories, had come to live—and die—in distinct environments. The pattern of mortality from stroke was opposite that for coronary heart disease, which increased from Japan to Hawaii and California. This observation of diverging “natural histories” was to become the basis for a three-part collaborative study. On the presumption that atherosclerosis was a common underlying condition for both stroke and ischemic heart disease, Stallones expected to find a correlation in mortality rates for these two causes when rates for the two diseases were compared among the

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United States.3 However, there was no relation between the distributions of these causes of death among the states. Different factors seemed to influence the occurrence of stroke and ischemic heart disease within this country. A concentration of high stroke mortality rates in the southeastern states was noted, a pattern first termed “the stroke belt” by Borhani (personal communication, George Howard, 1997). A striking secular trend of decreasing stroke mortality in the United States from 1900 onward was also demonstrated. Little information was available about possible risk factors for stroke other than age and sex. A steep age gradient in risk was present. For Whites in the United States, rates were higher for males than for females, whereas for non-Whites, females had the higher rates. Gorelick and Alter presented an assessment of stroke and its epidemiology and prevention, The Prevention of Stroke, in 2002.4 Distribution, risk factors, and approaches to prevention including recurrent events are addressed by multiple contributors. Although important questions remain, substantial progress has been made in the decades since Stallones’s early review.

POPULATION STUDIES: DEFINITION, CLASSIFICATION, AND DIAGNOSTIC METHODS As was the case for coronary heart disease, definitions and criteria for epidemiologic studies of stroke were developed by the Criteria and Methods Committee of the Council on Epidemiology and Prevention of the American Heart Association.5 The methodologic report of the World Health Organization (WHO) MONICA Project, in which community surveillance for stroke was an optional addition to the central focus on coronary heart disease, demonstrates the resulting classification of strokes (Table 5-1).6 Surveillance methods require uniform criteria for case ascertainment and validation. These are described in the situation of the WHO MONICA Project as follows: Stroke was defined as rapidly developing signs of focal (or global) disturbance of cerebral function lasting more than 24 hours (unless interrupted by surgery or death), with no apparent nonvascular cause; the definition included patients presenting with clinical signs and symptoms suggestive of subarachnoid hemorrhage, intracerebral hemorrhage, or cerebral infarction. . . . Events were characterized as either definite stroke, not stroke, or unclassifiable. Criteria for definite stroke were fulfilled when the available

Table 5-1

A Diagnostic Classification for Fatal and Nonfatal Strokes in Population Studies

Diagnostic categories (classification based on the most severe findings obtained within 28 days of onset): • Definite stroke • Not stroke • Definite stroke associated with definite myocardial infarction • Insufficient data Subcategories of stroke (classification based on confirmatory findings from necropsy in fatal cases or computerized axial tomography [CT] scan in nonfatal cases; specific criteria are given for each subcategory): • • • • •

Subarachnoid hemorrhage Intracerebral hemorrhage Brain infarction due to occlusion of precerebral arteries Brain infarction due to cerebral thrombosis Embolic brain infarction

Source: Data from K Asplund, et al., Diagnostic Criteria and Quality Control of the Registration of Stroke Events in the MONICA Project, Acta Med Scand Suppl 728, pp 26–39, © 1988.

information permitted a clinical stroke diagnosis. Unclassifiable was used when no diagnosis other than stroke was present to explain the event but the available information was insufficient for determining whether symptoms and duration fully met the MONICA criteria for definite stroke. . . . Stroke events were subdivided into first or recurrent and into fatal or nonfatal. A period of 28 days was used to define case fatality and to distinguish one event from another.7, pp 500–501 The types of stroke are correspondingly distinguished in the classification system of the International Classification of Diseases and Related Health Problems (ICD), as summarized in Table 5-2.8 TIAs are not included with these classes of stroke in ICD 10. Because their inclusion or exclusion affects reported rates of both nonfatal and total stroke (being excluded from fatal strokes by definition), proper comparison among studies requires knowledge of the inclusion criteria used. Epidemiologic study of stroke has been hampered by the infrequent identification of stroke subtypes, especially lack of differentiation between occlusive and hemorrhagic strokes. Advent and wider use of diagnostic brain imaging procedures (e.g., computed tomography, or CT scans) offers a potential solution to this problem, and use of magnetic-resonance imaging, or MRI, appears to improve identification of stroke type and assessment of the extent of tissue damage significantly over the CT scan.9 But many fatal stroke

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Table 5-2 160 161 162 163 164 165 166 167 168 169

Categories of Cerebrovascular Diseases in ICD 10 (160–169)

Subarachnoid hemorrhage Intracerebral hemorrhage Other nontraumatic intracranial hemorrhage Cerebral infarction Stroke, not specified as hemorrhage or infarction Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction Other cerebrovascular diseases Cerebrovascular disorders in diseases classified elsewhere Sequelae of cerebrovascular disease

Note: Transient ischemic attacks are not included.

cases are out-of-hospital deaths even in the highincome countries, and on a global basis a great many cases occur where no such technology is available. As a result, lack of data on specific stroke types is a continuing limitation of minor to major degree depending on the setting in which stroke data are collected. Recent advances in treatment of occlusive strokes with thrombolytic therapy have placed new emphasis on quality of acute stroke care, including differentiation among stroke types in the first minutes to hours after onset of a stroke. This is because use of thrombolytic therapy to reduce morbidity and mortality requires identifying those cases of occlusive stroke that are eligible for this treatment, which is contraindicated in hemorrhagic stroke. For identifying barriers to timely access to high-quality care, a hospital-based stroke surveillance program has been established on a limited scale in the United States called the Paul Coverdell National Acute Stroke Registry, operated by several state health departments in cooperation with the Centers for Disease Control and Prevention (CDC). Through collaboration among interested national nongovernmental organizations and other federal agencies, agreement was reached on definition of data elements in 12 core areas. Implementation of this registry and parallel work in Canada, Germany, Japan, and Korea has been reported recently and indicates current issues for hospitalbased surveillance of stroke in various settings.10 A further difficulty is to know how death in a stroke victim is classified, whether as caused by stroke or distinct from the stroke itself. Study of a sample of 200 cases of stroke or TIA in the Brain Attack Surveillance in Corpus Christi (TX) Project indicated poor agreement between raters on this question.11 Agreement between two neurologists as to whether a

93

death would be attributed to stroke was only between 40% and 50%. This finding implied that stroke mortality data may be based on methods of uncertain unreliability and should be interpreted with caution.

RATES In the United States, 143,579 deaths were attributed to stroke as the underlying cause in 2005, while WHO in 2004 estimated more than 5 million stroke deaths from this second leading cause of death worldwide.12,13 The United States’ national target for reduced stroke death rates by 2010 is 50/100,000, a 20% improvement from the baseline rate of 62/100,000 in 1999. By 2002, half of the projected gain for the decade had already occurred for the population as a whole.14 Mortality The United States Numbers of deaths due to stroke by age, sex, and race for non-Hispanic Whites and Blacks in the United States for 2005 are shown with other population-level indicators in Table 5-3, from data reported by the National Center for Health Statistics and other sources.12 For both Whites and Blacks, numbers of stroke deaths among females far exceed those for males. This pattern by sex occurs despite higher age-specific stroke death rates for males (shown elsewhere) because greater numbers of females reach the ages where rates are highest. Figure 5-3 illustrates the steep age gradient for stroke for these four sex-race groups.15 Like the corresponding patterns for coronary heart disease (Figure 2-1), stroke death rates are higher for Blacks

Table 5-3

Stroke Mortality, United States, 2005 Stroke Deaths Total 143,579 All males 56,586 % of total 39.4 All females 86,993 % of total 60.6 Non-Hispanic white males 47,194 % of subgroup 35.2 Non-Hispanic white females 74,674 % of subgroup 64.8 Non-Hispanic black males 7,519 % of subgroup 42.9 Non-Hispanic black females 10,022 % of subgroup 57.1 Source: Data from Heart Disease and Stroke Statistics—2009 Update. A Report from the American Heart Association Statistics Committee and Stroke Statistics Committee. D Lloyd-Jones et al., © 2009, Courtesy of the American Heart Association/American Stroke Association.

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700

Deaths/100,000 Population

600

Black Male White Male Black Female White Female

500 400 300 200 100 0 35–44

45–54

55–64

65–74

75–84

Age (Years)

Figure 5-3 Death Rates for Stroke by Age, Race, and Sex, US, 2004. Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute, June 2007.

than Whites at every age. In contrast to the picture for coronary heart disease, the difference in age-specific rates between males and females is narrower for Blacks and nearly absent for Whites. Stroke mortality does not exhibit the apparent advantage for women found for coronary heart disease. Nearly one-third of stroke deaths in the United States occur at younger than age 75, and slightly more than two-thirds occurred at ages 75 and older. For this reason there is special concern about stroke among the older population. Analogous to the atlases of county-level coronary heart disease mortality by sex and race/ethnicity for the United States illustrated in Figure 2-6, data on stroke mortality by race/ethnicity and geographic area are presented in two publications and on an interactive Web site (accessible at http://www.cdc.gov/chv/ maps).16,17 The underlying data are for United States counties for the period 1991–1998 and demonstrate continuing appearance of the “stroke belt,” the concentration of high stroke death rates in southeastern states. Additional areas of concentration include the Mississippi River Valley and, more prominently for women than men, Washington, Oregon, and Idaho as well as northern counties of California. Special importance is attached to the Atlas of Heart Disease and Stroke Among American Indians and Alaska Natives, a heterogeneous population group for whom the exceptionally high burden of heart disease and stroke has been largely unrecognized. This publication includes mapping of risk-factor information for this population, as obtained through the Behavioral Risk Factor Surveillance System of the Centers for Disease Control and Prevention on a state-by-state basis.

Location of death from stroke—whether out of hospital, in the hospital emergency department, or after hospital admission—is of interest especially from the viewpoint of access to emergency transport and medical services immediately after onset of warning signs for a stroke. On the basis of data from 1999 for the United States, deaths were attributed to subarachnoid hemorrhage (2.4/100,000), intracerebral hemorrhage (9.4/100,000), ischemic stroke (42.2/ 100,000), or sequelae of stroke (7.8/100,000).18 Nearly half of all stroke deaths (48.3%) occurred “prior to transport” or by the time of arrival at the emergency department. This was a much less frequent occurrence among younger than older stroke victims and somewhat less frequent among other race/ethnic groups than non-Hispanic Whites. “Pretransport” deaths, including those in persons who died before transportation could be (or would be) provided, were about twice as frequent for ischemic stroke (23.3%) as for subarachnoid or intracerebral hemorrhage (12–14%). Deaths due to sequelae of stroke (69.1%) were exceptionally common. This may reflect difficulty in assigning cause of death for victims of unobserved strokes who were found dead after significant delays. Another factor to be considered is the occurrence of stroke death in nursing homes, rather than in hospital, especially among older stroke victims. Europe and Elsewhere Population differences in stroke mortality are well documented for the baseline period of the WHO MONICA Project from 1985 to 1987 (Figure 5-4).19 Stroke surveillance was reported for 18 populations

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Figure 5-4 Annual Mortality from Stroke in 18 Populations in the WHO MONICA Project, by Sex, 1985–1987. For key to MONICA abbreviations, see Appendix 4-A. Source: Reprinted with permission from P Thorvaldsen, K Asplund, K Kuulasmaa, AM Rajakangas, and M Schroll, Stroke, Vol 26, p 366, American Heart Association.

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in 10 countries located in eastern and western Europe and the People’s Republic of China. Both men and women who died at ages 35–64 years were included. The figure indicates stroke mortality for each country and reporting area, separately for men and women in descending order of their observed rates for definite stroke. Stroke mortality ranged about fourfold from lowest to highest for both men and women. Rates were considerably lower for women than for men in each of the 18 populations. Stroke types were not described. Global estimates of stroke deaths are summarized in Table 5-4.13 Exceptionally large numbers are attributed to portions of southeast Asia and the Western Pacific regions, dominated by the large populations of India and China, respectively, and Europe, with the low child–high adult mortality in its central and eastern states, many in the former Soviet Union. Here, too, differentiation of stroke types is lacking.

and 6.3 for White men and women, respectively, and 12.1 and 10.5 for Black men and women, respectively. Men and Blacks experienced the greater rates at every age. Stroke surveillance in one community (Corpus Christi, TX) provided an opportunity to compare stroke incidence under the same study protocol in Mexican Americans and non-Hispanic Whites. Higher rates occurred for every stroke type in Mexican Americans, another racial/ethnic group at increased risk over Whites.12 Corresponding findings from the Northern Manhattan Stroke Study in the mid-1990s indicated population-based stroke incidence 2.4 times as great among Blacks and 2 times as great among Hispanics as among Whites.21 Additional incidence data have been reported from the Mayo Clinic/Olmsted County population and from the Greater Cincinnati/Northern Kentucky studies. The Chart Book presents age-specific stroke incidence data from ARIC and FRS, the latter spanning the years 1980–2003.20 Rates for Framingham men and women, though including an earlier decade, are lower at comparable ages than those for ARIC: For example, at age 55–64, rates per 1000 personyears were 6.1 and 4.6 for men and women in ARIC but only 4.3 and 2.2 for FRS. These different local estimates would yield markedly different projections for the US population. Perhaps different ascertainment methods account for the variation: ARIC used self-reported physician diagnosis of stroke or TIA, whereas FRS utilized in-hospital examination or review of hospital records. In the absence of standardization of methods, such variation is not surprising but nonetheless limits the value of the data for projection to other populations.

Incidence The United States As is the case with coronary heart disease, incidence of stroke is unknown for the United States nationally for any or all types.12 Compilation of information from the Greater Cincinnati/Northern Kentucky Stroke Study, the Framingham Heart Study (FRS), the Atherosclerosis Risk in Communities (ARIC) Study, and the National Heart, Lung and Blood Institute yields an estimate of 500,000 cases of first stroke each year and 200,000 recurrent strokes, a total of 700,000 new and recurrent attacks at all ages. The Incidence and Prevalence 2006 Chart Book (see Chapter 4) reports stroke incidence from the ARIC cohort, with data pooled over the years 1987–2001 for stroke and TIA combined, at ages 45–84 years.20 The rates, per 1000 person-years of follow-up, were 7.7 Table 5-4

Africa 1 172

2 187

Europe and Elsewhere In addition to mortality, the MONICA Project provides valuable data on incidence and survival from

Numbers of Deaths (ⴛ1000) Due to Cerebrovascular Disease by Mortality Strata in Each WHO Region, 2002 South-East Eastern Western The Americas Asia Europe Mediterranean Pacific Total 3 187

4 239

5 26

4 162

5 897

3 414

4 284

6 749

1. high child, high adult mortality 2. high child, very high adult mortality 3. very low child, very low adult mortality 4. low child, low adult mortality 5. high child, high adult mortality 6. low child, high adult mortality Source: Data from The World Health Report 2004, Statistical Annex, Table 2, pp 122–123.

4 55

5 172

3 150

4 1807

5509

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stroke.19 The total stroke event rates presented in Table 5-5 combine initial and recurrent definite strokes of all types. These rates ranged threefold for men, from 121 per 100,000 population in Italy (Friuli) to 359 in Finland (Kuopio), and fivefold for women, from 58 per 100,000 in Germany (Rhein-Neckar Region) to 294 in Russia (Novosibirsk). These stroke events, all classified as definite stroke in keeping with the MONICA protocol, constituted a very high proportion of all strokes reported in each population, typically well over 90%. The proportion of strokes that were recurrent, rather than truly incident, events was below 10% in only one population for both men and women but above 25% in only two populations each for men and for women. Thus generally from 75% to 90% of these definite strokes were initial events. Two other approaches to assessing incidence of stroke in Europe are noteworthy. The European Registers of Stroke (EROS) Collaboration established population-based registers in three areas—Erlangen, Germany; Dijon, France; and London, UK.22 Firstoccurring strokes of all types in 1995–1997 were ascertained by several standardized methods in all three areas. Relative to reference rates in Dijon, the rate in London was 20% higher and that in Erlangen was nearly 40% higher. Types of stroke varied among the communities and case-fatality ranged from 27% in Table 5-5

Locationa CHN-BEI DEN-GLO FIN-KUO FIN-NKA FIN-TUL GER-HAC GER-KMS GER-RDM GER-RHN ITA-FRI LTU-KAU POL-WAR RUS-MOC RUS-MOI RUS-NOI SWE-GOT SWE-NSW YUG-NOS

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Dijon to 41% in London after adjusting for differences in age, sex, and stroke type. The potential for rigorous comparison of stroke experience across diverse populations was clearly demonstrated. Another approach was to estimate current and projected stroke incidence and prevalence for the European Union countries plus Iceland, Norway, and Switzerland (members of the European Fair Trade Association), on the basis of review of 44 populationbased studies of stroke incidence from 14 European countries.23 The report of this project outlines details of methods used, shortcomings of data available from the multiple independent studies cited, and the resulting estimates by which the World Health Organization can forecast the stroke burden to 2025. Current incidence was estimated to be 1.1 million new cases per year in the included countries. The urgency of collecting standardized stroke data for the region was emphasized, and surveillance through the WHO STEPS Stroke System was proposed as the mechanism. Case-Fatality Reported case-fatality from stroke varies among data sources depending upon age, sex, race/ethnicity, and aspects of case definition, as well as possible differences in initial severity, accessibility and quality of

Stroke Attack Rates (per 100,000/yr), Recurrence, and 28-Day Case-Fatality in 18 Populations of the WHO MONICA Project, by Sex, 1985–1987 Males Females Stroke % % CaseStroke % % CaseRate Recurrent Fatality Rate Recurrent Fatality 240 177 359 293 264 150 167 136 137 121 286 152 251 229 344 128 216 235

27 21 18 17 25 17 23 17 23 13 25 13 21 25 27 9 20 20

28 22 17 27 21 36 32 30 16 34 23 49 32 38 25 18 15 28

169 93 194 124 105 84 102 74 58 63 146 76 136 123 294 67 115 110

27 17 16 15 15 17 21 19 13 11 14 12 24 26 23 6 18 15

37 26 18 31 22 36 34 36 23 39 22 57 38 39 22 25 21 44

a

For key to MONICA abbreviations, see Appendix 4-A.

Source: Reprinted with permission from P Thorvaldsen, K Asplund, K Kuulasmas, AM Rajakangas, and M Schroll, Stroke, Vol 26, © American Heart Association.

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treatment, and other factors. For persons aged 45–64 in the ARIC Study, death occurred within 30 days (a nonstandard interval) in 8–12% of ischemic strokes and 37–38% of hemorrhagic strokes. Similar rates were described in a four-community study of persons aged 65 years or older enrolled in Medicare: 1-month case-fatality of 8.1% for ischemic strokes and 44.6% for hemorrhagic strokes.12 The finding that hemorrhagic strokes confer substantially higher early mortality is consistent with other sources. This observation also underscores the importance of distinguishing among stroke types, given marked differences in their clinical course. Case-fatality in the MONICA stroke centers was assessed for all strokes, regardless of type, for new and recurrent events together (Table 5-5).19 Casefatality ranged, for men, from 15% to 49%, and for women from 18% to 57%. The upper limits were in Warsaw, Poland, for both men and women, and were “outliers,” being uniquely high values. This suggests exceptional circumstances in Warsaw that were not typical of other centers. Excluding Poland, the range was limited to 38% for men and 44% for women, still at a level seen only for hemorrhagic stroke in the US data, but the comparison may be inappropriate on several grounds. Threefold variation in casefatality raised questions about possible differences among reporting areas in case severity, treatment, or other influences.

stroke among respondents (Table 5-6).24 In response to the interview question “has a doctor ever told you that you had a stroke?” 2.6% of 356,112 respondents in all 50 states and other jurisdictions indicated “yes,” leading to the estimate of 5,839,000 prevalent cases of stroke in the noninstitutionalized US population age 18 years or older. Prevalence increased with age (65 years and older, 8.1%), male sex (2.7%), race/ ethnicity (Blacks 4.0%, American Indian/Alaska Native 6.0%), and education (less than high school 4.4%, college graduate 1.8%). Variation by state was about twofold, with Connecticut (1.5%) and Mississippi (4.3%) the lower and upper extremes. The analysis of European population studies of stroke cited previously included assessment of agespecific prevalence and projection to estimate prevalence for each European Union country and European Fair Trade Association participant, including those lacking relevant data altogether.23 At age 65–74 years, for example, prevalence was estimated to be as high as 14.2% for men in Portugal and as low as 1.5% for women in Cyprus. This nearly 10-fold range calls attention to the need for countries to assess their own burdens of stroke and other major chronic conditions in order to devise and implement effective preventive strategies. Lack of data is a serious handicap, but the interim device of estimation from the most extensive available data—recognizing their limitations—is an expedient approach.

Prevalence The prevalence of stroke in the adult US population aged 20 years and older was estimated for the year 2006 for the total population and separately for males and females: 6.5 million, 2.6 million, and 3.9 million, respectively.12 The basis for these estimates is a selfreported history of a nonfatal stroke by participants in the National Health and Nutrition Examination Survey, 1999–2004. Percent frequencies of persons living with a history of stroke were also given, for the total population and for multiple racial/ethnic groups. The highest prevalence, for American Indians/Alaska Natives at 6.0%, was noted as being unreliable. This suggests that adequate data are not being collected for this population, already seen to have exceptionally high stroke mortality. For Black men and women, prevalence was also relatively high in comparison with non-Hispanic Whites—for men, 3.9% versus 2.3% and for women 4.1% versus 3.2%. Prevalence was lowest for Mexican American males at 2.1%. In the United States, the Behavioral Risk Factor Surveillance System also provided an opportunity for the year 2005 to include inquiry about history of

Disability The aftermath of stroke for those who do survive is often one of significant disability. According to the Atlas of Stroke Hospitalizations among Medicare Beneficiaries, among beneficiaries hospitalized for stroke, just half (51.0%) are discharged home, nearly one in ten die in hospital, and nearly 40% are discharged to a skilled nursing or other care facility.25 At three months after hospital discharge, 20% of stroke survivors require institutional care, and 15–20% are permanently disabled. Within 5 years, 13% of men and 22% of women 40 to 69 years old at the time of stroke have a recurrence.12 Participants in the Medical Expenditure Panel Survey (MEPS) of a representative sample of the US population for the years 2000 and 2002, described in Chapter 4, were asked whether they “had ever been diagnosed as having had a stroke or transient ischemic attack.”26 Compared with survey participants without a history of stroke, after adjustment for differences in sociodemographic factors, risk factors, and comorbidities, stroke survivors had significantly poorer ratings on all four of the HRQoL scales—

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Table 5-6

99

Percentage of Respondents Who Reported a History of Stroke by Selected Characteristics—Behavioral Risk Factor Surveillance System, United States, 2005 Estimated No. of Total No. of Prevalence of US residents Respondents* Stroke† 95% Cl‡ living with stroke§

Characteristic Age (yrs) 18–44 45–64 65 Sex¶ Male Female Race/Ethnicity¶ White, non-Hispanic Black, non-Hispanic Asian Hispanic American Indian/Alaska Native Multiracial Education¶ Less than 12 years High school graduate Some college College graduate Total

128,328 137,738 87,351

0.8 2.7 8.1

0.7–0.9 2.5–2.9 7.7–8.5

852,000 1,926,000 3,036,000

136,201 219,911

2.7 2.5

2.5–2.8 2.4–2.7

2,694,000 3,145,000

279,419 27,925 5974 25,539 5535 6519

2.3 4.0 1.6 2.6 6.0 4.6

2.3–2.4 3.6–4.5 1.0–2.7 2.1–3.3 4.5–7.8 3.7–5.6

4,017,000 772,000 60,000 616,000 126,000 136,000

38,202 109,830 93,228 113,944 356,112

4.4 2.6 2.7 1.8 2.6

4.0–4.9 2.5–2.8 2.5–2.9 1.6–1.9 2.5–2.7

1,365,000 1,863,000 1,474,000 1,108,000 5,839,000

*The sums of the sample sizes in each category may not add up to the total number of respondents because of unknown or missing information. There are 2695 respondents with unknown or missing age, 5201 with unknown or missing race/ethnicity, and 908 with unknown or missing level of education. † Weighted percentage of respondents who report a history of stroke. ‡ Confidence interval. § Estimated number of US residents with a stroke history. ¶ Weighted percentages are age-adjusted to the 2000 US standard population. Source: Centers for Disease Control and Prevention. The Prevalence of Stroke—United States, 2005. MMWR 2007; Vol 56, pp 470–474.

mental health, physical health, health utility, and selfrated health (Table 5-7). Black–White disparities in HRQoL among survey participants overall were amplified among those who were stroke survivors. On a global level, disability due to stroke was described in Chapter 1 as contributing increasingly to disability worldwide as measured by disabilityadjusted life years (DALYs), ranking sixth in 1990 and projected to rank fourth by 2020.27 Disparities Variation in the frequency and burden of stroke by age, sex, race/ethnicity, and geography has been alluded to previously in this chapter and in Chapter 2 (Figure 2-5), which illustrates striking excess prevalence of stroke among Native Hawaiians/Pacific Islanders and American Indians/Alaska Natives relative to non-Hispanic Whites.28 Vital statistics and health-related surveys have provided evidence of racial/ ethnic disparities in death from each major stroke subtype, with different groups being most affected;29 in overall stroke death rates, age at death and years

of potential life lost;30 and prevalence of cardiovascular risk factors among those who have survived a stroke.31 Multiple groups experience these differential risks and consequences of stroke, which are to be eliminated as one of two overarching goals of the health blueprint for the decade in the United States, Healthy People 2010.32 Attention has been called especially to the burden of stroke in Blacks, for whom numbers of deaths increased in the 1990s as the decline in rates (see below) slowed, and for whom the excess burden is especially great in nonmetropolitan areas of the southeast.33 Achievement of the Healthy People objective of 20% reduction in the overall stroke death rate and elimination of disparities would entail reduction by 40% among Blacks in the same time period. Review of studies on stroke incidence or mortality in relation to socioeconomic status in Europe, the United Kingdom, and the United States points to increased risks among lower socioeconomic groups.34 This aspect of disparities in atherosclerotic and hypertensive diseases is discussed in Chapter 16.

51.1 (0.1) 51.3 (0.2) 52.5 (0.2) 51.8 (0.3) 51.8 (0.5) 52.2 (0.1) 50.4 (0.1) 51.3 (0.1) 51.1 (0.2) 51.2 (0.3) 50.9 (0.2) 51.3 (0.1) 51.2 (0.2) 51.6 (0.2) 51.2 (0.1) 51.3 (0.1) 50.3 (0.2) 51.5 (0.1) 49.2 (0.3) 51.4 (0.1) 49.4 (0.3) 51.4 (0.1) 49.2 (0.2) 51.9 (0.1)

45.1 (1.2) 45.9 (1.0) 48.5 (0.9) 48.9 (0.7) 46.5 (1.5) 49.1 (0.6) 45.0 (0.7) 47.9 (0.5) 45.4 (1.0) 43.3 (3.4) 44.6 (1.4) 47.5 (0.5) 46.7 (1.0) 48.3 (0.9) 47.0 (0.7) 47.4 (1.0) 47.4 (0.5) 47.4 (0.9) 46.1 (0.9) 47.8 (0.5) 46.2 (0.8) 48.0 (0.5) 45.4 (1.0) 48.0 (0.5)

36.7 (1.0) 35.1 (0.5)

31.9 (0.8) 37.4 (0.5)

31.3 (0.7) 36.9 (0.5)

34.1 (0.5) 38.5 (0.8)

34.4 (1.1) 35.8 (1.0) 34.8 (0.9) 37.4 (0.7)

33.6 (1.4) 35.7 (0.5)

35.5 (0.1) 35.3 (1.1) 37.8 (2.7)

48.9 (0.2) 49.8 (0.1)

37.8 (0.4) 50.2 (0.1)

40.9 (0.3) 50.1 (0.1)

43.3 (0.2) 50.1 (0.1)

50.1 (0.2) 50.0 (0.2) 48.9 (0.2) 49.9 (0.1)

50.3 (0.2) 49.5 (0.1)

49.6 (0.1) 49.3 (0.2) 50.1 (0.3)

50.4 (0.1) 48.8 (0.1)

52.0 (0.1) 47.6 (0.2) 43.8 (0.3) 39.4 (0.3) 35.5 (0.5)

49.6 (0.1)

0.71 (0.01) 0.69 (0.01)

0.65 (0.04) 0.71 (0.01)

0.62 (0.02) 0.72 (0.01)

0.68 (0.01) 0.72 (0.01)

0.67 (0.02) 0.71 (0.01) 0.69 (0.01) 0.71 (0.02)

0.59 (0.04) 0.70 (0.01)

0.70 (0.01) 0.67 (0.02) 0.64 (0.07)

0.72 (0.01) 0.67 (0.01)

0.73 (0.02) 0.67 (0.01) 0.72 (0.01) 0.70 (0.01) 0.60 (0.03)

0.69 (0.01)

0.84 (0.00) 0.88 (0.00)

0.74 (0.01) 0.88 (0.00)

0.77 (0.01) 0.88 (0.00)

0.80 (0.00) 0.89 (0.00)

0.88 (0.00) 0.87 (0.00) 0.86 (0.00) 0.88 (0.00)

0.88 (0.00) 0.87 (0.00)

0.87 (0.00) 0.86 (0.00) 0.89 (0.01)

0.88 (0.00) 0.86 (0.00)

0.90 (0.00) 0.84 (0.00) 0.82 (0.00) 0.78 (0.01) 0.73 (0.01)

0.87 (0.00)

Source: Reprinted with permission from Stroke, Vol 37, pp 2567–2572. © 2006, American Heart Association, Inc.

59.1 (1.9) 62.5 (0.9)

55.5 (1.4) 66.7 (0.9)

55.4 (1.8) 63.9 (0.9)

59.7 (0.9) 65.8 (1.4)

59.9 (2.3) 63.3 (1.4) 59.9 (1.4) 63.7 (1.6)

53.9 (3.0) 62.1 (0.8)

61.9 (0.9) 60.5 (2.2) 58.8 (4.1)

62.5 (1.3) 60.9 (0.9)

60.6 (2.2) 61.0 (1.5) 62.8 (1.8) 62.6 (1.4) 58.2 (3.3)

61.6 (0.8)

77.2 (0.3) 81.4 (0.2)

64.7 (0.6) 81.3 (0.1)

67.3 (0.5) 81.3 (0.2)

72.5 (0.3) 82.4 (0.2)

81.0 (0.3) 81.1 (0.3) 80.1 (0.3) 80.0 (0.3)

80.4 (0.4) 80.5 (0.2)

80.6 (0.2) 79.9 (0.4) 80.1 (0.6)

81.5 (0.2) 79.5 (0.2)

82.9 (0.2) 78.1 (0.3) 76.1 (0.4) 71.1 (0.6) 66.0 (1.0)

80.5 (0.2)

3:25 PM

37.0 (0.7) 34.3 (0.5)

40.5 (1.2) 37.0 (1.0) 35.6 (0.7) 34.1 (0.8) 29.9 (1.0)

35.6 (0.5)

Self-Rating of Health (EQ VAS) Stroke Nonstroke Mean (SE) Mean (SE)

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Note: The sample included 1040 stroke and 38,640 nonstroke participants. All were significant between stroke and nonstroke populations based on Z tests (p 0.05).

51.3 (0.1)

47.4 (0.4)

HRQoL in Stroke and Nonstroke Populations by Selected Characteristics, MEPS 2000 and 2002 Mental Health Score Physical Health Score Health Utility Score (MSC-12) (PCS-12) (EQ-5D Index, US) Stroke Nonstroke Stroke Nonstroke Stroke Mean Nonstroke Mean (SE) Mean (SE) Mean (SE) Mean (SE) Mean (SE) Mean (SE)

100

Overall Age 18–49 50–64 65–74 75–84 85 Gender Male Female Race White Black Others Hispanic Yes No Region Northeast Midwest South West Hypertension Yes No Diabetes Yes No Coronary artery disease Yes No Smoking Yes No

Table 5-7

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RISKS Factors predictive of the occurrence of stroke have been investigated in many cohort studies, in which characteristics at entry (baseline) were evaluated for their relation to stroke incidence over several years of follow-up. Because of particular interest in the relation of blood cholesterol concentration and blood pressure to the individual risks of stroke, a group of investigators constituting the Prospective Studies Collaboration undertook to review cohort studies of stroke in which these two particular characteristics were measured.35 Altogether, 45 studies were included, with nearly 450,000 participants followed from 5 to 30 years (mean follow-up, 16 years) and a total of 13,397 persons with stroke in 7.3 million personyears of experience. The stroke events were predominantly deaths. By adjustment for variation in measurements of blood pressure (here, diastolic only) and cholesterol within individuals on repeated occasions of observation, the “usual diastolic blood pressure” and “usual total cholesterol” were estimated.

Usual diastolic blood pressure was examined first in terms of proportional rates, or the ratio of the stroke rate in each successive stratum (category) of blood pressure to the rate in the lowest stratum. The analysis addressed the possibility that for younger persons, these ratios at successively higher levels of pressure might increase more steeply than for older persons, as shown in Figure 5-5. For example, in the highest stratum (100 mm Hg or greater) versus the lowest (below 80 mm Hg), the rates were 10 times as high at younger than age 45, five times as high at ages 45–64, and only two times as high at age 65 or older. Thus, the relative importance of blood pressure was greatest for the younger adults and least for the oldest ones. However, the total or absolute impact on the rate of strokes was much greater for the oldest group because the stroke rate even in the lowest blood pressure category was many times greater for older than for younger adults. Figure 5-6 shows that the doubling of the reference rate for those 65 years and older at entry reflected an absolute increase in stroke rate of 8.4

Figure 5-5 Proportional Stroke Risk by Age and Usual Diastolic Blood Pressure. Source: Reprinted with permission from Prospective Studies Collaboration, The Lancet, Vol 346, p 1651, © 1995, The Lancet, Ltd.

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Figure 5-6 Absolute Stroke Risk, by Age and Usual Diastolic Blood Pressure. Source: Reprinted with permission from Prospective Studies Collaboration, The Lancet, Vol 346, p 1651, © 1995, The Lancet, Ltd.

per 1000 (18.4–10.0), whereas the 10-fold increase among the youngest group added less than 2 per 1000. Crude estimation of the numbers of years of life lost due to stroke death emphasized the relative cost of fatal strokes in younger adults. From one or another vantage point, then, the cost of stroke to both younger and older adults can be argued. No difference was reported in results for women and men. The largest single follow-up study of stroke mortality was not included in the Prospective Studies Collaboration. In the six-year follow-up study, strokes were ascertained through the National Death Index for the decedents among 350,977 middle-aged US men screened for the Multiple Risk Factor Intervention Trial, or MRFIT.36 The relation of age, systolic and diastolic blood pressure, serum cholesterol concentration, cigarette smoking, and race (as reflected in the percentage of Blacks in each stroke category) was examined among three types of stroke: subarachnoid hemorrhage (55 deaths), intracranial

hemorrhage (83 deaths), and nonhemorrhagic (that is, thrombotic or embolic) stroke (92 deaths). These comparisons of factors distinguished between men who died of each type of stroke and those who did not die of stroke. For each type of stroke death, there were significantly higher mean values of systolic and diastolic blood pressure, a higher prevalence of diastolic pressure of 90 mm Hg or greater, and a greater proportion of cigarette smokers than among men without stroke death. In the Prospective Studies Collaboration, results for total cholesterol indicated no relation to stroke rates adjusted for study, age, sex, diastolic blood pressure, history of coronary heart disease, and ethnicity. It was noted that this result might reflect opposite effects of high and low cholesterol concentrations on different types of stroke, which could not be distinguished for this analysis. In MRFIT, the mean values of serum cholesterol concentration among the groups with subarachnoid

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and intracranial hemorrhage (212.2 and 211.4 mg/dl, respectively) were slightly less than those of the group without stroke (214.4 mg/dl), but in the group with nonhemorrhagic stroke, they were significantly greater. This observation indicates type-specific differences in the relation between cholesterol concentrations and stroke. There were not equal and opposite effects of cholesterol concentration on hemorrhagic and nonhemorrhagic stroke, as suggested by the Prospective Studies Collaboration. However, in further analysis (not shown), the lowest stratum of cholesterol concentration (less than 160 mg/dl) was associated with a risk three times that of men with cholesterol concentrations of 160 mg/dl or greater. Thus, there were in fact opposite associations as discussed in the report of the collaborative review, but in this study the effect of the inverse relation with hemorrhagic stroke was dominated by the increased risk of nonhemorrhagic stroke with increased cholesterol concentration. Ability to investigate associations of blood lipids, and possibly other factors, on risk of stroke appears to depend crucially on identification of specific stroke types, as urged by Stallones 40 years ago.3 The MRFIT data also show that cigarette smoking was significantly more frequent among subjects in each stroke group than among subjects without stroke. The percentages of Blacks among the stroke deaths were greater in all groups than in the group without strokes, significantly so for both intracranial hemorrhage and nonhemorrhagic stroke. Other prominent predictors of stroke are prior cardiovascular conditions, such as coronary heart

disease, cardiac failure, and atrial fibrillation (chronic irregularity of contraction of the upper chambers of the heart). These conditions, in addition to hypertension, were found in the Framingham Heart Study to occur especially commonly among older persons with stroke (Table 5-8).37 Even these conditions, however, with their direct pathological connections to risks of embolic stroke, contributed less than hypertension to the attributable risk (the proportion of events explained by the presence of that condition). Hypertension (high blood pressure) remains the dominant characteristic in the prediction of stroke. Many of these factors are discussed in subsequent chapters. A compendium of more than 30 “well-documented and modifiable risk factors” for stroke is presented in an American Heart Association/American Stroke Association Guideline, Primary Prevention of Ischemic Stroke, published in 2006.38 Data presented for each factor are its prevalence, population-attributable risk, relative risk, and evidence—when available—of reduction of risk with treatment. For several factors, separate estimates of these measures are given by sex or age. A greatly simplified list constitutes the Modified Framingham Stroke Risk Profile, one of several scoring schemes for clinical use to identify patients at high risk of stroke. Separately for men and women, the scheme incorporates information on eight factors, each weighted according to the strength of its association with stroke as observed in the Framingham Heart Study. Age and systolic blood pressure are both scored from 0 to 10 on a graded scale. Systolic blood pressure is scored differently for a given range of values according to treatment status.

Table 5-8

Contributions of Other Cardiovascular Conditions to Risk of Stroke, by Age, Framingham Heart Study Age (Yr) Cardiovascular Condition 50–59 60–69 70–79 80–89 Number of stroke events 92 213 192 75 Hypertension Attributable risk (%) 48.8 53.2 48.6 33.4 % of events in persons with condition 72.8 80.3 83.9 84.0 Coronary heart disease Attributable risk (%) % of events in persons with condition

11.1 25.0

12.4 32.9

12.6 38.0

0.0 28.0

Cardiac failure Attributable risk (%) % of events in persons with condition

2.3 9.8

3.1 11.7

5.6 18.2

6.0 18.7

Atrial fibrillation Attributable risk (%)a % of events in persons with condition

1.5 6.5

2.8 8.5

9.9 18.8

23.5 30.7

Significant increase with age (p 0.01).

a

Source: Reprinted with permission from PA Wolf, Circulation, Vol 88, p 2475, © 1993, American Heart Association.

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For example, if the systolic pressure is 130 mm Hg in a patient not being treated with antihypertensive medication, three points are entered into the score; if the patient is at that blood pressure level and on treatment, five points are added. (It is noteworthy that risks are unequal under these two scenarios at the same level of blood pressure.) Each of the remaining elements of the score—history of diabetes, cigarette smoking, cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy on the electrocardiogram—is scored in a similar manner but with different levels of risk. Absence of the condition adds zero, whereas its presence adds from two to six points depending on the factor and sex of the patient. The second part of the assessment translates the score into a percentage risk of experiencing a stroke in the next 10 years. Scores of 1 (lowest), 10, 20, and 30 (highest) indicate risks for men of 3, 10, 37, and 88%. For women, scores of 1, 10, 20, and 27, the maximum attainable for women, correspond to risks of 1, 6, 37, and 84%. These risk factors, based on a single community in the United States, have much in common with the main contributors to risk of stroke death globally, as

estimated by the Global Burden of Diseases and Risk Factors Study, illustrated in Table 1-8.39 Blood pressure far exceeds other factors in importance. Cholesterol (perhaps because of mixed stroke types in the mortality data) is second by a wide margin, followed by overweight and obesity and smoking. Low fruit and vegetable intake and physical inactivity are the remaining major factors.

TRENDS The United States Stroke mortality has decreased in the United States throughout the 20th century. This was demonstrated clearly for the period from 1900 to 1960 in the epidemiologic review and analysis of stroke by Stallones published in 1965 (Figure 5-7).3 This reconstruction of historical vital statistics for the United States was based on the nearest equivalent of the category, “vascular lesions of the central nervous system,” in the first through sixth revisions of the International Classification of Diseases. Age-adjusted rates were pre-

Figure 5-7 Secular Trend of Mortality from Stroke in the United States, 1900–1960. Source: Reprinted with permission from RA Stallones, Journal of Chronic Diseases, Vol 18, p 864, © 1965, Elsevier Science Inc.

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sented to reflect a constant age structure of the population over this period and to remove the effect of the actual increased proportions of older persons, with the highest stroke rates, over time. (This results in a different picture than Figure 1-2, which reflects crude death rates from stroke as essentially constant from 1900 to 1970 at about 100/100,000 population per year.) The figure illustrates for these six decades a continuous decrease from more than 125 stroke deaths per 100,000 population per year to 75 or fewer, allowing for the noticeable effects of change in classification under the Sixth Revision, as shown. Stroke mortality in the United States continued to decline through the late 1980s, as was shown in the context of such changes in 26 other countries in Figure 2-9. A more current update to 2004 shows the still downward trend in age-adjusted stroke mortality reaching approximately 50/100,000 (Figure 5-8).15 The observation made in previous chapters in connection with cardiovascular deaths and coronary heart disease deaths applies to stroke deaths as well: although age-adjusted mortality has declined dramatically, the numbers of deaths have declined much less. The epidemiologic good news about rates is dampened by the public health message about a continuing and expected increasing burden.

Further observations about stroke trends in the United States indicate a geographic shift over the three decades of the 1960s through the 1980s.40 While stroke mortality was declining nationally, the stroke belt of the southeastern United States became less clearly defined. This region continued to have some of the highest stroke mortality in the nation but was less homogeneous at the end of the period. Meanwhile, areas of equally high stroke mortality emerged in the Mississippi River Valley, a trend that has continued. Europe and Elsewhere The WHO MONICA Project was able to monitor trends in stroke mortality and event rates in 15 centers in 9 countries—in western, central, and eastern Europe and China.41 Figures 5-9a, b, and c present 10-year changes in stroke rates from the mid-1980s to the mid-1990s, among 35- to 64-year-old men (left panels) and women (right panels) based on 10,442 stroke events in 23.4 million person-years of observation. Both coronary heart disease (CHD) and stroke events are shown: mortality (a), event rates (b), and casefatality (c). Stroke rates for all three classes of events exhibited mixed trends among the several populations. Increases in case-fatality and mortality occurred in several centers in eastern Europe, while decreases

125

Deaths in Thousands (Bar)

100 150

75 100 50

50 25

0

79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 Years * The comparability ratio 1.0502 was applied to the deaths and rates reported in vital statistics for 1979–1998.

Deaths/100,000 Population (Line)

200

0

Figure 5-8 Deaths and Age-Adjusted Death Rates for Stroke, US, 1979–2004. Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute, June 2007.

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*

*

*

* 0

4

*

* *

*

*

*

24

*

*

28

212

8

Coronary Stroke

*

*

*

**

* *

*

Coronary Stroke

*

FIN-TUL FIN-NKA RUS-MOC FIN-KUO SWE-GOT ITA-FRI SWE-NSW POL-WAR RUS-MOI DEN-GLO CHN-BEI LTU-KAU RUS-NOC YUG-NOS RUS-NOI

*

212

A

*

Women

*

Men SWE-NSW FIN-NKA FIN-KUO FIN-TUL SWE-GOT ITA-FRI DEN-GLO YUG-NOS RUS-NOC POL-WAR LTU-KAU RUS-MOC RUS-MOI CHN-BEI RUS-NOI

28

24

0

* *

* **

*

*

*

*

210 28 26 24 22

6

8 10

* * *

*

*

4

Coronary Stroke

*

*

* 2

% change over 10 years

POL-WAR ITA-FRI FIN-TUL LTU-KAU FIN-NKA RUS-NOC SWE-NSW YUG-NOS FIN-KUO SWE-GOT CHN-BEI RUS-MOC RUS-MOI DEN-GLO RUS-NOI

*

* 0

4

*

*

*

*

Coronary Stroke

*

28 26 24 22

2

Women

*

Men

C

0



SWE-NSW ITA-FRI FIN-NKA POL-WAR YUG-NOS FIN-TUL RUS-NOC SWE-GOT FIN-KUO LTU-KAU CHN-BEI RUS-NOI DEN-GLO RUS-MOC RUS-MOI

*

4

Coronary Stroke

*

2

*

* * **

*

0

*

*

* * *

*

26 24 22

*

RUS-MOC FIN-NKA FIN-TUL FIN-KUO SWE-GOT RUS-MOI DEN-GLO SWE-NSW ITA-FRI CHN-BEI POL-WAR RUS-NOI RUS-NOC LTU-KAU YUG-NOS

*

Coronary Stroke

210 28

B

8

Women

*

Men FIN-NKA FIN-KUO SWE-NSW FIN-TUL DEN-GLO SWE-GOT RUS-MOC ITA-FRI RUS-MOI YUG-NOS POL-WAR RUS-NOC LTU-KAU CHN-BEI RUS-NOI

4



28 26 24 22

0

2

4

6

8 10


*Statistically significant changes (p 0.05)

Figure 5-9 Percentage Change Over 10 Years in Age-Standardized CHD and Stroke Mortality Rates (Panel a), Event Rates (Panel b), and Case Fatality (Panel c) in Men and Women Aged 35 to 64 Years. Source: Reprinted with permission from Truelsen T et al., Stroke, Vol 34, pp 1348, 1349, and 1350, © 2003 American Heart Association, Inc.

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REFERENCES 107

occurred elsewhere. Changes in event rates were less consistent. Stroke and CHD trends were generally, though not always, in the same direction in any given population. Trends in blood pressure levels and other risk factors were of particular interest in seeking an explanation of the stroke trends.42 For women, but not for men, trends in blood pressure accounted for a significant component (38%) of the variation in stroke event trends, after including a 3- or 4-year time lag in the analysis. Combining other risk factors—smoking, serum cholesterol, and body mass index—did not add significantly to explanation of the trends. When the components of stroke occurrence were investigated, it appeared that changes in case-fatality were more important than changes in event rates in explaining the overall mortality trends.43 The original expectation was that case-fatality would unambiguously indicate improvement in case management rather than risk-factor improvement or, more generally, primary prevention. It was concluded instead that reduced severity of incident cases could affect case-fatality favorably, so that effects of primary prevention could not be excluded. On a broader scale, investigation of the World Health Organization Data Bank for stroke mortality from 1968 to 1994 provided information on trends especially in the latest 5-year period.44 Mortality for all strokes was analyzed for 51 industrialized and developing countries, each of which submitted data to WHO for at least 80% of all deaths over this 27-year period. Among all 51 countries, a range of about threefold was observed between the highest- and lowest-rate countries. The highest rates, as in the WHO MONICA Project experience, were in eastern Europe and countries of the former Soviet Union. Lowest rates were in the countries with steepest declining trends—the United States, Canada, Switzerland, France, and Australia. Japan, included in the WHO data analysis, has also been the subject of separate investigation, revealing that the very rapid decline in stroke mortality from the mid-1960s changed abruptly with a greatly reduced pace of change in the 1990s.45 The need for stroke surveillance especially in high-mortality countries is underscored by these findings, in order both to monitor changes in components of stroke occurrence and to study determinants of stroke in the many varied settings that comparative studies can exploit.

ening picture for decades to come. The forecast of the Global Burden of Disease Study ranks stroke second among causes of death worldwide in 1990 and 2020; seventh in years of life lost in 1990 and third in 2020; and sixth in DALYs in 1990 and fourth in 2020 (see Table 1-6).27 With special concern about impending increases in the burden of stroke in low- and middle-income countries, The Lancet Neurology presented a series of reports in early 2007 addressing needs for improved surveillance and application of preventive strategies.46,47 It is observed that success in reducing case-fatality from stroke will have the effect of increasing prevalence and disability, increasing the demand for rehabilitation and long-term care. Primary prevention of stroke becomes in this scenario a fundamental and urgent approach in addressing stroke at the population level.

CURRENT ISSUES Among current issues in the epidemiology and prevention of stroke, the foremost questions from the US perspective are: Can the historical decline in mortality due to stroke be sustained and, while continuing, achieve elimination of the longstanding racial/ ethnic disparities among populations? On a global basis, especially in regions where stroke predominates over coronary heart disease among the atherosclerotic and hypertensive diseases, can stroke be prevented effectively on a populationwide scale, so as to avert the forecasts of continuing contributions of stroke to death and disability? Can the experience of investigators in many centers with diverse methods of population surveillance be exploited to establish a global network of community-based stroke surveillance centers, collaborating under a common protocol, so as to monitor and evaluate trends in occurrence of stroke as well as the impact of change in policies and practices aimed at stroke prevention? REFERENCES 1. Albers GP, Cutler RWP. Cerebrovascular diseases. In: Dale DC, Federman DD, eds. Scientific American Medicine. New York: Scientific American, Inc; 1994:1–13.

FORECASTS

2. National Center for Health Statistics. Health, United States, 2008. With Chartbook. Hyattsville, MD: 2009.

The future of the world’s burden of stroke is uncertain, but currently adopted projections suggest a wors-

3. Stallones RA. Epidemiology of cerebrovascular disease: a review. J Chronic Dis. 1965;18:859–872.

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4. Gorelick PB, Alter M. The Prevention of Stroke. New York, NY: The Parthenon Publishing Group; 2002. 5. Gillum RF, Fortmann SP, Prineas RJ, Kottke TE. International diagnostic criteria for acute myocardial infarction and stroke. Am Heart J. 1984;108:150–158. 6. Asplund K, Tuomilehto J, Stegmayr B, et al. Diagnostic criteria and quality control of the registration of stroke events in the MONICA Project. Acta Med Scand. 1988;728(suppl): 26–39. 7. Thorvaldsen P, Kuulasmaa K, Rajakangas AM, Rastenyte D, Sarti C, Wilhelmsen L. Stroke trends in the WHO MONICA Project. Stroke 1997;28(3):500–506. 8. World Health Organization. International Statistical Classification of Diseases and Related Health Problems. 10th rev. Geneva (Switzerland): World Health Organization; 1992:1. 9. Chalela JA, Kidwell CD, Nentwich LM, et al. Magnetic resonance imaging and computed tomography in emergency assessment of patients with suspected acute stroke: a prospective comparison. Lancet. 2007;369:293–298. 10. Labarthe DR, Broderick JP, Atkins D, Zheng ZJ, Yoon SS, eds. Paul Coverdell National Acute Stroke Registry Prototypes. Assessing acute stroke care in the U.S. and beyond. Am J Prev Med. 2006;31(suppl):S189–S259. 11. Brown DL, Al-Senani F, Kisabeth LD, et al. Defining cause of death in stroke patients. The Brain Attack in Corpus Christi Project. Am J Epidemiol. 2007;165:591–596. 12. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009; 119:e1–e161.

Washington, DC: US Government Printing Office, December 2006. 15. National Heart, Lung and Blood Institute. Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: US Department of Health and Human Services. Public Health Service, National Institutes of Health; June, 2007. 16. Casper ML, Barnett E, Williams GI Jr, Halverson JA, Braham VE, Greenlund KJ. Atlas of Stroke Mortality: Racial, Ethnic, and Geographic Disparities in the United States. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. 17. Casper ML, Denny CH, Coolidge JN, et al. Atlas of Heart Disease and Stroke Among American Indians and Alaska Natives. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention and Indian Health Service; 2005. 18. Centers for Disease Control and Prevention. State-specific mortality from stroke distribution of place and death—United States, 1999. MMWR. 2002;51:429–433. 19. Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas AM, Schroll M. Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease. Stroke. 1995;26: 361–367. 20. National Heart, Lung and Blood Institute. Incidence & Prevalence: 2006 Chart Book on Cardiovascular and Lung Diseases. Washington, DC: US Department of Health and Human Services, Public Health Service, National Institutes of Health; 2006.

13. World Health Organization. World Health Report 2004. Geneva (Switzerland): World Health Organization; 2004.

21. Sacco RL, Boden-Albala B, Gan R, et al. Stroke incidence among White, Black, and Hispanic residents of an urban community. The Northern Manhattan Stroke Study. Am J Epidemiol. 1998;147:259–268.

14. US Department of Health and Human Services. Healthy People 2010 Midcourse Review.

22. Wolfe CDA, Giroud M, Kolominsky-Rabas P, et al. Variations in stroke incidence and sur-

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vival in 3 areas of Europe. European Registries of Stroke (EROS) Collaboration. Stroke. 2000;31:2074–2079. 23. Truelson T, Piechowski-Józ´wiak B, Bonita R, Mathers C, Bogousslavsky J, Boysen G. Stroke incidence and prevalence in Europe: a review of available data. Eur J Neurol. 2006;13: 581–598. 24. Centers for Disease Control and Prevention. The prevalence of stroke—United States, 2005. MMWR. 2007;56:469–474. 25. Casper ML, Nwaise IA, Croft JB, Nilasena DS. Atlas of Stroke Hospitalizations among Medicare Beneficiaries. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2008. 26. Xie J, Wu EQ, Zheng ZJ, et al. Impact of stroke on health-related quality of life in the noninstitutionalized population in the United States. Stroke. 2006;37:2567–2572. 27. Murray CJL, Lopez AD. Alternative visions of the future: projecting mortality and disability, 1990–2020. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston, MA: The Harvard School of Public Health; 1996. 28. Mensah GA, Brown DW. An overview of cardiovascular disease burden in the United States. Health Affairs. 2007;26:38–48. 29. Ayala C, Greenlund KJ, Croft JB, et al. Racial/ethnic disparities in mortality by stroke subtype in the United States, 1995–1998. Am J Epidemiol. 2001;154:1057–1063. 30. Centers for Disease Control and Prevention. Disparities in deaths from stroke among persons aged 75 years—United States, 2002. MMWR Morb Mortal Wkly Rep. 2005;54(19): 477–481. 31. McGruder HF, Malarcher AM, Antoine TL, Greenlund KJ, Croft JB. Racial and ethnic disparities in cardiovascular risk factors among stroke survivors. United States 1999 to 2001. Stroke. 2004;35:1557–1561.

32. US Department of Health and Human Services. Healthy People 2010. 2nd ed. With Understanding and Improving Health and Objectives for Improving Health. 2 vols. Washington DC: US Government Printing Office; 2000. 33. Gillum RF. Stroke mortality in blacks. Disturbing trends. Stroke.1999;30(8):1711–1715. 34. Cox AM, McKevitt C, Rudd AG, Wolfe CD. Socioeconomic status and stroke. Lancet Neurol. 2006;5(2):181–188. 35. Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts. Lancet. 1995;346:1647–1653. 36. Iso H, Jacobs DR Jr, Wentworth D, et al., for the MRFIT Research Group. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med. 1989; 320:904–910. 37. Wolf PA. Contributions of epidemiology to the prevention of stroke. Lewis A. Conner Lecture. Circulation. 1993;88:2471–2478. 38. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: The American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37: 1583–1633. 39. Mazzati E, Vander Hoorn S, Lopez AD, et al. Comparative quantification of mortality and burden of disease attributable to selected risk factors. In: AD Lopez, CD Mathers, M Ezzati, DT Jamison, CJL Murray, eds. Global Burden of Disease and Risk Factors. Washington, DC: The International Bank for Reconstruction and Development/The World Bank; 2006:241–396. 40. Casper M, Wing S, Strogatz D. Variation in the magnitude of Black-White differences in stroke

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mortality by community occupational structure. Epidemiol Community Health. 1991;45: 302–306. 41. Truelsen T, Mahonen M, Tolonen H, Asplund K, Bonita R, Vanuzzo D. Trends in stroke and coronary heart disease in the WHO MONICA Project. Stroke. June 2003;34(6):1346–1352. 42. Tolonen H, Mahonen M, Asplund K, et al. Do trends in population levels of blood pressure and other cardiovascular risk factors explain trends in stroke event rates? Comparisons of 15 populations in 9 countries within the WHO MONICA Stroke Project. World Health Organization Monitoring of Trends and Determinants in Cardiovascular Disease. Stroke. 2002;33(10):2367–2375. 43. Sarti C, Stegmayr B, Tolonen H, Mahonen M, Tuomilehto J, Asplund K. Are changes in mortality from stroke caused by changes in stroke

event rates or case fatality? Results from the WHO MONICA Project. Stroke. 2003;34(8): 1833–1840. 44. Sarti C, Rastenyte D, Cepaitis Z, Tuomilehto J. International trends in mortality from stroke, 1968 to 1994. Stroke. 2000;31(7):1588–1601. 45. Liu L, Ikeda K, Yamori Y. Changes in stroke mortality rates for 1950 to 1997. A great slowdown of decline trend in Japan. Stroke. 2001; 32:1745–1749. 46. Editorial. STEPS in the right direction. Lancet Neurol. 2007;6:93. 47. Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. Lancet Neurol. 2007;6:182–187.

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C H A P T E R

6 Related Conditions nificant contributions to the overall burden of cardiovascular diseases—whether in terms of mortality, hospitalizations, or physician office visits, for example—or due to other consequences.

SUMMARY In addition to coronary heart disease and stroke, five other conditions contribute substantially to the overall burden of cardiovascular diseases. Two of these conditions are manifestations of atherosclerosis in regions of the circulation other than the heart and brain: peripheral arterial disease, in which the blood supply of the lower extremities is compromised, and aortic aneurysm, or localized dilatation with potential for rupture of the arterial trunk connecting the heart with the peripheral circulation. The third condition is chronic heart failure, or impairment of the fundamental function of the heart as a pump and prime mover of the circulatory system. Fourth, deep vein thrombosis is a condition affecting the venous side of the circulation with local occlusion of blood flow, especially in the lower extremities and pelvic veins. It has the potential to cause the grave complication of pulmonary embolism, in which a thrombus or fragment dislodges from its point of origin and is carried through the venous circulation to obstruct blood flow in the lung. Fifth, cardiac arrhythmias, or disturbances of heart rhythm, reflect dysfunction of electrophysiologic control of the rate and rhythm of the cardiac cycle. One very serious consequence is disturbance of blood flow through the left atrium of the heart due to atrial fibrillation, promoting formation and dislodging of thrombi that can be carried through the circulation to the brain and result in a thromboembolic/occlusive stroke. Another is an increased rate of ventricular contraction (ventricular tachycardia or fibrillation), with loss of effective pumping action of the heart, potentially leading to cardiac arrest and sudden cardiac death. The importance of these conditions lies in their sig-

INTRODUCTION Four of the five major conditions addressed here are represented in Table 6-1, based on the International Classification of Diseases and Related Health Conditions, Tenth Revision (ICD 10).1 “Peripheral arterial disease” (PAD) appears as a subclass of diseases of the arteries, arterioles, and capillaries (I70-I79). It is likely to be coded nearly always as I70.2, although some cases might be described only as “peripheral vascular disease” or “intermittent claudication” (a condition characterized by pain in the calf muscles during walking) and require coding as I73.9. A single broad category, aortic aneurysm and dissection (I71), includes subclasses according to location of the aneurysm, whether in the abdominal or thoracic portion or both, and whether there is mention of rupture of the aneurysm. The abdominal aortic aneurysms (AAA) alone will be addressed here. “Congestive heart failure,” by contrast, is coded in any of several different categories, depending on the underlying condition. The term refers to left ventricular failure specifically. It includes right ventricular failure if this has resulted from left ventricular failure. This occurs when a sequence of events develops gradually: poor emptying of the left ventricle into the arterial circulation; backup of blood flow from the lungs to the left ventricle; back-pressure on the right ventricle due to passive congestion of the lungs; and failure of the right ventricle. “Deep vein thrombosis”

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Table 6-1

Classification of Peripheral Arterial Disease, Abdominal Aortic Aneurysm, Heart Failure, and Deep Vein Thrombosis and Pulmonary Embolism

a. Peripheral arterial disease I70 Atherosclerosis I70.2 Atherosclerosis of arteries of extremities I73 Other peripheral vascular disease I73.9 Peripheral vascular disease, unspecified b. Aortic aneurysm I71 Aortic aneurysm and dissection I71.3 Abdominal aortic aneurysm, ruptured I71.4 Abdominal aortic aneurysm, without mention of rupture c. Congestive heart failure I50 Heart failure I50.0 Congestive heart failure I50.1 Left ventricular failure I50.9 Heart failure, unspecified I09 Other rheumatic heart disease I09.9 Rheumatic heart disease, unspecified I11 Hypertensive heart disease I11.0 Hypertensive heart disease with (congestive) heart failure I13 Hypertensive renal disease I13.0 Hypertensive heart and renal disease with (congestive) heart failure I13.2 Hypertensive heart and renal disease with both (congestive) heart failure and renal failure d. Deep vein thrombosis and pulmonary embolism I80 Phlebitis and thrombophlebitis I80.1 Phlebitis and thrombophlebitis of femoral vein I80.2 Phlebitis and thrombophlebitis of other deep vessels of lower extremities I80.3 Phlebitis and thrombophlebitis of lower extremities, unspecified I80.8 Phlebitis and thrombophlebitis of other sites I80.9 Phlebitis and thrombophlebitis of unspecified site I26 Pulmonary embolism I26.0 Pulmonary embolism with mention of acute cor pulmonale I26.9 Pulmonary embolism without mention of acute cor pulmonale Source: Data from International Statistical Classification of Diseases and Related Health Problems: Tenth Revision. World Health Organization © 1992. World Health Organization, Geneva, Switzerland.

(DVT, clotting of blood in the larger veins, especially in the lower extremities or pelvis) is especially common among hospitalized patients confined to bed. It is often complicated by transport or embolization of a portion of the thrombus through the venous system and right side of the heart to reach the lung, causing acute respiratory compromise and sometimes death (pulmonary embolism, PE). ICD 10 provides for coding of the initial thrombosis by its venous location and of PE by the presence or absence of mention of acute failure of the right ventricle of the heart (cor pulmonale). Cardiac arrhythmias, the fifth group of cardiac conditions of interest, are classified in six separate categories in ICD 10 (I44-I49). They constitute a heterogeneous group, of which two are addressed here, atrial fibrillation and ventricular arrhythmias. As a measure of the importance of these five conditions, several indicators of their occurrence are pre-

sented in Table 6-2, based on US data for 2003 and 2004.2 The numbers of hospital discharges for which each condition was the first-listed diagnosis, the number of physician office visits, and the number of deaths attributed to each condition are shown. To provide some perspective on these numbers, the corresponding figures are also given for cerebrovascular diseases (mainly stroke) and coronary heart disease. PAD (atherosclerosis of arteries) greatly exceeded aortic aneurysm (abdominal and thoracic together) as a cause of hospitalization but was similar in numbers of deaths and represented only a small fraction of cardiovascular diseases relative to coronary heart disease. Physician office visits were about 50% more frequent for aortic aneurysm than for atherosclerosis of arteries. In contrast, heart failure (of which nearly all cases are specifically coded as congestive heart failure) was about half as frequent a hospital dis-

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Table 6-2

Condition

Frequencies of Selected Conditions Relative to Cerebrovascular Diseases and Coronary Heart Disease, United States, 2003 and 2004 First-Listed Physician ICD 10 Hospital Discharge Office Visits Code(s) Diagnosis (2004) (2003) Deaths (2004)

Atherosclerosis of arteries Aortic aneurysm Heart failure Deep vein thrombosis Pulmonary embolism Cardiac arrhythmias Cerebrovascular diseases Coronary heart disease

I70 I71 I50 I80.2 I26 I48, Other I43–I49 I60–I69 I20–I25

123,000 61,000 1,099,000 7000 121,000 762,000 906,000 1,981,000

445,000 709,000 2,890,000 — 53,000 4,733,000 3,538,000 9,389,000

11,861 13,753 57,120 2843 8113 37,606 150,074 451,326

Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

charge diagnosis as coronary heart disease and led to nearly one-third as many physician office visits. The number of deaths coded as congestive heart failure in one year was a little more than one-tenth of that coded as coronary heart disease, perhaps reflecting diagnostic or coding practices that give preference to coronary heart disease when both conditions are present. Deep vein thrombosis is probably omitted often when pulmonary embolism occurs as a complication. Its frequency as a reason for physician office visits is unknown, and deaths attributed to it are probable miscoding of deaths due to pulmonary embolism. It may be more reliable to combine DVT and PE as a single category in view of these types of misclassification. Pulmonary embolism, on the other hand, appears to have been about as common as peripheral arterial atherosclerosis as a first hospital discharge diagnosis, an infrequent cause of office visits, and less common as a cause of death. There are striking differences between these indicators for deep vein thrombosis and pulmonary embolism since a decade earlier:3 hospitalizations for DVT decreased from 27,000 to 8000, whereas those for PE increased from 59,000 to 99,000. The increase in the combined frequency is consistent with the increase in numbers of deaths attributed to the two conditions. These distinct changes are likely a reflection of changes in diagnostic and treatment practices between 1993 and 2001–2002, such that hospitalizations for the two conditions have changed differentially and are therefore unreliable for understanding of trends. Other notable changes over the ten years were an increase of about 50% in hospital admissions and decrease of 25% in office visits for atherosclerosis of arteries, a decrease of about 50% in office visits for aortic aneurysm, and an increase of about 35% in office visits and deaths due to congestive heart failure.

Coronary heart disease far dominates the distribution of cardiovascular deaths, with stroke following and also far outweighing the other five conditions. Among all cardiovascular hospitalizations, however, heart failure and cardiac arrhythmias are on the same high level of frequency as cerebrovascular diseases (stroke), and coronary heart disease is more than twice as frequent a discharge diagnosis as stroke. Heart failure and cardiac arrhythmias far exceed stroke in numbers of office visits. They represent about 35% and 50% as many visits, respectively, as for coronary heart disease. Each of the five conditions addressed here adds importantly to the burden of cardiovascular diseases in the United States, whether in terms of one or more of these indicators or because of its serious prognostic implications, as discussed hereafter.

PERIPHERAL ARTERIAL DISEASE Typical Course Typically, an older person with recognized PAD, or atherosclerotic impairment of arterial blood flow to the lower extremities, may experience intermittent claudication, or pain in the calf muscles after walking a short distance (e.g., 100 yards or fewer) that is relieved temporarily by stopping. This condition may persist with little change for several years. But the presence of diagnosed PAD is often a marker for advanced coronary or cerebral atherosclerosis, which may lead to death within one to two years. The condition may also progress to the degree that vascular surgery is required to improve blood flow, or amputation may be required because adequate flow cannot be restored.4

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Background The early epidemiology of PAD was the epidemiology of the symptom, intermittent claudication. Perception and reporting of pain by patients or study participants is highly subjective. Medical histories elicited by physicians or other health personnel are variable in quality. These circumstances make diagnosis of PAD by history unreliable and of very uncertain comparability between observers or between studies. For these reasons, and to support international comparative cardiovascular surveys, standardization was needed. Rose reported in 1962 on studies that led to development of a standard questionnaire to determine presence or absence of intermittent claudication as well as pain typical of myocardial infarction.5 The “Rose questionnaire” (or “London School of Hygiene questionnaire”) was a method which standardized use of the term “intermittent claudication,” if the questionnaire was properly administered. This method was used in many subsequent studies, and intermittent claudication was often incorporated as a component of prevalence of atherosclerosis in population surveys. Development of this questionnaire represented an important early advance in cardiovascular survey methods and is reflected in most of the knowledge of the epidemiology of PAD well into the 1980s. Limitations of this approach to detecting arterial pathology and estimating its prevalence could not be fully appreciated until newer techniques became available and were applied in population studies. Population Studies: Definition and Classification By the mid-1980s, noninvasive techniques to assess peripheral arterial blood flow had advanced to permit evaluating these approaches in comparison with interview/questionnaire methods. One technique was to calculate the ratio of blood pressure measured at each of several points between the thigh and the toes to blood pressure measured in the brachial artery of the arm (the “ankle-brachial index,” or “ABI”). In the absence of impairment of blood flow in the artery to the lower extremity, these measurements would be approximately equal, and the expected ratio would be 1. Obstruction of blood flow would reduce the blood pressure distal to an obstruction in the lower extremity, so the ratio would be less than 1. Several values of this ratio have been proposed as the criterion for detecting PAD. Ultrasound techniques permit measuring blood flow through specific vessels. Other indicators are also available, recently including magnetic resonance angiography, which has been evalu-

ated in the context of clinical use.6 Through these methods, vascular disease can be detected at an earlier stage, before intermittent claudication has developed. Disease of the large, or “major,” vessels to the lower extremity can be distinguished from that of small vessels. As a result, the focus has shifted to large-vessel PAD (LV-PAD) as assessed, for example, by combined ABI and ultrasound measurement of blood flow through one major artery, the posterior tibial artery in the calf. These methods have been compared with the history of intermittent claudication as determined by the Rose questionnaire.7 Physical examination to check the presence and character of the pulse at several points in the extremities has sometimes been included. A wide range of prevalence estimates results, depending on the indices included. Relative to the most extensive set of measurements available, history of intermittent claudication detected only 9.2% of cases identified by other means, and only one-half of those positive by history had demonstrable disturbances of vascular flow. Early studies of causes and outcomes of PAD, based on history of intermittent claudication, were evidently limited by inaccurate identification of true arterial disease.8 Table 6-3 presents results of an assessment of three classes of LV-PAD identified by two criteria advocated as of the mid-1990s: ABI was 0.8 or less and forward blood flow through the posterior tibial artery was 3 cm/sec or less.8 When all evidence of disease was taken as the reference standard, this two-test combination detected 89% of limbs with LV-PAD; 99% of limbs classified as negative by these tests were judged so by the full battery of tests; positive classification by the two tests was associated with 90% confirmation from the full battery; and negative classification was confirmed in 99% of the limbs tested by the full battery. Accuracy, defined as the numbers of true positives added with true negatives, divided by the total number of limbs, was 96%. These favorable findings for all LV-PAD were essentially the same after exclusion of cases with isolated posterior tibial artery disease and restriction to those with asymptomatic disease or those who had previous surgical treatment. Relative to the history of intermittent claudication, then, the combination of ABI and posterior tibial artery flow provided a far superior index of true arterial disease. Interest focuses, then, on studies evaluating PAD by these measures, even though specific criteria have differed somewhat among studies, and ABI alone has become the current standard.

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Table 6-3

Case Group

Evaluation of Measures of Large-Vessel Peripheral Arterial Disease (LV-PAD) Among 484 Adults Originally Screened Between 1979 and 1981 Ankle-to-Arm Pressure Ratio 0.8 ⴙ Posterior Tibial Peak Forward Flow 3 cm/sec Positive Negative Predictive Predictive Sensitivity Specificity Value Value Accuracy No. No. No. No. No. % of Limbs % of Limbs % of Limbs % of Limbs % of Limbs

All LV-PAD LV-PAD with isolated posterior tibial cases excluded Asymptomatic LV-PAD cases only

89.0 82.4

81/91 42/51

99.0 99.0

867/876 864/876

90.0 82.4

81/90 42/51

99.0 99.0

867/876 867/876

98.0 98.1

948/967 909/927

88.1

59/67

98.9

823/832

86.8

59/68

99.0

823/831

98.1

882/899

Source: Reprinted with permission from HS Feigelson, American Journal of Epidemiology, Vol 140, No 6, p 531, © 1994.

Rates Prevalence of PAD, based separately on history of intermittent claudication or on ABI, was reported for men and women in 11 studies reviewed in 2003.9 Table 6-4, parts (a) and (b), presents results of these studies, all from the United States or Europe, published chiefly in the 1990s. Age groups studied include middle-aged adults in some but not all instances, and data were reported separately for women and men in some but not all studies. Three main observations are that prevalence was estimated to be several times higher by ABI than by history in every study but one; prevalence was greater in men than in women in the majority of studies where reported separately; and studies with age-specific results or including older age groups demonstrated higher prevalence with increasing age. The range of prevalence was from less than 1% to 12.7% by history and from 1.6% to 29.1% by ABI with a criterion of 0.90 in the majority of studies. The distribution of ABI was explored in a more recent report that focused on the concept of “borderline peripheral arterial disease” and the full range of ABI in the population.10 Data were taken from the US National Health and Nutrition Examination Survey, 1999–2002, for 4895 qualifying participants aged 40 years or older. Categories of ABI were defined as: PAD, 0.90; borderline PAD, 0.90–0.99; lownormal ABI, 1.00–1.09; and normal ABI, 1.10–1.29. Higher values were excluded as representing severe arterial rigidity. Distributions of these categories are presented by age (Figure 6-1) and by race/ethnicity and gender (Figure 6-2). The age gradient in prevalence suggested above is clearly shown here, with a fourfold increase from ages 40–59 to 60–74 and dou-

bling from 60–74 to 75 years. Prevalence of borderline PAD also increased with age, although less sharply. Non-Hispanic Blacks exceeded other groups in prevalence of less than normal ABI at each level, whereas non-Hispanic Whites and Mexican Americans were similar in distribution of ABI. Prevalence of less than normal levels of ABI was greater for women than for men at each level. A further general observation about prevalent PAD is its contribution to the spectrum of subclinical atherosclerosis and cardiovascular disease, as discussed in Chapter 3. The report of the Cardiovascular Health Study on the prevalence of subclinical disease indicated that undiagnosed PAD identified 16% of men and 19.9% of women who were free of known cardiovascular disease but were classified as having subclinical disease.11 These cases were identified chiefly by ABI without blood flow measurements. Therefore, they represent an underestimate of the true prevalence of subclinical disease. Rose questionnaire responses identified few cases not detected by ABI. Risks The prognostic importance of PAD was demonstrated nearly 2 decades ago from the mortality experience of persons followed for up to 10 years from diagnosis, as examined by various subclasses in Table 6-5.12 The overall results, not shown in the table, are as follows: Among 569 study participants available for analysis, 67 had been found to have LV-PAD at baseline. There were 32 deaths in this group, constituting 61.8% of the 34 affected men and 33.3% of the 33 affected women. Corresponding frequencies among those without PAD at baseline were 16.9% and

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Table 6-4 Location, Study Type, Author

Prevalence of Peripheral Arterial Disease (PAD) by (a) Intermittent Claudication and (b) Ankle-Brachial Index (ABI) Prevalence (%) (b) ABI Prevalence (%) (a) Year n Ages Men Women cutoff Men Women 12.7b,c

12.7b,c

0.90d

29.1b

29.1b

55

2.2

1.2

0.90

16.9

20.5

15,792

45–64

1.0

1.0

0.90

3.0

3.0

1996

3171

45–54 55–64 65–74

0.5 0.9 2.4

0.3 2.2 3.7

0.95 0.95 0.95

1.6 7.7 16.4

3.1 6.8 11.2

Cardiovascular Health Study, four US communities, Newman et al.

1993

5084

65

2.0b

2.0b

0.90

13.8

11.4

Pittsburgh, CrossSectional, Vogt et al.

1993

1491

65–93

—

7.4

0.90

SHEPf study, sub-group, Newman et al.

1993

1775

65

6.4b

6.4b

0.90

California, CrossSectional, Criqui et al.

1992

613

38–82

2.2

1.7

Edinburgh, Cohort Study, Fowkes et al.

1991

1592

55–74

4.5b

4.5b

Jerusalem, CrossSectional, Gofin et al.

1987

1592

35–64

1.3

Denmark, CrossSectional, Schroll & Munck

1981

661

60

5.8

PARTNERSa, 320 primary care practices in US, Hirsch et al.

2001

6417

70 or 50–69 (smokers and/or diabetic)

Rotterdam, CrossSectional, Meijer et al.

1998

7715

ARICe study, four US communities Zheng et al.

1997

Limburg, CrossSectional, Stoffers et al.

5.5

—

26.7b

26.7b

11.7

11.7

0.90

18.3b

18.3b

1.8

0.90

4.2

5.4

1.3

0.90

16

13

testsg

a

Peripheral arterial disease Awareness, Risk and Treatment: NEw Resources for Survival Program. Prevalence in the total population; no separate estimates for gender were reported. The PARTNERS program gave data for “chart history of claudication;” Rose claudication numbers were not given, though they do state “charted claudication was much more common than classic (questionnaire-based) Rose claudication.”71 d The PARTNERS program defined PAD as either an ABI 0.09, a previous history of PAD, or prior limb revascularization. e Atherosclerosis Risk In Communities Study. f Systolic Hypertension in the Elderly Program. g Criqui et al. used a different approach to assess the prevalence of PAD; the standared ABI was not used, but rather 4 different noninvasive tests (segmental blood pressure, flow velocity by doppler ultrasound, post-occlusive reactive hyperemia, and pulse reappearance half-time) were used to diagnose PAD. b c

Source: Reprinted with permission from Journal of Epidemiology, Vol 13, Higgins JP and Higgins JA, © 2003, pp 5–6.

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70

PAD† Borderline PAD‡ Low-Normal ABI§ Normal ABI||

61.9* 60

Prevalence (%)

50 44.9* 40 34.0*

30.8

30

28.8

26.5

20

17.5 16.5

12.3 10

6.0

8.1

1.9 0 40–59

60–74 Age (Years)

751

Percentages do not equal 100% because 3.7% of the population was excluded due to severe arterial rigidity (ABI 1.3). *p trend 0.001. †ABI 0.90; ‡ABI 0.90 to 0.99; §ABI 1.00 to 1.09; ||ABI 1.10 to 1.29.

Figure 6-1 Prevalence of ABI Categories by Age Group. Source: Reprinted from American Journal of Cardiology, Vol 98 (I9), Menke A, Muntner P, Wildman RP, Dreisbach AW, Raggi P, Relation of Borderline Peripheral Arterial Disease to Cardiovascular Disease Risk, page 1227, © 2006, with permission from Elsevier.

11.6%, respectively. Adjustment for differences among groups for age, sex, and other cardiovascular risk factors resulted in relative risk estimates of 3.1 (95% confidence interval, 1.9–4.9) for death from all causes, 5.9 (3.0–11.4) for all cardiovascular deaths, and 6.6 (2.9–14.9) for coronary heart disease death. The detailed subgroup analysis shown in the table indicates greater relative risks for bilateral, symptomatic, and severe disease. A relative risk of 15 was reported for cardiovascular or coronary heart disease death among those with severe, symptomatic disease versus those free of disease. A recent analysis evaluated the contribution of ABI to prediction of 10-year cardiovascular outcomes in men and women beyond those resulting from the Framingham risk score alone.13 It was found that ABI 0.90 approximately doubled the predicted total and cardiovascular mortality and major coronary event rate. Its inclusion in the score would have the effect of modifying treatment recommendations for approximately 1 in 5 men and 1 in 3 women. These findings underscore the importance of PAD in evaluating risk of future cardiovascular outcomes. The cross-sectional relation of PAD to the major risk factors for atherosclerosis and coronary heart disease was compared between two methods of classification, the Rose questionnaire and ABI.14 The results for ABI included findings of less disease among women, taller subjects, and those with greater HDLcholesterol concentrations. More extensive disease

was present in relation to greater non-HDL cholesterol and triglyceride concentrations, combined measures of glucose intolerance or diabetes mellitus, and cigarette smoking. The results were not strikingly different between methods of classifying PAD, except that ABI was the more sensitive indicator for evaluating cross-sectional associations with sex, height, and glucose tolerance and diabetes. From the study of borderline PAD cited above, additional information is provided regarding crosssectional relationships between several risk factors and ABI.10 In Table 6-6, the four categories of ABI defined previously are compared. A trend test based on regression analysis is applied to the distribution of each factor across the four categories of ABI. For example, mean age for “PAD present” was 59.3 years and was 58.1, 57.6, and 56.9 years for successively more favorable ABI, a statistically significant trend. Similarly, the proportion of the “PAD present” group who were men was 39.9%, while it increased across categories to be 54.7% of the “normal” category, also significant. Significant trends indicated association with less favorable classification by ABI for older age, non-Hispanic Black race/ethnicity, less than high school education, physical inactivity, hypertension, diabetes mellitus, current smoking, abdominal obesity, chronic kidney disease, and elevated C-reactive protein. A similar trend for serum total cholesterol 240 mg/dl or greater was suggestive but not significant. Being non-Hispanic White was associated with more

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70 60 Prevalence (%)

3:26 PM

Non-Hispanic White Non-Hispanic Black Mexican American

50 36.8*

40 30

26.4

20 10

9.7* 7.0 5.4

56.2

55.8 37.2*

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25.5

14.9* 8.3 8.3

0 PAD†

Borderline PAD‡

Low-Normal ABI§

Normal ABI||

(A) 70

Prevalence (%)

60

Men Women

61.0 47.4*

50 40

33.4*

30 21.8

20 11.7*

10

5.2 5.9

6.0

0 PAD†

Borderline PAD‡

Low-Normal ABI§

Normal ABI||

(B)

Figure 6-2 Age-Adjusted Prevalence of ABI Categories by (A) Race/Ethnicity and (B) Gender. *p 0.05. Source: Reprinted from American Journal of Cardiology, Vol 98 (I9), Menke A, Muntner P, Wildman RP, Dreisbach AW, Raggi P, Relation of Borderline Peripheral Arterial Disease to Cardiovascular Disease Risk, page 1227, © 2006, with permission from Elsevier.

favorable ABI. Being Mexican American also tended to be more favorable. The disadvantage of nonHispanic Blacks was the dominant racial/ethnic trend. In a US study of risk factors in relation to location of PAD in the affected vessel or vessels, it was observed that both smoking and elevated systolic blood pressure were related to stenosis of the aortoiliac or femoropopliteal arteries, but not of the tibioperoneal arteries.15 In the latter region, diabetes was more clearly related, but only among men. Mortality 5 and 10 years after diagnosis was from two to seven times greater for persons with aortoiliac or femoropopliteal lesions than for persons free of disease, and there was no significant increase in mortality for those with tibioperoneal lesions alone. In the study of borderline PAD, a further step in analysis was to calculate a multivariable risk score for probability of coronary heart disease within 10 years

as well as other outcomes.10 The several odds ratios were calculated after adjustment for age, race/ ethnicity, and gender, and trends for the odds ratios across categories of ABI were tested for statistical significance. Significant trends were found for a 20% or greater CHD risk in 10 years as well as CHD and stroke outcomes. After adjustment for confounding factors, the trends for stroke and CHD outcomes were not significant. The authors emphasized the importance of ABI assessment and of risk-factor intervention for those with low-normal ABI or borderline PAD. Recommendations regarding screening for PAD are debated after publication of a report by the United States Preventive Services Task Force in 2005, which recommended against PAD screening. They judged that little or no benefit results from this practice and that it could be harmful.16 A counterargument has since been published that proposes targeted screening to reach high-risk patients defined by age, other risk factors, symptoms, or abnormal peripheral pulses on physical examination. This position is consistent with previously published guidelines of the American College of Cardiology and American Heart Association.17 An analysis by Beckman and others projected mortality reductions after targeted screening under the assumption of prevalence of 29%; mortality rates from 27% to 57%, from previous studies; and benefits of intervention of 25% or 50%: In a targeted population in which 29% of screenees would be found positive, from 2 to 9 lives/100 population would be saved in 7 years through screening and treatment to reduce cardiovascular risk. Further supporting the latter view is a review focusing on the morbidity and mortality implications of PAD.18 Here the argument is advanced that PAD is strongly associated with risk of cardiovascular morbidity and mortality, by having a prognostic importance possibly stronger than prior myocardial infarction (see also the Framingham Heart Study report19); it is less often evaluated than other contributors to risk; when identified it leads less often to appropriate risk reduction intervention than presence of coronary artery disease; clinical trial evidence demonstrates the benefit of lipid and antiplatelet therapy in patients with PAD; and the increasing proportion of older persons in the population will add to the importance of addressing PAD effectively in the future. Current Issues The foregoing discussion underscores the question of whether differences regarding screening recommendations can be resolved and appropriate guide-

Source: Reprinted with permission from MH Criqui, The New England Journal of Medicine, Vol 326, No 6, p 384, © 1992, The Massachusetts Medical Society. All rights reserved.

Note: CVD, cardiovascular disease; CHD, coronary heart disease. Relative risks have been adjusted for age, sex, number of cigarettes smoked per day, systolic blood pressure, HDL cholesterol level, LDL cholesterol level, logarithm of the triglyceride level, fasting plasma glucose level, body mass index, and selection criterion.

CHD

Other LV-PAD (N ⴝ 33) 3.4 (1.9–6.0) 7.0 (3.2–14.9) 6.8 (2.7–17.5)

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Cause of Death All causes CVD

Relative Risk of Death Among Subjects with Various Categories of Large-Vessel Peripheral Arterial Disease (LV-PAD) Relative Risk (95% Confidence Interval) Isolated Posterior Unilateral Bilateral Asymptomatic Symptomatic Moderate Severe Tibial LV-PAD LV-PAD LV-PAD LV-PAD LV-PAD LV-PAD LV-PAD (N ⴝ 34) (N ⴝ 30) (N ⴝ 49) (N ⴝ 18) (N ⴝ 49) (N ⴝ 18) (N ⴝ 31) 3.3 2.9 2.7 4.7 2.8 3.9 2.9 (1.9–5.9) (1.5–5.5) (1.6–4.5) (2.3–9.6) (1.6–4.8) (1.9–8.0) (1.6–5.4) 5.5 5.8 4.7 11.2 4.8 8.4 4.2 (2.5–12.1) (2.5–13.3) (2.3–9.8) (4.5–27.9) (2.3–10.3) (3.4–20.8) (1.7–10.4) 5.5 7.2 5.6 11.4 5.6 8.9 5.5 (2.0–15.2) (2.6–19.7) (2.3–13.5) (3.6–35.8) (2.2–14.2) (3.0–26.8) (1.8–16.7)

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Table 6-6

Variable

Age-Adjusted Prevalence of Cardiovascular Disease (CVD) Risk Factors by Ankle-Brachial Index (ABI) Category PAD ABI Present Borderline Low-Normal Normal (ABI 0.90) (ABI 0.90–0.99) (ABI 1.00–1.09) (ABI 1.10–1.29) (n ⴝ 368) (n ⴝ 524) (n ⴝ 1455) (n ⴝ 2548) p Trend

Age (yrs) Men Non-Hispanic White Non-Hispanic Black Mexican American Less than high school education Physically inactive Hypertension Serum total cholesterol 240 mg/dl Diabetes mellitus Current smoking Abdominal obesity Chronic kidney disease Elevated C-reactive protein

59.3 (0.7) 39.9 (6.8%) 77.8 (2.9%) 17.4 (3.3%) 3.2 (1.2%) 37.7 (4.9%)

58.1 (0.4) 31.3 (2.8%) 70.6 (3.0%) 16.4 (2.9%) 3.8 (0.9%) 28.8 (2.7%)

57.6 (0.2) 37.7 (1.1%) 73.9 (2.2%) 12.1 (1.6%) 4.0 (0.7%) 24.5 (1.4%)

56.9 (0.1) 54.7 (1.3%) 80.9 (1.7%) 6.2 (0.8%) 4.6 (0.7%) 19.7 (1.4%)

0.001 0.001 0.001 0.001 0.065 0.001

55.6 (4.9%) 58.4 (5.6%) 25.7 (5.9%)

42.5 (2.8%) 50.6 (3.3%) 25.8 (2.7%)

42.3 (1.7%) 49.2 (1.1%) 22.4 (1.5%)

34.1 (2.0%) 38.3 (1.2%) 19.8 (1.6%)

0.001 0.001 0.119

13.2 (2.1%) 38.3 (3.5%) 62.8 (5.4%) 14.3 (2.6%) 22.1 (5.3%)

10.3 (1.3%) 29.2 (3.6%) 62.6 (2.4%) 8.2 (1.2%) 13.9 (2.4%)

9.2 (0.8%) 24.8 (1.1%) 54.9 (1.5%) 6.1 (0.6%) 11.2 (1.0%)

9.5 (0.6%) 15.8 (1.0%) 53.7 (1.8%) 6.2 (0.7%) 8.2 (0.7%)

0.003 0.001 0.037 0.001 0.001

Data are presented as means or percentages (SE). Source: Reprinted from American Journal of Cardiology, Vol 98 (I9), Menke A, Muntner P, Wildman RP, Dreisbach AW, Raggi P, Relation of Borderline Peripheral Arterial Disease to Cardiovascular Disease Risk, page 1228, © 2006, with permission from Elsevier.

lines then implemented to reduce risks of severe and fatal cardiovascular outcomes associated with PAD and suboptimal ABI. Prevention of PAD itself has been a less prominent topic and warrants consideration in parallel with atherosclerosis in other regions of the circulation. Could wider use of ABI as a screening tool serve this purpose, building on the evidence presented previously on the gradient of ABI? Is it a reasonable inference that “low normal ABI” represents a stage at which progressive disturbance of lower extremity circulation might be arrested or reversed by effective intervention?

AORTIC ANEURYSM Unlike PAD, aortic aneurysm may be directly fatal as a consequence of rupture or complications of attempted surgical repair. Its often rapid course may explain the data in Table 6-2 showing equal contributions from these two conditions to numbers of cardiovascular deaths, although aortic aneurysm leads to only half as many hospitalizations or physician office visits. Until about 1950, aortic aneurysm in the United States was predominantly due to

syphilis and was most often located in the thoracic aorta. A transition in factors causing aortic disease led to dominance of atherosclerosis as the underlying process and more common appearance of abdominal aneurysms, consistent with the anatomic distribution of this disease. Pathology of atherosclerosis in the abdominal aorta was discussed in Chapter 3, and discussion here also focuses specifically on abdominal aortic aneurysm (AAA). Typical Course An aneurysm may first be recognized when it causes pain in the abdomen or lower back in an adult aged 60 years or older and leads to physical examination and X-ray. More often, detection is incidental and precedes any symptoms, a result of routine palpation of the abdomen during physical examination by an examiner sensitized to the possibility of such an unanticipated finding. The typical course involves progressive enlargement of the aneurysmal mass, with mounting risk of rupture because increasing diameter of the aneurysm increases tension on the aortic wall. The normal diameter of the abdominal aorta is 2.5 cm. Aneurysms of less than 6 cm in diameter have a 15–20% risk of rupture within 10 years. If the aneurysm is not surgically repaired when

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AORTIC ANEURYSM 121

a diameter of about 6 cm has been attained, the 10year risk of rupture increases sharply, to 45–50%. Surgery carries significant risks even when done as an elective procedure, with 5–10% mortality. But rupture followed by emergency surgery may be fatal in half of the cases.20 In the absence of adequate facilities, the risk of death is 100%. Background An early investigation of the epidemiology of aortic aneurysm was based on mortality statistics for the United States from 1951 to 1981.21 These early data included thoracic as well as abdominal aneurysms. They also included “dissecting aneurysms,” a different disease now classified separately. Age-adjusted mortality due to aortic aneurysm increased from 1951 to a peak in about 1970, followed by a decline to 1981, for White and Black males and females. Over this period, persons born in more recent years were more likely than those born earlier to die of aortic aneurysm on attaining any given age; that is, a cohort effect was evident, with increased risk among more recent cohorts. Abdominal aneurysm rates, analyzed separately from 1968 to 1981, were several times higher than thoracic aneurysm rates and remained fairly constant. This contrasted with the trend in mortality from coronary heart disease, whose sharp decrease in the United States began in the mid- or late 1960s. Typical of the race–sex differences in mortality from abdominal aneurysm over this period were the rates for 1981, the latest year in that study: for White males, 4.97/100,000; for nonWhite males, 1.49/100,000; for White females, 0.91/100,000; and for non-White females, 0.64/ 100,000. Deaths from unspecified types of aneurysms were relatively more frequent than those for abdominal aneurysm in some groups. Population Studies: Definition and Classification Data on AAA depend on physical examination, noninvasive imaging techniques or contrast aortography, and statistical coding of deaths and hospital discharges by use of the International Classification of Diseases. Because methods differ among studies, results must be considered carefully. On physical examination, a characteristically pulsating mass may be felt in the midabdomen, and on X-ray the image of a calcified band may appear that marks a zone of advanced atherosclerosis in the wall of the aorta. More detailed evaluation is possible by ultrasound examination, computed tomography, or arteriography.

Rates The community of Rochester/Olmsted County, Minnesota, has an integrated medical records system for inpatient and outpatient experience of the total population. Incidence of both abdominal and thoracic aortic aneurysm was studied there over the period from 1951 to 1980.22 The diagnosis was accepted on the basis of the medical record if made by physical examination and confirmed by a second physician; if the radiologist made a firm diagnosis by ordinary X-ray (KUB, or kidney-ureter-bladder, X-ray); or if it was based on ultrasonography, aortography, surgery, or autopsy. Total incidence increased over this period, despite a continual decrease in incidence of thoracic aneurysm, because of changing incidence of abdominal aneurysm. For investigating the possibility that the increased incidence of abdominal aneurysm was due to greater frequency of smaller, previously less detectable lesions, the trends were examined specifically for small, medium, and large aneurysms. The greatest increase was for small lesions, but medium and large ones increased in incidence also. This issue was further evaluated by considering the basis for diagnosis. Increased incidence was apparent from each method from the 1950s to the 1960s. During the 1960s and 1970s, ultrasound examination became a major component of the diagnostic procedure and tended to displace physical examination and X-ray. Ultrasound contributed disproportionately more to detection of small lesions (less than 5 cm diameter) in contrast to large ones. Overall, the smaller, asymptomatic, and uncomplicated lesions became more readily detected. These observations indicate that data regarding occurrence of abdominal aneurysm should not be expected to be comparable over time or between settings, when methods of detection differ. On the basis of coded hospital discharges and deaths, investigators in England and Wales similarly observed increased incidence of abdominal aneurysms over the period from 1950 to 1984.23 The increase in mortality was 20-fold for men and 11-fold, beginning a decade in age later, for women. By 1981–1983, the numbers of hospital admissions had increased to nearly three times the numbers in 1968–1971. Over this interval the percentage of admissions that were emergencies decreased only slightly (from 63% to 56%) and case-fatality also diminished only slightly from 45% to 39%. Thus the marked rise in hospital admissions could not be explained by increased admission of cases milder than those admitted in the earlier period. It was noted that hospital data on deaths from AAA in the United Kingdom gave only limited insight because one-half to two-thirds of such deaths occurred out of the hospital.

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Prevalence studies of AAA at autopsy have also shown increased occurrence of these lesions in recent decades, in Sweden, Australia, and Japan. From 1965 to 1989, in Japan rates of unsuspected abdominal aneurysm discovered at death in national autopsy surveys increased by 80% in men and by 50% in women.24 Only AAA became more frequent over this period, whereas thoracic aneurysm became much less frequent and the occurrence of dissecting aneurysm fluctuated with no overall change. What changes have occurred in the population as a whole, beyond the hospitalized population alone, remains unknown. Prevalence of AAA in the United Kingdom based on several surveys through the mid-1990s varied widely depending on age and the measurement criterion selected.25 In six of seven studies, only men were included, mainly age 65 years or older; several hundred to several thousand persons were screened; and the aortic diameter exceeded 40 mm in three instances, 29 or 30 mm in six, and 25 mm in one. Even with the same measurement criterion and similar age range, 29 mm and ages 65 to 75 years, prevalence varied from 1.3% to 8.4%. As noted above, comparability of studies is limited by differences in criteria, but even with apparently similar design studies present quite divergent results. Analogous data from several European and one American study indicated a range of estimates from 0.7% to 10.7%. Here diagnosis involves more than a single measurement, with dimensions compared between different segments of the aorta. These limitations leave open to question interpretation of any reported population differences or trends in measures of occurrence of AAA, as well as possible risk-factor associations. With that qualification, reported risk factors for this condition include male sex, smoking, hypertension, PAD, and cardiovascular disease. In contrast with coronary heart disease, differences in risk factors for this condition and differences in trends of occurrence raise the question of whether AAA is fundamentally an atherosclerotic condition. A more recent assessment of frequency in the United Kingdom indicates increasing hospitalization rates and mortality from AAA in men, and even greater increases in women, from 1979 to 1999.26 Case-fatality declined from about 25% to 10% for elective repair of nonruptured aneurysms and from about 70% to 50% for ruptured lesions. Risks On the basis of a cross-sectional survey of more than 5000 adults aged 55 years and over, investigators in the Rotterdam Study in the Netherlands identified cases of AAA by ultrasound examination.27 Aneurysm was diagnosed if the diameter of the most distant sec-

tion of the abdominal aorta was 35 mm or greater or if that diameter exceeded by 50% or more that of the most proximal section. Aneurysm was found in 91 of 2217 men and 21 of 3066 women examined. Prevalence increased sharply with age and was several times greater for men than women at every age, from 55–59 years to 80 years and older. Concurrent assessment (separately for men and women) of characteristics of the cases relative to noncases, or controls, indicated associations as shown in Table 6-7. Current smoking was the most striking associated factor in both men and women, with serum cholesterol concentration in men and past stroke in women being additional statistically significant associated factors. Aortic aneurysm has also been found to aggregate in families, as illustrated by a study of 91 first-degree relatives (parents and siblings but not, in this case, offspring) of cases identified in a regional hospital in Pittsburgh, Pennsylvania.28 Compared with the corresponding relatives of persons without AAA, the relative risks among fathers and mothers of cases were approximately 4, but with wide confidence limits that included 1. For siblings, however, the relative risks were large and the lower confidence bounds were greater than 1, being 9.9 (4.3–19.5) for brothers and 22.9 (8.4–50.0) for sisters. This is strong evidence of a familial component, but further investigation would be necessary to establish a meaningful pattern of inheritance. How much of this striking familial resemblance might reflect increased probability of detection due to diagnostic suspicion after the initial case is an unanswered question. A recent study of smoking and aortic aneurysms pursued the issue of whether this condition might be more specifically smoking-related than are other cardiovascular diseases.29 Ten studies were reviewed. Pooled estimates of relative risk were calculated for aortic aneurysm, coronary artery disease, cerebrovascular disease, chronic obstructive pulmonary disease (COPD), and lung cancer. Relative risk of aortic aneurysm among smokers was 2.5 times as great as that for coronary artery disease and 3.5 times as great as for cerebrovascular disease; it was 0.56 times the relative risk of COPD. The authors concluded that the findings were consistent with a nonatherosclerotic cause of aortic aneurysms. It is noteworthy, however, to recall discussion of atherosclerosis in Chapter 3 and evidence of its relation with smoking. Another recent report, from the Health Professionals Follow-up Study, addressed the relation of alcohol to AAA.30 After adjustment for other risk factors (smoking, hypertension, and body mass index), and with use of updated alcohol exposure from periodic questionnaires, alcohol consumption of two

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CHRONIC HEART FAILURE 123

Table 6-7

Potential Risk Factors in Men and Women with and Without an Aneurysm of the Abdominal Aorta, Adjusted for Differences in Age, Rotterdam Study, 1989–1993 Men Women Aneurysm of the Aneurysm of the Abdominal Aorta Abdominal Aorta Present Absent P Present Absent P Risk Factor (N ⴝ 91) (N ⴝ 2126) Value (N ⴝ 21) (N ⴝ 3066) Value Body mass index (kg/m2), mean 25.4 25.7 0.29 27.4 26.6 0.30 Systolic blood pressure (mm Hg), mean 142.0 138.6 0.14 142.8 139.5 0.48 Diastolic blood pressure (mm Hg), mean 76.5 74.7 0.14 75.5 73.5 0.41 Current smoking (%) 37.6 23.9 0.01 56.0 19.1 0.01 Serum cholesterol (mmol/l), mean 6.6 6.3 0.04 7.3 6.9 0.11 Serum HDL cholesterola (mmol/l), mean 1.2 1.2 0.53 1.4 1.5 0.32 Hypertension (%) 29.2 26.5 0.59 42.1 32.9 0.37 Stroke (%) 1.8 3.9 0.31 9.0 2.3 0.05 Diabetes mellitus (%) 8.6 10.4 0.61 0.0 9.4 — Intermittent claudication (%) 4.8 1.8 0.04 4.5 1.0 0.12 History of angina pectoris (%) 8.3 6.1 0.39 13.4 6.8 0.24 History of myocardial infarction (%) 15.7 11.0 0.17 8.7 3.3 0.37 a

HDL cholesterol, high-density lipoprotein cholesterol.

Source: Reprinted with permission from HJCM Pleumeekers, American Journal of Epidemiology, Vol 142, No 12, p 1297, © 1995, The Johns Hopkins University School of Hygiene and Public Health.

or more drinks per day was found to be associated with AAA (relative risk 1.65, 95% confidence interval: 1.03–2.64). How best to reconcile this information with other aspects of alcohol use in relation to cardiovascular diseases requires further consideration (see Chapter 15). As encountered in connection with PAD, the question arises of screening for this condition, in view of its risk of fatal complications. Subsequent to an earlier inconclusive assessment by the US Preventive Services Task Force in 1996, four trials of screening among men age 65 or older by ultrasound imaging were reported. The new studies were reviewed in an evidence synthesis that concluded by recommending screening for men aged 65 to 75 years.31 It was noted that although screening would reduce mortality from this condition by 43%, harms of treatment include an operative mortality rate of 2–6%, as well as risks of myocardial infarction, respiratory and renal failure, and others. Insufficient information was available on screening for women to support a recommendation. Questions regarding surgical repair versus surveillance of aneurysms in the 30–54 mm range and harms associated with these were not addressed in this report. Current Issues Intervention when an AAA of critical size is identified reduces the risk of rupture and death by less than half, and intervention itself has substantial other risks.

At or above the threshold of 55 mm, surgical intervention is considered to have a favorable balance of risk against no treatment. Rupture can occur with fatal outcome in lesions of smaller size. Given that prevention is preferable, two appropriate questions are: How can development of AAA be prevented in the first place? And how can lesions now detectable by ultrasound while below the intervention threshold be arrested or reversed in their progression, thereby diminishing the risks of the advanced lesions and avoiding the risks of treatment?

CHRONIC HEART FAILURE “Chronic heart failure” or more simply, “heart failure,” is a condition that reflects impairment of the pumping function of the left ventricle of the heart, as described previously. As a result, blood flow from the left ventricle into the aorta and to the peripheral arterial circulation is reduced. In addition, failure to eject the blood from the left ventricle leads to increased back-pressure in the pulmonary circulation, with reduced blood flow through the lungs and exudation (seepage of fluid) from the blood to the tissue spaces in the lung, exacerbating the accompanying impairment of respiratory function. Mechanisms of heart failure include both “systolic dysfunction,” with a diminished proportion of blood contained in the

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left ventricle being ejected with each contraction (diminished ejection fraction), and “diastolic dysfunction,” with incomplete relaxation of the left ventricle and therefore reduced volume of blood entering the left ventricle to be ejected with the next contraction. These are features of left heart failure; right ventricular failure can occur as well with adverse consequences for the pulmonary circulation, as a consequence of obesity or sleep-disordered breathing. Heart failure may result from any of several underlying processes, such as myocardial infarction, which causes significant localized damage to the ventricular wall; longstanding high blood pressure, inadequately controlled; cardiomyopathies such as Chagas disease, which results in more generalized loss of heart muscle cell function; or valvular heart disease, such as in chronic rheumatic heart disease, which can cause valvular obstruction to outflow from and leakage or regurgitation of blood flow back into the left ventricle.3 Typical Course Compensatory physiologic changes can maintain adequate left ventricular function, even while the underlying disease progresses. Once heart failure develops, its main clinical manifestations are generally similar regardless of its cause. However, in the case of coronary heart disease, as in acute myocardial infarction, the onset of heart failure may be very sudden. The presence of heart failure in the acute phase of myocardial infarction is a poor prognostic sign, and its effective treatment is important for immediate survival. Recovery may be complete, however, with no recurring signs or symptoms. Chronic heart failure may persist after an acute onset and partial recovery, or progressive ventricular decompensation may occur over weeks, months, or years. Fatigue and shortness of breath on minimal exertion are among the clinical indications of heart failure. Treatment may improve function and prolong life for several years, but progressive decompensation or other complications result in death in a large proportion of cases. In 2005, with an update in 2009, a new practice guideline for diagnosis and management of heart failure in adults was developed by the American College of Cardiology Foundation and American Heart Association (ACCF/AHA Guidelines).32,33 This guideline presented a schematic view of the progressive development of heart failure from being at risk to exhibiting symptomatic disease. Four stages were defined: A, “At high risk for HF [heart failure] but without structural heart disease or symptoms of HF”; B, “Structural heart disease but without signs or symptoms of HF”; C, “Structural heart disease with prior or current symptoms of HF”; D, “Refractory HF re-

quiring specialized interventions.”33 Approaches to therapeutic intervention were described for each stage. Background Epidemiologic investigation of heart failure has been impeded by some of the features just described. Its character as an end-stage development in the course of several distinct diseases has prevented its clear and consistent identification in mortality or hospital statistics. Gradual onset delays its recognition, so case incidence is difficult to define. Given its often prolonged clinical course, death due to an intervening coronary event or stroke may overshadow the presence of heart failure and lead to its omission from the diagnosis entered or coded on the death certificate. Alternatively, a death may be attributed simply to heart failure when a more specific disease could have been indicated. Clinical definitions and classification have also been limited by the nonspecific nature of the symptoms of heart failure, in contrast, for example, to the classical (if not universal) pain of myocardial infarction or intermittent claudication. A comprehensive overview of the Framingham Study experience, based on 32and 40-year follow-ups, addresses the main features of the epidemiology of heart failure and preventive approaches to reduce the mounting public health burden of this condition.34 Population Studies: Definition and Classification Epidemiologic studies of heart failure have required criteria by which to identify cases. A prominent example is the Framingham Study, whose 40-year follow-up was published in 1993 and included criteria for congestive heart failure as shown in Table 6-8.24 They take the form of a list of symptoms, physical findings, and physiological measurements grouped as “major” and “minor” criteria. Classification as a case required that at least two major or one major and two minor criteria be present, with no other medical explanation than heart failure for the presence of the minor criteria. (“Dyspnea” is shortness of breath; “edema” is swelling especially in the feet and ankles, due to fluid retention and reduced efficiency of venous return of blood to the heart; and “rales” are sounds heard by stethoscope on physical examination that indicate presence of fluid near the base of the lungs.) The 2005 ACCF/AHA Guidelines defined heart failure as “a clinical syndrome that is characterized by specific symptoms (dyspnea and fatigue) in the medical history and signs (edema, rales) on the physical examination. There is no single diagnostic test for HF because it is largely a clinical diagnosis that is based on a careful history and physical examination.”32, p 1828 The 2005 ACC/AHA report adopted the

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Table 6-8

Criteria for Congestive Heart Failure, the Framingam Heart Study

Major Criteria Paroxysmal nocturnal dyspnea Neck vein distention Rates Radiographic cardiomegaly (increasing heart size on chest X-ray film) Acute pulmonary edema Third sound gallop Increased central venous pressure ( 16 cm water at the right atrium) Circulation time 25 seconds Hepatojugular reflux Pulmonary edema, visceral congestion, or cardiomegaly at autopsy Weight loss 4.5 kg in 5 days in response to treatment of CHF Minor Criteria Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion Decrease in vital capacity by 33% from maximal value recorded Tachycardia (rate 120 beat/min) Note: The diagnosis of congestive heart failure (CHF) required that two major and two minor criteria be present concurrently. Minor criteria were acceptable only if they could not be attributed to another medical condition. Source: Reprinted with permission from the American College of Cardiology, Journal of the American College of Cardiology, 1993, Vol 22, No 4, p 7A.

simpler term “heart failure” because not all cases present evidence of “congestion” at a given time. This term then included structural or functional cardiac disorders impairing the ability of the ventricle either to fill with or to eject an adequate volume of blood. The 2009 Update included discussion of certain biomarkers now considered useful in diagnostic evaluation of patients with possible heart failure, the natriuretic (sodium-excreting) peptides produced and released by the heart.33 These substances, BNP (B-type natriuretic peptide) and NT-proBNP (Nterminal pro-B-type natriuretic peptide), may be increased in concentration due to other factors than heart failure, however, and are therefore not specific to this condition. Also discussed is increasing use of the echocardiogram in detection and evaluation of heart failure. Several elements of the Framingham Study criteria as well as the ACCF/AHA definition depend on subjective and qualitative judgment. This approach is unlike case definition for PAD or AAA, for example, by measurement of ABI or aortic dimensions. Coding of heart failure as a hospital discharge diagnosis or cause of death also poses difficulties. This is because heart failure may be the result of any of several underlying conditions—hypertension, coronary heart disease, rheumatic heart disease, cardiomyopathies (heart muscle disorders), and others. Heart failure

may not always be indicated when appropriate as the first diagnosis or underlying cause of death. Kannel has estimated that four times the number of coded heart failure deaths include this condition as a contributing cause, indicating a major underestimate of the impact of heart failure in currently available mortality data.34 The extent of misclassification and admixture of cases would be expected to vary with the relative frequencies of the underlying diseases in different populations. Clearly, comparison of studies on heart failure between populations or over periods of decades could be misleading if diagnostic practices or variations in underlying disease frequencies were not taken into account, and to do so is difficult. Rates With this understanding of case identification, several sources of data can be highlighted regarding mortality, hospitalization, case-fatality, incidence, and prevalence. Mortality Interpretation of mortality data in heart failure is compromised by variation in methods for coding or analysis of heart failure, which may be listed as the underlying cause of death, a contributing cause, or an incidental condition unrelated to the cause of death.

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This limitation should be borne in mind in considering such data as the following: Data compiled by the National Heart, Lung and Blood Institute for deaths due to heart failure in 2004 are shown in Figure 6-3 for four sex-race groups.2 The nearly 57,000 deaths shown in Table 6-2 are seen here as strongly related to age, with highest rates across the age span for Black males and lowest rates for White females. Black males and Black females both reach higher death rates from heart failure at earlier ages than Whites. Age-adjusted death rates for heart failure between ages 35 and 74 years for 15 countries are compared, separately for females and males, in Figure 6-4.2 The rates for the United States are intermediate between the extremes of Poland and Romania, and in all countries except Denmark, rates for males appear to exceed those for females. The extreme high rates for Poland may reflect differences in coding practices or real variation in frequency of the underlying causes of heart failure. A special aspect of mortality in heart failure is the high proportion of deaths that are sudden. The Framingham Heart Study reported that 40–50% of deaths in the presence of heart failure were sudden, defined as occurring within one hour in a previously stable patient.35 On the basis of 30 years of followup in the Framingham population, the presence of previous heart failure increased the risk of sudden death sevenfold when coronary heart disease was absent and nearly ninefold in the additional presence of coronary heart disease.

Another estimate of the impact of heart failure on subsequent mortality is based on long-term follow-up of participants in the first US National Health and Nutrition Examination Survey (NHANES I) of noninstitutionalized persons aged 25–74.36 Here the strategy was to identify cases of heart failure by criteria applied at the initial survey, conducted from 1971 to 1975, and to determine their subsequent mortality over a 15-year follow-up period. All deaths were included, irrespective of their cause according to the death certificate. Two methods were used for case definition at the baseline. The first method was selfreport, based on survey responses to the medical history questionnaire that asked participants whether a physician had ever told them they had heart failure. The second method used a clinical score based on an adaptation of the Framingham criteria, discussed previously, which took into account the relevant observations from the survey. For women aged 55–64 and 65–74 years, respectively, the 15-year postsurvey mortality rates were approximately 40% and 60% for those identified by self-report and 25% and 50% for those identified by clinical score. For men, the corresponding frequencies were 50% and 75% (selfreport) and 65% and 80% (clinical score) for age groups 55–64 and 65–74 years, respectively. Mortality was clearly very high in all age-sex groups, especially for men, by either method of case identification. Especially for the younger age group, mortality was higher for self-reported than for clinically identified heart failure at baseline for women, suggesting that

Deaths/100,000 Population

200

150

Black Male White Male Black Female White Female

100

50

0 35–44

45–54

55–64

65–74

75–84

Age (Years)

Figure 6-3 Death Rates for Heart Failure by Age, Race, and Sex, United States, 2004. Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

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POL JPN GER SPA CZR NTH FRA (2003) DEN (2001) USA NOR (2003) HUN (2003) EW AUL (2003) SCO KOR SWE (2002) FIN ROM (2000)

Male Female

30

20

10

0 10 20 30 Deaths/100,000 Population

40

50

60

Figure 6-4 Age-Adjusted Death Rates* for Heart Failure by Country, and Sex, Ages 35–74, 2004†. Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007. *Age adjusted to European standard. † Data for 2004 unless otherwise noted in parentheses.

the score identified milder cases, but the reverse was true for men. Hospitalization As with mortality data, hospitalizations attributed to heart failure may represent different circumstances in data from different sources. Heart failure may be the primary reason for admission or only an ancillary condition; admission may reflect a case of unstable heart failure; or it may represent another illness, such as pneumonia, threatening effective management of otherwise stable heart failure. The 2009 ACCF/AHA Guidelines identified several factors that could lead to readmission of patients with heart failure that might be considered in interpreting such data.33 Given these qualifications, the available data can be discussed as follows. The rate of hospitalization for heart failure has increased more than threefold over the past three decades (Figure 6-5).2 This pattern is almost entirely due to cases aged 65 years or older, although the direction of the trend is seen, at much lower rates, in the 45–64 year age group as well. Heart failure is now the leading cause of hospitalization in the United States among the elderly. Among objectives for heart disease and stroke prevention in Healthy People 2010 is a

50% reduction in age-specific hospitalization rates for heart failure in each of three age groups, 65–74, 75–84, and 85 years and older.37 The specific targets would in effect reduce the rate in each group to the baseline rate for the next younger age group. Relative to the 1997 reference data, progress was insufficient at the midcourse review in 2007 (based on earlier data) to anticipate complete success by 2010. Hospital discharge data presented earlier by Gillum indicated the effect of choosing only the firstlisted diagnosis or all diagnoses to identify cases.38 On the basis of the first-listed discharge diagnosis alone, from 1986 to 1990 heart failure was responsible for 103,000 to 117,000 hospitalizations per year at ages 45–64 and 461,000 to 560,000 per year at ages 65 and older. The estimated frequency of such discharges was about two and one-half to three times greater when all diagnoses were identified rather than when using the first diagnosis alone. Undercounting of hospitalizations to which heart failure contributes is analogous to the undercounting of deaths based on underlying cause alone. Hospital case-fatality rates for heart failure have fallen by more than 50% during the 1980s and 1990s, for both age groups, 45–64 years and 65 and older (Figure 6-6).2 More common hospitalization of milder cases and more frequently repeated admissions for

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250

Hospitalizations/10,000 Population

Ages 45–64 Years Ages $65 Years

200

150

100

50

0 1970

1975

1980

1985

1990

1995

2000

2005

Years

Figure 6-5 Hospitalization Rates for Congestive Heart Failure, Age 45–64 and 65 and Over, US, 1971–2004. Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

individual cases could explain both increasing rates and decreasing in-hospital case-fatality. To what extent this and other factors such as more effective treatment contribute to these trends is presently unclear. Data on trends in severity of cases at admission, numbers of persons rather than hospitalizations, and numbers of deaths occurring in and out of hospital

would be helpful to understand the reported changes in these measures. Incidence Incidence of heart failure is reported from the Framingham Heart Study (FHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardio-

14 Ages 45–64 Years* Ages $65 Years

Percent Discharged Dead

12 10 8 6 4 2 0 1980

1985

1990

1995

2000

2005

Years * Unreliable estimate for 1981

Figure 6-6 Hospital Case-Fatality Rates for Congestive Heart Failure, Ages 45–64 and 65 and Over, US, 1981–2004. Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

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vascular Health Study (CHS) over the past one to two decades, in the Incidence & Prevalence 2006 Chart Book.39 Incidence approximately doubled with each decade of age from 65–74 to 85–94 years in the FHS, from 9.2 to 43.0 per 1000 person-years among men and from 4.7 to 30.7 per 1000-person years for women. Men had higher rates than women of the same race/ethnicity in all studies and age groups except in ARIC, where at age 65–74 the rate for Black women exceeded that for Black men (15.9 versus 15.2 cases per 1000 person-years). Prevalence Prevalence of heart failure in the United States as of 2006 is indicated in Table 1-4a and included 5.7 million persons, or 2.5% of adults aged 20 years or older, ranging from 1.4% of Mexican American females to 4.2% of Black females and males.40 The recent history of prevalence, from 1971–1974 through 1999–2004, is illustrated in Figure 6-7.2 Separately for Whites, Blacks, males, and females, estimates from successive National Health and Nutrition Examination Surveys indicate a major increase in prevalence at the midpoint of this period, between 1976–1980 and 1988–1994. Prevalence in the first three groups approximately doubled, with a somewhat lesser increase for females than for males. A slight decline in prevalence is apparent for the most recent period. The abrupt change in the midperiod is so striking as to suggest a change in case definition. Risks The predictors of heart failure based on 40 years of follow-up in the Framingham Heart Study are shown

for men in Figure 6-8 and for women in Figure 6-9.41 These figures show, separately by age groups 35–64 and 65–94 years, the relative risk of developing congestive heart failure in relation to cholesterol concentration, smoking, hypertension, diabetes, and presence of left ventricular hypertrophy (enlargement) as determined by electrocardiography (ECG-LVH). In addition, the age-adjusted incidence of heart failure in the presence or absence of each factor is shown. Inclusion of left ventricular hypertrophy as a risk factor is questionable, both because this finding is indicative of the disease process itself and because it appears to diminish the relative importance of the other predictors. Among the other factors, those most strongly related to the risk of heart failure were hypertension and diabetes, for both men and women at both age levels. A more recent presentation of the Framingham experience provides further insight into these results.34 Regarding ECG-LVH, when the hazard ratio was adjusted for age and the other major risk factors, the values were 2.2 for men and 2.9 for women, greatly reduced from the univariate estimates in the earlier report. Further evaluation of these relations to include prevalence of each factor showed ECG-LVH to occur in 4% of men and 3% of women, resulting in populationattributable fractions of 4% and 5%, respectively. High blood pressure (systolic or diastolic pressure 140 90 mm Hg) with hazard ratios of 2.1 and 3.4 and prevalence of 60% and 62% resulted in populationattributable fractions of 39% and 59% for men and women, respectively. For prior myocardial infarction, the population-attributable fractions were 34% for men and 13% for women. On the basis of this analy-

Percent of Population

4

3

1971–1974 1976–1980 1988–1994 1999–2004

2

1

0

White

Black

Male

Female

Figure 6-7 Prevalence (Age-Adjusted) of Congestive Heart Failure by Race and Sex, Ages 25–74, US, 1971–74 to 1999–2004. Source: From Morbidity & Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases. National Institutes of Health, National Heart, Lung and Blood Institute. June 2007.

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Risk Factor Absent Risk Factor Present

Age 35–64 yrs

RR

Age 65–94 yrs

RR

1.2

Cholesterol

0.9

*1.5

Smoking

1.0

*4.0

Hypertension

1.9*

*4.4

Diabetes

2.0*

*14.9

ECG-LVH

4.9*

50 40 30 20 10 0 *P 102 cm (M)

15

14

Yes

12

Assess reasons for failure to lose weight

No

Progress being made/goal achieved?

10

9

Clinician and patient devise goals and treatment strategy for weight loss and risk factor control

8

Maintenance counseling: • Dietary therapy • Behavior therapy • Physical activity

Yes

Yes

Yes

11

No

Does patient want to lose weight?

No

BMI 30 OR {[BMI 25 to 29.9 7 OR waist circumference > 88 cm (F) > 102 cm (M)] And 2 risk factors}

Figure 10-17 Treatment Algorithm. Source: Reprinted from Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. The Evidence Report. NIH Publication No. 98-4083, September 1998. National Institutes of Health, p 66.

*This algorithm applies only to the assessment for overweight and obesity and subsequent decisions based on that assessment. It does not include any initial overall assessment for cardiovascular risk factors or diseases that are indicated.

• Measure weight, height, and waist circumference • Calculate BMI

BMI measured in past 2 years?

3:31 PM

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Examination Treatment

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Hx of 25 BMI?

Patient Encounter

258

2

1

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PREVENTION AND CONTROL 259

The WHO Expert Committee report on anthropometry offered specific recommendations for individuals in each BMI category, from normal to grade 3 overweight. The recommendations reflect understanding of causes and consequences of overweight and its relation to risk factors for cardiovascular and other chronic conditions:19, pp 329–330 For individuals with BMI 18.50–24.99: avoid becoming overweight. There are no recommendations for weight loss. For individuals with BMI 25.00–29.99: avoid weight gain. Before recommending any type of intervention, assess other risk factors. If there are additional risk factors (high abdomen:hip ratio, hypertension, hyperlipidaemia, glucose intolerance or NIDDM [non–insulin-dependent diabetes mellitus], strong family history of diabetes mellitus or premature coronary heart disease), recommend a healthy lifestyle that will contribute to improvement of the risk profile: cessation of smoking, increased physical activity, reduced intake of (saturated) fat. Moderate weight loss is recommended but weight loss per se should not be the primary target of intervention. A large proportion of the adult population will usually fall into this category, and most will receive advice on healthy nutrition and physical activity appropriate for the general population. Regular (yearly) weight measurement will be helpful in monitoring weight development, and weight histories should be noted. Individuals who have continued to gain weight (e.g. 5 kg during the previous 2 years) should be identified for weight maintenance programs designed to halt the weight gain. For individuals with BMI 30.00–39.99: the same recommendations as for grade 1 overweight, although the prevalence of risk factors and of overweight-associated disorders that require medical attention is usually markedly higher and moderate weight loss is therefore more urgently recommended. In many populations, the proportion of adults falling into this category is still considerable, and treatment priorities will have to be set on the basis of, among other things, the prevalence of health problems in the community concerned. The higher the prevalence of chronic diseases such as diabetes and CVD [cardiovascular disease], the greater is the need for individuals with BMI 30.00–39.99 to lose weight. In other words, the potential impact of weight modification in preventing these problems is likely to be influenced by the disease

rates in the population. The risks related to grade 2 overweight in adults depend on other, coexisting, risk factors for chronic noncommunicable diseases. Obese individuals with no additional risk factors or conditions that require medical supervision may be referred to self-help organizations. Such organizations are effective if their leaders have sufficient training in the principles of healthy weight loss (a maximum of about 0.5 kg/week) and of balanced nutrition. For individuals with conditions that do require medical supervision, the focus should be on normalizing the risk factors or alleviating health problems (e.g., improving respiratory function or arthritis in weight-bearing joints) rather than on achieving weight loss per se. For individuals with BMI 40: intensive action to reduce weight. The proportion of adults with grade 3 overweight is small; for these individuals, weight loss per se may be the primary target and options such as surgical treatment for obesity should be considered. Community and Population-Wide Measures Because obesity in adolescence or early adulthood tracks into later life, and weight loss is difficult to achieve and maintain once obesity has become established, prevention of obesity in the first place is the logical priority. The difficulty of sustaining weight loss by already overweight or obese individuals— even if short-term weight loss is possible with one or another of the popular diets—remains a significant obstacle to control.98 This circumstance serves as a stimulus to prevention as the much preferred strategy and makes it the primary focus of community and population-wide measures. This implies early intervention to establish or maintain environmental conditions favoring optimum growth and development without lasting excess weight gain. The population-wide measures advocated for improving dietary patterns and increasing physical activity are the principal means proposed for preventing obesity at the population level.99 The 2008 AHA Scientific Statement Population-Based Prevention of Obesity describes approaches “designed to produce large-scale changes in eating behaviors and levels of physical activity to stabilize the distribution of BMI levels around a mean level that minimizes the percent who become overweight and obese, without increasing prevalence at the underweight end of the continuum.”99, p 436 The Statement adopts the concepts of the WHO report Obesity: Preventing and Managing the Global Epidemic of “universal prevention” with

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population-wide reach irrespective of individual screening and identification; “selective prevention” for groups at high risk by virtue of demographic, health-related, or other characteristics; and “targeted prevention” intended for individuals at high risk.100 A framework is presented that links international factors—globalization of markets, development, and media programs and advertising—with national/regional, community/local, and work/ school/home-based policies and practices (Figure 10-18). Location of multiple influences at one or another of these levels points to avenues of intervention appropriate at each level. Several components of a comprehensive “spectrum of prevention” are identified, each with its rationale and examples related to increasing physical activity. The report also highlights 13 systematic reviews of intervention studies on obesity prevention, the majority addressing children and adolescents. The authors of the AHA report noted the relatively small number of studies and limited evidence of ability to im-

INTERNATIONAL FACTORS

Globalization of markets

The rapid rise in obesity on a population level––associated with changes in the quantities of food available, marketed, and consumed, along with the very low level of obligatory physical activity for most people––makes obesity prevention efforts as a primary focus truly daunting. Furthermore, the inability to specify––at a population or individual level––the exact behaviors expected to result in energy balance considerably adds to the challenge. Avoiding unhealthy weight gain goes beyond the success of individ-

NATIONAL/ REGIONAL

COMMUNITY LOCALITY

WORK/ SCHOOL/ HOME

Transport

Public Transport

Leisure Activity/ Facilities

Urbanization

Public Safety

Labor

Health

Health Care

Development Social security

Media programs & advertising

prove average BMI levels in the groups studied:99, p 447 “The relatively limited breadth of studies identified, mainly school based and mainly individually oriented, indicates an urgent need to explore preventive interventions in other settings and at multiple levels upstream. Ongoing research may broaden the evidence base, but there is an overall impression that this critical area of research has far too little focus.” The report concluded:99, p 451

Media & Culture

Education

Food & Nutrition

Sanitation

System Manufactured/ Imported Food

Agriculture/ Gardens/ Local markets

INDIVIDUAL

POPULATION

Energy Expenditure

Infections

% OBESE

Worksite Food & Activity

Family & Home

OR UNDER Food intake : Nutrient density

WT

School Food & Activity

National perspective

Figure 10-18 Societal Policies and Processes Influencing the Population Prevalence of Obesity. Source: Reprinted with permission from Circulation, Vol 108, S Kumanyika, E Obarzanek, N Stettler et al., p. 15, © 2008 American Heart Association.

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ual efforts to achieve good dietary quality and adequate physical fitness. It requires a broad range of strategies that include environmental and societal efforts. The fourth group reporting on the AHA Prevention Conference VII addressed prevention and treatment.101 Potential actions were identified across multiple settings—home/family, schools, worksites, healthcare settings, and communities and neighborhoods. The latter were characterized as promising, but relatively unexplored. The concluding discussion addressed “sector-based changes”:101, p e487 Although little research exists on the effectiveness of broad-based policies to influence the prevention of obesity, it seems clear that such programs should be developed and extensively evaluated. Policies to be considered should include changes in physical and social environments, financial incentives and tax policies, factors related to the delivery of health care, and school and work site policies. The Task Force on Community Preventive Services reported its Public Health Strategies for Preventing and Controlling Overweight and Obesity in School and Worksite Settings in 2005.102 Of 44 studies in school settings, 10 were found to be suitable for evaluation. Evidence was considered insufficient to determine the effectiveness of any of the interventions. Of 35 studies in worksites, 7 were found adequate for evaluation with comparable outcomes. Combined interventions with physical activity and nutrition components were recommended, but evidence was found to be insufficient to recommend any single-component interventions. Global Strategies The WHO Global Strategy on Diet, Physical Activity and Health was discussed earlier as an explicit strategy for achieving healthy weight as well as promoting health and prevention of chronic diseases.13 Details of the strategy regarding its potential global impact are noted in the preceding two chapters and need not be repeated here. Also working at the global level is the IOTF which, in support of objectives of the WHO strategy, has developed and released the Sydney Principles, concerning marketing of food products to children.103 The Principles were presented and reviewed at the International Congress on Obesity in Sydney, Australia, in September 2006 and posted for comment through April 2007. In accordance with the Principles, as adopted:103, pp 2–3

Actions to reduce commercial promotions to children should: 1. 2. 3. 4.

Support the rights of children. Afford substantial protection to children. Be statutory in nature. Take a wide definition of commercial promotions. 5. Guarantee commercial-free childhood settings. 6. Include cross-border media. 7. Be evaluated, monitored, and enforced. The intended impact is to counter the predominant marketing to children of energy-dense, nutrientpoor foods and the effects of such marketing on children’s food preferences, beliefs, and consumption: “If applied, the Principles should ensure a substantial level of protection for children against exposure to commercial promotions of obesogenic foods and beverages, and make a significant contribution to a multi-strategy approach to reduce childhood obesity across society.”103, p 2 The Disease Control Priorities in Developing Countries Project reviewed together interventions for blood pressure, cholesterol, and body weight from the perspective of needs in low- and middle-income countries.48 Several principles for effective population-level interventions were presented:48, p 856 • clear responsibility for coordinating prevention efforts, with credible agencies with good communication methods carrying out longterm education programs • intersectoral collaboration, with multiple messages sourced from different organizations, including health sector entities, nonhealth government agencies, schools, workplaces, religious organizations, and voluntary agencies • collaboration with the food industry to ensure the availability of reasonably priced healthier food options, with food labeling that presents relevant information in a clear, reliable, and standardized format • realistic multiyear timeframes Regarding the lifestyle and dietary interventions relevant to obesity prevention or weight reduction, it was noted that some degree of weight reduction has been achieved in a number of multi-intervention trials. However, the overall results in terms of weight reduction and maintenance of weight loss have been “relatively poor.” Given interest in this context of assessing the cost-effectiveness of interventions, it was found that no large-scale randomized trials of weight reduction as

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an isolated intervention had been conducted, providing no basis for suitable analysis. Again, the need for further research was indicated to address fully any potential policy for obesity prevention and weight reduction. The tentative conclusion was that currently available personal interventions for these purposes were unlikely to be cost effective. The importance of population-wide initiatives against societal determinants of high-energy diets and decreasing physical activity was emphasized as the means to reduce risks of cardiovascular diseases and the need for personal interventions in developing countries in the decades ahead.

CURRENT ISSUES In its report on prevention of childhood obesity, the Institute of Medicine presented an action plan with 10 recommendations and specific steps for implementing each of them.10 One year later, a follow-up report presented an assessment of progress—Progress in Preventing Childhood Obesity: How Do We Measure Up?104 The conclusions of that report, although presented in a context specific to prevention of childhood obesity in the United States, seem relevant to the broader issues of prevention and control of overweight and obesity on a global scale:104, p 9 1. The country is beginning to recognize that childhood obesity is a serious public health problem that increases morbidity and mortality and that has substantial economic and social costs. However, the current level of investment by the public and private sectors still does not match the extent of the problem. 2. Government, industry, communities, schools, and families are responding to the childhood obesity epidemic by implementing a variety of policies, programs, and other interventions. All people bring strong values and beliefs to obesity-related issues, and evidence-based approaches are needed to guide the nation’s collective actions in this response. 3. Current data and evidence are inadequate to comprehensively assess progress in preventing childhood obesity across the United States. Although the best available evidence should be used to develop an immediate response to the childhood obesity epidemic, a more robust evidence base should be developed that identifies promising practices so that such interventions can be scaled-up and supported in diverse settings.

4. Evaluation serves to foster collective learning, accountability, responsibility, and costeffectiveness to guide improvements in childhood obesity prevention policies and programs. Multiple sectors and stakeholders should commit adequate resources to conduct evaluations. Surveillance, monitoring, and research are fundamental components of childhood obesity prevention evaluation efforts. 5. Multiple sectors and stakeholders should conduct evaluations of different types and at different levels to assess and stimulate progress over the short term, intermediate term, and long term to reverse the childhood obesity trend and improve the health of the nation’s children and youth. How to deal effectively with the public health challenges presented by overweight and obesity is the current issue. The four recommendations of the 2006 IOM report can be applied to overweight and obesity generally: lead and commit to prevention; evaluate policies and programs; monitor progress; and disseminate promising practices.

REFERENCES 1. National Institutes of Health Consensus Development Panel on the Health Implications of Obesity. Health implications of obesity. Ann Intern Med. 1985;103(suppl 6):1073–1077. 2. Brown PJ. The biocultural evolution of obesity: an anthropological view. In: Björntorp P, Brodoff BN, eds. Obesity. Philadelphia, PA: JB Lippincott Co; 1992:320–329. 3. Bray GA. Historical framework for the development of ideas about obesity. In: Bray GA, Bouchard C, James WPT, eds. Handbook of Obesity. New York: Marcel Dekker, Inc.; 1998:1–29. 4. Bray GA, Bouchard C, James WPT, eds. Handbook of Obesity. New York: Marcel Dekker, Inc.; 1998. 5. Fletcher GF, Grundy SM, Hayman L, eds. Obesity: Impact on Cardiovascular Disease. Armonk, NY: Futura Publishing Company, Inc.; 1999.

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52. Dietz WH. Childhood obesity. In: Björntorp P, Brodoff BN, eds. Obesity. Philadelphia, PA: JB Lippincott Co; 1992:606–609. 53. Manson JE, Colditz GA, Stampfer MJ, et al. A prospective study of obesity and risk of coronary heart disease in women. N Engl J Med. 1990;322:882–889. 54. Seidell JC. Relationships of total and regional body composition to morbidity and mortality. In: Roche AF, Heymsfield SB, Lohman TG, eds. Human Body Composition. Champaign, IL: Human Kinetics; 1996:345–353. 55. Gregg EW, Cheng YJ, Cadwell BL, et al. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA. 2005;293:1868–1874. 56. Sowers JR. Obesity as a cardiovascular risk factor. Am J Med. 2003;115:37S–41S. 57. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss. An Update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113:898–918. 58. Hall JE, Crook ED, Jones DW, Wofford MR, Dubbert PM. Mechanisms of obesity-associated cardiovascular and renal disease. Am J Med Sci. 2002;324:127–137. 59. US Department of Health and Human Services. Health, United States, 2008 with Special Feature on the Health of Young Adults. Washington, DC: US Department of Health and Human Services. Centers for Disease Control and Prevention. National Center for Health Statistics; 2008. 60. Gortmaker SL, Dietz Jr WH, Sobol AM, Wehler CA. Increasing pediatric obesity in the United States. Am J Dis Child. 1987;141: 535–540. 61. Freedman DS, Kettel Kahn L, Serdula MK, Ogden CL, Dietz WH. Racial and ethnic

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differences in secular trends for childhood BMI, weight, and height. Obesity. 2006;14: 301–308. 62. Williamson DF, Kahn HS, Remington PL, Anda RF. The 10-year incidence of overweight and major weight gain in US adults. Arch Intern Med. 1990;150:665–672. 63. Vasan R, Pencina MJ, Cobain M, Freiberg MS, D’Agostino RB. Estimated risks for developing obesity in the Framingham Heart Study. Ann Intern Med. 2005;143:473–480. 64. Fielding JE, Kominski GF, Hayes-Bautista DE, van Meijgaard J. Trends and forecast of health and economic costs of overweight and obesity in California. Issue Brief; July 2007. UCLA Health Forecasting Project. http://www.health forecasting.org. Accessed August 15, 2007. 65. York DA, Rössner S, Caterson I, et al. Prevention Conference VII: obesity, a worldwide epidemic related to heart disease and stroke. Group I: Worldwide demographics of obesity. Circulation. 2004;110:e463–e470. 66. Yach D, Stuckler D, Brownell KD. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nature Med. 2006;1:62–66. 67. Bundy DAP, Shaeffer S, Jukes M, et al. Schoolbased health and nutrition programs. In: Jamison DT, Breman JG, Measham AR, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006: 1091–1108. 68. Dowse G, Zimmet P, Collins V, Finch C. Obesity in Pacific populations. In: Björntorp P, Brodoff BN, eds. Obesity. Philadelphia, PA: JB Lippincott Co; 1992:619–639. 69. Hodge AM, Dowsxe GK, Gareeboo H, Tuomilehto J, Alberti KGMM, Zimmet PZ. Incidence, increasing prevalence, and predictors of change in obesity and fat distribution over 5 years in the rapidly developing population of Mauritius. Int J Obesity. 1996;28: 137–146.

70. Keys A. Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease. Cambridge, MA: Harvard University Press; 1980. 71. The Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: Final Report of the Pooling Project. J Chronic Dis. 1978;31:201–306. 72. Garrison RJ, Feinleib M, Castelli WP, McNamara PM. Cigarette smoking as a confounder of the relationship between relative weight and long-term mortality: the Framingham Heart Study. JAMA. 1983;249: 2199–2203. 73. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation. 1982;67: 968–977. 74. Garrison RJ, Castelli WP. Weight and thirtyyear mortality of men in the Framingham Study. Ann Intern Med. 1985;103: 1006–1009. 75. Dyer AR, Stamler J, Greenland P. Obesity. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology: From Aetiology to Public Health. 2nd ed. Oxford (England): Oxford University Press; 2005:291–310. 76. Kurth T, Gaziano JM, Rexrode KM, et al. Prospective study of body mass index and risk of stroke in apparently healthy women. Circulation. 2005;111:1992–1998. 77. Wilson PWF, Bozeman SR, Burton TM, Hoaglin DC, Ben-Joseph R, Pashos CL. Prediction of first events of coronary heart disease and stroke with consideration of adiposity. Circulation. 2008;118:124–130. 78. Bjørge T, Engeland A, Tverdal A, Davey Smith G. Body mass index in adolescence in relation to cause-specific mortality: a follow-up of 230,000 Norwegian adolescents. Am J Epidemiol. 2008;168:30–37.

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88. Krebs NF, Himes JH, Jacobson D, Nicklas TA, Guilday P, Styne D. Assessment of child and adolescent overweight and obesity. Pediatrics. 2007;120(suppl 4):S193–S228. 89. Davis MM, Gance-Cleveland B, Hassink S, Johnson R, Paradis G, Resnicow K. Recommendations for prevention of childhood obesity. Pediatrics. 2007;120(suppl 4): S229–S253. 90. Spear BA, Barlow SE, Ervin C, et al. Recommendations for treatment of child and adolescent overweight and obesity. Pediatrics. 2007; 120(suppl 4):S254–S288. 91. US Department of Health and Human Services. Agency for Healthcare Research and Quality. US Preventive Services Task Force. The Guide to Clinical Preventive Services 2006. Recommendations of the U.S. Preventive Services Task Force. AHRQ Publication No. 06-0588. Washington, DC: Agency for Healthcare Research and Quality; 2006. http://www.ahrq.gov/clinic/uspstf/uspstbac .htm. Accessed October 14, 2007. 92. Whitlock EP, Williams SB, Gold R, Smith PR, Shipman SA. Screening and interventions for childhood overweight: a summary of evidence for the US Preventive Services Task Force. Pediatrics. 2005;116:e125–e144.

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public-health/general-resources. Accessed June 20, 2009. 97. US Department of Health and Human Services. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. The Evidence Report. NIH Publication No. 98-4083. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute; September 1998. 98. Eckel RH. The dietary approach to obesity. Is it the diet or the disorder? JAMA. 2005;293: 96–97. 99. Kumanyika SK, Obarzanek E, Stettler N, et al. Population-Based Prevention of Obesity: The Need for Comprehensive Promotion of Healthful Eating, Physical Activity, and Energy Balance: A Scientific Statement from American Heart Association Council on Epidemiology and Prevention, Interdisciplinary Committee for Prevention (Formerly the Expert Panel on Population and Prevention Science). Circulation. 2008;118:428–464. 100. World Health Organization. Obesity: Preventing and Managing the Global Epidemic. WHO Technical Report Series No. 894. Geneva (Switzerland): World Health Organization; 2000.

101. Mullis RM, Blair SN, Aronne LJ, et al. Prevention Conference VII. Obesity, a Worldwide Epidemic Related to Heart Disease and Stroke. Group IV: Prevention/ Treatment. Circulation. 2004;110: e484–e488. 102. Centers for Disease Control and Prevention. Public health strategies for preventing and controlling overweight and obesity in school and worksite settings: a report on recommendations of the Task Force on Community Preventive Services. MMWR. 2005;54 (No. RR-10):1–12. 103. International Obesity Task Force. The Sydney Principles: Guiding principles for achieving a substantial level of protection for children against the commercial promotion of foods and beverages. http://www.iotf.org/sydney principles/index.asp. Accessed June 28, 2009. 104. Koplan JP, Liverman CT, Kraak VI, Wisham SL, eds. Progress in Preventing Childhood Obesity: How Do We Measure Up? Washington DC: Food and Nutrition Board, Board on Health Promotion and Disease Prevention, Institute of Medicine. Washington, DC: The National Academies Press; 2006.

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11 Adverse Blood Lipid Profile proved with systematic intervention, but these appear to be exceptional situations. It is clear that behavioral or societal factors that lead to dietary imbalance, physical inactivity, and obesity, and then to unfavorable blood lipids, call for strategies beyond the immediate public health arena alone to prevent development of adverse lipids in the first place.

SUMMARY “Adverse blood lipid profile” denotes blood concentrations of several types of fatty substances, such as cholesterol and its subfractions, LDL- and HDLcholesterol, that are an essential part of the causation of atherosclerotic cardiovascular diseases. On the basis of well-standardized laboratory methods and studies conducted in many diverse population settings, a very large body of epidemiologic evidence has established the determinants, distribution, and risks of cardiovascular diseases related to blood lipids. Laboratory research on metabolism and transport of these substances in the blood and tissues and clinical research on effects of diet and drugs as potential interventions to improve lipid profiles are other major components of the research. The totality of evidence strongly supports strategies for prevention and control of adverse blood lipids at both the individual or high-risk level and at the community or populationwide level. Not only in the United States and other developed countries, but in low- and middle-income countries as well, the mortality and burden of ischemic heart disease and stroke are largely attributable to high cholesterol and related lipid disturbances. Guidelines and policies for prevention and control of adverse levels of blood lipids are therefore of global as well as local and national importance. Personal interventions with lipid-lowering medications are addressed in detail in national and international guidelines. However, low prevalence of effective control of cholesterol found in national surveys and other sources indicates only limited success of efforts to implement them. In some healthcare systems and workplace programs, control levels have been im-

INTRODUCTION The “blood lipid profile” refers to concentrations of several fatty substances, mainly cholesterol and triglycerides, circulating in the blood. An “adverse” blood lipid profile represents levels of these components that together increase the extent and severity of atherosclerosis and risk of coronary heart disease and ischemic stroke. “High cholesterol” (hypercholesterolemia), unless otherwise specified, usually refers to elevated total cholesterol concentrations, although common reference to “bad” and “good” cholesterol indicates wide recognition of two subfractions of cholesterol, LDL- (low density lipoprotein) cholesterol and HDL- (high density lipoprotein) cholesterol, respectively. Optimum levels are low in the case of LDL-cholesterol and high for HDL-cholesterol. Because these components of total cholesterol relate to risk in opposite ways, “high cholesterol” does not fully characterize blood lipid-related risks, and reference to the “profile” is therefore often preferred. However, over much of the period in which the causal role of blood lipids in atherosclerosis and its consequences was established, “cholesterol” meant total cholesterol, and this is reflected in much of the literature cited here.

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The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, ATP III”), published in 2002, provides an extensive review of the blood lipid profile and its components, including the rationale for intervention, with evidence-based recommendations; procedures for detection and evaluation; approaches to lifestyle and medical intervention; and related topics.1 (For the forthcoming update to ATP III, see www.nhlbi.nih .gov/about/ncep.) The progression from early animal experimental research on diet and atherosclerosis to contemporary understanding of the roles of blood lipids at both population and individual levels is documented in reviews by Stamler,2 Keys,3 the National Research Council,4 and others. In the early 1900s, it was discovered that cholesterol was the necessary dietary constituent to produce experimental atherosclerosis in rabbits and other species. The significance of this knowledge for human atherosclerosis was recognized only later. However, as early as 1916, plasma cholesterol concentrations were observed to be lower in the native population of Indonesia than in Dutch immigrants; coronary heart disease was much less frequent in the indigenous population, and this difference in cholesterol levels was considered to be the explanation. This and other observations cited by Keys “seemed to fit into one picture” suggesting the importance of differences in population distributions of blood cholesterol concentration.3, p 1 In the mid- to late 1950s, as background to the Seven Countries Study, cholesterol surveys were conducted in several populations including countries in Europe as well as Japan and the United States. These studies were the foundation of work that would establish the causal relation between blood cholesterol concentration and coronary heart disease. During the 1950s and 1960s, the relation between dietary intake of fat and cholesterol and blood cholesterol concentration was quantified, as described in Chapter 8, “Dietary Imbalance.” Through the 1970s and 1980s, the composition of blood lipids and their transporting proteins (lipoproteins) was investigated further. Mechanisms of lipid transport and metabolism were also being described at a new level of detail. Epidemiologic studies over this period established the inverse relation of the concentration of HDL-cholesterol to risk of coronary heart disease. At the same time, clinical trials were undertaken to test the efficacy of dietary or drug interventions to reduce total cholesterol concentrations. Resulting evidence that incidence of coronary heart disease could

be reduced stimulated increased public health attention to blood cholesterol. A significant outcome of this progression of research on blood lipids has been development of clinical guidelines and public health policies for prevention of atherosclerosis and its consequences. More recently, a major research focus has been on genetics of blood lipids and atherosclerosis, discussed in Chapter 7, “Genes and Environment.”

CONCEPTS AND DEFINITIONS How blood lipids are described at a molecular level is basic to estimating cardiovascular risk, developing guidelines for classification and treatment, and monitoring risk-factor prevention and control. From both clinical and public health perspectives, it is helpful to understand this aspect of blood lipids. This provides background for discussion of the potential place of various lipid components in policy and practice. Lipoprotein Molecules Table 11-1 presents a broad classification of plasma lipoproteins and indicates several of their properties, which include, in the second column, the major lipids associated with each.5 One or more apolipoproteins, shown in the third column, occupy the surface of the lipoprotein molecule. Apolipoproteins give the molecule surface properties that determine its potential interactions with specific enzymes and cell-surface receptors.6 Electrophoretic mobility is described for each lipoprotein class, in the last column. This property is the extent to which molecules of each lipoprotein class migrate across a suitable transport medium under the influence of an electrical potential. This technique of lipid separation, used for many years, was the basis for an earlier classification in which the distance of migration was characterized for example as “Origin” (no migration), or “” (intermediate migration)—therefore low-density lipoprotein or LDL is equivalent to “ lipoprotein” and LDL-cholesterol or LDL-C is equivalent to lipoprotein cholesterol. Often, inconveniently, LDL-cholesterol is referred to simply as “LDL,” which strictly refers only to the lipoprotein itself and not the cholesterol it contains. The listed lipoprotein classes are arrayed in order of decreasing molecular size and increasing density (fourth and fifth columns). Chylomicrons carry dietary, or exogenous, triglycerides and cholesterol from the intestine into the circulation, and 80–95% of their lipid content is triglycerides. Remnants are portions of cholesterol-laden lipoprotein remaining after breakdown of chylomicrons. Very-low-density

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Table 11-1 Lipoprotein Class Chylomicrons Remnants VLDL IDL LDL HDL2 HDL3

Classification and Properties of Plasma Lipoproteins Major Lipids Dietary triglycerides, cholesteryl esters Dietary cholesteryl esters Endogenous triglycerides Cholesteryl esters, triglycerides Cholesteryl esters Cholesteryl esters Cholesteryl esters

Apolipoproteins A-I, A-II, A-IV, B-48, C-I, C-II, C-III, E B-48, E

Density (g/ml) 0.95

Diameter (Å) 800–5000

Electrophoretic Mobility Origin

1.006

300

Origin

B-100, C-, C-II, C-III, E B-100, E

1.006

300–800

Pre-

1.006–1.019

250–350

Pre-/

B-100 A-I, A-II A-I, A-II

1.019–1.063 1.063–1.125 1.125–1.210

180–280 90–120 50–90

Note: VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; HDL, high-density lipoprotein. Source: Reprinted with permission from PH Jones, J Patsch, and AM Gotto Jr. The Biochemistry of Blood Lipid Regulation and the Assessment of Lipid Abnormalities, in the Heart: Arteries and Veins, RC Schlant and RW Alexander, p 975, © 1994, The McGraw-Hill Companies.

and intermediate-density lipoproteins (VLDL and IDL) both carry endogenous triglycerides as about 55–80% and 20–50% of their lipid content, respectively. IDL carries endogenous cholesterol as about 20–40% of its lipid content. LDL and HDL both carry endogenous cholesterol—40–50% and 15–25% of their lipid content, respectively. But these two lipoprotein classes are associated with different apolipoproteins (third column) and have different metabolic pathways, resulting in opposite roles in atherogenesis. Examples of other molecular components of the blood lipid profile that have been investigated both in the laboratory and in population studies are lipoprotein(a) (Lp(a), or “L P little a”) and apolipoprotein E (apoE, or “apo E”). Lp(a) is a circulating protein whose blood concentration appears to be primarily genetically controlled. Its metabolism and mechanisms of action may include effects on blood coagulation and binding of materials within the atherosclerotic plaque. It is linked with triglyceride metabolism and with cardiovascular risk.7 ApoE is also genetically determined, with three alleles (designated ε2– ε4) accounting for most of the observed genotypes. These apolipoproteins can be associated with severe lipid disorders and risk of coronary artery disease even when blood lipid profiles are within the usual range of variation.8 Blood Lipid Phenotypes A second approach to classification of blood lipids is the so-called Fredrickson classification. This scheme addresses a series of phenotypes, or clinical patterns, characterized by specific combinations of lipoproteins, total cholesterol levels, and triglyceride levels;

different degrees of atherogenicity; and associations with particular genetic disorders (rare disorders with dominant genetic defects) (Table 11-2).5 The Fredrickson types I–V and their equivalent terms, such as “familial hypercholesterolemia” for type II a or b, are encountered in much of the clinical and some of the epidemiologic literature of the past. This classification does not take HDL-cholesterol concentration into account and has, in this respect, been superseded by more recent approaches.1 The place of HDL-cholesterol and of triglycerides in prevention of coronary heart disease was reviewed in a National Institutes of Health consensus conference in the early 1990s.9 Because high triglyceride levels and low levels of HDL-cholesterol are associated, their independent contributions to risk have been difficult to evaluate. Investigators continue to argue the importance of addressing these lipid components. In the case of HDL-cholesterol, multiple mechanisms have been identified by which it can protect against atherosclerosis and coronary artery disease,10 and treatment has been proposed for low HDL-cholesterol, beginning with lifestyle interventions and progressing as needed to specifically HDL-cholesterol-raising drugs.11,12 Regarding elevated triglycerides, the case continues to be made for treatment on the basis that this is an independent risk factor found in more than 30 percent of the United States adult population.13 Except at extreme high levels, triglyceride is proposed to be treated by lifestyle interventions, although drugs are available. Other approaches to defining risk in relation to blood lipids include a category denoted as “non-HDLcholesterol.” This includes all cholesterol except the

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Table 11-2

Phenotype I IIa

Fredrickson Classification of the Hyperlipidemias Serum Serum Lipoprotein(s) Cholesterol Triglyceride Elevated Level Level Atherogenicity Chylomicrons Normal to ↑ ↑↑↑↑ None seen LDL ↑↑ Normal

IIb

LDL and VLDL

↑↑

↑↑

III IV

IDL VLDL

↑↑ Normal to ↑

↑↑↑ ↑↑

V

VLDL and chylomicrons

Normal to ↑

↑↑↑↑

Associated with Genetic Disorders Familial lipoprotein lipase deficiency Familial hypercholesterolemia LDL receptor abnormal Familial combined hyperlipidemia Polygenic hypercholesterolemia Familial hypercholesterolemia Familial combined hyperlipidemia Familial dysbetalipoproteinemia Familial hypertriglyceridemia Familial combined hyperlipidemia Familial hypertriglyceridemia Familial multiple-lipoprotein-type hyperlipidemia

Note: LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein; IDL, intermediate-density lipoprotein. Relative degrees of atherogenicity are indicated by plus signs. High-density lipoprotein (HDL) cholesterol levels are not considered in the Fredrickson classification. Source: Reprinted with permission from AM Gotto Jr, Lipid and Lipoprotein disorders, in TA Pearson et al., Primer in Preventive Cardiology, © 1994, American Heart Association, and by permission from Southern Medical Journal, Vol 88, No 4, pp 379–391, 1995.

portion included in HDL-cholesterol, from which it is therefore independent.1 It includes the cholesterol associated with apolipoprotein B, excludes that associated with apolipoprotein A, and includes triglycerides (see Table 11-1). Because total and HDLcholesterol can both be measured in nonfasting blood samples, testing is convenient and a simple calculation provides the result. Determining optimum treatment goals and evaluating treatment options separately for non-HDL-cholesterol from those for LDL-cholesterol alone are problematic but may offer greater overall public health impact.14 Use of ratios among blood lipid components has also been advocated, such as total or LDL-cholesterol/HDL-cholesterol, as compared with total or LDL-cholesterol alone.15 Advantage has been shown for the ratio in predicting coronary risk and therapeutic risk reduction.15 Further, measurement of apolipoproteins A and B has been advocated in place of measurement of the corresponding cholesterol concentrations on grounds of more complete assessment of blood lipid contributions to risk.16 Current Classification in the United States and Europe In the United States currently, classification of blood lipid concentrations for adults under ATP III gives priority to LDL-cholesterol, the “primary target of therapy.”17 Five categories of LDL-cholesterol are defined by cut-points in mg/dl: optimal, 100; near optimal/above optimal, 100–129; borderline high, 130–159; high, 160–189; and very high, 190. For total cholesterol, categories are consistent with past definitions: desirable, 200; borderline high,

200–239; and high, 240. HDL-cholesterol categories are also defined in ATP III: low, 40; and high, 60. Reflecting recent attention to HDL-cholesterol, “low” is now defined at a higher—that is, less extreme—cut point than the previous levels of 30 or 35 mg/dl. Treatment algorithms are based on these categories after consideration of other risk factors that may modify therapy. In Europe, recommendations for cardiovascular disease prevention have been developed jointly by several multinational societies, as discussed in Chapter 20, “Recommendations, Guidelines, and Policies.” Rather than retaining risk categories for single factors, the joint recommendations incorporate other risk factors with total cholesterol concentration within a multivariable risk prediction.18 Nonetheless, target treatment levels are specified for total and LDL-cholesterol. With respect to HDL-cholesterol and triglycerides, levels are specified as markers of increased cardiovascular risk, but no treatment goals are defined. The World Health Organization guidelines, with potential global reach, closely resemble the European recommendations.19 They differ, however, in avoiding specific target levels for treatment on the argument that no level has been found below which there is no further benefit to reduction. Therefore, it is reasoned, no target should be set that could limit the effort to reduce cholesterol to the lowest attainable level. For children (age 2–19 years) in the United States, the NCEP guidelines remain unchanged since their publication in 1991.20 “Acceptable,” “borderline,” and “high” categories are defined by total cholesterol concentrations of 170, 170–199, and 200

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mg/dl, respectively. Corresponding values for LDLcholesterol are 110, 110–129, and 130 mg/dl. No HDL-cholesterol criteria are indicated for this age group. Because levels of each component of the blood lipid profile vary systematically on different trajectories during childhood and adolescence, it has been suggested that uniform criteria for classification throughout this period of life are inappropriate.21 The American Academy of Pediatrics now recommends age-specific percentile standards (50th, 75th, 90th, 95th) separately by sex and age (5–9, 10–14, and 15–19 years) for total, LDL-, and HDLcholesterol and for triglycerides.22 Cut-points by other percentile values have also been proposed, by single year of age from 12 to 20 years.23

MEASUREMENT Concerns about measurement of blood lipids center on accuracy of laboratory methods. For epidemiologic studies, an additional concern is within-person variation and the limited reliability of a single determination for characterizing the lipid profile or its components in an individual. Laboratory Standardization Issues regarding between-laboratory variation in methods and reliability of cholesterol determination led to establishment in 1958 of the Lipid Standardization Program by the (US) Centers for Disease Control and Prevention (CDC) and the National Bureau of Standards. Through this program, a reference method (the Abell-Kendall method) and a detailed quality-control program have been maintained for more than 50 years, and laboratories throughout the United States and around the world can become certified as meeting published standards. Because of the longstanding operation of this program, it has been possible to determine cardiovascular risks attributable to blood lipids; assure reliability of test results for multicenter clinical trials; monitor distributions and trends in cholesterol levels in many populations; and provide the foundation for policies and practices regarding blood lipids. Separate issues arise in connection with desktop cholesterol analyzers, of which numerous models are available. An assessment of these devices by the US General Accounting Office (GAO) found that measurement performance was generally good under controlled laboratory conditions.24 However, their reliability in practice settings is less certain. Their use to process capillary, or finger-stick, rather than venous blood samples entails further difficulties because of

possible sample dilution through poor finger-stick technique. Variability Within Individuals Because of within-individual variability associated with single cholesterol measurements, multiple measurements provide a more reliable characterization of the individual. The ranges of actual values represented by single test results were estimated by the GAO.24 Both analytical variability, based on current goals for measurement performance, and biological variability, due to true individual variability from dietary and other factors, were considered, first separately and then jointly. For example, a test result of 200 mg/dl, which for an adult would represent a borderline-high value, was taken to represent a range of 40 to 60 mg/dl around that value. There are clear implications of this phenomenon for dependence on single measurements of blood cholesterol, as is typical in epidemiologic studies. In some epidemiologic studies, two or more measurements have been recorded, whether in the recruitment phase of a trial or in the early follow-up experience of a long-term cohort study. The strength of association between cholesterol concentration and outcomes increases substantially when values from two occasions of measurement could be included in the analysis—an analytic approach described as adjustment for “regression-dilution bias.” Estimation of LDL Cholesterol Prominence of LDL-cholesterol and increased attention to triglycerides in risk classification broadens these concerns. This is especially so because LDLcholesterol is usually not directly measured but is calculated according to the equation:1, p III-6 LDL-C (total cholesterol) (HDL-C)

(triglycerides/5) The basis of this calculation is that total cholesterol is the sum of LDL-C, HDL-C, and VLDL-C. The latter quantity can be estimated, under appropriate conditions, as one-fifth of the triglyceride level. However, this estimate is unreliable if the triglyceride level is greater than 400 mg/dl; in this circumstance the LDL-cholesterol level cannot be estimated in this way. This poses difficulties because triglycerides increase acutely in response to fat intake, therefore meaningful determination requires a 9- to 12-hour fasting sample. It also carries substantial laboratory error. Further, the assumption that one-fifth of the triglyceride value represents VLDL-cholesterol is only approximate. Although direct measurement of LDLcholesterol has become available, it is not widely used because of issues of quality control.

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Other Measurement Issues More general considerations about cholesterol measurement in public-screening situations, including technician training, participant education and follow-up, and other aspects, were addressed by the NCEP and the American Heart Association.25 This is a helpful resource for planners of screening projects or other field studies in which cholesterol determinations will be performed. Units of measurement are either milligrams per deciliter (mg/dl) or millimoles/per Liter (mmol/L). Values of cholesterol concentration in mg/dl are equivalent to values in mmol/L obtained by multiplying mg/dl 0.02586; the reverse conversion requires multiplying mmol/L by 38.67. For triglycerides, the corresponding conversion factors are 0.0112 and 89.29.20 Values frequently noted include: Cholesterol mg/dl mmol/L 240 6.2 200 5.2 170 4.4

Triglyceride mg/dl mmol/L 1000 11.3 400 4.5 250 2.8

Finally, blood lipid determinations may be made in two kinds of samples—serum or plasma. Concentrations in plasma are slightly higher than in serum. To determine serum values equivalent to values reported as plasma concentrations requires multiplication by the adjustment factor 1.03; the reverse adjustment factor is 0.971.

DETERMINANTS Age, Sex, and Race/Ethnicity Across the life span, age-specific mean cholesterol concentrations first increase sharply from birth through infancy. They peak in the preteen years and decrease to the mid- to late teens before resuming an extended phase of increasing levels to midadulthood. A final phase of decreasing levels characterizes later adulthood. Differences in levels of total cholesterol by sex vary across these phases. The preteen peak is similar for boys and girls but, because the decrease that follows is greater for boys, and girls experience a greater increase in HDL-cholesterol, girls emerge from the teens with higher total cholesterol than boys.26 In early adulthood men have higher total cholesterol levels than women, but from the mid-50s on women have the higher levels.27 Differences by race/ethnicity in the United States are reported for adults from the National Health and Nutrition Examination Survey for non-Hispanic Whites and Blacks/African Americans, and for Mexicans (see Distribution, below). In 2003–2006,

age-adjusted mean values for persons 20–74 years were highest for Mexican men (203 mg/dl) and nonHispanic White women (also 203 mg/dl). Lowest levels were found for Blacks/African Americans. Persons with the highest levels may be on treatment to lower cholesterol, and mean values are sensitive to influences at the extremes of the distribution. Further, there may be interaction between race/ethnicity and treatment status for high cholesterol. For these reasons, comparisons of mean values of cholesterol by race/ethnicity may be misleading. Family History Family history of coronary heart disease occurring in early to midadulthood was shown by Williams and colleagues to be a simple and useful means for identifying relatives with high cholesterol.28 The MEDical PEDigree, or MED PED, program was noted in Chapter 7, “Genes and Environment,” as successful in detection of familial hypercholesterolemia in 50,000 persons within 3000 families with positive histories of coronary heart disease, from a total of 90,000 Utah families. The practice of evaluating immediate relatives of patients with known coronary heart disease is supported by this and other evidence of familial occurrence of risk factors and cardiovascular diseases, especially at midadult or earlier ages. However, it is generally believed that this practice is seldom implemented. Family history is more likely influential in practice in the area of blood lipid screening in children and adolescents.20 Recommendations from the NCEP Expert Panel on Blood Cholesterol Levels in Children and Adolescents were based on a principle of “selective screening” in which family history was the criterion for selection:29, p 545 The Panel reached consensus that a low density lipoprotein (LDL)-cholesterol value of 130 mg/dl or higher (95th percentile), when associated with family history of cardiovascular disease (CVD) or parental hypercholesterolemia, is sufficiently elevated to warrant further evaluation and probable treatment and followup. The panel deliberately targeted the family unit and the familial aggregation of CVD and/or inherited lipid problems because hypercholesterolemia in a child from such a family is of clinical significance. Children with parents and grandparents who have premature CVD often have high cholesterol levels. Thus cholesterol levels in a child are linked to familial CVD. Children are to be screened, then, if a parent or grandparent at age 55 years or younger has been found by diagnostic or interventional procedures to

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have coronary atherosclerosis, if a parent or grandparent at age 55 years or younger has had a documented myocardial infarction, angina pectoris, peripheral vascular disease, cerebrovascular disease, or sudden cardiac death, or if a parent (age not specified) has been found to have high cholesterol ( 240 mg/dl). Inability to obtain a family history, or presence in the child of other risk factors, could warrant screening on an exceptional basis. The implication that in the absence of a positive family history a child’s cholesterol level is not significant has been challenged, as discussed further under Prevention and Control, as follows. Dietary Imbalance, Physical Inactivity, and Obesity The essential role of diet in determining blood lipid levels is addressed in some detail in Chapter 8, “Dietary Imbalance.” It is appropriate to note again here the prediction equations of Keys and of Hegsted, linking dietary fat and cholesterol intake with the blood total cholesterol concentration:30, p 875 1) Saturated fatty acids increase and are the primary determinants of serum cholesterol, 2) polyunsaturated fatty acids actively lower serum cholesterol, 3) monounsaturated fatty acids have no independent effect on serum cholesterol and, 4) dietary cholesterol increases serum cholesterol and must be considered when the effects of fatty acids are evaluated. More limited data on low-density-lipoprotein cholesterol (LDL-C) show that changes in LDL-C roughly parallel the changes in serum cholesterol but that changes in high-density-lipoprotein cholesterol cannot be satisfactorily predicted from available data. These and other dietary influences on blood lipids and the roles of physical inactivity and obesity are addressed in the immediately preceding chapters.

MECHANISMS Blood Lipid Profile Mechanisms of metabolism and transport interact with dietary fats in the digestive tract, endogenously produced lipids, and circulating lipids in the blood. These mechanisms tend to balance the normal and the pathophysiological phenomena involving blood lipids that operate continuously, throughout the life span. Three sets of such regulatory processes have been described.6 First are those involved in transport of exogenous lipids, via the chylomicron system, from the intestine to the liver and peripheral tissues. Second is

transport of lipids synthesized in the liver, whether from the liver to peripheral tissues, as circulating free fatty acids, or from the circulation back to the liver. Third, reverse cholesterol transport—which depends on HDL metabolism—removes cholesterol from tissues such as the walls of blood vessels. Each of these mechanisms comprises multiple enzymatic reactions and molecular changes, adding great complexity to the intricate balance measured at any moment as the blood lipid profile. Beyond diet and other such factors and internal regulatory mechanisms, a number of specific conditions or disease states are associated with increased blood lipid concentrations.5 “Secondary hyperlipidemia” describes this group of lipid disorders, which are subclassified as to whether cholesterol or triglyceride concentration is primarily affected (Table 11-3). Fewer of these conditions, mainly endocrinologic disorders, cause hypercholesterolemia. The greater number causes hypertriglyceridemia and includes some of the same endocrinologic disorders as well as alcoholism, diabetes, obesity, and certain specific diseases. Several classes of drugs have similar effects, including beta-blockers and diuretics, which are commonly used in treatment of high blood pressure, heart failure, or coronary heart disease. In addition to secondary hyperlipidemia, genetically caused dyslipidemias are illustrated by several examples in Table 11-2.

Atherosclerosis How adverse blood lipid profiles lead to atherosclerosis was addressed briefly in Chapter 3. Figure 11-1 presents a detailed representation based on the review by St. Clair, who noted:31, p 16 “any hypothetical scheme of the pathogenesis of atherosclerosis will be revised as new information becomes available . . . the pathogenic scheme will also be complex, because it must account for the fact that atherosclerosis is a disease of multiple etiologies and is influenced by a variety of environmental and genetic factors.” His scheme remains useful as an overview of the processes that link blood lipids with vascular pathology. The early stages of the process are shown at the left, later ones at the right. The row of elongated cells represents the single-layer endothelium (inner lining) of an arterial wall; the space above is the lumen and circulating blood (not shown), and below is the intimal layer of the arterial wall, with both cellular and extracellular components. The earliest steps shown involve the influx of cholesterol-laden lipoproteins through the endothelial cells and into the intima. This flow is counterbalanced by cholesterol efflux, mediated by HDL. Within the intima, biochemical modifications such as oxidation of LDL may occur,

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Table 11-3

Selected Causes of Secondary Hyperlipidemia

Related to hypercholesterolemia Hypothyroidism Nephrotic syndrome Chronic liver disease (mainly primary biliary cirrhosis) Dysglobulinemia Cushing’s syndrome Hyperparathyroidism Acute intermittent porphyria

Cushing’s syndrome Glucocorticoid use Beta-blocker use Diuretic use, hypopituitarism Hypothyroidism Pancreatitis Dysglobulinemia Glycogen storage disease

Related to hypertriglyceridemia Alcoholism Diabetes mellitus Obesity Estrogen use Chronic renal failure

Lipodystrophy Acute intermittent porphyria Pregnancy Stress Uremia

Source: Reprinted with permission from AM Gotto Jr, Lipid and lipid disorders, in TA Pearson et al., Primer in Preventive Cardiology, © 1994, American Heart Association.

producing molecular forms that damage endothelial cells. These products also convert macrophages, or “scavenger” blood cells, that have migrated from the circulating blood into the intima, into macrophagederived “foam” cells (so named from their microscopic appearance, because they are filled with bubble-like aggregates of cholesterol esters). Foam cells in turn release several substances that affect endothelial cell function and stimulate growth of arterial smooth-muscle cells. Late in the process, smooth-muscle cells also may become foam cells with high-cholesterol ester content. Connections between

endothelial cells become disrupted, and changes in endothelial cell function occur. Together, these alterations promote adhesion of blood platelets, leading in turn to localized thrombosis, or clot formation. The effect of small thrombi is to increase the size of the growing atherosclerotic plaque. Large thrombi can result in occlusion of the vessel, causing blockage of blood flow to the heart muscle and consequent clinical manifestations of myocardial ischemia or infarction. On the basis of this discussion, it would be expected that a blood lipid profile with high LDL and

Figure 11-1 Schematic of Cellular and Molecular Events in Pathogenesis of Atherosclerosis. Source: Reproduced with permission from RW St. Clair, Biology of atherosclerosis, in TA Pearson et al., Primer in Preventive Cardiology, p 123, © 1994, American Heart Association.

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low HDL cholesterol would foster and accelerate development of atherosclerosis. By contrast, when a favorable balance is maintained, with optimum absolute and relative levels of the blood lipid components, the essential cause of atherogenesis is lacking. It appears that in the absence of an adverse blood lipid profile, the other identified risk factors have only weak atherogenic effects. That atherosclerosis can progress at all under this circumstance appears paradoxical. However, evidence was noted earlier that risk of coronary events continues to be reduced with reduction in LDL-cholesterol from levels well below those conventionally thought to confer increased risk. Perhaps atherogenesis is stimulated when factors are present to increase oxidation of LDL or produce other adverse molecular changes, even at relatively low concentrations of LDL-cholesterol. This understanding supports rethinking assumptions in risk estimation and target-setting for treatment based on particular levels of blood lipids.

DISTRIBUTION Prevalence and Trends United States The percentage frequencies of high serum total cholesterol concentration ( 240 mg/dl) for US adults, aged 20–74 years, are shown in Table 11-4.27 Prevalence is in this instance defined by the measured values alone, regardless whether participants reported use of medication or other interventions to reduce cholesterol. (This contrasts with the approach for high blood pressure, as discussed in Chapter 12.) As noted above, age-adjusted data are shown for all persons, for each sex group, and by sex for each of three groups self-identified by race/ethnicity. The most recent data, from the National Health and Nutrition Examination Surveys conducted from 2003 to 2006, indicate overall prevalence of 16.3%. Prevalence was slightly greater for females than for males overall but, among those who were identified as Mexican, prevalence was less for females than for males. Prevalence was least (11.2%) among Black or African American men and greatest (17.9%) among White females. Poverty level, determined by family income and family size, is represented at three levels. The stratum below 100% of the poverty level had greater prevalence (18.2%) than higher strata (16.2 to 16.5%), a level higher than for any single sex–race/ethnicity group. Age-specific data, not shown here, indicate a doubling of prevalence for

males aged 35–44 years (20.5%) in comparison with those aged 20–34 years (9.5%). For females, prevalence at ages 20–34 years (10.3%) was not doubled until ages 45–54 years (19.7%), then increased an additional 50% at ages 55–64 years (30.5%). Trends in both prevalence of high serum total cholesterol levels and mean values from 1960–1962 to 2003–2006 are also indicated in Table 11-4, although data were not available by race/ethnicity prior to 1976–1980. Overall, prevalence decreased sharply—by more than 50%—from 33.3% to 16.3%. From 1976–1980 to 2003–2006, the greatest decreases in prevalence were among Blacks or African Americans and least among Mexicans. Mean values decreased over this period in a pattern similar to that for prevalence. Because treatment of high cholesterol is not taken into account, some of the apparent changes in prevalence and mean values over time, and differences between groups, may reflect differential effects of treatment. These changes are of special interest in relation to national goals for improving cholesterol levels in the population as a whole. Objectives set by the Healthy People 2010 process, within the focus area of heart disease and stroke prevention, were to reduce prevalence of high cholesterol to 17% and mean serum total cholesterol among adults to 199 mg/dl.32 Data from 1988–1994 were taken as the baseline. The prevalence target was already reached by 1999–2002, and the overall target for the mean level was nearly attained (reached for males but not females) by 2003–2006 (Table 11-4). A different approach to assessing changes in cholesterol over time was taken by Goff and colleagues, who conducted a birth cohort analysis based on the full frequency distribution of cholesterol values reported in each of these same national surveys, from 1960–1962 to 1988–1994.33 Figure 11-2 presents the observed (left panel) and estimated (right panel) distributions by age for persons born in successive decades (legend in the right panel). For example, persons born as early as 1920 but before 1930 would have been as young as age 30 in 1960–1962 and as old as age 70 in 1988–1994. For each decade of attained age at the time of a survey, for each cohort, the distribution of total cholesterol could be described by percentile values; the figure illustrates the 50th percentile, or median, values for each of these distributions. The observed data indicate, in general, lower median values of cholesterol at every age among successively more recent birth cohorts. The estimated data represent a model that extends beyond the observed data as though each age at observation were available for each birth cohort.

216 216 217 ------------211 217 217

222 220 224 -------------------

24.4 28.9 28.9

-------------

28.6 27.9 29.1 18.7 20.7 16.4 19.9 18.7 17.7

19.7 18.8 20.5

211 213 216

213 216 211 216 209 209

203 203 206

204 206 201 204 206 204

23.5 19.3 26.5 19.4 29.0 19.6 Mean Serum Cholesterol Level, mg/dl 215 205 213 204 216 205

26.4 29.6 25.5 26.3 20.3 20.5

27.8 26.4 28.8

200 203 203

202 204 195 200 205 198

203 203 202

17.8 18.8 16.5

17.0 17.4 12.5 16.6 17.6 12.7

17.0 16.9 17.0

203 201 200

199 203 193 194 203 199

200 199 201

18.2 16.5 16.2

16.0 17.9 11.2 13.0 17.7 13.8

16.3 15.6 16.9

Sources: CDC/NCHS, National Health and Nutrition Examination Survey, Hispanic Health and Nutrition Examination Survey (1982–1984), and National Health Examination Survey (1960–1962). Data from Health, United States, 2008, Table 72, pp 314–315.

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33.3 30.6 35.6

Percent of Population with High Serum Total Cholesterol (Greater Than or Equal to 240 mg/dl)

2/25/10

- - - Data not available. 1 Persons of Mexican origin may be of any race. Starting with 1999 data, race-specific estimates are tabulated according to the 1997 Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity and are not strictly comparable with estimates for earlier years. The two non-Hispanic race categories shown in the table conform to the 1997 Standards. Starting with 1999 data, race-specific estimates are for persons who reported only one racial group. Prior to data year 1999, estimates were tabulated according to the 1977 Standards. Estimates for single-race categories prior to 1999 included persons who reported one race or, if they reported more than one race, identified one race as best representing their race. See Appendix II, Hispanic origin; Race. 2 Data for Mexicans are for 1982–1984. See Appendix I, National Health and Nutrition Examination Survey (NHANES). 3 Age-adjusted to the 2000 standard population using five age groups: 20–34 years, 35–44 years, 45–54 years, 55–64 years, and 65 years and over (65–74 years for estimates for 20–74 years). Age-adjusted estimates may differ from other age-adjusted estimates based on the same data and presented elsewhere if different age groups are used in the adjustment procedure. See Appendix II, Age adjustment. 4 Includes persons of all races and Hispanic origins, not just those shown separately. 5 Percent of poverty level is based on family income and family size. Persons with unknown percent of poverty level are excluded (4% in 2003–2006). See Appendix II, Family income; Poverty. Notes: High serum cholesterol is defined as greater than or equal to 240 mg/dl (6.20 mmol/L). Borderline high serum cholesterol is defined as greater than or equal to 200 mg/dl and less than 240 mg/dl. Risk levels have been defined by the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. National Heart, Lung and Blood Institute, National Institutes of Health. September 2002. (Available from: http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm and summarized in JAMA 2001;285(19):2486–97). Individuals who take medicine to lower their serum cholesterol levels and whose measured total serum cholesterol levels are below the cut-offs for high and borderline high cholesterol are not defined as having high or borderline high cholesterol, respectively. See Appendix II, Cholesterol, serum. Standard errors for selected years are available in the spreadsheet version of this table. Available from: http://www.cdc.gov/nchs/hus.htm. Data for additional years are available. See Appendix III.

Both sexes Male Female Not Hispanic or Latino: White only, male White only, female Black or African American only, male Black or African American only, female Mexican male Mexican female Percent of poverty level:5 Below 100% 100%–less than 200% 200% or more 20–74 years, age-adjusted3 Both sexes4 Male Female Not Hispanic or Latino: White only, male White only, female Black or African American only, male Black or African American only, female Mexican male Mexican female Percent of poverty level:5 Below 100% 100%–less than 200% 200% or more

4

278

20–74 years, age-adjusted3

Serum Total Cholesterol Levels Among Persons 20–74 Years of Age or Over, by Sex, Age, Race and Hispanic Origin, and Poverty Level: United States, Selected Years 1960–1962 Through 2003–2006 [Data are based on interviews and laboratory work of a sample of the civilian noninstitutionalized population] Sex, Age, Race and Hispanic Origin,1 1960–1962 1971–1974 1976–19802 1988–1994 1999–2002 2003–2006 and Percent of Poverty Level

Table 11-4

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Cholesterol, mg/dL

275

50th Percentile

50th Percentile

250 1890 1900 1910 1920 1930 1940 1950 1960

225 200 175 150 10

20

50 60 30 40 Attained Age, y

70

80

10

20

30

40 50 60 Attained Age, y

70

80

Figure 11-2 Observed (Left Panel) and Estimated (Right Panel) 50th Percentile Curves for Serum Total Cholesterol Concentration for the Age Range 18 Through 74 Years by Birth Cohort. In the panels depicting estimated patterns, the solid lines reflect the ranges for which data were observed and the dotted lines reflect the ranges for which the values were extrapolated from the observed data. The models used to derive these estimates included the following independent variables: age, age2 (quadratic), birth year, and age2 by birth year. Scale intervals are equal in all panels, whereas the ranges differ as appropriate to each percentile shown. To convert cholesterol from milligrams per deciliter to millimoles per liter, multiply by 0.02586. Source: Reprinted with permission from Archives of Internal Medicine, Vol 162, © 2002, American Medical Association.

high cholesterol; 12.0% of the total were on treatment; and 5.4% of the total had a total cholesterol concentration below 200 mg/dl. An update to 2005–2006 reported that the proportion of persons with high cholesterol who had it controlled had increased to 17.1%.35 Medication use was reported by 54.4% of persons told of having high cholesterol,

1.5

Prevalence, %

The resulting picture is one of a marked downward shift in the cholesterol distribution among adults in the United States, over a period of more than three decades. Changes in peak values, at ages in the 50s, were greatest, and those at the earliest adult ages were least. These changes were not subject to effects of drug treatment of high cholesterol, both because people with median-level values were not considered to require treatment and because, in any case, effective treatment was not widely available. Comparable results were found across the whole distribution, with somewhat greater decreases in the 90th and 75th than in the 50th percentile, which in the more recent years probably indicate treatment effects additional to the population-wide shift in distribution. Figure 11-3 presents the whole cholesterol distribution for persons born in 1910 (dashed line) or in 1940 (solid line) who were examined at age 50 years. Again, it is evident that the entire distribution shifted downward over the three-decade interval, illustrated by these two birth cohorts. From a public health perspective, it is of further interest to know the extent to which people with high cholesterol are aware of the condition, are receiving appropriate intervention for it, and have it controlled. Ford and others reported on such data from the 1999–2000 cycle of the National Health and Nutrition Examination Survey (NHANES):34 High cholesterol was defined as a concentration 200 mg/dl or reported use of cholesterol-lowering medication. Prevalence by this definition was 55.7%; 69.5% of this total group had had a prior cholesterol check; 35.0% of the total were aware of having

1910 1940

1.0

0.5

0 100

150 200 250 300 350 Serum Total Cholesterol Concentration, mg/dL

400

Figure 11-3 The Estimated Distributions of Serum Total Cholesterol Concentration for 50-Year-Old Persons Born in 1910 and 1940. The models used to derive these estimates included the following independent variables: age, age2 (quadratic), birth year, age by birth year, and age2 by birth year. The prevalence is the estimated proportion of people with an exact cholesterol concentration. To convert cholesterol from milligrams per deciliter to millimoles per liter, multiply by 0.02586. Source: Reprinted with permission from Archives of Internal Medicine, Vol 162, © 2002, American Medical Association.

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a marked increase from 39.1% in 1999–2000. Another report, specific to LDL-cholesterol, indicated that nearly 30% of adults were eligible for treatment under ATP III guidelines—16% by “therapeutic lifestyle change,” or TLC, and 13.4% by drugs.36 But only 43.7% of those found with high LDL-cholesterol had been diagnosed previously, and only 77.4% of those—or 33.8% of the total group— reported being told to undertake TLC. Regarding elevated triglycerides, an evaluation of detection and treatment based on NHANES 1999–2004 suggested that recommended lifestyle changes—the principal approach at all but extreme elevations—are implemented infrequently, despite a high prevalence of overweight or obesity, physical inactivity, and smoking among those affected.37 Information regarding distributions of total cholesterol levels in children and adolescents is available from the 2005–2006 cycle of NHANES.38 Mean values were reported by sex and race/ethnicity for two age groups. For age 4 to 11 years, mean values ranged from 160.8 to 166.5 mg/dl, being lowest for Mexican American girls and highest for both Black and White non-Hispanic boys. For age 12–19 years, mean values ranges from 154.5 to 165.0 mg/dl, being lowest for

non-Hispanic White boys and highest for non-Hispanic White girls. Prevalence of total cholesterol levels 200 mg/dl was 9.6% of adolescents aged 12–19 years. For the reasons discussed above regarding age patterns of blood lipids in childhood and adolescence, these observations as reported by broad age groups give only limited insight to the dynamic changes in blood lipids during this period of life. The data are too sparse to permit reliable estimates of mean values by year of age for each sex–race/ethnicity group, as would be more informative.26 However, contrasting even these data for boys reveals a shift in distributions between the two age groups: for non-Hispanic Whites, from a mean value of 166.5 to 154.5 mg/dl; for non-Hispanic Blacks, from 166.5 to 161.7 mg/dl; and for Mexican Americans, from 162.3 to 158.2 mg/dl. Prevalence would have been considerably higher for the younger age group than that found at age 12–19 years, on the basis of a constant cut-point for all ages. Europe and Global Differences between populations in distributions of total cholesterol concentration were recognized several decades ago and were emphasized especially by Keys (Figure 11-4).39 In the absence of central stan-

Figure 11-4 Mean Values of Serum Cholesterol Concentration by Age in Clinically Healthy Men in Selected Populations. Source: Reprinted with permission from A Keys, Serum Cholesterol and the Question of Normal, in Multiple Laboratory Screening, ES Benson and PE Strandjord, eds, p 169, © 1969 Academic Press, Inc.

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DISTRIBUTION 281

dardization of laboratory methods at that time, comparison of these absolute values between populations is at best tenuous. Here the differences are very large, however, and even if not precise in terms of absolute differences in cholesterol levels at any given age, the overall distributions are clearly distinct between Japan, at the lower extreme, and Germany, New Zealand, and Minnesota, all at higher levels. In each of these populations, increases with age are apparent from the 20s to the 40s or beyond. Decreasing values at older ages in each of the populations, except those in Japan, are also notable. This pattern could reflect selective mortality of older persons with the highest cholesterol concentrations or cohort effects in which the oldest persons escaped the increased cholesterol levels that were experienced by younger ones. In Minnesota, data were also obtained for women. Their age curve for total cholesterol concentration also fell at the oldest ages, but with a peak in the age curve 15 years later than for men. Knuiman and colleagues studied a wider range of populations, in 1980, including Ghana, Ivory Coast, and Nigeria in Africa; Surinam in South America; Pakistan and the Philippines in the Pacific and Asia; and three groups in Europe (East and West Finland and Hungary).40 With a centralized laboratory to assure comparability, they found total cholesterol concentrations to vary widely among adults age 33–38 and 43–48 years across these populations. For example, total cholesterol concentration ranged from about 116 mg/dl in Nigerian men to 247 mg/dl in East Finnish men. A twofold range in HDL-cholesterol concentrations was also found, and HDL-cholesterol as a proportion of the total varied from 15–18% in Pakistani men to 29–32% in Ghanaians. Body mass index was positively associated with total cholesterol concentration and inversely related to HDL-cholesterol concentration across these populations. The most informative comparison of cholesterol levels, including awareness, treatment, and control, beyond the United States was provided by the WHO MONICA Project.41 Final risk-factor surveys in the 10-year project were conducted between 1989 and 1997, among adults aged 35–64 years, in 32 populations in 19 countries on three continents. Countries included were mainly in Europe, but China, Australia, New Zealand, Canada, and the United States were also represented. Hypercholesterolemia was defined for this analysis as 6.5 mmol/L (250 mg/dl) or reporting use of prescribed lipid-lowering medication within 2 weeks prior to the survey. Other cut-points were also displayed, as shown in Figure 11-5. The populations are ranked, separately for men and women, by decreasing prevalence of hypercholes-

terolemia defined as concentrations 5.0 mmol/L (195 mg/dl). In the figure, the solid bars represent prevalence at 6.5 mmol/L; the dotted bar adds prevalence due to positive history of recent lipidlowering medication use; the cross-hatched bar adds prevalence at 6.2 mmol/L (240 mg/dl); and the stippled bar adds prevalence attributed to levels 5.0 mmol/L. Total prevalence was greater for men than for women in this age range. At 6.5 mmol/L, the range of prevalence was from 3 to 53% among men and from 4 to 40% among women across populations. For each of the 32 populations, the mean serum total cholesterol concentration was reported, as well as the prevalence of values 6.5 mmol/L or reporting medication use; the proportion of the prevalent subgroup reporting treatment with drugs alone, diet alone, both, or neither; and the proportion of the prevalent subgroup defined as controlled, that is, having total serum cholesterol levels below 6.5 mmol/L. From 0 to 41% of those with hypercholesterolemia were treated with drugs alone; from 0 to 46% were treated with diet alone; from 0 to 48% were treated with both; and from 0 to 100% reported receiving no treatment. The proportion controlled, defined as 6.5 mmol/L, ranged from 0 to 100%, the median being about 55%. These observations present stark evidence of the gap between widely recommended goals for control of hypercholesterolemia and actual practice in the first comparative analysis of this kind. In childhood and adolescence, too, international comparisons have been made by various researchers, as illustrated in Figure 11-6.42 Again, absolute values are not comparable between these independent surveys, but overall patterns by age are generally similar. Very sharp increases occur from birth to age 1 year, as also found in other data, and mean values by age appear rather stable within each population across the school-age years. However, closer evaluation reveals a systematic pattern of a decrease and subsequent increase in total cholesterol concentration in adolescence in each population, although with some population differences in ages at the inflection points in the curve. This pattern of variation in total cholesterol concentration with age, and its difference by about 1 year in timing between sexes, is sufficient to raise concern about a fixed value as the screening criterion in youth, as noted previously.43 Knuiman, who surveyed adults in multiple countries, similarly surveyed populations of boys aged 13 years in 16 countries in Africa, Europe, and South Asia.44 Again, a central laboratory was used. Standardized determinations of total and HDL-cholesterol levels were carried out for all populations. Marked population differences were found

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Men

Women

SWI-TIC SWI-VAF GER-BRE SWE-NSW YUG-NOS CZE-CZE FRA-STR ICE-ICE UNK-GLA DEN-GLO BEL-GHE BEL-CHA UNK-BEL FRA-LIL FRA-TOU ITA-BRI LTU-KAU GER-EGE ITA-FRI AUS-NAW CAN-HAL POL-WAR SWE-GOT SPA-CAT AUS-PER POL-TAR RUS-NOI RUS-MOI USA-STA RUS-MOC RUS-NOC CHN-BEI

GER-BRE SWI-TIC SWI-VAF BEL-CHA CZE-CZE YUG-NOS SWE-NSW UNK-GLA LTU-KAU ICE-ICE BEL-GHE FRA-STR ITA-BRI FRA-LIL CAN-HAL DEN-GLO UNK-BEL FRA-TOU GER-EGE POL-WAR AUS-NEW ITA-FRI POL-TAR SPA-CAT SWE-GOT AUS-PER RUS-MOC RUS-MOI RUS-NOI RUS-NOC USA-STA CHN-BEI

0

20 80 40 60 Prevalence (%) of hypercholesterolemia 6.5 mmol/l

100

0

6.5 mmol/l or treatment

20 40 60 80 Prevalence (%) of hypercholesterolemia

6.2 mmol/l

100

5.0 mmol/l

Figure 11-5 The Age-Standardized Prevalence of Hypercholesterolemia for Men and Women in Age Group 35–64, WHO MONICA Project. Source: Reprinted with permission from International Journal of Epidemiology, Vol 34. H Tolonen, U Keil, M Ferrario, A Evans, for the WHO MONICA Project, Prevalence, Awareness and Treatment of Hypercholesterolemia in 32 Populations: Results from the WHO MONICA Project. pp 181–192 © International Epidemiological Association 2004.

at this age, not attributable to laboratory variation but perhaps due in part to differences in growth tempo across populations, in relation to the preadolescent peak described above. Some insight into population differences in total cholesterol levels is provided by Project HeartBeat!, a mixed longitudinal follow-up study in which children and adolescents were examined in Shibata, Japan, and The Woodlands and Conroe, Texas (Figure 11-7)43 (Darwin R. Labarthe, unpublished data, 2009). All determinations were conducted in CDCstandardized laboratories. Unexpectedly, given prior knowledge of exceptionally low cholesterol levels among adults in Japan, total cholesterol levels were higher for Japanese than American children and adolescents across the age range from 8 to 18 years. For both girls and boys, however, the difference was entirely attributable to greater HDL-cholesterol levels in Japan than the United States—and, in both popu-

lations, girls had higher HDL-cholesterol concentrations than did boys, from the early teens. Disparities Differences in cholesterol levels by age, sex, and race/ethnicity were described above. Whatever the underlying causes of these differences, once hypercholesterolemia is recognized, appropriate action to control it is expected under widely recognized guidelines. However, the report by Ford and others of an overall rate of 17% control at the level of 5.2 mmol/L in 2005–2006 also indicated marked variation in this indicator within the adult population.34 Control was especially poor among Mexican Americans— being 4.6% among men and 9.3% among women. Older persons, Whites or African Americans, and men had better rates of control than younger persons, Mexican Americans, and women. The benefits of es-

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Cholesterol (mg/dl) 200

150

100

North America (Black)

Finland (White)

Japan (Japanese)

Native American (Pima Indians)

50 0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

Age, Years Figure 11-6 Mean Values of Serum Total Cholesterol Concentration Among US Black, White, Japanese, and Native American Male Children, and Adolescents, Aged 0–19 Years. Source: Reprinted with permission from D Labarthe, B O’Brien, and K Dunn, International Comparisons of Plasma Cholesterol and Lipoproteins, in Hyperlipidemia in Childhood and the Development of Atherosclerosis, CL Williams and EL Wynder, eds, Vol 623, p 117, © 1991, Annals of the New York Academy of Sciences.

tablished guidelines are clearly not reaching all groups equally, nor any group to the intended degree.

RELATION TO RATES AND RISKS Population Differences The question of how the blood lipid profile relates to population differences in risk of coronary heart disease or other complications of atherosclerosis must be addressed mainly in relation to total cholesterol concentration. This is because at the inception of the long-term follow-up studies contributing such information only total cholesterol determination was practical and considered important. This is the case, for example, with the Seven Countries Study, which is uniquely valuable for such population comparisons.45 The 10-year mortality experience in that study shows the relation between coronary heart disease death rates and median serum total cholesterol

concentration for each population across the 16 cohorts of men age 40–59 years at entry, in the late 1950s to mid-1960s (Figure 11-8). Median cholesterol values ranged from about 160 mg/dl to 265 mg/dl, and 10-year coronary mortality varied from 1/1000 or less in Crete (K) to about 70/1000 in East Finland (E). The resulting regression equation indicates the positive coefficient for the relation between cholesterol concentration and coronary mortality. A correlation coefficient calculated with adjustment for age, systolic blood pressure, and smoking history was 0.82; the square of this value indicates the proportion of variation in rates among populations that is accounted for by median cholesterol concentration, approximately 67%. As is evident in this figure and as noted by Keys, there was little relation with population differences in mortality when cholesterol concentrations were below 200 or 210 mg/dl. In general, however, within-population relationships were strong at levels above 200 mg/dl, except in the lowestrate populations.

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4.9

Total Cholesterol (mmol/l)

4.7 Japanese girls

4.5

Japanese boys

4.3 4.1

US white girls

3.9 US white boys

3.7 3.5 3.3 7

8

9

10

11

12 13 Age (year)

14

15

16

17

18

HDL-Cholesterol (mmol/l)

1.7 1.6

Japanese girls

1.5

Japanese boys

White girls

1.4 White boys

1.3 1.2 1.1 1.0 7

8

9

10

11

12 13 Age (year)

14

15

16

17

18

Figure 11-7 Concentrations of Total Cholesterol and HDL-Cholesterol Among Japanese and US White Children and Adolescents, by Age, from 8 to 18 Years, Project HeartBeat!. Source: Unpublished data from Project Heartbeat!.

Further follow-up of the Seven Countries Study cohorts to 25 years permitted more detailed analysis, given greater numbers of events, especially when cohorts were grouped on the basis of geography, culture, and patterns of interim change in cholesterol concentration.46 Figure 11-9 illustrates the results of analysis by quartiles of baseline serum total cholesterol concentration. Coronary mortality increased with baseline cholesterol concentration in every group of populations except Japan, especially steeply for the higher observed cholesterol values. Further analysis took advantage of the repeated cholesterol determinations in most of the cohorts, at a 5-year follow-up

examination, to estimate and adjust for misclassification due to measurement variability (or regression dilution bias, discussed previously). This latter analysis showed, for all cohorts taken together, an overall average increase of 17% in coronary mortality for an increment of 20 mg/dl in median cholesterol concentration (relative risk 1.12, 95% confidence interval 1.09–1.16; risk estimate after adjustment, 1.17). The figure also shows wide population differences in mortality at fixed levels of cholesterol concentration, which overlap across regions at levels from between 175 mg/dl and 200 mg/dl to between 250 mg/dl and 275 mg/dl. The range in mortality for a fixed choles-

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E

Y = 10-Year Coronary Deaths per 1,000

70

60

50 R 40 N 30

20 S Z 10 U

V

T

W

I B

C

Y = –66 + 0.43X G

M

r = 0.80

D K

150

200

250

X = Median Cholesterol, mg/dl of Serum

Note: B, Belgrade; C, Crevalcore; D, Dalmatia; E, East Finland; G, Corfu; I, Italian Railroad; K, Crete; M, Montegiorgio; N, Zutphen; R, American Railroad; S, Slavonia; T, Tanushimaru; U, Ushibuka; V, Velika Krsna; W, West Finland; Z, Zrenjanin.

Figure 11-8 Ten-Year Coronary Death Rates and Median Serum Cholesterol Concentration. Source: Reprinted with the permission of the publisher from Seven Countries by Ancel Keys, Cambridge, Mass: Harvard University Press, © 1980 by the President and Fellows of Harvard College.

terol concentration was threefold or greater and indicates the collective influence of factors other than age, smoking, and systolic blood pressure, for which adjustment was made in the analysis. Individual Differences Total cholesterol concentration was also measured in each of the early cohort studies included in the US Pooling Project, with results as shown in Table 11-5.47 Among 8274 men age 40–59 years at entry, 647 events were recorded over 8.6 years of follow-up. The data are presented first for the standard pool of the five most comparable studies, together and separately (Albany, Chicago Gas, Chicago Western Electric, Framingham, and Tecumseh), and then for the three remaining studies (Los Angeles, Minnesota executives, and Minnesota Railroad workers). For each quintile category of baseline serum total cholesterol concentration, the incidence of first major coronary events is expressed as the ratio (times 100) of that rate to the overall rate in the total group.

Incidence below the population average results in a standardized incidence ratio less than 100; greater than average incidence results in a standardized incidence ratio greater than 100. For example, the standardized incidence ratio for the lowest quintile of total cholesterol concentration (below 195 mg/dl) was 72, whereas that for the highest quintile (greater than 268 mg/dl) was 158. It was noted that for several of the cohorts, including all of those in Pool 5, the lowest incidence ratio was in the second, not the first, quintile of cholesterol concentration. Therefore, the overall risk ratios were defined arbitrarily by relating incidence for quintile group V to that for quintile groups I and II combined. This risk ratio was 2.4 for Pool 5 and varied from 1.5 to 4.9 among studies. The 95% confidence intervals, having lower limits greater than 1 in all but one study, supported the presence of an association between serum cholesterol and coronary event rates. On the basis of the follow-up of men screened for the Multiple Risk Factor Intervention Trial, much

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35

Northern Europe Southern Europe, Mediterranean United States

30

Serbia Southern Europe, Inland Japan

CHD Mortality Rates, %

25

20

15

10

5

0 2.60 (100)

3.25 (125)

3.90 (150)

4.50 (175)

5.15 (200)

5.80 (225)

6.45 (250)

7.10 (275)

7.75 (300)

8.40 (325)

9.05 (350)

Serum Total Cholesterol, mmol/l (mg/dl)

Figure 11-9 Twenty-Five Year Coronary Death and Quartiles of Serum Cholesterol Concentration, Adjusted for Age, Cigarette Smoking, and Systolic Blood Pressure. Source: Reprinted from WMM Verschuren et al., Journal of the American Medical Association, Vol 274, p 131, © 1995.

more detailed analysis of this relation was possible.48 This very large study population of 361,662 men with, on average, 6 years of follow-up could be grouped in 20 units of 5 percentile levels, in contrast to the 5 units of 20 percentiles in the Pooling Project example. This offers greater resolution in examination of risk gradients, as shown in Figure 11-10. From the extreme values of 150 to nearly 300 mg/dl in cholesterol concentration, an exponential pattern of increasing risk was observed. Minimum risk was at the lowest levels, in contrast to the Pooling Project findings. The risk ratio between the highest and lowest of the 20 strata would be greater than 4 on the basis of this analysis. A study of the longer-term prediction of cardiovascular disease occurrence beginning at an average age of 22 years at baseline was reported from the 27- to 42-year follow-up of medical students in Johns

Hopkins University.49 The predictive value of cholesterol concentration was again demonstrated, although event rates increased sharply only after 20 years of follow-up. As shown in Figure 11-11, the lowest quartile group of baseline cholesterol concentration (118–172 mg/dl) was found to have the lowest cardiovascular disease incidence rates, still reaching 10%, whereas rates for the highest quartile group (209–315 mg/dl) reached nearly 40%. The studies cited above pertain mainly to total cholesterol concentration in men, chiefly White men of middle age. From studies in women, such as the Framingham Heart Study, individual risks in relation to blood lipids are in some ways similar to those in men but also importantly different.50,51 The age course of the blood lipid profile differs in women, with total and LDL-cholesterol increasing especially from age 40 to 60 years. VLDL-cholesterol and

MI-EX 100 70 (64) (78) (117) (117) (189) ( ) ( ) ( ) 283 4,008 28

LA 100 (42) (37) (46) 116 73 143 ( ) ( ) ( ) 1,104 10,137 72

100 49 (47) 50 77 96 194 4.0 3.4 7.6 2,551 12,484 112

MI-RR

Source: Reprinted with permission from Journal of Chronic Diseases, The Pooling Project Research Group, Vol 31, p 230, © 1978, Elsevier Science, Inc.

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Note: ( ), Based on fewer than 10 first events; ALB, Albany Civil Servants; CH-GAS, Chicago Gas Company; CH-WE, Chicago Western Electric Company; FRAM, Framingham; TECUM, Tecumseh, Michigan; LA, Los Angeles Civil Servants; MI-EX, Minnesota Businessmen; MI-RR, Minnesota Railroad Workers.

Serum Cholesterol: Parameters of the Bivariate Model for First Major Coronary Events, Pooling Project Study Group Pool 5 ALB CH-GAS CH-WE FRAM TECUM Quintile and Level (mg/dl) Standardized Incidence Ratio All All 100 100 100 100 100 100 I II 218 66 70 79 60 62 49 I 194 72 72 100 62 74 (10) II 194–218 61 67 61 57 50 (83) III 218–240 78 72 89 70 88 (56) IV 240–268 129 129 124 99 160 145 V 268 158 177 118 159 167 242 Risk ratio: V/(I II) 2.4 2.5 1.5 2.7 2.7 4.9 95% confidence interval: Low 1.9 1.7 0.9 1.7 1.7 2.0 High 2.9 3.8 2.4 4.6 4.0 13.1 Number of men at risk 8,274 1,765 1,264 1,980 2,130 1,135 Person-years of experience 70,781 16,878 11,064 16,505 19,480 6,854 Number of first events 647 156 123 142 177 49

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Figure 11-10 Serum Cholesterol Concentration and 6-Year Mortality from Coronary Heart Disease (CHD). Multiple Risk Factor Intervention Trial Screenees Aged 35–57 Years. Each point represents the median value for 5% of the population. Source: Reprinted with permission from MJ Martin et al., Serum cholesterol, blood pressure, and mortality: implications from a cohort of 361,662 men. Lancet, Vol 2, pp 933–936, © 1986, The Lancet, Ltd.

triglycerides also increase during this period, and HDL-cholesterol declines. The resulting adverse change in the HDL-/LDL-cholesterol ratio, with individual values ranging from greater than 7 to less than 5, was associated with a sharp gradient of 8year coronary risk in the Framingham Heart Study. Increased triglyceride levels also confer increased risk, as shown in a 19-year follow-up study of women aged 39–64 years, in Sweden.52 Over the period of

that study, total cholesterol and smoking prevalence both decreased among women, but triglyceride concentrations increased and offset the benefits of the other risk factor changes. It has been suggested that, whereas in general both LDL- and HDL-cholesterol relate to coronary risk in women as in men, the inverse risk gradient for HDL-cholesterol is stronger for women and that a given level of LDL-cholesterol may be less atherogenic for women.53

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0.40 0.35

209–315 mg/dl 190–208 mg/dl 173–189 mg/dl 118–172 mg/dl

Cumulative Incidence of Cardiovascular Disease

0.30 0.25

P159 and/or diastolic blood pressure >94; not on treatment for hypertension. IV. Systolic blood pressure 94; not on treatment for hypertension. IV. Systolic blood pressure 0.85 for females

Type 2 diabetes Impaired glucose tolerance or impaired fasting glucose

Raised triglycerides ( 1.7 mmol/l) and/or low HDL (< 0.9 mmol/l for men; < 1.0 mmol/l for women)

Insulin resistance

Microalbuminuria: urinary albumin excretion rate 20 g/min or albumin creatinine ratio 30 mg/g

At least 1 of

At least 2 of

Metabolic syndrome

Figure 13-2 Metabolic Syndrome as Defined by the WHO (WHO Consultation 1999). Source: Reprinted with permission from Coronary Heart Disease Epidemiology from Aetiology to Public Health, G Hu, Q Qiao, J Tuomilehto, p 312. © 2005 Oxford University Press.

simply be additional manifestations of another, yet unidentified, underlying cause; and that the inclusion of some weakly associated factors and exclusion of others more strongly related to insulin resistance further cloud the picture.15 In addition to the fundamental issue of definition, the meaning of this syndrome for risks of atherosclerotic and hypertensive diseases is debated as to whether it represents simply the aggregation of risk factors that often coexist or signifies a single underlying pathophysiologic entity as a potential target for prevention and treatment. In contrast, a still

Abdominal Obesity

broader interpretation of this complex set of interrelated conditions linked with insulin resistance has been suggested by Keen, that it results from “some much more general disturbance of adaptation to the conditions of modern life.”16, p xxviii The question of meaning and utility of the concept of the metabolic syndrome in children and adolescents was examined in an American Heart Association (AHA) Scientific Statement, which noted the lack of a universally accepted definition.17 Varying criteria limited comparability of the 15 identified studies in this age group.

Metabolic Syndrome Multiple Borderline Risk Factors

Cardiovascular Disease & Complications

Multiple Categorical Risk Factors Type 2 Diabetes

Diabetic Complications

Figure 13-3 Progression and Outcomes of the Metabolic Syndrome. The metabolic syndrome arises largely out of abdominal obesity. With aging and increasing obesity, metabolic risk factors worsen. Many persons with the metabolic syndrome eventually develop type 2 diabetes. As the syndrome advances, risk for cardiovascular disease and its complications increase. Once diabetes develops, diabetic complications other than cardiovascular disease often develop. The metabolic syndrome encompasses each stage in the development of risk factors and type 2 diabetes. Source: Reprinted with permission from the Journal of the American College of Cardiology, Vol 47, No 6, SM Grundy, p 1094. © 2006 by the American College of Cardiology Foundation.

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CHAPTER 13 DIABETES AND THE METABOLIC SYNDROME

Insulin Resistance Metabolic Syndrome (MetS)

PreDiabetes (75% MetS) Type 2 Diabetes (86% MetS)

Cardiovascular Disease

Figure 13-4 Interrelations and Overlap of Metabolic Syndrome with Insulin Resistance, Prediabetes, and Type 2 Diabetes. According to the insulin resistance hypothesis, the metabolic syndrome is caused predominantly by insulin resistance. The latter also contributes to prediabetes and, ultimately, to type 2 diabetes. About 75% of people with prediabetes and 86% of people with type 2 diabetes have the metabolic syndrome. Both metabolic syndrome and type 2 diabetes are known to predict cardiovascular disease. Source: Reprinted with permission from the Journal of the American College of Cardiology, Vol 47, No 6, SM Grundy, p 1095. © 2006 by the American College of Cardiology Foundation.

MEASUREMENT Diagnostic Criteria The unifying element of all diagnostic categories in diabetes mellitus is elevated blood glucose concentration, or hyperglycemia. Measurement of blood glucose concentration and the criteria for classification on this basis are the foundation of population studies as well as comparability of case identification in clinical research. Because blood glucose concentration varies in Table 13-1

relation to the timing of food intake, values based on casual samples, uncontrolled for food intake, are of little use. Reliable screening or diagnostic testing requires standardization, either through assurance of fasting for a fixed minimum period or through feeding a known quantity of glucose. In the latter approach, blood samples can be obtained in the fasting state and at one or more fixed intervals, such as 2 hours, after ingestion of a known glucose load. This approach is indicated in the diagnostic values for the oral glucose tolerance test as recommended by the WHO, shown in Table 13-1.18 Values in mmol/L are given for classification of diabetes mellitus, IGT, or IFG in either fasting or postload status and whether obtained as venous or capillary (finger stick) samples of whole blood or plasma. Even under these standardized conditions, classification for clinical purposes requires confirmatory testing because of intraindividual and laboratory variation and the prognostic importance of the diagnosis. As noted earlier, prediabetes as determined by either fasting plasma glucose (FPG) or oral glucose tolerance test (OGTT), corresponds to blood glucose levels of 100–126 mg/dl or 140–200 mg/dl, respectively. Screening Tests for Type 2 and Type 1 Diabetes Mellitus Additional measures are available for classifying individuals with respect to type 1 and T2DM.11 The oral glucose tolerance test is equal or superior in performance to other tests for T2DM, although at intermediate cost, whereas most tests to distinguish type 1 are higher in cost. These considerations enter into the design of population surveys to estimate prevalence of diabetes as well as other epidemiologic investigations. Population screening for purposes of case detection has previously been considered unjus-

Values for Diagnosis of Diabetes Mellitus and Other Categories of Hyperglycemia Glucose Concentration (mmol/L) Whole Blood Venous Capillary

Diabetes mellitus Fasting or 2 h post glucose load IGT Fasting (if measured) and 2 h post glucose load IFG Fasting and (if measured) 2 h post glucose load

Plasma Venous

ⱖ 6.1 ⱖ 10.0

ⱖ 6.1 ⱖ 11.1

ⱖ 7.0 ⱖ 11.1

6.1 and ⱖ 6.7

6.1 and ⱖ 7.8

7.0 and ⱖ 7.8

ⱖ 5.6 and 6.1 6.7

ⱖ 5.6 and ⱖ 6.1 7.8

ⱖ 6.1 and 7.0 7.8

Source: Reprinted with permission from Coronary Heart Disease Epidemiology from Aetiology to Public Health, M Marmot, P Elliott eds, DG Johnston, KGMM Alberti, IF Godsland, M Pierece, S Sheppard, p 715. © 2005 Oxford University Press.

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DETERMINANTS 367

tified because of lack of overall benefit of early detection and treatment.

DETERMINANTS Pathways of Insulin Action T2DM and insulin resistance together are the most relevant aspects of diabetes for risks of atherosclerosis and hypertension in the population at large. It is therefore especially important to appreciate the current understanding of the determinants of these conditions and the mechanisms by which they may contribute to these risks. The pathogenesis of insulin resistance is outlined schematically in Figure 13-5.19 Decrease in either glucose-induced insulin secretion from the pancreas, or in tissue response to insulin and uptake of glucose from the circulation, leads to

a chain of events that results in or intensifies insulin resistance. This is true, according to this scheme, even if the initiating process is impairment of beta-cell function in the pancreas, wherein which insulin is produced, although this is considered the less common sequence. The Thrifty Gene Hypothesis Neel introduced a genetic concept to explain the paradoxical observation that diabetes is detrimental to reproduction yet has also been a common condition in human populations, presumably over many generations.20 He postulated that if there was a selective disadvantage of diabetes, there must be a genetically determined selective advantage to counterbalance it. Under conditions of most of human evolution, this would operate by facilitating energy conservation against periods of acute starvation. Neel attributed

Insulin Deficiency

Glucose-Induced Insulin Secretion

Tissue Response to Insulin

Hepatic Glucose Production

Cellular Glucose Uptake

Impaired B-Cell Function Hyperglycemia Basal Hyperinsulinemia Glucose Transport

Postreceptor Defect

Insulin Binding Insulin Resistance

Note: Whether the primary defect initiating the glucose intolerance resides in the B cell or in per ipheral tissues, development of insulin resistance will eventually ensue or become aggravated, respectively. By the time that overt fasting hyperglycemia (>140 mg/dl) develops, both impaired insulin secretion and severe insulin resistance are present. Broken arrows represent positive feedback loops, which result in self-perpetuation of primary defect. Figure 13-5 Pathogenesis of Insulin Resistance in Non-Insulin Dependent Diabetes Mellitus (NIDDM). Source: RA DeFronzo, RC Bonadonna, E Ferrannini, Pathogenesis of NIDDM: A Precarious Balance Between Insulin Action and Insulin Secretion, in International Textbook of Diabetes Mellitus, KGGM Alberti et al., eds. Vol 1, p 617, Copyright © 1992, John Wiley & Sons Limited. Reproduced with permission.

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this advantage to what he termed a “thrifty” genotype, once advantageous but becoming detrimental under the dietary conditions of modern societies. The same argument, in principle, has been advanced to explain epidemic obesity. An extensive review of current knowledge concerning specific genetic mechanisms in type 1 diabetes and T2DM was given in Goldbourt and others’ Genetic Factors in Coronary Heart Disease, as well as by Vadheim and Rotter.21,22 Congruence of type 2 between identical twins has been reported to be approximately 90%, indicating strong genetic determination of susceptibility. In type 2, the gene NIDDM1 was identified and reported in a Mexican American population in 1996, but establishing its correspondence to the population-level phenomena of diabetes has been challenging.23 A recent review of genomewide association studies in connection with T2DM noted that some 20 loci had been identified and replicated, with allele frequencies considered as common though with only “modest to small” effects on disease risk.24 Studies of nonobese healthy subjects with a strong family history of T2DM have revealed subclinical metabolic disorders with tissue insulin resistance and pancreatic beta-cell susceptibility to toxic effects of free fatty acids.25 Genetic studies of the metabolic syndrome have also been reported, for example, from a multicenter study under the aegis of the ADA that identified linkages for three distinct metabolic syndrome components—obesity, blood pressure, and blood lipids—at different gene locations between Mexican American and non-Hispanic White participants.26 Predisposing Factors Population studies have suggested a number of predisposing factors for diabetes, such as those reported for men in the British Regional Heart Study.27 Men age 40–59 years were followed for more than 12 years on average, and 178 of 7097 participants developed T2DM. Factors studied included BMI, prevalent coronary heart disease, physical activity, alcohol intake, current smoking, systolic blood pressure, HDLcholesterol, triglycerides, heart rate, and uric acid concentration. Each characteristic was evaluated for its contribution to relative risk of T2DM, with adjustment for all of the others. BMI was clearly the strongest positive predictor of later T2DM, whereas physical activity was strongly inverse or negative as a predictor. Serum triglyceride concentration was second only to BMI in its estimated relative risk. An epidemiologic follow-up study after the first NHANES found incident diabetes to be significantly related to race (Blacks Whites), sex (women

men), age, BMI, subscapular-to-triceps skinfold ratio, systolic blood pressure, and having fewer than 9 years of education.28 Other studies of T2DM, IGT, or insulin resistance in diverse populations, including women, support the finding of BMI, central adiposity, and other anthropometric indices of obesity as consistent predictors. There is conflicting evidence of whether fetal or neonatal influences bear on risk of T2DM. This question is addressed further in Chapter 16, “Social and Physical Environment.” The ADA has defined prediabetes in terms of IFG or IGT by levels of fasting or postload plasma glucose considered most predictive of progression to diabetes—crossing the threshold to levels above 126 or 200 mg/dl, respectively. These are considered the strongest predictors of diabetes, although consideration of other factors such as those indicated above add to reliability of prediction. The ADA includes family history of diabetes and waist–hip ratio as factors independently related to risk of diabetes.29 Other predictors identified in various population studies include fasting insulin levels, fasting and 2-hour postload proinsulin (an insulin precursor also produced in the pancreas), and diminished insulin response to oral glucose.18 Studies of determinants of the metabolic syndrome have identified family history as a predictor, without distinction between genetic and environmental contributions. Racial/ethnic group comparisons have noted variation in prevalence of specific components of the syndrome, but little insight is offered as to whether there are aspects of race/ethnicity that predispose to the syndrome itself. Review of lifestyle behaviors similarly recognizes well-known relations between television watching and other forms of “screen time,” physical inactivity, and dietary patterns on the component risk factors.17 Analysis of follow-up data in the Framingham Heart Study showed consumption of soft drinks to be modestly associated (odds ratios ranging from 1.18 to 1.44) with new-onset metabolic syndrome (defined as three or more of five components: high waist circumference, fasting blood glucose, serum triglycerides, blood pressure, or low HDL-cholesterol) and each of the five components alone.30

MECHANISMS How diabetes and states now recognized as insulin resistance contribute to exacerbation of atherogenesis has been a long-standing question.1 Stout advanced the proposition, later incorporated in the concept of the insulin resistance syndrome, that insulin has a direct

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atherogenic effect in addition to potential secondary effects on other risk factors.31 Isolating the postulated effects of insulin from those of concomitant factors affecting atherosclerosis has been a major challenge, addressed, for example, by the Insulin Resistance Atherosclerosis Study (IRAS).32 In that study, insulin sensitivity, rather than insulin resistance, was assessed. Measures of atherosclerosis in IRAS were internal and common carotid arterial thickness, measured by B-mode ultrasound examination. In a cross-sectional analysis of these measurements in several hundred Hispanic and non-Hispanic White men and women with an average age of about 55 years, an inverse relation was found between insulin sensitivity and arterial wall thickness, especially of the internal carotid artery. This association was attenuated by adjustment for other risk factors. No such association was found for Blacks. With this latter exception, and with the limitation of the cross-sectional design, the results suggested a direct role of insulin in atherogenesis. Several mechanisms at the molecular level support the concept of a direct effect of insulin on cardiovascular pathology, as well as indirect effects on inflammation and a prothrombotic state.17,33–35 Mechanisms linking the metabolic syndrome with cardiovascular death, beyond the well-established links with its defining components, have been investigated to include several factors in adipose tissue regulation (adiponectin, leptin, and ghrelin) and the proinflammatory factors interleukin-6 (IL-6) and C-reactive protein (CRP).36 Association of the metabolic syndrome with coronary mortality appeared to account for its modest association with CRP. IL-6 appeared to be independent of the metabolic syndrome.

RELATION TO OTHER FACTORS It seems clear that the presence of diabetes is a marker for multiple influences on development and progression of atherosclerosis. Roots of these disturbances in dietary imbalance and physical inactivity, with their many known adverse effects, would predict these relationships. Diabetes, insulin resistance, and all of the conditions proposed to define the metabolic syndrome are closely related. Additional indirect roles of insulin operating through dyslipidemia and hypertension are supported by evidence of several mechanisms linking diabetes with these conditions.37 Other factors may participate in the increased atherogenesis of insulin resistance and diabetes, such as elevated blood concentrations of glucose, triglyceride, and fibrinogen.

Association of elevated insulin concentrations with obesity, hypertension, and adverse blood lipid profiles is evident in early adulthood and even in childhood.38,39 For example, already at ages 9–10 years, Mexican American children were found to have, in comparison with non-Hispanic White children, significantly greater clustering of elevated blood sugar and insulin concentrations with high triglyceride and low HDL-cholesterol concentrations, high systolic blood pressure, and high BMI. Features of the insulin resistance syndrome or metabolic syndrome appeared early in this population, whose risk of diabetes in adulthood is also especially high. Factors by which diabetes and hyperinsulinemia accelerate atherosclerosis can clearly be present well before adulthood. The Bogalusa Heart Study demonstrated clustering of metabolic syndrome components both in childhood and in early adulthood, with higher levels predicting greater changes from childhood into adulthood.40 Increases in BMI accounted for approximately 50% of the clustering of risk factors in this population. In Quebec, children and adolescents were examined at age 9, 13, or 16 years to investigate patterns of factors implicated in the insulin resistance syndrome.41 Prevalence of the syndrome was 11.5% overall without variation by age or sex. Adiposity was a stronger determinant of clustering of factors than was insulin concentration. Factor analysis revealed three clusters of risk factors: BMI/insulin/ lipids, BMI/insulin/glucose, and diastolic/systolic blood pressure. This finding suggested that characteristics identified with the syndrome were influenced by multiple underlying factors rather than reflecting a single pathophysiologic process.

DISTRIBUTION The United States Prevalence of diabetes among US adults is estimated on the basis of self-reported physician diagnosis of diabetes, with or without addition of laboratory measurement of blood glucose. Data from the NHANES 2003–2006 are shown in Table 13-2, with comparisons from 1988–1994 and 1999–2002.42 For 2003–2006, total prevalence at ages 20 years and older was 10.2%, with 7.7% and 2.5% diagnosed and undiagnosed, respectively. Prevalence was somewhat greater among males, nearly twice as great for non-Hispanic Blacks or African Americans and for Mexicans as for non-Hispanic Whites, and increased sharply with age. Total prevalence increased across

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Sources: CDC/NCHS, National Health and Nutrition Examination Survey. Data from Health, United States, 2008. National Center for Health Statistics, p 276.

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*Estimates are considered unreliable. Data preceded by an asterisk have a relative standard error (RSE) of 20%–30%. Data not shown have an RSE of greater than 30%. 1 Physician-diagnosed diabetes was obtained by self-report and excludes women who reported having diabetes only during pregnancy. 2 Undiagnosed diabetes is defined as a fasting blood glucose (FBG) of at least 126 mg/dl and no reported physician diagnosis. Respondents had fasted for at least 8 hours and less than 24 hours. Estimates in some prior editions of Health, United States included data from respondents who had fasted for at least 9 hours and less than 24 hours. In 2005–2006, FBG testing was performed at a different laboratory and using a different instrument than testing in earlier years. NHANES conducted a crossover study to evaluate the impact of these changes on FBG measurements. As a result of that study, NHANES recommended that 2005–2006 data on FBG measurements be adjusted to be compatible with earlier years. Undiagnosed diabetes estimates in Health, United States were produced after adjusting the 2005–2006 FGC data as recommended. For more information, see http://www.cdc.gov/nchs/data/nhanes/nhanes_05_06/glu_d.pdf. 3 Persons of Mexican origin may be of any race. Starting with 1999 data, race-specific estimates are tabulated according to the 1997 Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity and are not strictly comparable with estimates for earlier years. The two non-Hispanic race categories shown in the table conform to the 1997 Standards. Starting with 1999 data, race-specific estimates are for persons who reported only one racial group. Prior to data year 1999, estimates were tabulated according to the 1977 Standards. Estimates for single-race categories prior to 1999 included persons who reported one race or, if they reported more than one race, identified one race as best representing their race. See Appendix II, Hispanic origin; Race. 4 Estimates are age-adjusted to the year 2000 standard population using three age groups: 20–39 years, 40–59 years, and 60 years and over. Age-adjusted estimates in this table may differ from other age-adjusted estimates based on the same data and presented elsewhere if different age groups are used in the adjustment procedure. See Appendix II, Age adjustment. 5 Includes all other races and Hispanic origins not shown separately. Notes: Standard errors are available in the spreadsheet version of this table. Available from: http://www.cdc.gov/nchs/hus.htm. Starting with Health, United States, 2007, data use a revised weighting scheme. Data have been revised and differ from previous editions of Health, United States. Data for additional years are available. See Appendix III.

Diabetes Among Adults 20 Years of Age and over, by Sex, Age, and Race and Hispanic Origin: United States, 1988–1994, 1999–2002, and 2003–2006 (Data are based on interviews and physical examinations of a sample of the civilian noninstitutionalized population) Sex, Age, and Race Physician-Diagnosed and Physician-Diagnosed Undiagnosed and Hispanic Origin3 Undiagnosed Diabetes1,2 Diabetes1 Diabetes2 1988–1994 1999–2002 2003–2006 1988–1994 1999–2002 2003–2006 1988–1994 1999–2002 2003–2006 20 years and over, Percent of population age-adjusted4 All persons5 8.3 9.4 10.2 5.4 6.6 7.7 2.9 2.8 2.5 Male 8.8 10.7 11.2 5.4 7.0 7.6 3.4 3.6 3.6 Female 7.9 8.3 9.4 5.4 6.2 7.8 2.5 2.1 *1.6 Not Hispanic or Latino: White only 7.5 7.9 8.8 5.0 5.2 6.4 2.5 2.7 2.4 Black or African American 12.6 14.9 16.0 8.6 11.3 13.2 4.0 3.6 2.8 only Mexican 14.2 13.7 15.7 9.7 10.5 12.4 4.5 3.1 *3.3 20 years and over, crude All persons5 7.8 9.3 10.3 5.1 6.5 7.7 2.7 2.8 2.5 Male 7.9 10.2 10.9 4.8 6.7 7.4 3.0 3.5 3.5 Female 7.8 8.5 9.7 5.4 6.3 8.1 2.4 2.2 1.7 Not Hispanic or Latino White only 7.5 8.4 9.5 5.0 5.5 6.9 2.5 2.9 2.6 Black or African American 10.4 13.4 14.4 6.9 10.1 11.8 3.4 *3.3 2.5 only Mexican 9.0 8.3 10.9 5.6 6.5 7.9 3.4 1.8 *3.0 Age 20–39 years 1.6 *2.3 2.5 1.1 1.7 1.7 *0.6 * * 40–59 years 8.8 9.8 10.6 5.5 6.6 8.3 3.3 3.3 *2.3 60 years and over 18.9 20.9 22.9 12.8 15.1 16.9 6.1 5.8 6.0

Table 13-2

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the three survey periods in every sex–race category, as did diagnosed diabetes; undiagnosed diabetes declined slightly or remained constant. The National Diabetes Fact Sheet, a Web-based information service from the Centers for Disease Control and Prevention (CDC), provides updated estimates of prevalence, incidence, and general information about diabetes in the United States.43 Projecting 2003–2006 NHANES data to the 2007 US population estimates, 23.6 million Americans or 7.8% of the population have diabetes and nearly 200,000 people younger than age 20 have diabetes, type 1 or 2. Prediabetes was estimated to affect 57 million adults aged 20 or older, or 25.9% of the adult population, in 2006.44 Among adults, more than 1.5 million new cases are estimated to occur each year. State-specific incidence was estimated for 33 states from self-reported data in the Behavioral Risk Factor Surveillance System.45 Persons with diabetes reported as diagnosed within the year preceding the survey were in-

Table 13-3

cluded in the calculation of incident cases, over two time periods—1995–1997 and 2005–2007. Overall incidence increased from 4.8/1000 per year in the first period to 9.1/1000 in the second. Rates increased in every state, ranging from an increase of 15% in Wyoming to 216% in Idaho. Reasons for these increases may include improved case detection, but this has been deemed unlikely as a full explanation. Rates are among the highest in American Indians and Alaska Natives, according to data from the Indian Health Service.46 Increasing prevalence among women and men younger than age 35 from 1994 to 2004 based on health services data may represent a mix of increasing incidence and increasing detection, but reached 17.1% by 2004. T2DM is now known to occur in childhood and adolescence but has not yet been tabulated in Health US as has been the case for adults. Difficulty in comparing estimates in children is readily apparent in Table 13-3, drawn from varied population- and clinic-based sources in North America.47 Depending on data type,

Estimates of the Magnitude of Type 2 Diabetes in North American Children Age Years Race/Ethnicity (Years)

Study types Population-based studies Arizona

1992–1996

Pima Indians

Manitoba NHANES III, all US

1996–1997 1988–1994

First Nations Whites, African Americans, Mexican Americans

Clinic-based studies Indian Health Services (all US)

10–14 15–19 10–19 12–19

1996

American Indians

1998

First Nations

Cincinnati, OH Case series

1994

Whites, African-Americans

10–19

Cincinnati, OH

1994

Whites, African-Americans

Charleston, SC San Diego, CA

1997 1993–1994

0–19 10–19 0–19 0–16

San Antonio, TX Ventura, CA

1990–1997 1990–1994

Manitoba

371

0–14 15–19 5–14 15–19

Clinic-based studies

Blacks Whites, African-Americans, Hispanics, Asian Americans Hispanics, Whites Hispanics

0–17

Estimates Prevalence per 1,000 22.3 50.9 36.0 in girls 4.1*

1.3* 4.5* 1.0 2.3 Incidence per 100,000/year 7.2 Percentage of type 2 diabetes among new cases of diabetes 16 33 46† 8 18 45

*Estimates include type 1 and 2 diabetes; †percentage of type 2 diabetes among nonincident cases of diabetes. Adapted from A. Fagot Campagna, D.J. Pettitt, MM Engelgau, NR Burrows, LS Geiss, R Valdez, G Beckles, J Saaddine, EW Gregg, DF Williamson, KM Venkat Narayan, J Pediatrics. In press. Source: Reprinted with permission from Diabetes Care, Vol 23, No 3, March 2000. American Diabetes Association, Consensus Statement, Type 2 Diabetes in Children and Adolescents, p 383.

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race/ethnicity, and age, prevalence is reported from 1.0 to 50.9%. One report of incidence indicates a rate of 7.2/100,000 per year among mixed Whites and African Americans aged 10–19 years. Clinical diabetic populations with newly diagnosed diabetes are described as 8–45% T2DM, whereas historically virtually all diagnoses at this age were type 1. Healthy People 2010 identified 17 objectives for improvement in diabetes.48 The objective of preventing diabetes was represented by a baseline (1997–1999 data) incidence of 5.5/1000/year and a target level of 3.8/1000/year. At the Midcourse Review evaluation (2000–2002 data) incidence had increased rather than decreased, as data above indicated. Similarly, the total prevalence of diagnosed diabetes had increased—baseline 40/1000, target 25/1000, midcourse evaluation, and prevalence increased. However, large gains were made in reducing diabetes-related deaths and cardiovascular deaths in persons with diabetes, as well as performance of annual examinations for microalbuminuria. Regarding the metabolic syndrome, prevalence among adults aged 20 years or older was estimated from NHANES III, 1988–1994, by Ford and others, using the ATPIII criteria (three of five measures at critical levels of: waist circumference, serum triglycerides, HDL-cholesterol, blood pressure, and serum

Table 13-4

glucose).49 Overall prevalence was 23.7%, with a steep age gradient—6.7% at age 20–29 years, and greater than 40% over age 60 years. The column “ⱖ 3” in Table 13-4 refers to all who qualified as having the metabolic syndrome. For both men and women, prevalence was highest among Hispanics. Striking variation appeared by sex and race/ethnicity in prevalence of the individual components of the syndrome. For each of the five components, shown in Table 13-5, the range from least to greatest prevalence (%) across the three major race/ethnic groups was abdominal obesity, 23.3 for African American men to 62.7 for Mexican American women; hypertriglyceridemia, 14.4 for African American women to 39.7 for Mexican American men; low HDL-cholesterol, 22.6 in African American men to 46.3 in Mexican American women; high blood pressure or medication use, 27.8 in White women to 46.3 in Mexican American women; and high fasting glucose or medication use, 8.5% in White women to 21.4% in Mexican American men. The metabolic syndrome, as defined, appears to be dominated by different components across sex and race/ethnic groups, although this analysis did not present the distribution of characteristics restricted to those who met criteria for the syndrome.

Age-Adjusted Prevalence of 1 or More Abnormalities of the Metabolic Syndrome Among 8814 US Adults ⱖ 20 Years, National Health and Nutrition Survey III, 1988–1994 No. of Metabolic Abnormalities, % (SE) ⱖ1 ⱖ2 ⱖ3 ⱖ4 5 71.2 (1.0) 43.9 (1.1) 23.7 (0.8) 10.4 (0.5) 2.7 (0.3) 71.5 (1.2) 44.9 (1.3) 24.0 (1.1) 11.1 (0.9) 2.4 (0.4) 70.9 (1.2) 42.7 (1.3) 23.4 (0.9) 9.6 (0.5) 2.9 (0.3)

Total Men Women Race or ethnicity White African American Mexican American Other Men White African American Mexican American Other Women White African American Mexican American Other

70.1 (1.2) 75.6 (0.8) 78.9 (1.0) 71.2 (3.1)

43.2 (1.2) 45.1 (1.0) 54.4 (1.1) 41.8 (4.0)

23.8 (1.0) 21.6 (0.8) 31.9 (1.3) 20.3 (3.3)

10.8 (0.6) 8.4 (0.7) 12.0 (1.0) 7.1 (1.5)

2.9 (0.3) 1.8 (0.4) 2.3 (0.4) 1.5 (0.6)

71.5 (1.4) 70.3 (1.3) 74.8 (1.5) 70.2 (4.6)

45.5 (1.5) 37.3 (1.5) 51.5 (1.5) 42.9 (4.2)

24.8 (1.4) 16.4 (1.1) 28.3 (1.8) 20.9 (4.7)

12.4 (1.1) 6.3 (0.8) 9.4 (1.0) 3.6 (1.2)

2.8 (0.5) 1.2 (0.3) 1.6 (0.4) 0.9 (0.5)

68.4 (1.5) 80.0 (1.0) 84.0 (0.9) 71.3 (4.6)

40.7 (1.5) 51.3 (1.3) 57.7 (1.4) 40.0 (4.6)

22.8 (1.1) 25.7 (1.3) 35.6 (1.5) 19.9 (3.1)

9.2 (0.6) 10.0 (0.9) 14.7 (1.3) 10.5 (2.5)

3.0 (0.3) 2.3 (0.5) 3.1 (0.6) 2.1 (1.2)

*See the “Methods” section for a description of the 5 criteria of the metabolic syndrome. Source: Reprinted with permission from Journal of the American Medical Association, Vol 287, No 3, ES Ford, WH Giles, WH Dietz, p 358, © 2002 American Medical Association.

30.5 (1.2) 23.3 (1.3) 30.6 (1.7) 26.4 (7.5) 43.5 (1.4) 62.1 (1.5) 62.7 (1.7) 40.0 (4.8)

1712 1116 1277 160 1887 1296 1172 194

25.0 (1.1) 14.4 (1.0) 35.2 (1.3) 26.0 (4.4)

36.9 (2.0) 21.4 (1.2) 39.7 (1.5) 29.4 (4.0)

31.1 (1.3) 17.7 (0.8) 37.7 (1.0) 27.3 (3.3)

39.3 (1.9) 34.0 (1.7) 46.3 (1.7) 39.6 (4.6)

36.8 (1.6) 22.6 (1.7) 33.7 (2.0) 33.2 (5.2)

37.9 (1.5) 28.8 (1.3) 39.6 (1.5) 37.1 (4.5)

27.8 (0.9) 43.3 (1.3) 32.4 (1.7) 23.7 (2.3)

37.2 (1.8) 49.6 (1.5) 40.2 (1.7) 34.4 (4.0)

32.8 (1.0) 46.3 (0.9) 36.6 (1.2) 29.6 (2.9)

Source: Reprinted with permission from Journal of the American Medical Association, Vol 287, No 3, ES Ford, WH Giles, WH Dietz, p 357, © 2002 American Medical Association.

*HDL indicates high-density lipoprotein.

37.2 (0.9) 44.6 (1.2) 45.7 (1.3) 33.6 (5.2)

3599 2412 2449 354

8.5 (0.6) 15.5 (1.3) 18.5 (1.2) 14.4 (2.9)

15.6 (1.0) 14.5 (1.1) 21.4 (1.5) 15.1 (3.3)

11.9 (0.6) 15.1 (0.9) 20.0 (1.0) 14.3 (2.0)

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Total Men Women Race or ethnicity White African American Mexican American Other Men White African American Mexican American Other Women White African American Mexican American Other

Age-Adjusted Prevalence of Individual Metabolic Abnormalities of the Metabolic Syndrome Among 8814 US Adults ⱖ 20 Years, National Health and Nutrition Survey III, 1988–1994* % (SE) High Blood High Fasting No. of Abdominal Low HDL Pressure or Glucose or Participants Obesity Hypertriglyceridemia Cholesterol Medication Use Medication Use 8814 38.6 (0.8) 30.0 (1.1) 37.1 (1.2) 34.0 (0.8) 12.6 (0.5) 4265 29.8 (1.2) 35.1 (1.7) 35.2 (1.5) 38.2 (1.4) 15.6 (0.8) 4549 46.3 (1.2) 24.7 (0.9) 39.3 (1.4) 29.3 (0.8) 10.0 (0.6)

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Table 13-5

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Global Distribution Figure 13-6 indicates the prevalence of diabetes (type 1 and type 2) and glucose intolerance according to WHO criteria in 33 population groups.51 The range is from less than 5% to more than 60% of affected persons in the group aged 30–64 years. These results combine sex groups and are age standardized to the world population. In most populations, the combined frequency was below 25% but in two it exceeded 50%. With the exception of Nauru and the Pima Indian population of the United States, prevalence varied along a continuous gradient. This suggests that common influences varying only in degree may account for differences in prevalence in most popula-

Another analysis from NHANES III presented data on prevalence of metabolic syndrome in participants aged 12–19 years, by use of the same characteristics as in the ATPIII definition but with cut-points defined for adolescents.50 Overall, 6.1% of males and 2.1% of females were affected, with a concentration of 30% among those who were overweight (partly, of course, because of abdominal circumference as one of the defining criteria). Prevalence varied by sex, race/ethnicity, region, and BMI status. As described above for adults, prevalence of the component conditions varied markedly by sex and race/ethnicity, giving the syndrome different meanings across the groups.

Mapuche Indian, Chile urban Chinese, Da Qing rural Melanesian, PNG Polish rural Polynesian, W. Samoa rural Bantu, Tanzania rural Indian, India Russian Brazilian rural Melanesian, Fiji Italian, Sanza Maltese urban Bantu, Tanzania Italian, Laurino White, USA Tunisian urban Hispanic, USA* rural Micronesian, Kiribati urban Polynesian, W. Samoa urban Indian, India urban Melanesian, Fiji rural Hispanic, USA Black, USA urban Indian, S. Africa Puerto Rican, USA urban Hispanic, USA# Chinese, Mauritius urban Hispanic, USA• rural Indian, Fiji urban Indian, Fiji urban Micronesian, Kiribati Micronesian, Nauru Pima Indian, USA

25%

0

10

20

30

50%

40

50

60

70

Prevalence (%) * upper income # middle income low income

Diabetes mellitus Impaired glucose tolerance

Figure 13-6 Prevalence of Total Glucose Intolerance (Diabetes and Impaired Glucose Tolerance) in Selected Populations Aged 30–64 Years, Age Standardized to the World Population of Segi, Sexes Combined. Source: Reprinted with permission from H King and M Rewers, WHO Ad Hoc Diabetes Reporting Group, Diabetes Care, Vol 16, p 170, © 1993, American Diabetes Association.

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tions, whereas determinants of prevalence in the two extreme cases may be qualitatively distinct. The impression from the figure is that the prevalence of diabetes contributed more than did IGT to these population differences. More detailed information from several populations demonstrates ethnic differences in prevalence of T2DM within the same country.52 In some instances, ethnic variation was marked, with a fourfold or greater difference among groups such as White and Aborigine groups in Australia. The gradient in the United States was from 6.1 to 9.9, 12.6, and 34.1% prevalence among Whites, Blacks, Mexican Americans, and Pima Indians, respectively. Similarly, the contrasting situation of Asians and Europeans in the United Kingdom has been of special interest, the former having prevalence of diagnosed diabetes 3.8 or more times that of Europeans in the same geographic area.53 Evidence suggests strongly that diabetes is a significant problem in developing countries and especially in their urban components. The global frequency of diabetes has been estimated by the Disease Control Priorities in Developing Countries Project, at a prevalence of 5.1% in 2003 and projected to 6.3%—more than a 20% increase—by 2025 (Table 13-6).8 Diabetes would then affect more than 330 million people worldwide. Current estimates are that 959,000 deaths and nearly 20 million DALYs (life years lost to disability) worldwide are attributable to diabetes annually. Developing countries have the greatest burden to date, although this is nearly equaled in the region of Europe and Central Asia. Overall, developing countries dominate by far in diabetes burden and are far short in medical expenditures to address it, relative to developed countries.

RATES AND RISKS The Seven Countries Study, so informative regarding population differences in coronary or all-cause death rates attributable to other factors, did not examine diabetes and related conditions. Keys ascribed this decision to the view that reliable assessment of blood glucose required both fasting and postglucose load blood samples, for which funding was insufficient. In addition, risk of loss to participation was considered to be high.54 At the level of individual differences in cardiovascular risks and outcomes due to diabetes and related conditions, many questions have been addressed through population surveys, case-comparison studies, cohort studies, and community surveillance programs.

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On this basis, several topics regarding the relation of diabetes to cardiovascular disease can be reviewed. Asymptomatic Hyperglycemia and Coronary Heart Disease A landmark international collaboration regarding blood glucose and coronary heart disease, reported in 1979, led to assembly of data from 14 population studies in Australia, Europe, Japan, and the United States.55 The purpose was to determine whether elevated blood glucose concentration, in the absence of diabetes, was associated with coronary heart disease. Because methods of glucose determination differed among studies, the focus was on the relation between blood glucose concentration and coronary disease as within-population associations. In four of the seven studies in which postload glucose determinations were available, prevalent coronary heart disease defined as definite post-myocardial infarction was associated with baseline blood glucose concentration. In most of the studies coronary heart disease, however defined, was significantly more frequent in the highest than in lower quintile groups of the blood glucose distribution. Mortality from coronary heart disease, cardiovascular diseases, and all causes at 5 years was examined in 11 of the studies. The independent contribution of blood glucose levels to risk was assessed after adjustment for age, body mass index, systolic blood pressure, serum cholesterol, and cigarette smoking. No significant relation was found for any of the three outcomes in most of the studies. A striking exception was the analysis based on postload glucose, unique to the Chicago Peoples Gas Study, which showed a highly significant association for each cause of death category. Casual—nonfasting—glucose in the same study was not associated with coronary or all-cause mortality. In the same 11 studies, the ratio of all-cause mortality in the highest quintile of baseline blood glucose concentration to that in the lowest quintile ranged from 0.34 to 6.07; five results were below 1.00, or inverse. Overall, the investigators concluded that “At this juncture, therefore, asymptomatic hyperglycemia cannot be designated an established risk factor for coronary heart disease and the major adult cardiovascular diseases.”55, p 837 The indication that results might differ between fasting and postload blood glucose levels as predictors of cardiovascular outcomes continued to stimulate interest that gained new attention when the ADA approved diagnostic criteria for diabetes based on fasting blood glucose (FBG). Comparison of the predictive role of FBG versus 2hBG (2 hour postload blood glucose) for death from all causes, cardiovascular disease,

Source: Number of persons with diabetes, prevalence of diabetes, and direct medical costs of diabetes, International Diabetes Federation 2003b; all other information WHO 2004. From Disease Control Priorities in Developing Countries, Second Edition, edited by DT Jamison et al., Copyright © 2006. Courtesy of The International Bank for Reconstruction and Development/ The World Bank.

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Estimated Numbers of People Aged 20 to 79 with Diabetes, Mortality, DALYs, and Direct Medical Costs Attributable to Diabetes, by Regions Number of People Prevalence Direct Medical Costs, 2003 Disability (Thousands) (Percent) (US$ million) Deaths Adjusted Life Low High 2001 Years, 2001 Region 2003 2025 2003 2025 Estimate Estimate (Thousands) (Thousands) Developing countries 140,849 264,405 4.5 5.9 12,304 23,127 757 15,804 East Asia and the Pacific 31,363 60,762 2.6 3.9 1368 2656 234 4930 Europe and Central Asia 25,764 33,141 7.6 9.0 2884 5336 51 1375 Latin America and the Caribbean 19,026 36,064 6.0 7.8 4592 8676 163 2775 Middle East and North Africa 10,792 23,391 6.4 7.9 2347 4340 31 843 South Asia 46,309 94,848 5.9 7.7 840 1589 196 4433 Sub-Saharan Africa 7595 16,199 2.4 2.8 273 530 82 1448 Developed countries 53,337 68,345 7.8 9.2 116,365 217,760 202 4192 World 194,186 332,750 5.1 6.3 128,669 240,887 959 19,996

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coronary heart disease, and stroke was undertaken by the DECODE (Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe) Study Group.56 Ten prospective studies in Europe, all based on 75 g glucose load for baseline blood glucose, included more than 22,000 participants followed for an average period of 8.8 years. It was found that 2hBG was significantly predictive of all-cause, cardiovascular, and coronary mortality (but not stroke), whereas FBG was significant only for all-cause mortality (hazard ratio 1.21, confidence interval 1.01–1.44, versus 1.73, confidence interval 1.45–2.06, for 2hBG). When the associations with 2hBG were adjusted by addition of FBG, no significant improvement in prediction was observed, but when the reverse analysis was done, 2hBG significantly improved the predictions found for FBG. This led the DECODE Group to conclude that 2hBG was the better predictor. The long-term cohort study of British civil service workers, the Whitehall Study, reported on the relation between 2 hour postload blood glucose levels determined at baseline examinations in 1967–1969 and deaths through 2002.57 They found a significant linear gradient of risk related to glucose levels upward from 4.6 mmol/L (83 mg/dl) as a threshold, with no increase in risk at lower levels, which ranged from 3.0 to 4.6 mmol/L. Adjustment for other factors (existing coronary disease and several risk factors assessed at baseline) attenuated the graded relation by 45%. Direct comparison of the observed glucose values with other studies was limited, because the glucose load in this study was 50 g rather than the more widely used 75 g, which would result in higher glucose concentrations. The report concluded that “our evidence is consistent with no association between 2hBG and CHD risk in the lower and central parts of the population distribution of postload glucose but a relatively low level at which CHD risk associated with postload glycemia begins to rise.”57, pp 29–30 A separate question concerns the relation between hyperglycemia, or elevated blood glucose, on the outcome of acute coronary events. This was the topic of an AHA Scientific Statement summarizing evidence that both 30-day and 1-year mortality after hospitalization for acute coronary syndromes (ACS) increased with the blood glucose level determined at hospital admission.58 Higher blood glucose was associated with 30-day mortality, which increased fourfold in patients without diabetes but only slightly in the presence of diabetes. Whether blood glucose is directly related to this increase or is only a marker of an unidentified mechanism was considered to be an important question for further research.

Insulin and Coronary Heart Disease Whether blood insulin concentration is itself a risk factor for coronary heart disease has been studied with respect to both endogenous insulin (hyperinsulinemia or insulin resistance) and exogenous insulin (insulin therapy). Studies of both aspects have been inconsistent. Possible reasons for differences in findings were discussed in a review in Diabetes in America (1995), by Wingard and Barrett-Connor, who concluded that “the role of insulin as a heart disease risk factor remains controversial.”59, p 444 McKeigue and Keen, evaluating the evidence available in 1991, expressed doubt that insulin caused the relation of the insulin resistance syndrome to coronary risk. They pointed to the possibility that proinsulin or split proinsulins, which are separately identifiable insulin-like molecules, may be more directly involved.60 Further population studies, they noted, may help to resolve this question. Diabetes and Coronary Heart Disease Wingard and Barrett-Connor also summarized the extensive literature on coronary heart disease and diabetes.59 The National Hospital Discharge Surveys between 1989 and 1991 reported the frequencies of cardiovascular diagnoses, including several categories of coronary heart disease, among persons whose discharge diagnoses did or did not include diabetes. In every category, the diagnosis of diabetes was associated with a higher percentage of cardiovascular diagnoses, for both women and men. Studies of prevalence of coronary heart disease in relation to concurrent findings of NIDDM, IGT, or normal blood glucose indicated higher frequency of coronary heart disease among women in each of four categories of coronary heart disease and among men in three of four categories. Excess prevalence was greater for women than for men, counter to the usually observed advantage of women over men in age-specific coronary heart disease rates; this suggested that diabetes may offset factors accounting for the usual advantage of women. Incident coronary heart disease was compared between categories of diabetes in four cohort studies. Three of these studies included women. The estimated risk ratio for new coronary events was greater in women than in men, whether adjusted for age alone or for multiple (unspecified) factors. Similarly, risks of reinfarction after acute myocardial infarction were reviewed and were found elevated for diabetics, variously defined. A subsequent meta-analysis of 8 studies with 10 race/ethnic group-specific analyses further established the absence of a female advantage

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in coronary mortality relative to men, in the presence of diabetes (Figure 13-7).61 A further report from the DECODE Study Group, cited previously, addressed a gender difference in all-cause and coronary mortality in the presence of hyperglycemia and newly diagnosed diabetes.62 These conditions had greater adverse effects on all-cause and cardiovascular mortality among women than among men. Mortality from ischemic heart disease in four US sex–race groups, at ages 45–64 years, was studied on the basis of national death certificate data, the National Health Interview Survey, and the 1986 National Mortality Follow-Back Survey.63 These data sources were used for improving estimates of the true relation of diabetes to coronary heart disease deaths. This report emphasized limitations of death certificate data as a basis for ascertaining the presence of diabetes: the follow-back data showed diabetes was present in from two to three times as many decedents as was indicated on their death certificates. For women and men, Blacks and Whites, there was a marked excess of ischemic heart disease mortality among persons with diabetes, after adjustment for underreporting of diabetes. The relation of diabetes to cardiovascular death has evidently been underestimated substantially in many studies. Mexican Americans were once thought to experience lower mortality from coronary heart disease than non-Hispanic Whites, on the basis of state-level statistical reports. However, in the one community, Corpus Christi, Texas, they have been found in direct community surveillance to have greater hospitalization rates and shorter survival after acute myocardial infarction than their non-Hispanic White counterparts.64 Because diabetes is more prevalent in the Mexican American population, analysis of the relation of a self-reported history of diabetes to coronary events was undertaken (Figure 13-8). The pattern of survival after myocardial infarction indicates that diabetes conferred similar losses in survival for both Mexican Americans and non-Hispanic Whites. Much, though not all, of the mortality differential between ethnic groups can be accounted for by the more frequent presence of diabetes among Mexican Americans. The contribution of diabetes to risk of subsequent coronary heart disease was the focus of a study by Stern and others in a Finnish cohort.65 They compared 7-year incidence of fatal and nonfatal coronary events between nondiabetic persons with or without prior myocardial infarction at baseline (18.8 and 3.5%, respectively) and diabetic persons in the corresponding subgroups (45.0 and 20.2%, respec-

tively). There was no significant difference in risk between persons with prior myocardial infarction but not diabetes and persons with diabetes but no prior myocardial infarction. It was concluded that treatment of cardiovascular risk factors in persons with diabetes should therefore be fully as aggressive as for persons with prior myocardial infarction. (This became the basis for regarding diabetes as a “CHD equivalent” in risk stratification in ATPIII—see Chapter 11, “Adverse Blood Lipid Profile.”) Several further studies of this question have supported this finding and also noted that greater duration of diabetes is associated with increased coronary heart disease mortality.66–69 For example, a 25-year follow-up of the men screened for the Multiple Risk Factor Intervention Trial (MRFIT) permitted comparison of cause-specific mortality among those who reported a previous hospitalization for heart attack, use of medications for diabetes, both conditions, or neither condition at screening (Table 13-7). Ageadjusted death rates for all causes and cardiovascular causes showed nearly identical rates for those with past history of MI only or diabetes only; differences between these groups in non-CVD causes were due largely to deaths from diabetes in the group with diabetes at entry. Metabolic Syndrome and Coronary Heart Disease Studies of the relation between metabolic syndrome and coronary heart disease can be illustrated by examples of cross-sectional analysis of data from NHANES III and the prospective British Regional Heart Study.70,71 The former analysis indicated that prevalence of coronary heart disease was greatest among persons with both diabetes and metabolic syndrome defined by the ATPIII criteria. Presence of diabetes in the absence of the metabolic syndrome was not associated with increased prevalence of coronary heart disease. The second of these reports compared the metabolic syndrome and the Framingham Risk Score regarding their predictive power for coronary heart disease, stroke, and T2DM mellitus. Metabolic syndrome predicted diabetes better than coronary heart disease, but Framingham risk score was the better predictor of coronary heart disease. Stroke Association between diabetes and stroke has been demonstrated in many studies, including autopsy examination of cerebral circulation and carotid arteries, clinical series of diabetics, and population studies in several countries. A review by Pyörälä and

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Summary Estimates for Coronary Heart Disease Mortality in Men Slievers et al77 (Pima Indian) Pan et al56 (White) Keil et al53 (Black) Keil et al53 (White) Kleinman et al54 (White) Vilbergsson et al13 (White) Jousilahti et al22 (White) Collins et al52 (Melanesian) Collins et al52 (Indian) Barrett-Connor et al51 (White) Random Effects 0.10

10.00

1.00

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(A) Summary Estimates for Coronary Heart Disease Mortality in Women Slievers et al77 (Pima Indian) Pan et al56 (White) Keil et al53 (Black) Keil et al53 (White) Kleinman et al54 (White) Vilbergsson et al13 (White) Jousilahti et al22 (White) Collins et al52 (Melanesian) Collins et al52 (Indian) Barrett-Connor et al51 (White) Random Effects 0.10

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10.00 Odds Ratio (B)

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Figure 13-7 Odds Ratios and 95% Confidence Intervals for the Risk of Coronary Heart Disease Mortality for Diabetic vs Nondiabetic Men (A) and Women (B). Source: Reprinted with permission from Archives of Internal Medicine, Vol 162, AM Kanaya et al., p 1741. © 2002 American Medical Association.

Source: Reprinted with permission from Archives of Internal Medicine, Vol 164, O Vaccaro et al., p 1440. © 2004 American Medical Association.

Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction; MRFIT, Multiple Risk Factor Intervention Trial. *A total of 688 deaths (646, 22, 19, and 1 in the Neither MI nor Diabetes, MI Only, Diabetes Only, and Both Diabetes and MI groups, respectively) had unknown causes. † Rates are given as age-adjusted deaths per 10,000 person-years.

Cause of Death All causes CVD CHD Stroke Other CVD Non-CVD Cancer Renal disease Diabetes Other

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All-Cause and Cause-Specific Mortality According to History of MI and Diabetes at Initial Screening for the MRFIT Neither MI nor Diabetes MI Only Diabetes Only Both Diabetes and MI (n 322,775) (n 4625) (n 4809) (n 338) No. of Age-Adjusted No. of Age-Adjusted No. of Age-Adjusted No. of Age-Adjusted Deaths* Rate† Deaths* Rate† Deaths* Rate† Deaths* Rate† 76,419 107.3 2715 278.0 2855 277.3 250 421.8 30,620 43.1 1852 193.7 1502 144.2 159 263.6 20,795 29.2 1498 159.4 1087 104.0 126 207.9 3168 4.5 90 8.1 154 14.2 10 11.7 6657 9.4 264 26.2 261 26.0 23 44.1 45,153 63.3 841 81.6 1334 131.5 90 156.1 28,244 39.6 470 45.5 431 40.2 32 52.4 665 0.9 24 2.0 55 5.8 3 2.7 1101 1.5 35 3.2 445 46.3 31 52.8 15,143 21.2 342 30.9 403 39.2 24 48.3

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Figure 13-8 Proportion of Patients Hospitalized with Acute Myocardial Infarction (MI) Surviving 0–44 Months, by Diabetic Status and Ethnicity, Corpus Christi Heart Project, 1988–1990. Source: Reprinted with permission from PRF Orlander et al., The Relation of Diabetes to the Severity of Acute Myocardial Infarction and Post-Myocardial Infarction Survival in Mexican Americans and Non-Hispanic Whites: The Corpus Christi Heart Project, Diabetes, Vol 43, p 900, © 1994, American Diabetes Association.

colleagues demonstrated increased risk of stroke by a factor of two to four times in diabetics when compared with nondiabetics.72 The 20-year follow-up of women and men in the Framingham Heart Study reported that fatal and nonfatal occlusive stroke, together, occurred 2.6 times more frequently in diabetic men and 3.8 times more frequently in diabetic women than in their nondiabetic counterparts. Again, as was the case for coronary heart disease, diabetes had a greater impact on risk of stroke for women than for men. The American Heart Association report on risk factors for stroke emphasized diabetes among the “potentially modifiable” factors in relation to occlusive stroke, implicating impaired glucose tolerance, hyperinsulinemia, and insulin resistance syndrome in the increased risk.73 Associations of diabetes with cardiovascular conditions extend beyond coronary heart disease and stroke. The review by Wingard and Barrett-Connor linked diabetes with congestive heart failure and cardiomyopathy, and Pyörälä and colleagues described associations of diabetes with atherosclerosis of the aorta and peripheral arteries as well.59,72

Large- and Small-Vessel Disease A leading source of information on factors associated with development of vascular disease among diabetics is the WHO Multinational Study of Vascular Disease in Diabetics.74 In this study, the prevalence of large-vessel disease (affecting the coronary, cerebral, and peripheral arteries) and small-vessel disease of the eyes and kidneys was determined among 6695 diabetic men and women in three age groups from 35 to 54 years in local centers in 14 countries. The results indicated an overall prevalence of large-vessel disease in nearly 30% of males and 40% of females. For all ages together, prevalence of this condition ranged from 21.9 to 52.9% for women and from 19.1 to 38.4% for men across 14 countries. Cultural differences in interpretation of questionnaire items for chest pain and other symptoms limit the interpretation of these population differences, however. In multivariate regression analysis, age, duration of diabetes, systolic blood pressure, body mass index, and total cholesterol were related to large-vessel disease in men; only age, blood pressure, and body mass index were related in women. In both men and

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women, small-vessel disease of the eye was associated with duration of diabetes, systolic blood pressure, body mass index, and treatment of diabetes, whereas vascular disease of the kidney was associated with duration of diabetes and cholesterol concentration alone. Microalbuminuria, another manifestation of renal involvement with diabetes, has been found to be significantly associated with all-cause mortality in several European studies. It has often, though not always, correlated with manifestations of coronary heart disease in cross-sectional surveys.59 It is unclear to what extent these associations are independent of other risk factors and whether microalbuminuria may be an expression of the underlying atherosclerotic process. Public Health Impact Diabetes has been estimated by the Global Burden of Disease and Risk Factors Study as the cause of 960,000 deaths at all ages worldwide in 2001.75 It ranked among the top 10 causes of death in Latin America and the Caribbean, but not other Regions. Yach and others estimated that 175 million persons worldwide had diabetes in 2000 and projected 353 million in 2030.76 Among the most populous countries, of which 12 have more than 100 million population, percentage prevalence ranged from 2.4 (China) to 8.8 (US) % in 2000 and from 3.7 (China) to 11.2 (US) % in 2030. Prevalence was projected to increase in each of these countries, as well as all developing countries (4.1 to 6.0%), developed countries (6.3 to 8.4%), and the world (4.6 to 6.4%). Given the evidence reviewed above regarding rates and risks of cardiovascular diseases in consequence of diabetes, these projected trends imply a significantly growing impact of diabetes in contributing to cardiovascular morbidity and mortality in the coming years.

PREVENTION AND CONTROL Recent demonstration, through controlled clinical trials, that T2DM mellitus could be prevented by lifestyle intervention has greatly broadened the scope of prevention and control of diabetes. Formerly the focus was on prevention or treatment of complications in people with diabetes. Much of the research addressed questions of improving control of blood glucose levels, and the benefits of doing so, in both type 1 and T2DM. The new emphasis on prevention of T2DM remains largely a high-risk oriented strategy, based on identification and selection of persons with above-average risk of developing diabetes- those with IGT, IFG, or prediabetes. Individual-level measures still predominate in discussion of diabetes prevention.

However, the conditions immediately predisposing to the early pathogenesis of diabetes—dietary imbalance, physical inactivity, and obesity—and the additional factors that lead to its macrovascular complications—adverse lipid profile, high blood pressure, and smoking—all offer community or population-wide dimensions to prevention and control. Prevention and control of diabetes therefore incorporates the population-wide strategy, as well as the global measures addressed in other chapters. Individual Measures Prevention of T2DM New knowledge established the efficacy of lifestyle modification (diet and physical activity) in preventing progression from IGT or IFG to reach the critical level for diagnosis of diabetes. On the basis of earlier epidemiologic studies of factors leading to progression of IGT or IFG to T2DM and efforts to modify this progression by drug or behavioral intervention, the World Bank and the Ministry of Health of The People’s Republic of China sponsored the Da Qing IGT and Diabetes Study to investigate this concept further.77 Screening in 33 healthcare clinics in 1986 identified persons with IGT, and mean BMI 25.8 kg/m2, who were randomly assigned by clinic to one of four groups: control (patient education and information only); diet only; physical activity only; or diet plus physical activity. Monitoring over a period of 6 years demonstrated incidence of T2DM to be 67.7% in the control group and from 41.1 to 46.0% in the intervention groups. Both lean and overweight participants showed benefit of intervention. Overall, the interventions resulted in a 54 to 69% decrease in diabetes incidence, as reported in 1997. A trial in Finland, with recruitment from 1993–1998, also implemented lifestyle interventions aimed at prevention of progression from IGT to diabetes, in middle-aged adults with mean BMI 31 kg/m2.7 Intervention targets were improvements in diet and physical activity that would bring about weight loss. Cumulative incidence of diabetes was 11% in the intervention group and 23% in the control group, a 58% reduction. Notable were statistically significant improvements in weight, fasting, and 2hPG blood glucose, HDL-cholesterol and triglycerides, and systolic and diastolic blood pressure attributable to the lifestyle intervention. Both lifestyle and pharmacologic intervention were tested in the Diabetes Prevention Program (DPP), a US trial of prevention in adults with mean BMI 34 kg/m2.78 After an average of 2.8 years of follow-up, incidence of diabetes was 11.0% in the placebo control group, 7.8%

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in the metformin-treated intervention group, and 4.8% in the lifestyle intervention group. Lifestyle intervention was more effective than medication and reduced diabetes incidence by 58%. A subsequent trial in India enrolled participants who were younger, leaner, and more insulin resistant, overall at greater risk of progression to diabetes, than the three preceding trial populations.79 Four groups studied were controls, lifestyle intervention alone, metformin alone, and lifestyle intervention plus metformin. Incidence of diabetes at 30 months was 55% in controls and ranged from 39.3 to 40.5% in the three other groups, with no advantage to combined intervention. Translation of the DPP intervention into practical management programs has received attention in a number of studies. A cost-effectiveness evaluation by use of the Archimedes model, a simulation model for assessment of clinical interventions, concluded that the lifestyle intervention of DPP:80, p 251 “. . . is likely to have important effects on the morbidity and mortality of diabetes and should be recommended to all high-risk people. The program used in the DPP study may be too expensive for health plans or a national program to implement. Less expensive methods are needed to achieve the degree of weight loss seen in the DPP.” A review of epidemiologic studies and clinical trials relevant to primary prevention of diabetes concluded:81, p 445 “Overall, a healthy diet, together with regular physical activity, maintenance of a healthy weight, moderate alcohol consumption, and avoidance of sedentary behaviors and smoking, could nearly eliminate T2DM. However, there is still a wide gap between what we know and what we practice in the field of public health; how to narrow that gap remains a major public health challenge.” Part of the gap is frequent lack of awareness of having prediabetes, a necessary step in the link to preventive measures.82 Data from the US National Health Interview Survey conducted in 2006 demonstrated that, although the estimated prevalence of prediabetes includes at least one-fourth of the adult population, only 4% of respondents reported awareness of having it. Even among those who were aware, taking action to prevent progression to diabetes was limited, according to self-report, to 68% for attempted weight loss, 60% for reduced dietary fat or calories, 55% for increased physical activity, and 42% for all three interventions. Diabetes Control Control of diabetes, once present, requires detection, evaluation, and long-term management. These are in principle clinical activities, although public health

support may be critical for development and adoption of relevant policies and practices, including assurance of guideline implementation. In addition, community resources can be instrumental in facilitating favorable long-term lifestyle patterns, self-management, and interaction with healthcare settings for recommended periodic follow-up and evaluation. Central to control of diabetes and the other factors contributing to cardiovascular complications, morbidity, and mortality is availability of recognized practice guidelines. Examples in the arena of diabetes are guidelines of the ADA and counterparts in Europe— the Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD) (Task Force).83,84 Highlights of the ADA Standards for Medical Care in Diabetes–2009 include aspects of screening, diabetes management, risk-factor assessment and control, monitoring for complications, and special considerations.83 Screening for prediabetes or T2DM in asymptomatic people is limited to people who are overweight or obese and have one or more additional risk factors or who are more than 45 years of age. Screening in children depends on family history, race/ethnicity, detection of associated conditions, and gestational history and should begin at the earlier of age 10 years or onset of puberty. IGT or IFG requires intervention to achieve 5–10% weight loss. Treatment goals for diabetes control are based on measurement of hemoglobin A1C (HgbA1C), a stable indicator of usual blood glucose levels; values 7% are considered a reasonable target for prevention of macrovascular complications. Medical Nutrition Therapy (MNT) is recommended in both prediabetes and diabetes and includes dietary change and physical activity. Diabetes Self-Management Education (DSME) is advised. Blood pressure, blood lipids, platelet function, and smoking are to be addressed. Monitoring for such complications as kidney, eye, and peripheral nerve complications, and attention to all of these issues in children with diabetes is also recommended. Special issues may arise in management of diabetes at school, at work, and in the event of hospitalization. The Task Force report, in addition to its recommendations, provides a valuable current overview of epidemiology and prevention of diabetes.84 Recommendations are presented in the context of applicable evidence, in more general form than those of the ADA. For example, assessment of risk of T2DM is recommended as part of routine health care, without qualification as to a target group or exclusions from screening. The link with cardiovascular risk is

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indicated in the recommendation that persons with CVD and without diabetes should be screened with an oral glucose tolerance test. High risk of diabetes should trigger lifestyle counseling, with pharmacologic therapy if needed, and drugs can be used to delay onset of diabetes in those with IGT. Treatment recommendations to reduce cardiovascular risk include lifestyle and comprehensive management, glycemic control, and attention to specific guidelines for addressing dyslipidemia, high blood pressure, and management of coexisting cardiovascular disease. Discussion of health economics is included, with the observation that diabetes is associated with a considerable share of healthcare costs in Europe, due mainly to its cardiovascular complications. The US Preventive Services Task Force recommendations either are silent or find evidence insufficient regarding screening for diabetes except in adults with hypertension or hyperlipidemia.85 Recent trials have provided evidence regarding glucose control among persons with diabetes and its role in preventing cardiovascular complications.86 This remains an area of uncertainty as to benefits and risks due to increased frequency of adverse decreases in blood glucose (hypoglycemia) when treatment is directed to strictly preventing above-target levels (“tight control”). The main protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, for example, was terminated early because of excess deaths in the intensive therapy group. The UK Prospective Diabetes Study (UKPDS) observed a decrease in microvascular but not macrovascular complications of diabetes, with increased frequency of hypoglycemia.87 (These results differ importantly from those in intensive treatment of type 1 diabetes, where the Diabetes Control and Complications Trial (DCCT) found at the close of the trial and after extended follow-up that tight glucose control reduced incidence of major cardiovascular events by 57%.88) Metabolic Syndrome A 2005 AHA Scientific Statement addressed diagnosis and management of the metabolic syndrome, as defined by ATPIII, as a strategy for prevention of both cardiovascular disease and T2DM:89, p e289 It is recognized that the metabolic syndrome is a complex disorder, with no single factor as the cause. . . . The presence of the syndrome is associated with increased long-term risk for both ASCVD [atherosclerotic cardiovascular disease] and type 2 diabetes mellitus, and thus requires attention in clinical practice. Lifestyle interven-

tions deserve prime consideration for risk reduction across a lifetime; these interventions include weight control, increased physical activity, and a diet designed to reduce the risk of ASCVD. . . . Drug therapies should be used according to current recommendations for individual risk factors. At the present time, drug therapy is not recommended specifically to reduce risk for type 2 diabetes mellitus independent of treatments to prevent ASCVD. Community or Population-Wide Measures On the basis of available intervention studies either in communities or in healthcare systems, the Community Preventive Services Task Force found some populationlevel interventions sufficiently supported to warrant recommendation.90 These were disease management and case management in the healthcare system and diabetes self-management education in community settings (for adults with T2DM) and in the home (for children and adolescents with type 1 diabetes). Intervention on disease management was characterized as using “organized, proactive, multicomponent approaches to healthcare delivery for people with diabetes” with care that is “focused on, and integrated across, the spectrum of the disease and its complications, the prevention of comorbid conditions, and the relevant aspects of the delivery system, with the goal of improving both short- and long-term health or economic outcomes.”90, p 193 The Task Force added to its definition inclusion of all members of a population with diabetes and enumerated essential components of disease management to be considered. Criteria for effective programs were achievement of glycemic control as measured by glycosylated hemoglobin, and the percentage of providers who perform annual monitoring for control and potential complications of diabetes. Case management, by contrast, “identifies people at risk for excessive use of healthcare resources, poor coordination of healthcare services, or poor health outcomes and addresses their needs through improved planning, coordination, and provision of care.”90, p 197 Criteria for effectiveness and essential components were elaborated for case management as for disease management. Diabetes self-management education (DMSE) has longstanding recognition in diabetes care and refers to the process of teaching people to manage their diabetes. The Task Force required evidence of quantitative improvement in community levels of glycosylated hemoglobin as a criterion of effectiveness and found this to be met only in the specific settings

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that are recommended. This was not the case for DSME in summer camps or at worksites. The focus of these measures is clearly on persons with diabetes, as individuals or as the affected group within a community. However, the interventions have a community or population-wide impact in establishing the policies or systems by which disease management or case management become established and are supported in a community. Other interventions at the community or population level that would contribute to diabetes prevention and control are those addressing dietary imbalance, physical inactivity, obesity, adverse blood lipid profile, high blood pressure, and smoking. These are discussed in other chapters as interventions for cardiovascular disease prevention. Diabetes prevention and control is an important additional benefit of effective interventions in these several areas. Global Strategies Prevention and control of diabetes mellitus were first addressed by the World Health Assembly in 1989 in a resolution calling on Member States to assess the problem, implement population-based measures for prevention and control, share training opportunities, and establish model community programs.91 The Director-General was requested to support these activities, develop collaborative arrangements with the IDF and other agencies, and engage the WHO collaborating centers on diabetes in these efforts. A Study Group convened in 1992 was a part of the response to this resolution.11 The concepts of prevention outlined in the Study Group report addressed both population-wide and high-risk strategies. On the basis that risks of morbid events in diabetes are low except for those with blood glucose values near the upper extreme, it was judged that the population strategy may be inappropriate in many populations and that high-risk approaches for those with familial risks or clusters of other risk characteristics may be more cost-effective. Assessment of the distribution of diabetes and its determinants in a given target population was recommended in establishing the best approach or combination of approaches for that population. Against this background, the Study Group report noted the importance of IGT as a target for intervention, given its intermediate position in the distribution between normal and diabetic categories. This is analogous, as noted earlier, to the identification of borderline high blood pressure or cholesterol concentration as especially warranting preventive measures. The report suggests, however, that IGT is

an entity in itself and not simply part of the continuum of the blood glucose distribution. A focus on the “putative risk factors”—physical inactivity, nutritional factors, and obesity—was proposed, with the conclusion that “there is general agreement that dietary modification and exercise should serve as the cornerstones in the prevention of diabetes and the treatment of people with the disease.”11, p 29 It was noted that malnutrition in utero leading to low birth weight may also predispose to diabetes in adult life, suggesting preventive measures in maternal health before and during pregnancy. High-risk individuals were characterized as those with strong family history of NIDDM; persons changing through migration or otherwise to Westernized, urban, or sedentary lifestyles; women with histories of gestational diabetes or IGT; and persons with other components of the metabolic (or insulin resistance) syndrome. Measures to be taken for such high-risk persons were control of obesity; maintenance of lowfat, high-fiber dietary habits; increased physical activity; and avoidance of specific drugs that may impair glucose metabolism. Guidelines and programs to implement these recommendations were addressed in publications from WHO.91,92 These reports provide references to a number of detailed manuals and materials valuable in the support of such programs. It is noteworthy that recommendations generally disfavor screening for purposes of case detection, even among family members of known cases, except in high-risk populations.93 The perspective of low- and middle-income countries is fundamental to the work of the Disease Control Priorities Project in addressing the broad range of major global health burdens. Accordingly, discussion of diabetes centers on cost-effectiveness in developing country settings of interventions for preventing and treating diabetes and its complications (Table 13-8).55 Three levels of intervention are distinguished: level 1, cost saving and feasible; level 2, cost saving but not entirely feasible or costing less than US$1500 per QALY (quality of life-adjusted years saved) and “at least moderately feasible”; and level 3, estimated cost from US$1640 to US$8550 per QALY and judged less feasible than level 1 or 2 interventions. As described in the table, the three levels of intervention are alike in identifying personal interventions that are heavily reliant on clinical care. Distinct from these are the “Essential background intervention,” diabetes education, and the “Other promising intervention,” a “polypill.” Diabetes education refers once again to the concept of self-management discussed previously. It was considered that this intervention may be cost-effective, and diabetes education

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Table 13-8 Intervention

Key Cost-Effective Interventions for Preventing and Treating Diabetes and Its Complications Description Applicable Population Major Effect

Level 1a • Glycemic control in people with poor control

Insulin, oral glucose-lowering agents, diet and exercise

People with diabetes, all ages, HbA1c greater than 9 percent

Reduction in microvascular disease

• Blood pressure control

Blood pressure control medications

People with diabetes, hypertensive, all ages

Reduction in macrovascular disease, microvascular disease, and mortality

• Foot care

Patient and provider education, foot examination, foot hygiene, and appropriate footwear

People with diabetes, middleaged or older

Reduction in serious foot diseases and amputations

Patient self-management

Women with diabetes who plan to become pregnant

Reduction in HbA1c level and hospital expenses of the mother and baby

• Lifestyle intervention to prevent diabetes

Behavioral change, including diet and physical activity, to reduce bodyweight

People who are at high risk (for example, prediabetes for type 2 diabetes)

Reduction in type 2 diabetes incidence by 58 percent

• Influenza vaccination

Vaccination

Elderly people with diabetes

Reduction in hospitalizations, respiratory conditions, and mortality

• Detection and treatment of eye diseases

Eye examination to screen for and treat eye diseases

People with diabetes, middleaged or older

Reduction in serious vision loss

• ACE inhibitors

Angiotensin-converting enzyme medication

People with diabetes

Reduction in nephropathy, cardiovascular disease, and death

• Smoking cessation

Physician counseling and nicotine replacement therapy

People with diabetes, all ages, smokers

Increase in quitting rate and reduction in cardiovascular disease

Metformin medication

People who are at high risk (for example, prediabetes for type 2 diabetes)

Reduction in type 2 diabetes incidence by 33 percent

• Intensive glucose control

Insulin, oral glucose-lowering agents, or both

Diabetes, all ages, with HbA1c less than 9 percent


• Lipid control

Cholesterol-lowering medication

Diabetes, all ages, with high cholesterol

Reduction in cardiovascular disease events and mortality

• Screening for microalbuminuria

Screening for microalbuminuria and treating those who test positive

Diabetes, all ages

Reduction in kidney diseases

• Screening for undiagnosed diabetes

Screening for undiagnosed diabetes and treating those who test positive

People who are at high risk for type 2 diabetes


Essential background interventiond Diabetes education Patient self-management

Diabetes, all ages

Reduction in HbA1c level and better compliance with lifestyle changes

Other promising interventione Polypill

Diabetes, all ages

Reduction in cardiovascular disease

Level 2b

• Preconception care for women of reproductive age

Level 3c • Metformin therapy for preventing diabetes

Hypothetical pill combining low doses of antihypertensive medication, aspirin, statin, and folate

a

Level 1 interventions are cost saving and highly feasible. Level 2 interventions are cost saving or cost less than US$1,500 per quality-adjusted life year but pose feasibility challenges. Level 3 interventions cost between US$1,640 and US$8,550 per quality-adjusted life year and pose significant feasibility challenges. d Diabetes education is the backbone on which many diabetes interventions depend, but empirical data on the effectiveness of diabetes education on outcomes and on the precise components of diabetes education are still lacking. e An intervention that appears promising but needs further research to document its effectiveness and/or safety. The polypill is only a theoretical concept at this time and is not available for implementation. b c

Source: Authors. From Disease Control Priorities in Developing Countries, Second Edition, edited by DT Jamison et al., Copyright © 2006. Courtesy of The International Bank for Reconstruction and Development/ The World Bank.

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CURRENT ISSUES 387

was recommended as “a high-priority intervention for all developing regions.”8, p 598 A combination tablet comprising three half-dose antihypertensive medications with aspirin, a statin, and folic acid remained hypothetical, not available for use, and not yet evaluated as to its benefits and side effects; it was thought to be cost-effective if available at US$1.28 or less per tablet. Analysis of effectiveness and cost effectiveness of interventions for developing countries was also presented, including preventing diabetes, screening for diabetes in the general population, and treating diabetes and its complications (Table 13-9). These interventions ranged from cost saving, for certain measures to prevent complications, to US$73,500/ QALY for general population screening. Prevention of diabetes through use of metformin was found to cost US$31,200/QALY, whereas lifestyle intervention would be considerably more cost-effective at US$1100 per QALY. In order for these interventions, singly or in combination, to become global strategies, their advocacy and adoption as policy would be required by many national governments or by regional or global health authorities. A research agenda was proposed that would be expected to clarify and support these interventions.

CURRENT ISSUES Natural History How early in the development of diabetes the risk of cardiovascular disease begins to increase is an important question. The emergence of cardiovascular risk factors long in advance of the diagnosis of diabetes was reported in a study of Mexican Americans in San Antonio, Texas;94 the clustering of risk factors in children by age 9–10 years in Mexican American versus non-Hispanic White children was noted previously;39 and detection of a genetic marker for insulin regulation and its relation to risk factors in 5-year-old children was reported from the Bogalusa Heart Study.95 These observations suggest the value of further investigation of early precursors of frank diabetes or IGT and their relation to cardiovascular risk. Better information is needed in many populations about blood glucose distributions, related risk factors for cardiovascular diseases, and needs for intervention at both population and high-risk levels, beginning in childhood and adolescence. Screening for Prediabetes and T2DM Methodologic issues remain, at the basic level of determining prevalence of diabetes and IGT. Various

criteria and sampling strategies have been advocated for prevalence surveys, and detailed protocols have been proposed.11,91,92,96,97 These proposals are relevant to population screening as well. Population screening, generally considered unwarranted on the basis of expected yield and benefit, may warrant reassessment in view of recognition of prediabetes and demonstrated prevention of T2DM by lifestyle intervention. Both developments add importance to recognizing the much greater number of individuals at increased risk of diabetes or cardiovascular disease than those detected as having frank diabetes. Diabetes, Insulin Resistance, Metabolic Syndrome, and Cardiovascular Disease Numerous factors link atherosclerosis with T2DM, and the insulin resistance syndrome or the metabolic syndrome. a more integrated view of these relations in terms of both natural history and intervention strategies is perhaps emerging. Grundy’s essay, “Metabolic Syndrome: Connecting and Reconciling Cardiovascular and Diabetes Worlds,” provides a promising perspective.4 Prevention and Control The case for prevention and control of diabetes depends on its prevalence and actual contribution to disability and mortality and, in turn, costs and costbenefit balances.98,99 The new concept of diabetes prevention that includes its primary prevention through lifestyle interventions changes the argument fundamentally. How best to develop comprehensive, long-range strategies with maximum public health impact has been addressed recently through system dynamics modeling, which offers valuable insights into policy alternatives. For example, it has been possible through this approach to simulate100, p 493 “. . . strategies that represent a mix of increased diabetes management and reduced obesity prevalence. Comparing a mixed strategy to one that focuses entirely on diabetes management, the [policy] experiments suggest that the focused diabetes management scenario may quickly reduce diabetes-related complications and deaths but is less effective in the long term than the mixed strategy.” From this perspective, prevention and control of diabetes calls for incorporating and reinforcing policies already well established and advocated in other areas––improving nutrition, increasing physical activity, achieving and maintaining healthy weight, and preventing or discontinuing tobacco use, in order to prevent chronic diseases broadly, including diabetes and cardiovascular disease.

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Table 13-9

Strategy

Effectiveness and Cost-Effectiveness of Interventions for Preventing and Treating Diabetes in Developed Countries Quality of Cost-Effectiveness Ratio Benefit Evidencea (US$/QALY)b

Preventing diabetes Lifestyle interventions for preventing type 2 diabetes

Reduction of 35–58 percent in incidence among people at high risk

I

1,100 (Diabetes Prevention Program Research Group forthcoming)

Metformin for preventing type 2 diabetes

Reduction of 25–31 percent in incidence among people at high risk

I

31,200 (Diabetes Prevention Program Research Group forthcoming)

Screening for diabetes Screening for type 2 diabetes in general population

Reduction of 25 percent in microvascular disease

III

73,500 (CDC Diabetes CostEffectiveness Study Group 1998)

Reduction of 30 percent in microvascular disease per 1 percent drop in HbA1c

I

Cost saving (CDC Diabetes CostEffectiveness Study Group 1998)

Glycemic control in people with HbA1c greater than 8 percent

Reduction of 30 percent in microvascular disease per 1 percent drop in HbA1c

I

34,400 (CDC Diabetes CostEffectiveness Study Group 1998; Klonoff and Schwartz 2000)

Blood pressure control in people whose pressure is higher than 160/95 mmHg

Reduction of 35 percent in macrovascular and microvascular disease per 10 mmHg drop in blood pressure

I

Cost saving (CDC Diabetes CostEffectiveness Study Group 1998)

Cholesterol control in people with total cholesterol greater than 200 milligrams/deciliter

Reduction of 25–55 percent in coronary heart disease events; 43 percent fall in death rate

II-1


Smoking cessation with recommended guidelines

16 percent quitting rate

I


Annual screening for microalbuminuria

Reduction of 50 percent in nephropathy using ACE inhibitors for identified cases

III

47,400 (Klonoff and Schwartz 2000)

Annual eye examinations

Reduction of 60–70 percent in serious vision loss

I

6,000 (Klonoff and Schwartz 2000; Vijan, Hofer, and Hayward 2000)

Foot care in people with high risk of ulcers

Reduction of 50–60 percent in serious foot disease

I

Cost saving (Ragnarson and Apelqvist 2001)

Aspirin use

Reduction of 28 percent in myocardial infarctions, reduction of 18 percent in cardiovascular disease

I

Not available

ACE inhibitor use in all people with diabetes

Reduction of 42 percent in nephropathy; 22 percent drop in cardiovascular disease

I

8,800 (Golan, Birkmeyer, and Welch 1999)

Influenza vaccinations among the elderly for type 2 diabetes

Reduction of 32 percent in hospitalizations; 64 percent drop in respiratory conditions and death

II-2

3,100 (Sorensen and others 2004)

Preconception care for women of reproductive age

Reduction of 30 percent in hospital charges and 25 percent in hospital days

II-2

Cost saving (Klonoff and Schwartz 2000)

Treating diabetes and its complications Glycemic control in people with HbA1c greater than 9 percent

a

I indicates evidence from at least one randomized, controlled trial; II-1 indicates evidence from a well-designed, controlled trial without randomization; II-2 indicates evidence from cohort or case control studies; and III indicates opinions of respected authorities (US Preventive Services Task Force 1996). b We adjusted cost-effectiveness ratios to 2002 US dollars using the consumer price index for medical care. In cases in which multiple studies evaluated the cost-effectiveness of an intervention, we report the median cost-effectiveness ratio. Note: mm Hg millimeters of mercury; QALY quality-adjusted life year. Source: Authors. From Disease Control Priorities in Developing Countries, Second Edition, edited by DT Jamison et al., Copyright © 2006. Courtesy of The International Bank for Reconstruction and Development/The World Bank.

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Diabetes Prevention Programme (IDPP). The Indian Diabetes Preventino Programme shows that lifestyle modification and metformin prevent T2DM in Asian Indian subjects with impaired glucose tolerance (IDDP-1). Diabetologia. 2006;49:289–297. 80. Eddy DM, Schlessinger L, Kahn R. Clinical outcomes and cost-effectiveness of strategies for managing people at high risk for diabetes. Ann Intern Med. 2005;143:251–264. 81. Schulze MB, Hu FB. Primary prevention of diabetes: What can be done and how much can be prevented? Annu Rev Public Health. 2005;26: 445–467. 82. Centers for Disease Control and Prevention. Self-reported prediabetes and risk-reduction activities – United States, 2006. MMWR. 2008;57:1203–1205. 83. American Diabetes Association. Executive summary: Standards of medical care in diabetes – 2009. Diabetes Care. 2009;32 (suppl 1):S6–S12. 84. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: Full text. J Europ Soc Cardiol. 2007;9(Suppl C):C1–C74. 85. US Preventive Services Task Force. The Guide to Clinical Preventive Services 2006. Recommendations of the US Preventive Services Task Force. Washington, DC: Agency for Healthcare Research and Quality; 2006. www.ahrq.gov/clinic/uspstf/uspstbac.htm. Accessed October 14, 2007. 86. Liebson PR. Diabetes control and cardiovascular risk: ACCORD, ADVACNE, AVOID, and SANDS. Prev Cardiol. 2008;11:230–236. 87. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with T2DM (UKPDS 33). Lancet. 1998;352:837–853.

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88. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353: 2643–2653. 89. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/ National Heart, Lung, and Blood Institute Scientific Statement. Executive Summary. Circulation. 2005;112:e285–e290. 90. Zaza S, Briss PA, Harrris K eds. The Guide to Community Preventive Services. What Works to Promote Health? Oxford, England: Oxford University Press; 2005. 91. Reiber GE, King H. Guidelines for the Development of a National Programme for Diabetes Mellitus. Geneva (Switzerland): Division of Noncommunicable Diseases and Health Technology, World Health Organization; 1991. 92. King H, Gruber W, Lander T, eds. Implementing National Diabetes Programmes: Report of a WHO Meeting. Geneva Switzerland: Division of Noncommunicable Diseases, World Health Organization; 1995. 93. Tuomilehto J, Tuomilehto-Wolf E, Zimmet P, et al. Primary prevention of diabetes mellitus. In: Alberti KGMM, DeFronzo RA, Keen H, Zimmet P, eds. International Textbook of Diabetes Mellitus. Chichester, England: John Wiley & Sons; 1992;2:1655–1673.

94. Haffner ST, Stern MP, Hazuda HP, et al. Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA. 1990;263: 2893–2898. 95. Amos CI, Cohen JC, Srinivasan SR, et al. Polymorphism in the 5-flanking region of the insulin gene and its potential relation to cardiovascular disease risk: observations in a biracial community: the Bogalusa Heart Study. Atherosclerosis. 1989;79:51–57. 96. Finch CF, Zimmet PZ, Alberti KGMM. Determining diabetes prevalence: a rational basis for the use of fasting plasma glucose concentrations? Diabetic Med. 1990;7: 603–610. 97. LaPorte RE, McCarty D, Bruno G. Counting diabetes in the next millennium. Diabetes Care. 1993;16:528–534. 98. Huse DM, Oster G, Killen AR, et al. The economic costs of non-insulin-dependent diabetes mellitus. JAMA. 1989;262:2708–2713. 99. Vaughan JP, Gilson L, Mills A. In: Jamison DT, Mosley WH, Measham AR, Bobadilla JL, eds. Disease Control Priorities in Developing Countries. Oxford (England): Oxford University Press; 1993:561–576. 100. Jones AP, Homer JB, Murphy DL, Essien JDK, Milstein B, Seville DA. Understanding diabetes population dynamics through simulation modeling and experimentation. Am J Public Health. 2006;96:488–494.

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C H A P T E R

14 Smoking and Other Tobacco Use prevalent. Decreasing prevalence of smoking in the United States and other developed countries has led to intensified marketing of tobacco products in lowand middle-income countries, where the great majority of tobacco-related deaths are occurring. Called “the risk factor of the [20th] century” as of the mid-1990s, smoking has become an increasingly common target of intervention not only by health professionals but also by legislative and regulatory bodies. Both smoking cessation and enforcement of clean indoor air standards are associated with marked reduction in morbidity and mortality caused by tobacco. The public health goals are to reduce both demand and supply of tobacco products by measures to reduce incidence and promote cessation of their use and to reduce their production, marketing, and illicit distribution. A wide array of available interventions ranges from individual-level assistance in quitting tobacco use to population-level regulatory actions, from local clean-air regulations to the WHO Framework Convention on Tobacco Control (FCTC), a global treaty to strengthen the ability of countries to resist the forces behind the tobacco pandemic. Among current issues concerning tobacco are the concept of “harm reduction” through development of questionably less toxic products, the continued efforts of the tobacco industry to discredit evidence regarding secondhand smoke, and the real prospects of the FCTC to enable low- and middleincome countries to reverse this pandemic.

SUMMARY Cigarette smoking, as well as use of tobacco in other forms, is associated with a resulting addiction to nicotine. The process of addiction begins with recruitment of the school-age population through marketing and distribution of tobacco products, which in many countries reach youth in violation of existing laws or regulations. The cigarette as a source of nicotine carries with it all the combustion products of tobacco, additives, and paper that together cause subclinical atherosclerosis, coronary heart disease, stroke, peripheral arterial disease, and abdominal aortic aneurysm, as well as other major chronic diseases. Passive smoking or secondhand smoke exposure, as well as active smoking, is causally related to the tobacco pandemic. Epidemiologic studies of smoking habits include population surveys to determine patterns of use and trends, cohort studies to measure the effects of smoking on individual risks and population rates of cardiovascular and other diseases, and trials of strategies for prevention or cessation of the smoking habit. Assessment of individual-level tobacco use and exposure depends on self-report or on measurement of biomarkers such as concentration of cotinine (a product of nicotine metabolism) in body fluids. Populationlevel exposures are estimated as per capita consumption based on sales or tax revenues or as environmental exposures based on air quality measurement in worksites, restaurants, and other public places. Despite widespread knowledge of the hazards of smoking, marketing of tobacco products and other influences account for more than 20% of adults in the United States and 1.1 billion people worldwide being smokers. Secondhand smoke exposure is even more

INTRODUCTION More than a decade ago, cigarette smoking was dubbed “the risk factor of the [20th] century” (attribution to

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Richard Peto unconfirmed). The WHO Report on the Global Tobacco Epidemic, 2008: The MPOWER package, begins with a page reading, “In the 20th century, the tobacco epidemic killed 100 million people worldwide.” The next page reads, “During the 21st century, it could kill 1 billion.”1, frontispiece Mortality, morbidity, and consumption of healthcare resources on a vast scale are attributable to the rising epidemic of cigarette smoking during the 20th century. Projections into the new century portend a stillmounting public health burden as a result of intensified marketing and use of tobacco products especially in low- and middle-income countries.2 The hazards of cigarette smoking for increased risks of lung cancer and other respiratory conditions are widely recognized. In fact, the resulting public health burden due to vascular diseases is much greater.3 Other forms of tobacco use have adverse health consequences as well, including nicotine addiction, an inherent aspect of habitual cigarette smoking.4 Additionally, passive exposure to tobacco smoke—“environmental tobacco smoke (ETS)” or “secondhand smoke (SHS)”—by nonsmokers has gained prominence as a major public health issue.5 Public health, or at least public, opposition to tobacco use especially in the form of cigarette smoking has a long history. Two notable recent accounts include Cigarette Wars: The Triumph of “The Little White Slaver” and Ashes to Ashes: America’s Hundred-Year Cigarette War, the Public Health, and the Unabashed Triumph of Philip Morris.6,7 These chronicles convey the flavor of controversy surrounding tobacco in a journalistic mode, complementing the extensive documentation of health research as provided in more than four decades of US Surgeon General’s Reports beginning in 1964.8 A concise history of the first 25 years of Surgeon General’s Reports was published in 1989.9 Global dimensions of the tobacco epidemic and control efforts are demonstrated in reports from the Global Burden of Disease Study, Disease Control Priorities Project, and the landmark Framework Convention on Tobacco Control, the world’s first global public health treaty, in force as of February 2005.10–13 Together, these sources provide valuable insight into social, political, and commercial as well as scientific perspectives on tobacco. These aspects are fundamental to understanding current discussion of policies and practices to address this major public health issue, on both national and global levels.

CONCEPTS AND DEFINITIONS Concepts and definitions of smoking and other tobacco use concern types of tobacco exposure, smok-

ing status, and categories of exposure. These aspects are encountered throughout the epidemiologic literature on smoking and tobacco use. Types of Tobacco Exposure The personal habit of cigarette smoking is important for the occurrence of cardiovascular diseases because of its attendant risks and very high prevalence in many populations. Accordingly, tobacco use has been studied extensively. For smokers, current or past, detailed information is sometimes sought about the particular brand or type of cigarette smoked, extent of smoke inhalation, or proportion of the cigarette usually smoked. Inquiry about pipe and cigar smoking is often included, but these practices are generally much less prevalent. Exposure to smoked tobacco occurs passively when nonsmoking persons share the environment of smokers. This form of exposure underlies studies of the effects of secondhand smoke exposure. In such studies, mainstream smoke (drawn through the cigarette and exhaled into the environment) may be distinguished from sidestream smoke (entering the air directly from the burning cigarette, whether or not it is actively being smoked). The 2006 Report of the Surgeon General, The Health Consequences of Involuntary Exposure to Tobacco Smoke, reviews the history of concern about this form of exposure, from at least as early as 1972.5 Smokeless tobacco is commonly used in the forms of a plug, dipping or chewing tobacco, or snuff. Among smokeless tobacco products in the United States, snuff is most common. This is powdered tobacco now usually in moistened form, fermented, and used orally by placing a quantity of it between the gum and cheek or lower lip.4 These forms of smokeless tobacco exposure cause local pathology, including cancer in the mouth and upper airway, but their immediate relevance is due to their yield of nicotine by solution into the saliva. This results in their potential for causing nicotine addiction, which may lead to cigarette smoking. Many forms of tobacco products, both smoked and smokeless, are used throughout the world. A report on tobacco control in India, for example, identifies as types of smoking tobacco beedies (the most common form, a loosely hand-rolled leaf containing tobacco), cigarettes, cigars, cheroots, chuttas, dhumti, and a variety of pipes; smokeless forms of tobacco for oral use are described as compounded with various other ingredients such as betel leaf, areca nut, and slaked lime. Several dental hygiene preparations also contain tobacco, are used by children as well as adults (chiefly women), and are potentially addicting because of their nicotine content.14

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Smoking Status and Categories of Exposure With respect to personal smoking behavior, a common classification system distinguishes three categories: “never smoked,” “former smoker,” and “current smoker.” Explicit criteria are necessary to define each class and may vary among studies. For both former and current smokers, quantitation of exposure may be approximated by determining the age at the start of smoking, present age (or the age at stopping if not a current smoker), and the average number of cigarettes smoked per day over the smoking lifetime, in units of cigarettes, packs, or portions of packs. This approach provides a rough estimate of exposure in units of pack-years (e.g., 36 years of smoking 1⁄2 pack of cigarettes per day 18 pack-years of exposure) for either former or current smokers. With growing recognition of the importance of exposure to secondhand smoke, classification becomes more complex. For nonsmokers this is the only source, whereas for smokers, there is often additional exposure to smoke generated by others. Beyond the determination of whether a nonsmoker shares a residence or workplace with a smoker, and if so over what interval of time, it is difficult to gauge the extent of previous exposure.5 Another aspect of smoking status concerns the time course of starting, decreasing, and stopping tobacco use especially for those who may have quit on multiple occasions. This is important for observational studies estimating pack-years of exposure and even more so for studies assessing behavioral responses to intervention for smoking cessation.

MEASUREMENT Measurement of exposure to tobacco smoke is of interest at both individual and population levels, and for both active and passive smokers. Active Smoking For individuals, self-reports of smoking and tobacco use are commonly elicited by means of interviews or questionnaires designed to permit classifying individuals as described previously. Where cultural factors make smoking undesirable or even illegal, response bias in the direction of underreporting is to be expected. Similarly, participants in smoking prevention or cessation programs might be expected to exaggerate their success and thereby to minimize their reported tobacco use. For such reasons, self-report alone is of uncertain reliability. Different issues arise when the respondent is a relative or an acquaintance of the index subject (a

surrogate respondent) or when existing records are searched for data on an individual’s smoking history. Even with the likely limitations of such indirect assessment, introduction of smoking history data to the state of Washington’s standard death certificate was considered a potentially valuable addition to data on smoking and causes of death.15 Biochemical markers of tobacco smoke or smokeless tobacco products can be used to supplement or replace self-report methods.16 Nicotine, cotinine, thiocyanate, and carbon monoxide can be tested for this purpose. Depending on the choice of marker, samples of saliva, urine, blood, or expired air may be used. In a strategy designed to improve the reliability of selfreported smoking behavior in school populations (the “bogus pipeline” method), such samples are obtained from all participants but are processed for only a small proportion of them. All participants are informed that the samples can be tested, and evidence suggests that more reliable reporting occurs as a result. Secondhand Smoke The methods just described, principally cotinine concentration in biological samples, are useful in estimating immediate secondhand smoke exposure of individuals. But because the half-life of cotinine in such samples is on the order of roughly 1⁄2 to 2 days, exposures over several days or weeks, much less cumulative lifetime exposures, cannot be assessed by these means. A marker such as cotinine is also limited in reflecting only one substance, nicotine, among the great many components of tobacco smoke—including not only chemical substances but also respirable suspended particles. For these reasons, environmental measures are important. These include assessing atmospheric concentrations of nicotine and particulate air pollutants, as well as effects of heating, ventilating, and air conditioning systems in clearing or distributing contaminated air. Exposure models can be used for estimating secondhand smoke exposure by accounting for multiple factors operating in homes, worksites, and other indoor locations where exposure typically occurs.5,17 Population Exposures As a convenient indirect indicator of tobacco use for the population of a geopolitical area, data on tobacco sales or tax revenues may be available. Knowledge of the tax rate and revenues permits estimating the quantity of tobacco sold in a given time period. Changes in tax rates over time must be taken into account. Potential error may result from use of imported tobacco products or those acquired through untaxed, black-market sources. The estimates that result are per capita cigarette consumption rates.

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DETERMINANTS Factors that influence the likelihood of smoking include marketing of cigarettes and other tobacco products, societal factors that may favor or oppose smoking, and individual behavioral characteristics. Marketing Manufacture of tobacco products in great quantity and their effective marketing by the tobacco industry through multiple media channels are powerful determinants of exposure to tobacco. Commercial profitability of cigarette manufacture is both a cause and a consequence of this phenomenon. The relation between government and this industry is often complex, especially in countries where the national government may be the producer of tobacco as well as the beneficiary of substantial tax revenues. In the United States, as of 1985, taxes on tobacco were estimated to bring $4.4 billion, $4.3 billion, and $0.2 billion to federal, state, and local government, respectively; corporate income tax of $1.7 billion was also received by the federal government. Of a total consumer expenditure of $30.2 billion for the purchase of cigarettes, the net profit to industry was $3.4 billion, or more than 10%. Industry expenditures for advertising and promotion of cigarettes in that year were estimated to be $2.5 billion.11 That figure, adjusted to 2006 dollars, amounted to $4.6 billion; by 2005, it had grown to $13.5 billion.18 An extensive study of the role of media examines their multifaceted influences on the tobacco epidemic through tobacco marketing, coverage of tobacco-related issues in news and entertainment media, communicating tobacco prevention and control messages, and addressing industry efforts to counter these messages.18 A key lesson from this study, in the words of its editors, is that “Most critical from a policy standpoint is the conclusion, supported by strong evidence, that both exposure to tobacco marketing and depictions of tobacco in movies promote smoking initiation. . . . The tobacco industry continues to succeed in overcoming partial restrictions on tobacco marketing in the United States, and tobacco marketing remains pervasive and effective in promoting tobacco use”18, p xvii–xviii Societal Influences To return to the historical perspective on society’s attitudes toward the cigarette, Tate’s Cigarette Wars depicts “The cigarette today” as “the most vilified product available legally in the United States, blamed for causing the premature deaths of more than

400,000 Americans a year, banned from most public buildings, besieged in the courts, and subject to increasing restrictions on advertising, promotion, and sales.”6, p 147 She notes that, regardless of this characterization of cigarettes, prevalence of smoking had not decreased substantially among US adults through the 1990s. By her account, the first wave of societal opposition to smoking, in the United States, began in the late 1880s, peaked in 1917, and waned over the next decade. The second wave, beginning in the 1960s and continuing to the present, has a scientific foundation not present in the earlier period and incorporates a strong focus on passive smoking. Today it appears that a change in culture has occurred making nonsmoking, rather than smoking, the norm and enabling rules, regulations, and legislation to be adopted that would have been implausible before the 1960s. (Related experience will be discussed later—see Prevention and Control.) Individual Behavior Initiation of smoking and other forms of tobacco use most often occurs in childhood and adolescence. This period of life was therefore the special focus of the 1994 report of the US Surgeon General, Preventing Tobacco Use Among Young People.19 Figure 14-1 outlines the stages of smoking initiation, described as the preparatory stage, trying stage, experimental stage, regular use, and addiction/dependent behavior. Factors that influence the progression from one stage to the next are described on the left of the figure, and particular patterns of behavior that define each stage are described on the right. These determinants of smoking behavior provide points of intervention in programs aimed at preventing progression from the preparatory stage to addiction or dependency. The same report presents a summary of studies indicating conditions predictive of progression in smoking behavior—socioeconomic, environmental, behavioral, and personal factors, as well as the influences of the tobacco industry.

MECHANISMS Active and Passive Smoking Cigarette smoke contains thousands of organic and inorganic compounds, components of tobacco itself or products of the combustion of both tobacco and cigarette additives. The toxic compounds include nicotine, carbon monoxide, hydrogen cyanide, acrolein, and mutagens and carcinogens (e.g., polycyclic aromatic hydrocarbons), in addition to respirable sus-

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MECHANISMS 399

Preparatory Stage Adolescent forms attitudes and beliefs about the utility of smoking.

Psychosocial risk factors include advertising and adult/sibling role models who smoke cigarettes.

Never smokes

Trying Stage Adolescent smokes first few cigarettes.

Psychosocial risk factors include peer influences to smoke, the perception that smoking is normative, and the availability of cigarettes.

No longer smokes Experimental Stage Adolescent smokes repeatedly, but irregularly.

Psychosocial risk factors include social situations and peers who support smoking, low self-efficacy in ability to refuse offers to smoke, and the availability of cigarettes.

No longer smokes Regular Use Adolescent smokes at least weekly across a variety of situations and personal interactions.

Psychosocial risk factors include peers who smoke, the perception that smoking has personal utility, and few restrictions on smoking in school, home, and community settings.

Quits smoking Addiction/Dependent Smoker

Adolescent has developed the physiological need for nicotine.

Figure 14-1 Stages of Smoking Initiation Among Children and Adolescents. Source: Reprinted from Preventing Tobacco Use Among Young People, a Report of the Surgeon General, p 126, 1994, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

pended particulates. These products are classified as components of either the tar (particulate) phase or the gas phase of cigarette smoke. Mainstream and sidestream smoke differ in the relative composition regarding these two phases, sidestream smoke having somewhat higher gas phase content. Secondhand smoke is about 85% sidestream and 15% exhaled mainstream smoke.20

Clinical and laboratory research provide extensive evidence of links between cigarette smoking and atherosclerosis through mechanisms including vasomotor dysfunction, inflammation, and modification of the lipid profile with lipid abnormalities such as increased low-density lipoprotein cholesterol, very-lowdensity lipoprotein cholesterol, and triglycerides and decreased high-density lipoprotein cholesterol. Several

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pathways are thought to converge in increased oxidative stress. Thrombosis is also related to cigarette smoking, through platelet dysfunction and alteration of anti- and prothrombotic factors and fibrinolysis.20 Some of these relationships are also addressed in epidemiologic data, such as those from the Third National Health and Nutrition Examination Survey (NHANES III). Inflammatory markers and other cardiovascular risk factors were found to follow a gradient from most adverse levels among the heaviest smokers to successively less adverse among persons who had stopped smoking from 1 to 9 or more years prior to examination.21 Consistent findings from a later analysis from NHANES III based on cotinine levels among never-smokers showed increased levels of both homocysteine and fibrinogen when cotinine was detectable, even at low levels in contrast with being nondetectable.22 The heightened interest in secondhand smoke exposure, reflected in the Report of the Surgeon General for 2006, occasioned a detailed review of evidence on toxicology including heart disease as well as carcinogenesis and respiratory injury.5 That review concluded that evidence was sufficient to infer that exposure to secondhand smoke has a prothrombotic effect, causes endothelial cell dysfunction, and causes atherosclerosis in animal models. Further, “the immediate effects of even short exposures to secondhand smoke appear to be as large as those seen in association with active smoking of one pack of cigarettes a day.”5, p 64 Smokeless Tobacco Smokeless tobacco is toxic because of constituents of tobacco juices, even without tobacco’s combustion products. Its use may result in higher nicotine absorption than from smoked tobacco because of the acidity of saliva and prolonged contact between oral tissues and the tobacco. Studies of its toxicity for the cardiovascular system have not provided consistent evidence of sustained effects as with smoking. It is, however, addicting and is associated with oral malignancies. Whether snuff, as a popular form of smokeless tobacco, should be considered as a replacement therapy for nicotine addiction due to smoking has been discussed.4

DISTRIBUTION Prevalence—United States The prevalence of cigarette smoking in the US adult population aged 18 years and older, based on the

2006 National Health Interview Survey, is shown in Table 14-1 for men, women, and the total population by race/ethnicity, education, age group, and poverty status.23 Smokers were defined as persons who reported smoking at least 100 cigarettes during their lifetimes and who, at the time of interview, reported smoking every day or some days. The overall frequency of smoking was 20.8%, slightly greater for men and less for women. The prevalence was notably less for Asians/Pacific Islanders (10.4%) and greater for American Indians/Alaska Natives (32.4%). The strong gradient of less frequent smoking among successively more highly educated groups is also striking. The lower prevalence among the older age group, 65 years or older, is also noteworthy and could reflect reduced survival of smokers to these ages, greater frequency of smoking cessation, or less incidence of smoking at earlier ages among these groups, born in 1940 or earlier. Poverty (below versus at or above federal poverty level) was related to greater prevalence of smoking by 50% (30.6% versus 20.4%). For younger persons, in school grades 9–12, the Youth Risk Behavior Survey of 2007 distinguished among “lifetime smoking” (ever tried cigarette smoking, even one or two puffs), “current smoking” (smoked cigarettes on at least 1 day during the 30 days before the survey), and “current frequent smoking” (smoked cigarettes on 20 or more days during the 30 days before the survey (Table 14-2).24 Comparable data for alternate years, beginning in 1991, are also shown. The prevalence of the three levels of smoking in 2007 was 50.3%, 20.0%, and 8.1%, respectively. In each case, prevalence was less than the level in 1991 by about one-third, although trends in the three categories were not consistent. A companion table (not shown) provides subclassification for current smokers by sex, race/ethnicity (White, non-Hispanic; Black, non-Hispanic; and Hispanic) and school grade (9–12). Males were current smokers slightly more often than females, in most but not all years. Current smoking was less frequent among Black boys and girls than among Whites and intermediate in frequency among Hispanics. By grade 11, the same proportion of students as adults were classified as current smokers (although not by the same definition—see the preceding). It is a widely held view that adopting the cigarette smoking habit is infrequent after school age and that progression to daily smoking begins early and is completed before the end of high school for most eventual regular smokers. Table 14-3 illustrates this progression. Persons interviewed at ages 30–39 years were asked to recall the ages at which they had first tried a cigarette and at which they began smoking daily.

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DISTRIBUTION 401

Estimated Percentage of Persons Aged 18 Years Who Were Current Smokers,* by Sex and Selected Characteristics—National Health Interview Survey, United States, 2006 Men Women Total (n 10,715) (n 13,560) (n 24,275) % (95% CI†) % (95% CI) % (95% CI)

Table 14-1

Characteristic Race/Ethnicity§ White, non-Hispanic Black, non-Hispanic Hispanic American Indian/Alaska Native, non-Hispanic¶ Asian, non-Hispanic**

24.3 27.6 20.1 35.6

(23.0–25.6) (24.2–31.0) (17.8–22.4) (18.7–52.5)

19.7 19.2 10.1 29.0

(18.6–20.8) (17.3–21.1) (8.5–11.7) (15.7–42.3)

21.9 23.0 15.2 32.4

(21.0–22.8) (21.1–24.9) (13.7–16.7) (19.7–45.1)

16.8

(13.1–20.5)

4.6

(3.0–6.2)

10.4

(8.4–12.4)

Education (yrs) 0–12 (no diploma) 8 9–11 12 GED§§ diploma High school diploma Associate degree Some college Undergraduate degree Graduate degree

30.6 22.3 40.1 27.9 51.3 27.6 25.4 26.1 10.8 7.3

(27.9–33.3) (18.5–26.1) (35.7–44.5) (21.5–34.3) (43.4–59.2) (25.3–29.9) (22.1–28.7) (24.2–28.0) (9.0–12.6) (5.4–9.2)

23.0 12.3 31.4 23.3 40.2 20.4 17.8 20.0 8.4 5.8

(20.7–25.3) (9.7–14.9 (27.7–35.1) (17.5–29.1) (33.2–47.2) (18.7–22.1) (15.2–20.4) (18.3–21.7) (7.0–9.8) (4.1–7.5)

26.7 17.4 35.4 25.6 46.0 23.8 21.2 22.7 9.6 6.6

(25.0–28.4) (15.1–19.7) (32.5–38.3) (21.2–30.0) (40.5–51.5) (22.3–25.3) (19.1–23.3) (21.4–24.0) (8.5–10.7) (5.3–7.9)

Age group (yrs) 18–24 25–44 45–64 65

28.5 26.0 24.5 12.6

(24.7–32.3) (24.3–27.7) (22.7–26.3) (10.6–14.6)

19.3 21.0 19.3 8.3

(16.7–21.9) (19.7–22.3) (17.9–20.7) (7.0–9.6)

23.9 23.5 21.8 10.2

(21.7–26.1) (22.4–24.6) (20.6–23.0) (9.2–11.2)

Poverty status¶¶ At or above federal poverty level Below federal poverty level Unknown

22.9 34.0 23.3

(21.6–24.2) (30.0–38.0) (21.0–25.6)

17.8 28.0 14.2

(16.8–18.8) (25.2–30.8) (12.6–15.8)

20.4 30.6 18.3

(19.6–21.2) (28.0–33.2) (16.9–19.7)

Total

23.9

(22.8–25.0)

18.0

(17.2–18.8)

20.8

(20.1–21.5)

††

*Persons who reported smoking at least 100 cigarettes during their lifetimes and who, at the time of interview, reported smoking every day or some days. Excludes 315 respondents whose smoking status was unknown. † Confidence interval. § Excludes 266 respondents of unknown race or multiple races. ¶ Wide variances in estimates reflect small sample sizes. **Does not include Native Hawaiians or Other Pacific Islanders. †† Among persons aged ≥ 25 years. Excludes 305 persons whose educational level was unknown. §§ General Educational Development. ¶¶ Based on family income reported by respondents and 2005 poverty thresholds published by the US Census Bureau. Source: Reprinted from MMWR, Vol 54, November 11, 2005, p 1123.

The prevalence of both experimentation and daily smoking increased from those younger than age 12 years to each successively older age category, most sharply over the groups from younger than age 12 years to younger than age 18 years. By the latter age, more than one-third of all persons had begun smoking daily. More than 70% of those who became daily smokers had done so by this age.19 Exposure to secondhand smoke among nonsmokers was estimated from NHANES 1999–2002 in

age groups from 3–11 to 60 or more years.5 By the criterion of serum cotinine levels 0.05 ng (nanograms)/ml, 47.0% of persons were exposed—nearly 40 million younger than age 20 years and more than 125 million overall. These proportions were declining at the time, however, as comparison between findings of NHANES 1988–1994 and 1999–2004 later showed.25 Exposure at home decreased between periods by approximately 40–60% for nearly all sex, age, race/ethnicity, and income groups. Prevalence of

Source: Reprinted from MMWR, Vol 55, July 7, 2006, p 1123.

*Ever tried cigarette smoking, even one or two puffs. † Smoked cigarettes on at least 1 day during the 30 days before the survey. § Smoked cigarettes on 20 or more days during the 30 days before the survey. ¶ Linear, quadratic, and cubic trend analyses were conducted using a logistic regression model controlling for sex, race/ethnicity, and grade. These prevalence estimates are not standardized by demographic variables. **Confidence interval. †† Significant linear and quadratic effects only (p 0.05). §§ Significant linear, quadratic, and cubic effects (p 0.05).

Current Frequent††

Current§§

Cigarette Use Lifetime¶†

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Percentage of High School Students Who Reported Lifetime Cigarette Use,* Current Cigarette Use,† and Current Frequent Cigarette Use§—Youth Risk Behavior Survey, United States, 1991–2007 1991 1993 1995 1997 1999 2001 2003 2005 2007 % (95% CI**) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) % (95% CI) 70.1 69.5 71.3 70.2 70.4 63.9 58.4 54.3 50.3 (67.8–72.3) (68.1–70.8) (69.5–73.0) (68.2–72.1) (67.3–73.3) (61.6–66.0) (55.1–61.6) (51.2–57.3) (47.2–53.5) 27.5 30.5 34.8 36.4 34.8 28.5 21.9 23.0 20.0 (24.8–30.3) (28.6–32.4) (32.5–37.2) (34.1–38.7) (32.3–37.4) (26.4–30.6) (19.8–24.2) (20.7–25.5) (17.6–22.6) 12.7 13.8 16.1 16.7 16.8 13.8 9.7 9.4 8.1 (10.6–15.3) (12.1–15.5) (13.6–19.1) (14.8–18.7) (14.3–19.6) (12.3–15.5) (8.3–11.3) (7.9–11.0) (6.7–9.8)

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DISTRIBUTION 403

Table 14-3

Age (yrs) 12 14 16 18 18 20 25 30 39 Never smoked Mean age

Cumulative Percentages of Recalled Age at Which a Respondent First Tried a Cigarette and Began Smoking Daily, Among Persons Aged 30–39, National Household Surveys on Drug Abuse, United States, 1991 Persons Who Had Ever Tried Persons Who Had Ever All Personsa a Cigarette Smoked Daily First Tried Began Smoking First Tried First Tried Began Smoking a Cigarette Daily a Cigarette a Cigarette Daily 14.1 0.9 18.0 15.6 1.9 29.7 3.9 38.0 36.7 8.0 48.2 12.2 61.9 62.2 24.9 63.7 26.0 81.6 81.9 53.0 68.8 34.9 88.2 89.0 71.2 71.0 37.8 91.0 91.3 77.0 76.6 46.5 98.2 98.4 94.6 77.4 48.1 99.3 99.4 98.1 78.0 49.0 100.0 100.0 100.0 100.0 100.0 NA NA NA NA NA 14.5 14.6 17.7

Note: NA, not applicable. a All persons (N 6388). Source: Reprinted from Preventing Tobacco Use Among Young People, a Report of the Surgeon General, p 65, 1994, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.

detectable cotinine levels in personal samples also decreased, but by a lesser degree and less consistently across groups—least for children, non-Hispanic Blacks, and persons of low income. These differences reflect group differences in reduction in secondhand smoke exposure outside the home. Prevalence—Global From the Disease Control Priorities Project, Table 14-4 presents estimates for the year 2000 of prevalence of smoking (definition not provided) by World Bank region, by sex, and overall.12 For each of six discrete geographic regions and two economic regions,

both percent of population and numbers of smokers (in millions) are shown, as well as the proportionate contribution of each region to the world total of more than 1.1 billion smokers. Low- and middle-income economies account for more than 80% of all smokers, nearly 40% in East Asia and the Pacific (including China) alone. Overall prevalence ranges from 18–21% in sub-Saharan Africa, South Asia, the Middle East, and North Africa to 34–35% in East Asia and the Pacific, and Europe and Central Asia. Males predominate over females by about 6:1 in lowand middle-income countries but only 2:1 in highincome countries.

Table 14-4

Estimated Smoking Prevalence (by Gender) and by Number of Smokers, 15 Years of Age and Older, 2000 Smoking Prevalence (Percent) Total Smokers World Bank Region Males Females Overall Millions Percentages of All Smokers East Asia and the Pacific 63 5 34 429 38 Europe and Central Asia 56 17 35 122 11 Latin America and the Caribbean 40 24 32 98 9 Middle East and North Africa 36 5 21 37 3 South Asia 32 6 20 178 15 Sub-Saharan Africa 29 8 18 56 6 Low- and middle-income economies 49 8 29 920 82 High-income economies 37 21 29 202 18 Source: Authors. Reprinted with permission from Disease Control Priorities in Developing Countries, Second Edition, edited by DT Jamison et al., Copyright © 2006. Courtesy of the International Bank for Reconstruction and Development/The World Bank.

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The Global Youth Tobacco Survey (GYTS) provides tobacco-control surveillance data for youth in all WHO Regions, with a total of 151 survey sites worldwide as of 2007.26 Grade levels corresponding to ages 13–15 years are targeted, and standardized methods of survey design and implementation are used throughout the network. Summary data on selected characteristics for each region and overall are shown in Table 14-5; site-specific data are available in the cited reference. Smoking ranged fourfold in prevalence from 4.9% in the Eastern Mediterranean Region to 19.2% in the European Region. The majority of current smokers in every region responded that they desired to quit—from 53.3% to 80.7%. From 20.2% to 61.7% reported purchasing their cigarettes from stores. Reported secondhand smoke exposure was common both at home and in public places—42.5% and 55.1% overall. These indicators of the global dimensions of smoking in youth have major implications for prevention of future morbidity and mortality from tobacco. Trends Trends in the prevalence of smoking among adults aged 18 years and older in the United States have indicated a marked reduction from 1965 to 2006, though more than 1 in 5 Americans still smokes (Table 14-6).27 The reduction for men was from 51.2% to 23.6%; for women it was from 33.7% to 18.1%. The proportionate declines have been very similar between Whites and Blacks, although prevalence remained higher among Black than White males. Trends of declining prevalence in US youth were noted previously. However, globally, and specifically in lowand middle-income countries, smoking prevalence is said to be increasing.12

RELATION TO RATES AND RISKS In folklore, smoking and other uses of tobacco have long been related to adverse health consequences and were cited by the late 19th century as the cause of 87 diseases, including heart disease, alongside baldness, insanity, and tooth decay, among other ills.28 An account presented by the late Sir Richard Doll leads from early anecdotes about tobacco to the history of more recent epidemiologic investigation, including case-control studies prior to the mid-20th century.29 By the time of the 1964 report of the US Surgeon General, evidence was considered sufficient to find that smoking causes lung cancer, but the only conclusion at that time regarding cardiovascular disease was: “Male cigarette smokers have a higher death

rate from coronary artery disease than non-smoking males, but it is not clear that the association has causal significance.”8, p 39 Two decades later, the 1983 Surgeon General’s Report focused on cardiovascular disease and concluded that: “Cigarette smoking is a major cause of coronary heart disease in the United States for both men and women. Because of the number of persons in the population who smoke and the increased risk that cigarette smoking represents, it should be considered the most important of the known modifiable risk factors for CHD.”30, pp 6–7 No less conclusive was the statement regarding atherosclerotic peripheral arterial disease. No such statement could be made at that time with respect to cerebrovascular disease. Through decades of study subsequent to the first report in 1964, sufficient evidence accumulated by 2004 to infer a causal relationship between smoking and subclinical atherosclerosis, coronary heart disease, stroke, and abdominal aortic aneurysm.31 The relation of cigarette smoking to the occurrence of coronary heart disease can be illustrated by comparing both rates between populations and risks among individuals within a population. In more recent studies, increased attention is found to secondhand smoke and, to a much lesser degree, other tobacco use. Population Differences The classic Seven Countries Study, described in Chapter 4, investigated the relation between cigarette smoking and population rates of coronary heart disease events in 13 of the 16 cohorts in the study. Use of cigarettes reported at the baseline examination was examined in relation to incidence of coronary heart disease over the next 10 years in these cohorts, grouped by geographic area (Figure 14-2).32 At the baseline examination, cigarette smoking was classified “never,” “stopped,” or, for current smokers, by amount smoked in intervals of less than 10, 10 to 19, or 20 or more cigarettes per day. Among nonsmokers, the number of “hard” coronary events per 100 men ranged from less than two for the Yugoslavian cohorts to four for the Northern European cohorts. With successively greater exposure, from those who had already stopped smoking to those smoking 20 or more cigarettes per day, this difference was amplified. The relation between level of smoking and increasing coronary heart disease event rates was strongest for the populations with the highest rates (Northern Europe) and notably less strong for the populations with lower rates (Yugoslavia, Italy, and Greece). This pattern suggests that smoking potenti-

Source: Data from Centers for Disease Control and Prevention, Global Youth Tobacco Surveillance, 2000–2007. Surveillance Summaries, January 25, 2008. MMWR, 2008;57 (No. SS-1).

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Selected Characteristics Regarding Tobacco Use, Secondhand Smoke Exposure, and Experience of Current Smokers by WHO Regions and Overall, Global Youth Tobacco Survey, 2000–2007 Desired to Stop Usually Bought Exposed to Smoke Exposed to Smoke % Currently Smoking Their Cigarettes at Home, in Public Places, Smoked (Current in a Store Preceding Preceding Cigarettes Smokers) (Current Smokers) Week Week WHO Region % (CI) % (CI) % (CI) % (CI) % (CI) African Region 8.0 (6.2–10.5) 74.5 (61.2–83.7) 34.2 (24.7–45.7) 27.6 (23.8–31.9) 43.7 (39.6–47.9) Region of the Americas 14.3 (12.4–16.6) 53.3 (47.3–59.0) 20.2 (16.3–24.4) 41.1 (38.2–44.1) 54.9 (52.1–57.8) Eastern Mediterranean Region 4.9 (3.5–6.9) 70.5 (58.1–80.6) 42.2 (31.9–53.4) 38.3 (35.2–41.6) 45.7 (41.7–49.8) European Region 19.2 (17.0–21.7) 62.5 (56.0–68.7) 61.7 (56.7–66.4) 77.8 (75.3–80.0) 86.1 (84.4–87.7) South-East Asia Region 5.9 (4.8–7.2) 72.5 (63.6–79.9) 53.2 (46.0–60.2) 34.3 (31.3–37.4) 48.5 (45.3–51.6) Western Pacific Region 13.4 (11.2–16.0) 80.7 (74.6–85.7) 46.1 (40.6–51.8) 50.6 (47.7–53.6) 64.1 (61.3–66.8) Total 9.5 (7.9–11.3) 68.7 (60.1–75.9) 46.7 (39.9–53.6) 42.5 (39.5–45.5) 55.1 (52.0–58.1)

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18.8 18.5

Data from Health, United States, 2007, National Center for Health Statistics, pp 266–267.

Sources: Centers for Disease Control and Prevention, National Center for Health Statistics, National Health Interview Survey. Data are from the core questionnaire (1965) and the following questionnaire supplements: hypertension (1974), smoking (1979), alcohol and health practices (1983), health promotion and disease prevention (1985, 1990–1991), cancer control and cancer epidemiology (1992), and year 2000 objectives (1993–1995). Starting with 1997, data are from the family core and sample adult questionnaires.

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20.8 23.6 18.1 23.5 26.1

2006

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*Estimates are considered unreliable. Data preceded by an asterisk have a relative standard error of 20%–30%. 1 Data prior to 1997 are not strictly comparable with data for later years due to the 1997 questionnaire redesign. See Appendix I, National Health Interview Survey. 2 Estimates are age-adjusted to the year 2000 standard population using five age groups: 18–24 years, 25–34 years, 35–44 years, 45–64 years, 65 years and over. Age-adjusted estimates in this table may differ from other age-adjusted estimates based on the same data and presented elsewhere if different age groups are used in the adjustment procedure. See Appendix II, Age adjustment. 3 Starting with 1993 data, current cigarette smokers were defined as ever smoking 100 cigarettes in their lifetime and smoking now on every day or some days. See Appendix II, Cigarette smoking. 4 The race groups, White and Black, include persons of Hispanic and non-Hispanic origin. Starting with 1999 data, race-specific estimates are tabulated according to the 1997 Revisions to the Standards for the Classification of Federal Data on Race and Ethnicity and are not strictly comparable with estimates for earlier years. The single-race categories shown in the table conform to the 1997 Standards. Starting with 1999 data, race-specific estimates are for persons who reported only one racial group. Prior to 1999, data were tabulated according to the 1977 Standards. Estimates for single-race categories prior to 1999 included persons who reported one race or, if they reported more than one race, identified one race as best representing their race. Starting with 2003 data, race responses of other race and unspecified multiple race were treated as missing, and then race was imputed if these were the only race responses. Almost all persons with a race response of other race were of Hispanic origin. See Appendix II, Hispanic origin; Race. For additional data on cigarette smoking by racial groups, see Table 65. Notes: Standard errors for selected years are available in the spreadsheet version of this table. Available from: www.cdc.gov/nchs/hus.htm. Data for additional years are available. See Appendix III.

Current Cigarette Smoking Among Adults 18 Years of Age and Over, by Sex, Race, and Age: United States, Selected Years 1965–2006 [Data are based on household interviews of a sample of the civilian noninstitutionalized population] Sex, Race, and Age 19651 19741 19791 19851 19901 19951 2000 2002 2003 2004 2005 18 years and over, Percent of Persons Who Are Current Cigarette Smokers3 age-adjusted2 All persons 41.9 37.0 33.3 29.9 25.3 24.6 23.1 22.3 21.5 20.8 20.8 Male 51.2 42.8 37.0 32.2 28.0 26.5 25.2 24.6 23.7 23.0 23.4 Female 33.7 32.2 30.1 27.9 22.9 22.7 21.1 20.0 19.4 18.7 18.3 White male4 50.4 41.7 36.4 31.3 27.6 26.2 25.4 24.9 23.8 23.0 23.3 Black or African 58.8 53.6 43.9 40.2 32.8 29.4 25.7 26.6 25.3 23.5 25.9 American male4 White female4 33.9 32.0 30.3 27.9 23.5 23.4 22.0 21.0 20.1 19.5 19.1 Black or African 31.8 35.6 30.5 30.9 20.8 23.5 20.7 18.3 17.9 16.9 17.1 American female4

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Hard CHD Incidence per 100, Age-Standardized

18 16 14 12 10 N. EUROPE Y = 4.0 + 1.2x

8 6

ITALY and GREECE Y = 2.3 + 0.3x

4

Y = 1.7 + 0.6x YUGOSLAVIA

2 0 x=0

1

2

3

(NEVER)

(STOPPED)

( Risk Additional studies with focused objectives needed

Benefit ⱖ Risk

Risk ⱖ Benefit No additional studies needed

Procedure/Treatment SHOULD be performed/administered

IT IS REASONABLE to perform procedure/administer treatment

Procedure/Treatment MAY BE CONSIDERED

Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL

• Recommendation that procedure or treatment is useful/effective • Sufficient evidence from multiple randomized trials or meta-analyses

• Recommendation in favor of treatment or procedure being useful/effective • Some conflicting evidence from multiple randomized trials or meta-analyses

• Recommendation’s usefulness/efficacy less well established • Greater conflicting evidence from multiple randomized trials or meta-analyses

• Recommendation that procedure or treatment not useful/effective and may be harmful • Sufficient evidence from multiple randomized trials or meta-analyses

Level B Limited (2–3) population risk strata evaluated*

• Recommendation that procedure or treatment is useful/effective • Limited evidence from single randomized trial or non-randomized studies

• Recommendation in favor of treatment or procedure being useful/effective • Some conflicting evidence from single randomized trial or non-randomized studies

• Recommendation’s usefulness/efficacy less well established • Greater conflicting evidence from single randomized trial or non-randomized studies

• Recommendation that procedure or treatment not useful/ effective and may be harmful • Limited exidence from single randomized trial or non-randomized studies

Level C Very limited (1–2) population risk strata evaluated*

• Recommendation that procedure or treatment is useful/effective • Only expert opinion, case studies, or standard-ofcare

• Recommendation in favor of treatment or procedure being useful/effective • Only diverging expert opinion, case studies, or standard-of-care

• Recommendation’s usefulness/efficacy less well established • Only diverging expert opinion, case studies, or standard-of-care

• Recommendation that procedure or treatment not useful/effective and may be harmful • Only expert opinion, case studies, or standard-of-care

Suggested phrases for writing recommendations

should is recommended is indicated is useful/effective/beneficial

is reasonable can be useful/effective/ beneficial is probably recommended or indicated

may/might be considered may/might be reasonable usefulness/effectiveness is unknown/unclear/uncertain or not well established

is not recommended is not indicated should not is not useful/effective/beneficial may be harmful

Level A Multiple (3–5) population risk strata evaluated* General Consistency of direction and magnitude of effect

Additional studies with broad objectives needed; Additional registry data would be helpful

Figure 19-2 Applying Classification of Recommendations and Level of Evidence. Source: Reprinted with permission from Methodology Manual for ACC/AHA Guideline Writing Committees, Methodologies and Policies from the ACC/AHA Task Force on Practice Guidelines. © 2006 American College of Cardiology and American Heart Association, Inc., p 37.

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APPROACHES TO EVALUATION OF EVIDENCE 577

Again taking recommendations regarding tobacco use for illustration, the American Heart Association/American Stroke Association (AHA/ ASA) recommendations in the context of primary prevention of stroke, following the ACC/AHA process, are as follows:24, pp e884–e885 Abstention from cigarette smoking and (for current smokers) smoking cessation are recommended . . . (Class I, Level of Evidence B). Avoidance of environmental tobacco smoke for stroke prevention should also be considered (Class IIa, Level of Evidence C). The use of counseling, nicotine replacement, and oral smoking-cessation medications has been found to be effective for smokers and should be considered (Class IIa, Level of Evidence B). Another approach sometimes used by the AHA and ACC to synthesize expert opinion is the Delphi method, useful in development of clinical performance measures. Here the task is to prioritize clinical practices for monitoring or performance evaluation as a tool to reinforce guideline implementation. The European Society of Cardiology has adopted guideline development practices closely similar to those of the ACC/AHA, in which classes of recommendations and levels of evidence are virtually identical. This close resemblance reflects wide consensus on approaches to clinical guidelines specifically in the cardiovascular arena.25

United States Preventive Services Task Force (USPSTF) The mission of the USPSTF is “1) to evaluate the benefits of primary and secondary preventive services in apparently healthy persons based on age, sex, and risk factors for disease; and 2) to make recommendations about which preventive services should be incorporated into primary care practice.”26, p v The reach of the Task Force recommendations may extend well beyond the individual practitioner, however, to include “professional societies, coverage policies of many health plans and insurers, health care quality measures, and national health objectives.”26, p v In formulating recommendations, the USPSTF assesses the strength of evidence for a given action and estimates both benefits and harms that may result. Recommendations are then graded on the basis of the strength of evidence and magnitude of net benefit. Tables 19-4 and 19-5 outline the assessment and the form of resulting recommendations from the USPSTF.26 Without specifying the study designs underlying acceptable evidence, the outline in Table 19-4 points to quality of studies, representativeness of populations, consistency of findings, and assessment of health outcomes as considerations in grading evidence of effectiveness as good, fair, or poor. On the basis of an estimate of benefits and harms, and importantly the net difference that ranges from “substantial” to “zero/negative,” the evidence is coded from “A” (good, substantial) to “D” (good or fair,

Table 19-4

Strength, Grade, and Quality of Overall Evidence Appendix A The USPSTF grades the quality of the overall evidence for a service on a 3-point scale (good, fair, poor). Good: Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes. Fair: Evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies, generalizability to routine practice, or indirect nature of the evidence on health outcomes. Poor: Evidence is insufficient to assess the effects on health outcomes because of limited number or power of studies, important flaws in their design or conduct, gaps in the chain of evidence, or lack of information on important health outcomes. Strength of Overall Evidence and Estimate of Net Benefit Determine the Grade. Strength of Overall Evidence of Effectiveness Good Fair Poor

Estimate of Net Benefit (Benefit Minus Harms) Substantial Moderate Small Zero/Negative A B C D B B C D I—Insufficient Evidence

Source: Reprinted with permission from the US Preventive Services Task Force, The Guide to Clinical Preventive Services 2006, US Department of Health and Human Services, Agency for Healthcare Research and Quality, p 187.

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CHAPTER 19 EVIDENCE AND DECISION MAKING

Table 19-5

How the US Preventive Services Task Force Grades Its Recommendations Appendix A

The US Preventive Service Task Force (USPSTF) grades its recommendations based on the strength of evidence and magnitude of net benefit (benefits minus harms). A. The USPSTF strongly recommends that clinicians provide [the service] to eligible patients. The USPSTF found good evidence that [the service] improves important health outcomes and concludes that benefits substantially outweigh harms. B. The USPSTF recommends that clinicians provide [the service] to eligible patients. The USPSTF found at least fair evidence that [the service] improves important health outcomes and concludes that benefits outweigh harms. C. The USPSTF makes no recommendation for or against routine provision of [the service]. The USPSTF found at least fair evidence that [the service] can improve health outcomes but concludes that the balance of benefits and harms is too close to justify a general recommendation. D. The USPSTF recommends against routinely providing [the service] to asymptomatic patients. The USPSTF found at least fair evidence that [the service] is ineffective or that harms outweigh benefits. I. The USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing [the service]. Evidence that [the service] is effective is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined. Source: Reprinted with permission from the US Preventive Services Task Force, The Guide to Clinical Preventive Services 2006, US Department of Health and Human Services, Agency for Healthcare Research and Quality, p 186.

zero/negative), or “I” (poor, no assessment of net benefit). These categories then translate into the language of recommendations, shown in Table 19-5. In an important caveat, the USPSTF emphasizes individuality of patients and of clinical decisions, which should not be based on evidence alone but tailored to the patient and the situation. This emphasis changes the sense of the recommendations from the language of Table 19-5, points A and B (“strongly recommends” or “recommends” “that clinicians provide [the service] to eligible patients [emphasis added]”). Instead, the clinician is advised to “discuss services with ‘A’ and ‘B’ recommendations with eligible patients and offer them as a priority [emphasis added]” (Table 19-6).26, pp vi–vii One effect of this change is to cloud the interpretation of the recommendations, which are based on the effect of the action, not the effect of clinician advice to consider the action. Left out of the assessment is the role of patient understanding or the physician-patient interaction in determining whether the action will be taken or the intended effect of the action will be sustained to confer the expected benefit. Recommendations of USPSTF regarding counseling on tobacco use (released November 2003) illustrate some outcomes of this process:26, p 120 The USPSTF strongly recommends that clinicians screen all adults for tobacco use and provide tobacco cessation interventions for those who use tobacco products. Rating: A Recommendation. The USPSTF strongly recommends that clinicians screen all pregnant women for tobacco

use and provide augmented pregnancy-tailored counseling to those who smoke. Rating: A Recommendation. The USPSTF concludes that the evidence is insufficient to recommend for or against routine screening for tobacco use or interventions to prevent and treat tobacco use and dependence among children or adolescents. Rating: I Recommendation.

Table 19-6

Actions to Be Taken According to the US Preventive Services Task Force Recommendations Preface

• Discuss services with “A” and “B” recommendations with eligible patients and offer them as a priority. • Discourage the use of services with “D” recommendations unless there are unusual additional considerations. • Give lower priority to services with “C” recommendations; they need not be provided unless there are individual considerations in favor of providing the service. • For service with “I” recommendations, carefully read the Clinical Considerations section for guidance, and help patients understand the uncertainty surrounding these services. Source: Reprinted with permission from the US Preventive Services Task Force, The Guide to Clinical Preventive Services 2006, US Department of Health and Human Services, Agency for Healthcare Research and Quality, p vii.

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World Health Organization (WHO) The WHO approach to assessing levels of evidence and grading recommendations differs in several ways from the others presented here.27 As shown in Table 19-7a, evidence appears to be categorized by level separately according on the one hand to features of the underlying study designs (column 1, “Clinical Trial Data”) or on the other to subject matter (column 2, “Behavioral Risk Factor Data”). On examination, however, “clinical trial data” range from level “1⫹⫹” based on “high-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias” to level 4 (“expert opinion”), with observational studies alone mentioned in levels 2 and 3 (“non-analytic studies”). Thus evidence other than clinical trials would be considered or expert opinion with no reference to study data. Behavioral risk-factor data could be categorized only in level 1 (1⫹⫹, 1⫹, 1⫺) or level 2⫹⫹, the latter defined as “Case-control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal.”27, p 20 Level 2⫹⫹ is far weaker for this body of evidence than

Table 19-7a

Levels of Evidence, WHO Clinical Trial Data

when it applies to case-control or cohort study findings in the first column. Recommendations for “a pattern of care” (Table 19-7b) are graded as A–D with successively lower levels of supporting evidence, including a designation (√) for “Recommended best practice based on the clinical experience of the guidelines development group.”27, p 21 Within this scheme, a pattern of care might be recommended by consensus on the basis of case report or case series observations alone, or expert opinion in the absence of data qualifying for higherlevel classification. One example of WHO recommendations based on this scheme addresses smoking cessation, which is strongly encouraged for all smokers, with health professional support to do so (grade 1⫹⫹, A). Community Intervention The Guide to Community Preventive Services (GCPS) At the community level, where public health decision making is primarily focused, the methods and procedures of the Task Force on Community Preventive

Behavioral Risk Factor Data

1⫹⫹

High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias

Systematic reviews of high-quality case-control or cohort studies with a very low risk of confounding, bias, or chance, and a high probability that the relationship is causal

1⫹

Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias

Well-conducted case-control and cohort studies with a very low risk of confounding, bias, or chance, and a high probability that the relationship is causal

1⫺

Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias

Case-control and cohort studies with a low risk of confounding, bias, or chance, and a moderate probability that the relationship is causal

2⫹⫹

High-quality systematic reviews of case-control or cohort studies. High-quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

Case-control or cohort studies with a high risk of confounding, bias, or chance, and a significant risk that the relationship is not causal

2⫹

Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

2⫺

Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

3 4

Non-analytical studies, e.g., case reports, case series Expert opinion

Source: Adapted with permission from World Health Organization, Prevention of Cardiovascular Disease: Guidelines for Assessment and Management of Total Cardiovascular Risk, © World Health Organization 2007, pp 20–21.

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Table 19-7b

Grades of Recommendation, WHO Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not reflect the clinical importance of the recommendation. A There is robust evidence to recommend a pattern of care. At least one meta-analysis, systematic review of RCTs or, RCT rated as 1⫹⫹ and directly applicable to the target population; or a body of evidence, consisting principally of studies rated as 1⫹, that is directly applicable to the target population, and demonstrating overall consistency of results. B There is evidence to recommend a pattern of care. A body of evidence, including studies rated as 2⫹⫹, is directly applicable to the target population and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1⫹⫹ or 1⫹. C On balance of evidence, a pattern of care is recommended with caution. A body of evidence, including studies rated as 2⫹, directly applicable to the target population and demonstrating overall consistency or results; or extrapolated evidence from studies rated as 2⫹⫹. D Evidence is inadequate, and a pattern of care is recommended by consensus. Evidence is of level 3 or 4; or extrapolated evidence from studies rated as 2⫹. √ Recommended best practice based on the clinical experience of the guideline development group. Source: Adapted with permission from World Health Organization, Prevention of Cardiovascular Disease: Guidelines for Assessment and Management of Total Cardiovascular Risk, © World Health Organization 2007, pp 20–21.

Services are of particular interest.28,29 At the time of this writing, Community Guide publications in areas most directly related to CVD prevention were those for nutrition, physical activity, tobacco, diabetes, and obesity.30 The work of the Task Force is to evaluate evidence and make recommendations for population-based and public health interventions. Effectiveness is judged on the basis of comparative studies with either concurrent or before/after evaluation of response to intervention versus no (or alternative) intervention. (There is no reference to RCTs.) Each study is reviewed to determine the quality of execution in accordance with several elements of its design and conduct. After assessing this evidence, the next step is translation into recommendations. These processes are outlined in Figure 19-329 and Tables 19-8 and 19-9.28 Figure 19-3 shows the algorithm for identifying types of studies contributing to

the review of a particular intervention. A wide diversity of study designs is identified and suggests that assessment of evidence would be inclusive of relevant data from many sources. Table 19-8 describes assessment of the strength of evidence regarding effectiveness of population-based interventions for Community Guide development. Strength of evidence is rated as “strong,” “sufficient,” “expert opinion,” or “insufficient” as summary conclusions from the indicators shown across the table—design, execution, number of studies, consistency in direction and size of effect, effect size, and contribution of expert opinion, if any. Reference to consistency and effect size is reminiscent of considerations in causal assessment, discussed in Chapter 17, “What Causes Cardiovascular Diseases?” A greater number of studies of lesser quality may be considered equivalent to fewer studies of high quality. Sufficiency and necessary effect size are not defined a priori but are to be judged in each case by Task Force opinion. On the basis of the identified and accepted evidence and its assessment, one of five categories of recommendation applies, as shown in Table 19-9. Strength of evidence translates directly to strength of recommendation, from “strongly recommended” to “discouraged.” Notably, the process does not end here with an unqualified, universal recommendation. Further discussion of GCPS procedures goes beyond this step to consider applicability, or generalizability, of a recommendation to a particular population; evidence of side effects or unintended consequences of intervention; data from economic evaluations, when available; and barriers to implementation. Also, as a by-product of this process, evidence gaps and research needs are identified in order that recommendations may be improved in the future. Examples of this approach are the Task Force recommendations regarding tobacco, summarized and compared with others after presentation of details of the Task Force’s own review.30,31 One of several types of intervention addressed was increasing unit price for tobacco products, for the purpose of reducing tobacco-use initiation by children and adolescents. The conclusion of the GCPS was: “Strongly Recommended . . . Increasing the price for tobacco products reduces the number of adolescents and young adults who use tobacco products and the quantity consumed.”30, p 81 The companion report describes details of the review process used by the Task Force on Community Preventive Services to reach its conclusions on each of several tobacco-related interventions.31 Regarding increasing the unit price for tobacco products, the interventions are first defined, being legislative actions

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Comparison between exposed and unexposed?

No

Non-Comparative Study e.g., Case series Focus gr oup Case study Descriptive epi. study

Yes

Cross Sectional

Yes

Exposure and outcome determined in the same population at the same time? No

Randomized trial

No Multiple measurements made before, during or after an intervention?

No

Exposure assigned at group level? (e.g., community, county, clinic)

More than one group studied?

No Yes BeforeAfter

Yes

Yes

Group randomized trial

Yes

Time Series Investigators assign exposure?

Yes

No

No

Case Control

Outcome

Exposure assigned randomly?

Non-randomized “trial” (Group or Individual)

Groups defined by?

Exposure Other designs with concurrent comparison groups (e.g., time series study with comparison group)

No

Cohort Design?

Yes

Prospective?

Yes

Prospective Cohort Study

No Retrospective Cohort Study

Figure 19-3 Study Design Algorithm. Source: Reprinted from American Journal of Preventive Medicine, Vol 18 (1S), S Zaza, LK Wright-De Agüero, PA Briss, et al., p 74, © 2000, with permission from Elsevier.

to increase the excise tax on tobacco products. The rationale and prior experience are cited. The review of evidence is summarized with respect to effectiveness, applicability, other positive or negative effects, and economic aspects. Barriers to implementation are discussed. The conclusion is then expressed as in the summary cited previously.

Because experience teaches that recommendations and guidelines for clinical or public health practice tend at best to be adopted only very gradually, it is also of interest that the Community Guide addresses dissemination of evidence-based interventions and not only development of the recommendations themselves (Figure 19-4).27 The dissemination process

Source: Reprinted from American Journal of Preventive Medicine, Vol 18(1S), PA Briss, S Zaza, M Papaioanou, et al., p 40, © 2000, with permission from Elsevier.

b

The categories are not mutually exclusive; a body of evidence meeting criteria for more than one of these should be categorized in the highest possible category. Studies with limited execution are not used to assess effectiveness. c Generally consistent in direction and size. d Sufficient and large effect sizes are defined on a case-by-case basis and are based on Task Force Opinion. e Expert opinion will not be routinely used in the Guide but can affect the classification of a body of evidence as shown. f Reasons for determination that evidence is insufficient will be described as follows: A. Insufficient designs or executions, B. Too few studies, C. Inconsistent, D. Effect size too small, E. Expert opinion not used. These categories are not mutually exclusive and one or more of these will occur when a body of evidence fails to meet the criteria for strong or sufficient evidence.

a

Insufficientf

Expert Opinion

Sufficient

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Evidence of Effectivenessa Strong

Assessing the Strength of a Body of Evidence on Effectiveness of Population-Based Interventions in the Guide to Community Preventive Services Design Suitability— Execution— Greatest, Moderate, Good or Fairb or Least Number of Studies Consistentc Effect Sized Expert Opinione Good Greatest At Least 2 Yes Sufficient Not Used Good Greatest or Moderate At Least 5 Yes Sufficient Not Used Good or Fair Greatest At Least 5 Yes Sufficient Not Used Meet Design, Execution, Number, and Consistency Criteria for Sufficient Large Not Used But Not Strong Evidence Good Greatest 1 Not Applicable Sufficient Not Used Good Greatest or Moderate At Least 3 Yes Sufficient Not Used Good or Fair Greatest, Moderate, At Least 5 Yes Sufficient Not Used or Least Varies Varies Varies Varies Sufficient Supports a Recommendation A. Insufficient Designs or Execution B. Too Few Studies C. Inconsistent D. Small E. Not Used

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Table 19-9

Relationship of Strength of Evidence of Effectiveness and Strength of Recommendations Strength of Evidence of Effectiveness Recommendation Strong Strongly recommended Sufficient Recommended Insufficient empirical information supplemented Recommended based on expert opinion by expert opinion Insufficient Available studies do not provide sufficient evidence to assess Sufficient or strong evidence of ineffectiveness or harm Discouraged Source: Reprinted from American Journal of Preventive Medicine, Vol 18(1S), PA Briss, S Zaza, M Papaioanou, et al., p 41, © 2000, with permission from Elsevier.

includes five stages (innovation development, awareness, adoption, implementation, and maintenance), each with multiple activities illustrated in the figure. The focus of dissemination discussed here is on the Community Guide as a whole rather than specific interventions, which might well be targeted in a similar manner. Beginning from the principle that evidencebased interventions are desired for sound policies and practice, effective communication to relevant audiences, assurance of actual adoption and implementation, and attention to sustained action in accordance with intended interventions are all required if proposed interventions are to have substantial public health impact. A continuing issue regarding the evidence base for intervention is the question of applicability of evidence from one population or setting to others. This recalls the tension between internal and external validity in design and interpretation of clinical trials discussed previously. Green and Glasgow have used an approach to program evaluation called RE-AIM (for reach, effectiveness, adoption, implementation, and maintenance) as a frame of reference for examining study results regarding this issue (Table 19-10).17 Each of these terms is defined, and questions are proposed by which to assess adequacy of any one study to predict suitability and outcomes of an intervention in another population than where it has been evaluated. The report anticipates limitations in applicability and offers guidance for integrating available evidence regarding an intervention with additional information about the target population and setting with both theory and local experience to adapt an intervention appropriately. Taking this issue a step further, the same authors propose a set of criteria by which to rate intervention studies as to their external validity. Again, several questions are posed that, if addressed in design, conduct, analysis, and reporting of studies, would potentially strengthen their external validity (Table 19-11). Strengthening applicability or generalizability of studies in these ways would enhance their con-

tribution to decision making for public health policy and practice. Economic Evaluations Economic considerations are often part of decision making for both clinical and community health policy and practice. The scope of these considerations may be as narrow as the unit cost of a daily dose of medication or as broad as the macroeconomic consequences of failure to act now to prevent the massive burden of cardiovascular diseases in low- and middleincome countries over the next two to four decades.33 The procedures for developing evidence-based recommendations have been seen to differ among various organizations regarding whether evidence on economic aspects is incorporated. Several standard methods for economic evaluation of health-related interventions are summarized in Table 19-12.34 A different question is addressed through each of these methods, and each results in answers that contribute in different ways to decision making. Basic principles and details of each method are presented in Prevention Effectiveness: A Guide to Decision Analysis and Economic Evaluation; a method used extensively in current health policy evaluations for developing countries is the focus of Cost-Effectiveness in Health and Medicine.35,36 Application of these methods as described for systematic reviews for the Guide to Community Preventive Services (illustrated for interventions to improve vaccination coverage) encounters the difficulties of finding and selecting relevant studies, accounting for methodological differences, abstracting and adjusting economic results from multiple studies, assessing consistency of adjustment methods across studies, and summarizing the results.37 Criticism of such reviews points to the limited availability and quality of relevant studies, including incomplete specification of pertinent costs and inconsistent methods for evaluation.38 For example, interest in economic

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Stage 1. Innovation development

Activity • •

2. Awareness

• • •

3. Adoption

• • • •

4. Implementation

• • • • • •

5. Maintenance

•

• •

Examples

Building the rationale for evidence-based interventions Development of Community Guide reviews and findings

•

Identifying target audiences and their needs Identifying communication channels Supporting knowledge transfer to promote understanding of the resource and the findings

•

Adoption of the Community Guide by the target audience(s) Targeting adoption to attitudes and values of intended audience Assessing degree to which intervention is adopted as planned Identification and address of barriers to and facilitators of adoption

Strategies to promote adoption have included the following: • Sharing findings at meetings • Having findings incorporated into CDC program or research guidance • Disseminating findings to public and private sector partners through established relationships

Assessing initial use of the Community Guide in practice Improving the skills of adopters Providing training and technical assistance Integrating with established materials and curricula Applying research on how to increase implementation Promoting additional research to fill gaps in research

•

Promoting ongoing implementation and continued use of the Community Guide recommendations Ensuring adequate financial and technical resources Continuing evaluations of audience needs and perceptions, the process of developing and disseminating the findings, and use of the resource and the findings

•

•

Development, communication testing, and improvement of the methods and process 130 reviews and findings (as of July 2003) across diverse public health areas ranging from tobacco use prevention, to physical activity promotion, to promotion of healthy social environments (by, for example, intervening on education or the environment) Audience analyses

Knowledge transfer has included combinations of the following: • Involving partners in setting priorities and developing findings • Publishing findings in various media and formats [ journal publications, Web site, other documents (brochures), press releases]

•

•

Specific dissemination and implementation activities such as workshops Additional educational efforts needed (such as incorporating Community Guide materials into training programs and academic curricula) Some efforts underway to work with funders and researchers to encourage additional research that may close gaps Efforts to institutionalize the Community Guide have included development or dissemination of Community Guide reviews by CDC staff not primarily assigned to the Community Guide, incorporation of Community Guide recommendations into Federal research and program guidance, and development of research networks to help fill Community Guide-identified research gaps

Figure 19-4 Stages and Activities in the Dissemination of Evidence-Based Interventions in the Community Guide. Source: Reprinted with permission from PA Briss, RC Brownson, JE Fielding, S Zaza, Annual Review of Public Health, Vol 25, p 295, 2004, license and copyright retained by the US Government.

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Table 19-10

RE-AIM Definitions and Questions to Ask to Assess Applicability (www.re-aim.org) RE-AIM Dimension Definition Questions to Ask What percentage of the target population Participation rate among intended Reach (individual level) came into contact with or began program? audience and representativeness Did program reach those most in need? of these participants Were participants representative of your practice setting? Effectiveness (individual level)

Impact on key outcomes and quality of life Consistency of effects across subgroups

Did program achieve key targeted outcomes? Did it produce unintended adverse consequences? How did it affect quality of life? What did program cost as implemented and what would it cost in your setting?

Adoption (setting and/or organizational level)

Participation rate and representativeness of settings in the evaluation

Did low-resource organizations serving highrisk populations use it? Did program help the organization address its primary mission? Is program consistent with your values and priorities?

Implementation (setting and/or organizational level)

Level and consistency of delivery across program components and different staff members

How many staff members delivered the program? Did different levels of staff implement the program successfully? Were different program components delivered as intended?

Maintenance (individual and setting levels)

At individual level: Long-term effectiveness At setting level: Sustainability and adaptation of program

Did program produce lasting effects at individual level? Did organizations sustain the program over time? How did the program evolve? Did those persons and settings that showed maintenance include those most in need?

Source: Reprinted with permission from LW Green, RE Glasgow, Evaluation of the Health Professions, Vol 29, p 133, © 2006 Sage Publications.

evaluation of the strong recommendation to increase the unit price for tobacco products was met with a dearth of studies meeting criteria for inclusion in a Community Guide review. Only one such study was found, leaving basic economic questions unanswered: What are the costs of interventions to bring about price increases, and what are the outcomes of economic evaluations when cost-effectiveness analysis includes costs of illnesses averted as a result of intervention?32 Such evaluations require cautious interpretation, especially by noneconomists who may be unfamiliar with assumptions and methods of analysis used. Despite such limitations and concerns, costeffectiveness is pivotal in policy development. This is especially true in the arena of priority-setting in the face of competing opportunities for disease pre-

vention and health promotion in low- and middleincome countries.39 Returning to the case of tobacco policy, for example, the estimated cost-effectiveness of increasing tobacco taxes by 33 percent lies anywhere from US$13 to US$195 per disability-adjusted life year (DALY) saved, versus US$55 to US$751 per DALY saved by nicotine replacement therapy. Smoking prevention appears substantially more costeffective than cessation, at least by these interventions and under the assumptions of this analysis.40 Estimating economic costs of disease is also challenging, but figures regarding state or national expenditures for treatment and national, regional, or global costs of disease in terms of lost economic productivity of victims are increasingly common. Further discussion of this dimension of the case for prevention follows in Chapter 24.

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Table 19-11

Proposed Quality Rating Criteria for External Validity I. Reach and representativeness A. Participation: Are there analyses of the participation rate among potential (a) settings, (b) delivery staff, and (c) patients (consumers)? B. Target audience: Is the intended target audience stated for adoption (at the intended settings such as worksites, medical offices, etc.) and application (at the individual level)? C. Representativeness—Settings: Are comparisons made of the similarity of settings in study to the intended target audience of program settings—or to those settings that decline to participate? D. Representativeness—Individuals: Are analyses conducted of the similarity and differences between patients, consumers, or other subjects who participate versus either those who decline, or the intended target audience? II. Program or policy implementation and adaptation A. Consistent implementation: Are data presented on level and quality of implementation of different program components? B. Staff expertise: Are data presented on the level of training or experience required to deliver the program or quality of implementation by different types of staff? C. Program adaptation: Is information reported on the extent to which different settings modified or adapted the program to fit their setting? D. Mechanisms: Are data reported on the process(es) or mediating variables through which the program or policy achieved its effects? III. Outcomes for decision making A. Significance: Are outcomes reported in a way that can be compared to either clinical guidelines or public health goals? B. Adverse consequences: Do the outcomes reported include quality of life or potential negative outcomes? C. Moderators: Are there any analyses of moderator effects—including of different subgroups of participants and types of intervention staff—to assess robustness versus specificity of effects? D. Sensitivity: Are there any sensitivity analyses to assess dose-response effects, threshold level, or point of diminishing returns on the resources expended? E. Costs: Are data on the costs presented? If so, are standard economic or accounting methods used to fully account for costs? IV. Maintenance and institutionalization A. Long-term effects: Are data reported on longer term effects, at least 12 months following treatment? B. Institutionalization: Are data reported on the sustainability (or reinvention or evolution) of program implementation at least 12 months after the formal evaluation? C. Attrition: Are data on attrition by condition reported, and are analyses conducted of the representativeness of those who drop out? Source: Reprinted with permission from LW Green, RE Glasgow, Evaluation of the Health Professions, Vol 29, p 133, © 2006 Sage Publications.

Table 19-12 Overview of Economic Evaluation Methods Economic Evaluation Method Comparison

Measurement of Health Effects

Economic Summary Measure

Cost analysis

Used to compare net costs of different programs for planning and assessment

Dollars

Net cost Cost of illness

Cost-effectiveness analysis

Used to compare interventions that produce a common health effect

Health effects, measured in natural units

Cost-effectiveness ratio Cost per case averted Cost per life-year saved

Cost-utility analysis

Used to compare interventions that have morbidity and mortality outcomes

Health effects, measured as years of life, adjusted for quality of life

Cost per quality-adjusted life year (QALY)

Cost-benefit analysis

Used to compare different programs with different units of outcomes (health and nonhealth)

Dollars

Net benefit or cost Benefit-to-cost ratio

Source: Reprinted with permission from GA Stone, AB Hutchinson, PS Corso, et al., p 451, Understanding and using the economic evidence. In S Zaza, PA Briss, KW Harris, eds. The Guide to Community Preventive Services: What Works to Promote Health? New York: Oxford University Press; 2005:449–463.

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REFERENCES 587

The next chapter presents examples of practice recommendations and public health policies for CVD prevention that are currently advanced by national and international authorities. They are largely based on application of the concepts and approaches described here. They also reflect evolving understanding of CVD risks and their distribution within populations, in specific groups, and across countries or regions.

CURRENT ISSUES In the area of decision making for clinical and public health policy and practice, there remain three broad areas of concern. There is continuing controversy over the nature of evidence needed to justify action. Is useful action being impeded by exaggerated or misplaced concern, especially the demand for RCT-type evidence when it may be inappropriate or infeasible? Existing evidence, whatever its strengths or limitations, is not being translated into recommendations and policies in a timely way. Is progress in translation delayed by lack or insufficiency of evidence, demands of current procedures for systematic review, influences beyond the science in decision making, or other factors, and can any or all of these be remedied? When recommendations are made, there is typically a lag of several years before they are widely implemented in practice. Do the decisions reached on the basis of current evidence and approaches lack credibility or persuasiveness, or are there other explanations for inaction despite development of “evidence-based” recommendations? REFERENCES 1. Levy RI. The National Heart, Lung, and Blood Institute. Overview 1980. The Director’s Report to the NHLBI Advisory Council. Circulation. 1982;65:217–225. 2. Stoto MA, Green LW, Bailey LA, eds. Linking Research and Public Health Practice. A Review of CDC’s Program of Centers for Research and Demonstration of Health Promotion and Disease Prevention. Washington, DC: National Academy Press; 1997. 3. Green LW. Public health asks of systems science: To advance our evidence-based practice,

can you help us get more practice-based evidence? Am J Prev Med. 2006;96;406–409. 4. Pearson TA. The prevention of cardiovascular disease: Have we really made progress? Health Aff. 2007;26:49–60. 5. Teutsch SM, Berger ML. Evidence synthesis and evidence-based decision making: related but distinct processes. Med Decision Making. 2005;25:487–489. 6. Brownson RC, Baker EH, Leet TL, Gillespie KN. Evidence-Based Public Health. Oxford: Oxford University Press; 2003. 7. Fielding JE. Foreword. In: Brownson RC, Baker EH, Leet TL, Gillespie KN. EvidenceBased Public Health. Oxford: Oxford University Press; 2003:v–vii. 8. Kohatsu ND, Robinson JG, Torner JC. Evidence-based public health. An evolving concept. Am J Prev Med. 2004;27:417–421. 9. Eddy DM. Evidence-based medicine: a unified approach. Health Aff. 2005;24:9–17. 10. McGinnis JM. With both eyes open. The Guide to Community Preventive Services. Am J Prev Med. 2005;28:223–225. 11. Anderson LM, Brownson RC, Fullilove MT, Teutsch SM, Novick LF, Fielding J, Land GH. Evidence-based public health policy and practice: promises and limits. Am J Prev Med. 2005;28(5S):226–230. 12. Swinburn B, Gill T, Kumanyika S. Obesity prevention: a proposed framework for translating evidence into action. Obes Rev. 2005;6:23–33. 13. Victora CG, Habicht J-P, Bryce J. Evidence-based public health: moving beyond randomized trials. Am J Public Health. 2004;94:400–405. 14. Ioannidis JPA. Contradicted and initially stronger effects in highly cited clinical research. J Am Med Assoc. 2005;294:218–228. 15. Rosen L, Manor O, Engelhard D, Zucker D. In defense of the randomized controlled trial for health promotion research. Am J Pub Health. 2006;96:1181–1186.

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16. Sanson-Fisher RW, Bonevski B, Green LW, D’Este C. Limitations of the randomized controlled trial in evaluating population-based health interventions. Am J Prev Med. 2007;33:155–161. 17. Green LW, Glasgow RE. Evaluating the relevance, generalization, and applicability of research. Eval Health Prof. 2006;29:126–153. 18. The Cochrane Collaboration. Evidence-based medicine and healthcare. Available at: http://www.cochrane.org/reviews/docs/ ebm.htm. Accessed March 8, 2008. 19. Starr M, Chalmers I. The evolution of The Cochrane Library, 1988–2003. 2003. Update Software: Oxford. Available at: http://www .cochrane.org/reviews/docs/ebm.htm. Accessed March 8, 2008. 20. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 [updated February 2008]. The Cochrane Collaboration, 2008. Available from: http://www.cochrane-handbook.org. Excerpt quoted available from: http://www .mrc-bsu.cam.ac.uk/Cochrane/handbook/ chapter12. Accessed March 8, 2008. 21. The Cochrane Collaboration. Cochrane reviews and the Cochrane Library; 2008. Available from: http://www.cochrane.org/ reviews. Accessed March 8, 2008. 22. Lancaster T, Stead LF. Physician advice for smoking cessation. Cochrane Database Syst Rev. 2004, Issue 4. Art. No.:CD00165. doi: 10.1002/14651858.CD00165.pub2. Available at: http://www.thecochranelibrary.com. 23. ACC/AHA Task Force on Practice Guidelines. Methodology Manual for ACC/AHA Guideline Writing Committees. Methodologies and Policies from the ACC/AHA Task Force on Practice Guidelines. American College of Cardiology Foundation and American Heart Association, Inc. April 2006. Available at: http://www.americanheart.org/print_presenter .jhtml?identifier=3039683. Accessed January 12, 2008. 24. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke. A guideline from the American Heart

Association/American Stroke Association Stroke Council; Cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2006;113: e873–e923. 25. Committee for Practice Guidelines (CPG) of the European Society of Cardiology (ESC). Recommendations for Guidelines Production. A document for Task Force Members Responsible for the Production and Updating of ESC Guidelines. 2006. Available at: http://www .escardio.org/escardio/Templates. Accessed January 13, 2008. 26. US Preventive Services Task Force. The Guide to Clinical Preventive Services 2006. Recommendations of the US Preventive Services Task Force. Washington, DC: Agency for Healthcare Research and Quality; 2006. Available at: http://www.ahrq.gov/clinic/uspstf/ uspstbac.htm. Accessed October 14, 2007. 27. World Health Organization. Prevention of Cardiovascular Disease. Guidelines for assessment and management of cardiovascular risk. Geneva: World Health Organization; 2007. 28. Briss PA, Zaza S, Pappaioanou M, et al. Developing an evidence-based Guide to Community Preventive Services––methods. Am J Prev Med. 2000;18(1S):35–43. 29. Zaza S, Wright-De Agüero LK, et al. Data collection instrument and procedure for systematic reviews in the Guide to Community Preventive Services. Am J Prev Med. 2000; 18(1S):44–74. 30. Guide to Community Preventive Services. The Community Guide. Available at: http://www .thecommunityguide.org/index.html. Accessed September 25, 2007. 31. Hopkins DP, Husten CG, Fielding JE, Rosenquist JN, Westphal LL. Evidence reviews and recommendations on interventions to reduce tobacco use and exposure to environmental tobacco smoke. A summary of selected guidelines. Am J Prev Med. 2001;20(2S):67–87.

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32. Hopkins DP, Briss PA, Ricard CJ, et al. Reviews of evidence regarding interventions to reduce tobacco use and exposure to environmental tobacco smoke. Am J Prev Med. 2001; 20(2S):16–66.

37. Carande-Kulis VG, Maciosek MV, Briss PA, et al. Methods for systematic reviews of economic evaluations for the Guide to Community Preventive Services. Am J Prev Med. 2000; 18(1S):75–91.

33. Leeder S, Raymond S, Greenberg H, et al. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries. The Trustees of Columbia University in the City of New York, New York; 2004.

38. Ramsey SD. Methods for reviewing economic evaluations of community preventive services: A cart without a horse? Am J Prev Med. 2000; 18(1S):15–17.

34. Stone GA, Hutchinson AB, Corso PS, Teutsch SM, Fielding JE, Carande-Kulis VG. Understanding and using the economic evidence. In: Zaza S, Briss PA, Harris KW. The Guide to Community Preventive Services: What Works to Promote Health? New York: Oxford University Press; 2005:449–463. 35. Haddix AC, Teutsch SM, Shaffer PA, Duñet DO, eds. Prevention Effectiveness. A Guide to Decision Analysis and Economic Evaluation. New York: Oxford University Press; 1996. 36. Gold MR, Siegel JA, Russell LB, Weinstein MC, eds. Cost-Effectiveness in Health and Medicine. New York: Oxford University Press; 1996.

39. Musgrove P, Fox-Rushby J. Cost-effectiveness analysis for priority setting. In: Jamison DT, Breman JG, Measham AR, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006:271–285. 40. Laxminarayan R, Chow J, Shahid-Salles SA. Intervention cost-effectiveness: overview of main messages. In: Jamison DT, Breman JG, Measham AR, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006:35–86.

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C H A P T E R

20 Recommendations, Guidelines, and Policies rated management algorithms. Examples developed in the United States, in Europe, and by the World Health Organization illustrate such clinical guidelines. Limitations of evidence may leave uncertainty about applying these guidelines to groups of special concern—particular racial/ethnic groups, women, the elderly, and children and adolescents, populations different from those represented in any particular prediction model. Regarding models, opinion may vary about risk factors to be included, outcomes of importance for risk prediction, and use of risk estimation for young adults, whose 10-year absolute risks are generally low. Community guidelines and public policies address the population-wide aspect of CVD prevention at multiple levels, from detailed recommendations for action by local communities and their leaders to broadly stated policies for implementation regionally or world-wide. In between are state- and nationallevel policies—in the United States, examples are state laws on tobacco taxation and the Healthy People goals and objectives for heart disease and stroke prevention. In substance these recommendations retain essentially the same targets of intervention as a half century ago, although they are generally more formal and much more detailed than those proposed in 1959. Current issues in this area concern, first, the extent to which existing recommendations, guidelines, and policies are actually implemented and evaluated and, second, the need for further research to advance policy development and implementation. Effective action in both respects is required to assure that the intended benefits of CVD prevention are realized for the whole population, as well as individuals at high risk.

SUMMARY Recommendations, guidelines, and policies comprise a variety of authoritative statements intended to influence individual behavior, professional practice, or public action. Such statements in the area of prevention of atherosclerotic and hypertensive diseases, from their beginning in 1959 to the present, have continually reflected contemporary knowledge and concepts of prevention. Recommendations for prevention and control of single risk factors, discussed throughout Part III, predominated early in this history and remain important. More comprehensive approaches to prevention that address multiple risk factors are emphasized currently and are illustrated by selected examples here. In some instances, chiefly the guidelines for clinical preventive practice, these statements result from formal synthesis and evaluation of evidence as described in Chapter 22. In others, expert opinion is the basis rather than a structured review of evidence. The concept that CVD risk depends on multiple risk factors, and not necessarily on extreme levels of any one factor, was discussed in Chapter 18. That concept translates into a composite definition of “high risk” based on various combinations of risk factors and outcomes. Prediction models derived from prospective epidemiologic studies are used for generating estimates of individual “absolute” or “total” risk of CVD events. Risks are then categorized, for example, in specified strata—such as from 0 to 10%, 10 to 20%, or greater than 20% risk in 10 years or some other interval from the point of assessment. On the basis of estimated risk, specific interventions would follow in accordance with sometimes highly elabo-

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CHAPTER 20 RECOMMENDATIONS, GUIDELINES, AND POLICIES

INTRODUCTION The terms “recommendations,” “guidelines,” and “policies” are often used interchangeably, although there may be a sense of narrower scope for “recommendations” and broader reach for “policies.” The intent here is to be inclusive of the wide range of authoritative statements whose purpose is to influence personal behavior, professional practice—in both clinical and public health settings—and public action for CVD prevention. Typically, one or another of the major, established risk factors has been the single focus of attention in clinical guidelines. Such statements have been noted in Part III under prevention and control of the respective factors. A contrasting multifactor approach began earlier in development of community interventions and is now widely adopted in clinical preventive approaches to risk prediction and management as well. Guidelines at the individual level are especially subject to change in response to new evidence from clinical trials. As a consequence, today’s recommendations may be revised importantly tomorrow, and any review may soon be outdated. It is nevertheless useful to illustrate the general character of current approaches by selected examples. It can then be seen how the processes of evidence synthesis and evaluation discussed in the preceding chapter culminate in specific guidelines, recommendations, and policies at this time. Links to major sources discussed here should provide access to new or updated guidelines in coming years. Although recommendations for community intervention can also change as new evidence dictates, change is less frequent owing to the relative paucity of research and program evaluation that can advance knowledge and practice at the community level. Here, too, examples that address multiple factors are discussed as follows. Beginnings A Statement on Arteriosclerosis. Main Cause of “Heart Attacks” and “Strokes,” a 21-page booklet published in 1959 by the National Health Education Committee, Inc., was the first known report to address prevention of atherosclerosis and related conditions.1 Chaired by Mrs. Albert D. (Mary) Lasker, the Committee requested a report from an eight-author panel that included five past presidents of the American Heart Association and Paul Dudley White, then President of the International Society of Cardiology, at the head of the list (see Reference). The report was endorsed by 106 members of the American Society for the Study of Arteriosclerosis,

the organization that was to become the Council on Arteriosclerosis of the American Heart Association. The document was intended to provide “a simple guide which would give the average man and woman something he or she could do in cooperation with the physician to minimize the hazards of arteriosclerosis, main cause of ‘heart attacks’ and ‘strokes.’”1, p 1 The factors identified as predisposing an individual to these events were overweight, elevated blood cholesterol level, elevated blood pressure, excessive cigarette smoking, and heredity. A family history of cardiovascular disease (CVD) was acknowledged as unchangeable but was an indication for special concern in the presence of any of the other factors. A further observation was that “regular, moderate, physical activity appears to lessen the hazards of arteriosclerosis.”1, p 1 Scientific support was cited for inclusion of each “contributing factor” from publications appearing in the 1940s and 1950s. It is instructive to recognize that this report antedated nearly 50 years of research since the 1960s. What has this further experience added, and in what respects have current recommendations, guidelines, and policy advanced from this “simple guide”? Interim Developments The intervening decades have provided an immense body of knowledge about atherosclerosis and hypertension, their causes, and their consequences. Results of population studies and clinical and laboratory research, together with years of public health practice, point to multiple strategies and methods of intervention. Part III focused on the epidemiology, including the distributions and determinants of these diseases, with brief attention to means of prevention and control of each factor. Chapter 18 traced development of concepts of prevention. Chapter 19 outlined current approaches to assembling and evaluating evidence regarding interventions in decision making for clinical and public health practice and policy. Here the focus is on the products of these concepts and procedures—major recommendations, guidelines, and policies for prevention of atherosclerotic and hypertensive diseases. An Abundance of Reports and Recommendations In addition to advances in knowledge and concepts of CVD prevention, the third critical ingredient has been the widening interest in prevention by official and voluntary health agencies, health professionals, and the public. As a result, countless formal recommendations on various aspects of cardiovascular disease prevention have been published.

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INTRODUCTION 593

One difficulty in attempting a comprehensive collection of these reports over past decades is the breadth of the subject area. The scope of recommendations now includes not only the risk factors themselves and their relation to primary prevention, as in the 1959 report, but also the underlying behaviors, later stages of prevention, population-wide and highrisk strategies, the circumstances of special population groups, information for health professionals and the general public, and materials for use in specific settings—schools, worksites, healthcare facilities, faith organizations, and communities. The wide range of health-related behaviors at issue also broadens the reach of many recommendations. Recommendations on diet, for example, have implications not only for CVD, diabetes, cancer, and other chronic conditions but also for health and well-being more generally. Overview of Current Recommendations, Guidelines, and Policies In 2004, the World Heart and Stroke Forum of the World Heart Federation presented principles for national and regional guidelines on CVD prevention.2 The report notes the importance of a societal approach to CVD prevention, in every country: Prevention of the causes of the risk factors is needed worldwide, and cardiovascular disease specialists are called on to join with epidemiologists and public health officials to address this need. Public health approaches are advocated, including governmental and industrial policy changes, education, and testing of individuals in medical or community settings. But the primary focus of the report is on clinical management of individuals at high risk of cardiovascular events and those with already-established CVD. A fundamental issue is defining high risk. In this as several current recommendations in CVD prevention, “major risk factors” continue to be recognized: high LDL-cholesterol concentration, blood pressure, and blood glucose; low HDL-cholesterol concentration; and tobacco smoking. Age is also included as a surrogate for the degree of underlying atherosclerosis. Two other categories of risk factors are recognized in the Forum report. First, “underlying risk factors” are “overweight/obesity, physical inactivity, atherogenic diet, socioeconomic and psychological stress, family history of premature CVD, and various genetic and racial factors.” Second, “emerging risk factors” are a mix of blood lipid components and nonlipid factors—insulin resistance, prothrombotic and proinflammatory markers, and subclinical atherosclerosis. These emerging factors were found in observational epidemiologic studies to be less strongly

associated with cardiovascular risk or less prevalent than the major risk factors.2, p 3113 Each of these factors is addressed in Part III, described previously. This distinction among categories of associated factors was necessary to define “total CVD risk,” a concept similar to “global risk” or “baseline risk,” discussed in Chapter 18. It is defined in this report as the estimated individual risk of suffering a CVD event on the basis of prediction equations derived from prospective epidemiologic studies. Total CVD risk is stratified as high, intermediate, or low. Factors incorporated in risk estimation are those identified here as major risk factors, including age. Underlying factors are not included in risk-prediction equations. However, they are regarded as important in determining population differences in absolute CVD rates and may be used to adjust or “calibrate” risk estimates between populations. Emerging factors are excluded from risk calculation on grounds of being less important than major risk factors. However, they are regarded as potentially useful when advising individual patients in clinical practice. The several principles proposed in this report are summarized in Table 20-1: Risk factors are the target of recommendations and remain fundamental to concepts of prevention. Guidelines should be evidencebased but at the same time allow for professional judgment. Applying estimates of absolute risk for any population requires data on risk-factor distributions specific to that population. Total risk should be the basis for treatment decisions—the greater the risk, the more stringent are the goal levels of risk reduction. Achieving national perspective on CVD prevention on the part of professional societies and others depends on adequacy of vital statistics and other nationallevel data regarding lifestyles, risk factors, and causes and outcomes of CVD. Engagement of such organizations in policy, education, and training is urged. Finally, prevention must become part of daily clinical practice. From the perspective of this report, recent clinical guidelines can now be reviewed as they have been published by organizations in the United States and Europe and by the World Health Organization (WHO). Typically, these refer to adults and are specific by sex and age. Separate guidelines for CVD prevention in women, the elderly, and children and adolescents are also noted. Some aspects of risk estimation warrant particular comment in relation to clinical guidelines. Community-level guidelines are the public health counterpart to those for patient care and have several distinguishing features. Finally, public policy for CVD prevention will be highlighted by examples that apply on a national, regional, or global scale.

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Table 20-1

Strategic Principles for the Development of National Clinical Guidelines

1. Governments, national societies, and foundations should collaborate to develop clinical and public health guidelines for CVD prevention that target risk factors. 2. Evidence-based guidelines should incorporate professional judgment on the translation of such evidence into effective and efficient care addressing all areas of CVD risk. 3. The assessment of total CVD risk should be based on epidemiological risk factor data appropriate to the population to which it is applied. 4. Policy recommendations and guidelines should emphasize a total risk approach for CVD prevention. 5. The intensity of interventions should be a function of the total risk of CVD, with lower treatment thresholds for higher-risk patients. 6. National cardiovascular societies/foundations should promote routine prospective collection of validated national vital statistics on the causes and outcomes of CVD for use in the development of national policies. 7. National professional societies should inform policymakers of risk factor targets and drug therapies for prevention of CVD that are culturally and financially appropriate to their nation and ask the government to incorporate prevention of CVD into legislation whenever relevant. 8. National professional societies/foundations should facilitate CVD prevention through education and training programs for health professionals. 9. National professional societies should assess the achievement of lifestyle, risk factor, and therapeutic targets defined in the national guidelines. 10. Health professionals should include prevention of CVD as an integral part of their daily clinical practice. Source: Adapted with permission from SC Smith Jr, R Jackson, TA Pearson, et al., Circulation, Vol 109, © 2004 American Heart Association, Inc., pp 3120–3121.

CLINICAL GUIDELINES The United States The US National Heart, Lung and Blood Institute (NHLBI) of the National Institutes of Health lists five clinical practice guidelines and reports that are directly relevant to CVD prevention published between 2002 and 2004.3 Guidelines for clinical CVD prevention have proliferated in recent years, as shown by the current listing of American Heart Association (AHA) publications in this area, 29 of them appearing from 2000 through 2007.4 Current clinical preventive guidelines will be illustrated by an example from each of these sources. (The US Preventive Services Task Force [USPSTF] procedure for developing clinical recommendations was also reviewed in Chapter 19. Each of these recommendations generally addresses a single intervention, such as screening for one particular condition.5 Pertinent USPSTF recommendations are noted in the corresponding chapters of Part III.) Prevention of Coronary Heart Disease (CHD) Estimation of cardiovascular risk as a guide to individual-level treatment decisions can be illustrated for the United States by the example of the Third Report on the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (often referred to

as “ATP III”).6 Although the main focus of this report is on blood cholesterol, its scope is far broader. As with the World Heart and Stroke Forum report, the need for population-wide, public health approaches for CVD prevention is discussed. The importance of lifestyle changes as the first line of prevention among persons free of recognized coronary heart disease is also emphasized. But in preference to the former practice of evaluating risk only in terms of individual risk factors in a categorical approach, ATP III adopted the concept of global risk assessment described previously. ATP III illustrates current guidelines and policies recommended through systematic review and evaluation of evidence. The process described in this report was much as outlined in Chapter 19:6, p I-2 The ATP III panel played four important roles in forging this evidence-based report. First, it systematically reviewed the literature and judged which reports provided relevant information. Second, it synthesized the existing literature into a series of evidence statements. This synthesis also required a judgment as to the category and strength of the evidence. Third, the panel developed recommendations based on the evidence statements; these recommendations represent a consensus judgment about the clinical significance of each evidence statement. Lastly, the panel created an integrated set of recommendations and guidelines based on individual recommendations.

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CLINICAL GUIDELINES 595

In addition to demonstrating this process, ATP III reflects a major expansion in scope beyond a focus on high blood cholesterol alone. It addresses for both risk assessment and management the full array of risk factors—here categorized as lipid risk factors, modifiable and nonmodifiable nonlipid risk factors, emerging risk factors, subclinical atherosclerotic disease, and metabolic syndrome. Risk is now global risk, and management is comprehensive. Recommendations of ATP III for intervention to achieve the established goals are described as evidence based, with classification of evidence by type and strength as in the American College of Cardiology/ American Heart Association approach discussed in Chapter 19. Throughout the report, conclusions are presented in the form of a recommendation with an accompanying evidence statement. Evidence types are: major randomized controlled clinical trials (RCTs) (A), smaller RCTs and meta-analyses of other clinical trials (B), and observational and metabolic studies (C). Level 1 strength is “very strong evidence.” For example:6, p II-4 Evidence statement: Multiple lines of evidence from experimental animals, laboratory investigations, epidemiology, genetic forms of hypercholesterolemia, and controlled clinical trials indicate a strong causal relationship between elevated LDL cholesterol and CHD (A1, B1, C1). Recommendation: LDL cholesterol should continue to be the primary target of cholesterollowering therapy. Further recommendations, accompanied in most instances by a similarly graded evidence statement, address a wide range of issues relevant to CHD prevention and reflect the multiple risk-factor approach. These concern: other risk factors and their treatment (triglycerides, remnant lipoproteins, low HDLcholesterol, lifestyle change for atherogenic dyslipidemia, hypertension treatment per JNC guidelines, smoking prevention and cessation, presence of diabetes as a separate risk category, obesity, physical inactivity, atherogenic diet, age, male sex, family history, and metabolic syndrome); goal levels of LDLcholesterol lowering and policies for routine cholesterol testing; clinical noncoronary atherosclerosis and type 2 diabetes as CHD risk equivalents, and use of multidisciplinary teams for their management; cost effectiveness of drugs for lowering cholesterol; dietary aspects of management (weight loss, saturated fatty acids, trans-fatty acids, dietary cholesterol, monounsaturated fatty acids, linoleic acid, unsaturated fatty acids, total fat intake, carbohydrate intake, viscous fiber intake, plant stanol/sterol

esters, soy protein, n-3 fatty acids, folate, dietary antioxidants, alcohol, salt, herbal and botanical dietary supplements, high protein, high total fat, and saturated fat weight loss regimens); lipid-lowering drugs (statins, bile acid sequestrants, nicotinic acid, and fibrates); and hormone replacement therapy. Subsequent sections of the report address issues in detection and evaluation, the general approach to treatment, lifestyle interventions, dietary interventions, drug therapy, management of specific dyslipidemias, special considerations for different population groups, and adherence to drug therapy. Detailed algorithms are presented to guide the physician at each step of decision making in management of the individual patient, reflecting the extensive evidence and numerous recommendations in the report (see also Chapter 11). This report presents detailed discussion of the rationale and methods of global risk estimation, as adopted for ATP III, based on a model from the Framingham Heart Study to predict “hard CHD,” in this case meaning myocardial infarction or CHD death. Table 20-2 presents the scoring weight derived from the model for each level of several contributing variables, separately for men and women. Variables included were total cholesterol concentration and smoking status by age, from 20–39 to 70–79 years; systolic blood pressure, separately for persons treated or untreated at the time of measurement; and HDLcholesterol concentration. The “points” for a given level of a risk factor differ by sex and are typically greater for women. This is because the baseline risk for men is already greater than for women and the effect of higher risk-factor levels in women is the tendency to catch up with the risk for men of the same age. For men, 10-year risks of acute coronary events increase from less than 1% to 30% over a range of total points from 0 to 17 or greater; for women, the same range of risks corresponds to a range of total points from 9 to 25 or greater. The number of points for a given level of total cholesterol or smoking declines with age. This does not mean that these predictors are less important at older age. Rather, it reflects the fact that at older versus younger ages fewer points represent as great or greater increase in absolute 10-year risk. In addition to this categorical approach to risk estimation, ATP III also calls attention to an electronic calculator that more precisely estimates risk by use of continuous values for the risk factors (available at www.nhlbi.nih .gov/guidelines/cholesterol).7 The risk score is used in decision making for treatment in the following way: Persons with existing CHD are considered separately from candidates for

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Table 20-2

10-Year Risk Estimates for Men and Women (Framingham Point Scores) Points at Points at Points at Points at Ages 20–39 Ages 40–49 Ages 50–59 Ages 60–69 Total Cholesterol M F M F M F M F 160 0 0 0 0 0 0 0 0 160–199 4 4 3 3 2 2 1 1 200–239 7 8 5 6 3 4 1 2 240–279 9 11 6 8 4 5 2 3 280 11 13 8 10 5 7 3 4 Nonsmoker 0 0 0 0 0 0 0 0 Smoker 8 9 5 7 3 4 1 2 SBP 120 120–129 130–139 140–159 160 Males Point Total 10-Year Risk (%) Point Total 10-Year Risk (%) Females Point Total 10-Year Risk (%) Point Total 10-Year Risk (%)

Points at Ages 70–79 M F 0 0 0 1 0 1 1 2 1 2 0 0 1 1

If untreated 0 0 0 1 1 2 1 3 2 4

If treated 0 1 2 2 3

0 1 9 5

0 1 10 6

1 1 11 8

2 1 12 10

3 1 13 12

4 1 14 16

5 2 15 20

6 2 16 25

7 3 17 30

8 4

9 1 18 6

9 1 19 8

10 1 20 11

11 1 21 14

12 1 22 17

13 2 23 22

14 2 24 27

15 3 25 30

16 4

17 5

0 3 4 5 6

HDL 60 1 50–59 0 40–49 1 40 2

M, male; F, female; HDL, high-density-lipoprotein cholesterol; SBP, systolic blood pressure. See text for explanation. Source: Data from National Cholesterol Education Program, Third Report from the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. NIH Publication No. 02-5215, September 2002, pp III-4–III-5.

primary prevention; they are defined a priori as highrisk patients for whom maximum intensity of cholesterol-lowering treatment is indicated. For persons without existing CHD, intensity of treatment is intended to match the severity of risk. The first consideration is the number of risk factors present beside LDL-cholesterol. Included in the risk-factor count are age, family history, smoking, hypertension, and low HDL-cholesterol (high HDL-cholesterol is protective and offsets 1 risk factor if present). Persons with two or more of these risk factors are then classified in one of three categories of 10-year CHD risk, based on the risk score: 20%, 10–20%, or 10%. Depending on the estimated risk, the goal level for LDLcholesterol lowering and the levels at which lifestyle change is instituted and, if necessary, drug therapy is added to lifestyle change are set successively lower. Higher goal levels are set for those with only zero to one other risk factors. Other guidelines developed under the aegis of NHLBI concern blood cholesterol in children and

adolescents; high blood pressure in adults and, separately, in children and adolescents; obesity; and other conditions. A new approach to this process at NHLBI, in some respects anticipated by ATP III, is expected to replace risk-factor-specific guidelines with more integrated recommendations. The NHLBI Web site cited previously will likely be useful as a continuing source for current information. Prevention of Ischemic Stroke A wide range of topics in CVD prevention is also represented in the many Scientific Statements and Guidelines published by the American Heart Association (AHA), whether as sole sponsor or in collaboration with its component organization, the American Stroke Association (ASA), or the American College of Cardiology (ACC). The ACC/AHA procedures for guideline development reviewed in Chapter 19 have been typical of these documents. Examples of topics addressed are diet and lifestyle, primary prevention of

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CVD and stroke, reducing delay in treatment-seeking with impending heart attack or stroke, and cardiac rehabilitation and secondary prevention for survivors with CHD.8–13 These clinical guidelines are updated from time to time, as new evidence dictates. One example is the 2006 AHA/ASA guideline on primary prevention of ischemic stroke, an update of previous reports.11 The process for rating levels of evidence and recommendations and the estimated certainty and size of treatment effects was as in Table 19-3 and Figure 19-3. Risk factors for stroke were reviewed and classified as “nonmodifiable,” “well-documented and modifiable,” or “less welldocumented or potentially modifiable.” Nonmodifiable factors identified were age, sex, race, low birth weight, and family history of stroke or TIA. For each modifiable or potentially modifiable factor, data were presented on its prevalence, populationattributable risk for stroke, relative risk, and risk reduction with treatment if known. A “modified Framingham stroke risk profile” was calculated on the basis of a subset of the welldocumented modifiable factors. Analogous to the coronary risk score used in ATP III, this profile assigned points to specified categories of each factor, for individual patients aged from 54 to 85 years. Assignable points ranged from 0 to 10 for both men and women; blood pressure levels were rated by age category; and diabetes, smoking, cardiovascular disease, atrial fibrillation, and left ventricular hypertrophy on electrocardiogram were rated as present or absent. Numbers of points corresponded to the relative potency of each factor’s contribution to risk. The 10-year probability of stroke ranged from 3% to 88% for men with scores from 1 to 30 points and from 1% to 84% for women with scores from 1 to 27 points. Recommendations for reducing risk were presented regarding for each identified factor. Blood pressure management was to be in accordance with the NHLBI-sponsored 7th Joint National Committee Report (see Chapter 12). Similarly, management of dyslipidemia was in accordance with ATP III. For each of 24 other factors, evidence was summarized and, where it was found to be sufficient, an intervention was recommended. Factors emphasized were atrial fibrillation, cigarette smoking, diabetes, asymptomatic carotid stenosis, sickle cell disease, poor nutrition, alcohol, drug abuse, oral contraceptive use, and sleep-disordered breathing. Europe The European Society of Cardiology (ESC) is extensively involved in development of clinical pre-

ventive guidelines, publishing 33 of them from 2000 through 2007.14 Growth of partnerships in guideline development among key organizations—initially the ESC, European Atherosclerosis Society, and European Society of Hypertension, was outlined in a 2005 report by Graham.15 Joint European recommendations were first developed in 1994. By the time the Third Joint Task Force Recommendations were published in 2003, organizations representing family practice, behavioral medicine, and diabetes were included, as well as the European Heart Network of lay-oriented foundations. As emphasized by Graham:15, p 431 The philosophy behind the European Recommendations is to harmonize the advice from as many major bodies as possible with an interest in prevention. Each individual partner is encouraged to develop their own, more detailed guidelines, but it is hoped that they will be seen as an extension of the basic Joint Recommendations and specifically compatible with them. . . . A key tenet of the Joint European Recommendations from the first has been the concept of total risk. The guidelines recognize that atherosclerotic CVDs are the product of the interaction of multiple causes. This supports the concept of Joint Recommendations, rather than separate expert groups on, for example, blood lipids, hypertension, and smoking. The Third Joint Task Force Recommendations represent further evolution of several underlying concepts. The target of prevention was CVD—not limited to CHD but including ischemic stroke and peripheral arterial disease. However, the European data for risk estimation were based on CVD death, not including non-fatal CVD, from 12 pooled cohort studies. These comprised 200,000 persons and more than 7000 fatal CVD events. The risk threshold for treatment was set at 5% or greater risk in 10 years, a level thought to include the majority of persons at risk of nonfatal CVD within the same time interval. The risk assessment model used was the “Systematic COronary Risk Evaluation (SCORE)” model. This model has flexibility to take into account different levels of population risk among European countries. The score is based on sex, smoking status, systolic blood pressure, and blood cholesterol concentration. The resulting risk scores were distributed as shown in “high-risk” and “low-risk” regions of Europe in Figures 20-1 and 20-2, respectively. Low-risk countries are identified in Table 20-3: Belgium, France, Greece, Italy, Luxembourg, Spain, and Portugal. All

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Women Non-Smoker

Systolic Blood Pressure

180 7

8

Men

Age

Smoker

9 10 12

Non-Smoker

Smoker

13 15 17 19 22

14 16 19 22 25

25 30 35 41 47

9 11 13 15 16

18 21 25 29 34

160 6

5

6

7

8

9 10 12 13 16

140 3

3

4

5

6

6

7

8

9 11

6

9

9 11 13

13 15 17 20 24

120 2

2

3

3

4

4

6

6

6

4

5

6

9

9 10 12 14 17

180 4

4

6

6

7

8

9 10 11 13

9 11 13 15 18

18 21 24 28 33

160 3

3

3

4

5

6

6

7

8

9

6

7

9 10 12

12 14 17 20 24

140 2

2

2

3

3

3

4

5

5

6

4

5

6

7

9

8 10 12 14 17

120 1

1

2

2

2

2

3

3

4

4

3

3

4

5

6

6

180 2

2

3

3

4

4

6

6

6

7

6

7

8 10 12

12 13 16 19 22

15% and over

160 1

2

2

2

3

3

3

4

4

6

4

5

6

7

8

8

9 11 13 16

10%–14%

140 1

1

1

1

2

2

2

2

3

3

3

3

4

5

6

5

6

8

9 11

120 1

1

1

1

1

1

1

2

2

2

2

2

3

3

4

4

4

5

6

180 1

1

1

2

2

2

2

3

3

4

4

4

5

6

7

7

8 10 12 14

1%

160 1

1

1

1

1

1

2

2

2

3

2

3

3

4

6

5

6

7

8 10

< 1%

140 0

1

1

1

1

1

1

1

1

2

2

2

2

3

3

3

4

5

6

7

120 0

0

1

1

1

1

1

1

1

1

1

1

2

2

2

2

3

3

4

6

180 0

0

0

0

0

0

0

0

1

1

1

1

1

2

2

2

2

3

3

4

160 0

0

0

0

0

0

0

0

0

0

1

1

1

1

1

1

2

2

2

3

1

1

1

2

2

65

7

60

55

7

7

8 10 12

8

SCORE 5%–9% 3%–4% 2%

50

40

140 0

0

0

0

0

0

0

0

0

0

0

1

1

1

1

120 0

0

0

0

0

0

0

0

0

0

0

0

1

1

1

1

1

1

1

1

4

5

6

7

8

4

5

6

7

8

4

5

6

7

8

4

5

6

7

8

Cholesterol mmol

10-year risk of fatal CVD in populations at high CVD risk

150 200 250 300 mg/dl

Figure 20-1 Ten-Year Risk of Fatal CVD in High-Risk Regions of Europe by Sex, Age, Systolic Blood Pressure, Total Cholesterol, and Smoking Status. Source: Reprinted with permission from IM Graham, Current Opinion in Cardiology, Vol 20, © 2005 Lippincott Williams and Wilkins, p 434.

other countries of Europe were high risk. In both high-risk and low-risk populations, risk at a given level of risk factors was greater for men, smokers, and older persons and increased with systolic blood pressure and total cholesterol concentration. Risks for men were about two times those for women at age 65 years and three times greater at ages 55 years and younger, in both categories of countries; risks for men in low-risk countries were about the same as for women in high-risk countries. Table 20-3 presents instructions on use of the tables in patient education to demonstrate an individual’s risk, the relative risk of different risk-factor combinations, and the effect on risk of reducing one or more factors from the present to a more favorable category. Two recommendations were especially note-

worthy: First, persons at low risk should be advised how to keep their risk low. Second, those whose currently estimated risk would be expected to increase to treatable levels simply by reaching middle age “should be given maximal attention.”15 p 436 In this way, the Joint European Guidelines extend beyond persons already at high short-term risk to reach a lower-risk stratum of the population and to distinguish between persons at higher and lower long-term risk. Worldwide The WHO approach to CVD risk assessment was reviewed in Chapter 19.16 The resulting management recommendations are presented in Table 20-4. The intended reach of these recommendations was world-

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Women

Systolic Blood Pressure

Non-Smoker

Men

Age

Smoker

Non-Smoker

Smoker

8

9 10 12 14

15 17 20 23 26

5

6

7

9 10

10 12 14 16 19

4

4

5

6

7

7

8

9 11 13

4

2

3

3

4

5

5

6

5

7

8

5

6

7

8

9

10 11 13 15 18

4

5

6

3

4

5

5

6

7

8

9 11 13

3

3

4

2

3

3

4

4

5

6

6

7

9

2

2

2

3

2

2

2

3

3

3

4

4

6

6

3

3

3

4

4

3

4

4

5

6

6

7

8 10 12

15% and over

2

2

2

3

3

2

2

3

3

4

4

5

6

7

8

10%–14%

1

1

1

1

2

2

1

2

2

2

3

3

3

4

6

6

5%–9%

1

1

1

1

1

1

1

1

1

1

2

2

2

2

3

3

4

1

1

1

1

1

2

2

2

2

2

3

3

4

4

4

5

6

7

1%

0

1

1

1

1

1

1

1

1

1

1

2

2

2

2

3

3

4

6

< 1%

140 0

0

0

0

0

1

1

1

1

1

1

1

1

1

2

2

2

2

3

3

120 0

0

0

0

0

0

0

0

1

1

1

1

1

1

1

1

1

2

2

2

180 0

0

0

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Figure 20-2 Ten-Year Risk of Fatal CVD in Low-Risk Regions of Europe by Sex, Age, Systolic Blood Pressure, Total Cholesterol, and Smoking Status. Source: Reprinted with permission from IM Graham, Current Opinion in Cardiology, Vol 20, © 2005 Lippincott Williams and Wilkins, p 435.

wide, as indicated in an accompanying table (Appendix 2, discussed in Chapter 21). This table shows the proportion of population in each category of estimated risk (from 10% to 40%) by sex and age (from 50 to 70 years), for 14 subregions representing all six WHO Regions of the world. Especially in low- and middle-income countries, where CVD was an already-present burden but resources to address it faced competing priorities, it was argued that “it is imperative to target the limited resources on those who are most likely to benefit.”16, p 2 As shown in Table 20-4, each recommendation was annotated as to the underlying evidence rating. Strong recommendations were considered likely to apply everywhere, whereas those that were weak would depend, at the individual level, on patient-specific considera-

tions and, on the population level, on views of a wide range of stakeholders. Recommendations were stratified by 10-year risk of a fatal or nonfatal vascular event ( 30%, 20–30%, 10–20%, and 10%). Persons with established cardiovascular conditions (coronary artery disease, cerebrovascular disease, and peripheral vascular disease) were presumed to require intervention appropriate to the risk factors present so are not included in these stratified recommendations. Policy interventions were considered important to establish conditions conducive to behavior change—such actions would benefit even those at low risk, especially when accompanied by lifestyle interventions. Some recommended interventions would apply regardless of risk score—improving smoking, diet, physical activity, weight, and alcohol

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Table 20-3

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Instructions on How to Use the Chart (Figures 20-1 and 20-2) The low-risk chart should be used in Belgium, France, Greece, Italy, Luxembourg, Spain, and Portugal; the high-risk chart should be used in all other countries of Europe. To estimate a person’s total 10-year risk of cardiovascular disease death, find the table for their sex, smoking status, and age. Within the table, find the cell nearest the person’s systolic blood pressure (mmHg) and total cholesterol (mmol/l or mg/dl). The effect of lifetime exposure to risk factors can be seen by following the table upward. This can be used when advising younger people. Low-risk individuals should be offered advice to maintain their low-risk status. Those who are at 5% risk or higher or will reach this level in middle age should be given maximal attention. To define a person’s relative risk, compare their risk category with that of a nonsmoking person of the same age and sex; blood pressure 140/90 mmHg and total cholesterol 5 mmol/l (190 mg/dl). The chart can be used to give some indications of the effect of changes from one risk category to another for example, when the subject stops smoking or reduces other risk factors.

Source: Reprinted with permission from IM Graham, Current Opinion in Cardiology, Vol 20, © 2005 Lippincott Williams and Wilkins, p 436.

intake. Other interventions would be tailored to specific risk strata, each with its own evidence rating— drugs for smoking cessation; antihypertensive drugs; lipid-lowering drugs; hypoglycemic drugs; and antiplatelet drugs. These worldwide recommendations were proposed as a universal approach to risk assessment and management for CVD prevention. At the same time, the need to adapt recommendations “to suit different political, economic, social, cultural and medical conditions” was recognized.16, p 3 Differences remain among national, regional, and worldwide guidelines for preventing first cardiovascular events, from ratings of evidence to strength of recommendations and scope of eligibility for intervention. Should the harmonizing advice of the World Heart and Stroke Forum prevail, these differences may be resolved in the future. Secondary Prevention Clinical guidelines are not limited to primary prevention but have also been developed for secondary prevention, or prevention of recurrent cardiovascular events. Secondary prevention includes reducing disability resulting from prior CVD events. Therefore, rehabilitation has been included in some secondary prevention guidelines. One example is the joint

Scientific Statement from AHA and the American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) on cardiac rehabilitation and secondary prevention.17 This update to a report in 2000 that addressed core components of cardiac rehabilitation programs was occasioned by the need for consistency with other, more current, recommendations for secondary prevention. This new guideline presented detailed directives as to several aspects of patient care and indicated goals for patient evaluation, interventions, and expected outcomes under seven areas: patient assessment; nutritional counseling; management of weight, blood pressure, lipids, and diabetes; tobacco cessation; psychosocial management; physical activity counseling; and exercise training. The intended impact of these recommendations was to establish in all cardiac rehabilitation/secondary prevention programs “specific core components that aim to optimize cardiovascular risk reduction, foster healthy behaviors and compliance to these behaviors, reduce disability, and promote an active lifestyle for patients with cardiovascular disease.”17, p 2675 Groups of Special Concern Recommendations for individual-level interventions depend heavily on evidence from RCTs. The question of whether findings in the study population of a trial (internal validity) predict the impact of intervention in the population at large (external validity) was discussed in Chapter 19. This question takes a special form when recommendations are desired for one or another subgroup of the general population that is not adequately represented in the relevant trials. This issue was addressed in ATP III, in a section titled “Special Considerations for Different Population Groups”:6, p VIII-1 . . . randomized clinical trials have not been carried out to address all therapeutic questions pertaining to all age groups, both sexes, and different racial/ethnic groups. Consequently, ATP III recommendations must be made by combining what has been learned from clinical trials with other lines of evidence such as epidemiologic findings. . . . No attempt will be made to grade the category and strength of evidence for all recommendations made in this section. Discussion follows on several specific groups: middle-aged men (35–65 years); women; older persons (men 65 years, women 75 years); younger adults (men 20–35 years, women 20–45 years); and racial and ethnic groups—African Americans, Hispanic Americans, Native Americans (American Indians), Asian and Pacific Islanders, and South Asians.

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Prevention of Cardiovascular Disease According to Individual Total Riska 10-Year Risk of 10-Year Risk of 10-Year Risk of Cardiovascular Event Cardiovascular Event Cardiovascular Event 30% 20–30% 10–20% Individuals in this category Individuals in this category Individuals in this category are at moderate risk of fatal are at high risk of fatal or are at very high risk of fatal or nonfatal vascular events. nonfatal vascular events. or nonfatal vascular events. Table 20-4

Monitor risk profile every 3–6 months.



10-Year Risk of Cardiovascular Event 10% Individuals in this category are at low risk. Low risk does not mean “no” risk. Conservative management focusing on lifestyle interventions is suggested.b

When resources are limited, individual counselling and provision of care may have to be prioritized according to cardiovascular risk. SMOKING CESSATION All nonsmokers should be encouraged not to start smoking. All smokers should be strongly encouraged to quit smoking by a health professional and supported in their efforts to do so. (1, A) It is suggested that those who use other forms of tobacco be advised to stop. (2, C) Nicotine replacement therNicotine replacement apy and/or nortriptyline therapy and/or nortriptyor amfebutamone (buproline or amfebutamone pion) should be given to (bupropion) should be motivated smokers who given to motivated smokfail to quit with couners who fail to quit with selling. (1, B) counselling. (1, B) DIETARY CHANGES All individuals should be strongly encouraged to reduce total fat and saturated fat intake (1+, A). Total fat intake should be reduced to about 30% of calories, saturated fat intake should be limited to less than 10% of calories and trans-fatty acids eliminated. Most dietary fat should be polyunsaturated (up to 10% of calories) or monounsaturated (10–15% of calories). (1, A) All individuals should be strongly encouraged to reduce daily salt intake by at least one-third and, if possible, to 5 g or 90 mmol per day. (1, A) All individuals should be encouraged to eat, at least 400 g a day, of a range of fruits and vegetables, as well as whole grains and pulses. (2, A) PHYSICAL ACTIVITY All individuals should be strongly encouraged to take at least 30 minutes of moderate physical activity (e.g., brisk walking) a day, through leisure time, daily tasks and work-related physical activity. (1, A) WEIGHT CONTROL All individuals who are overweight or obese should be encouraged to lose weight through a combination of a reduced-energy diet (dietary advice) and increased physical activity. (1, A) ALCOHOL INTAKE Individuals who take more than 3 units of alcohol per day should be advised to reduce alcohol consumption. (2, B) c

ANTIHYPERTENSIVE DRUGS ✓ All individuals with blood pressure at or above 160/100 mm Hg, or lesser degree of raised blood pressure with target organ damage should have drug treatment and specific lifestyle advice to lwer their blood pressure and risk of cardiovascular disease. (2, B) Individuals with persistent blood pressure 130/80 mm Hg should be given one of the flowing drugs to reduce blood pressure and risk of cardiovascular disease: thiazide-like diuretic, ACE inhibitor,

Individuals with persistent blood pressure 140/90 mm Hge who are unable to lower blood pressure through life style strategies with professional assistance within 4–6 months, should be

Individuals with persistent blood pressure 140/90 mm Hg,e should continue life style strategies to lower blood pressure and have their blood pressure and total cardiovascular risk reassessed annually

Individuals with persistent blood pressure 140/90 mm Hg,e should continue life style strategies to lower blood pressure and have their blood pressure and total cardiovascular risk reassessed every two continues

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Prevention of Cardiovascular Disease According to Individual Total Riska—continued 10-Year Risk of 10-Year Risk of 10-Year Risk of 10-Year Risk of Cardiovascular Event Cardiovascular Event Cardiovascular Event Cardiovascular Event 30% 10% 20–30% 10–20% depending on clinical cirto five years depending considered for one of the calcium-channel blocker, cumstances and resource on clinical circumstances following drugs to reduce beta-blocker.d availability. and resource availability. blood pressure and risk of A low-dose thiazide-like dicardiovascular disease: uretic, ACE inhibitor, or thiazide-like diuretic, ACE calcium-channel blocker is inhibitor, calcium-channel recommended as first-line blocker, beta-blocker.d therapy. (1, A) A low-dose thiazide-like diuretic, ACE inhibitor, or calcium-channel blocker is recommended as firstline therapy. (1, A) Table 20-4

LIPID-LOWERING DRUGS (STATINS) ✓ All individuals with total cholesterol at or above 8 mmol/l (320 mg/dl), should be advised to follow a lipid-lowering diet and given a statin to lower the risk of cardiovascular disease. (2, B) Individuals in this risk category should be advised to follow a lipid-lowering diet and given a statin. (1, A) Serum cholesterol should be reduced to less than 5.0 mmol/l (LDL-cholesterol to below 3.0 mmol/l), or by 25% (30% for LDLcholesterol) which ever is greater.f

Adults over the age of 40 years with persistently high serum cholesterol ( 5.0 mmol/l), and or LDL-cholesterol 3.0 mmol/l, despite a lipidlowering diet, should be given a statin. (1, A)

Should be advised to follow a lipid lowering diet.g

HYPOGLYCEMIC DRUGS ✓ Individuals with persistent fasting blood glucose 6 mmol/l despite diet control should be given metformin. (1, A)

Recommendations as for moderate risk, as resources permit.

ANTIPLATELET DRUGS ✓ Individuals in this risk category should be given lowdose aspirin. (1, A)

For individuals in this risk category cardiovascular risk, the balance of benefits and harms from aspirin treatment is not clear.h Aspirin should probably not be given to individuals in this risk category. (1, A)

For individuals in this risk category, the benefits of aspirin treatment are balanced by the harm caused. Aspirin should not be given to. (1, A)

For individuals in this risk category, the harm caused by aspirin treatment outweighs the benefits. Aspirin should not be given to individuals in this lowrisk category. (1, A)

DRUGS THAT ARE NOT RECOMMENDED Hormone replacement, vitamin B, C, E and folic acid supplements, are not recommended for reduction of cardiovascular risk. a

Excluding people with established coronary artery disease, cerebrovascular disease, and peripheral vascular disease. Policy measures that create conducive environments for quitting tobacco, engaging in physical activity, and consuming healthy diets are necessary to promote behavioral change. They will benefit the whole population. For individuals in low risk categories, they can have a health impact at lower cost, compared to individual counselling and therapeutic approaches. c One unit (drink) half pint of beer/lager (5% alcohol), 100 ml of wine (10% alcohol), spirits 25 ml (40% alcohol). b

continues

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Table 20-4

Prevention of Cardiovascular Disease According to Individual Total Riska—continued

d

Evidence from two recent meta-analyses indicates that beta-blockers are inferior to calcium-channel blockers and ACE inhibitors in reducing the frequency of hard endpoints. In addition, beta-blockers are less well tolerated than diuretics (see Part III, section 4). Most of this evidence comes from trials where atenolol was the beta-blocker used. e Reducing blood pressure by 10–15/5–8 mm Hg with drug treatment reduces combined CVD mortality and morbidity by about one-third, whatever the pretreatment absolute risk. However, applying this recommendation will lead to a large proportion of the adult population receiving antihypertensive drugs. Even in some high-resource settings, current practice is to recommend drugs for this group only if the blood pressure is at or above 160/100 mm Hg. f Reducing cholesterol level by 20% (approximately 1 mmol/l) with statin treatment would be expected to yield a coronary heart disease mortality benefit of 30%, whatever the pretreatment absolute risk. However, applying this to the general population may not be cost effective. It will lead to a large proportion of the adult population receiving statins. Even in some high-resource settings, current practice is to recommend drugs for this group only if serum cholesterol is above 8 mmol/l (320 mg/dl). g There are no clinical trials that have evaluated the absolute and relative benefits of cholesterol lowering to different cholesterol targets in relation to clinical events. h Consider aspirin in areas where coronary heart disease rates exceed stroke rates. ✓Best Practice point: Unless there are compelling indications to use a specific drug, the least expensive preparation of the above classes of drugs should be used. Good quality generic preparations of medicines listed in WHO essential medicines list are recommended. Source: Adapted with permission from World Health Organization, Prevention of Cardiovascular Disease. Guidelines for Assessment and Management of Cardiovascular Risk, © World Health Organization 2007, pp 22–26.

Details of special considerations for cholesterol management are tabulated for each of the identified agesex subgroups and for African Americans. Several points are noteworthy regarding these groups. For middle aged men, recommendations for cholesterol-lowering interventions were given separately according to risk level and emphasize lifestyle intervention at lower risk (10-year risk 10%). For women, the 10- to 15-year relative delay in onset of clinical CHD was the basis for providing recommendations at ages 45–75 years, in contrast to ages 35–65 years for men; there were no other substantial differences for women and for men. For older persons, the reliability of risk prediction is less certain and subclinical atherosclerosis may increase risk even though it is unapparent. Therefore noninvasive assessment of atherosclerosis was considered potentially useful in judging the appropriate intensity of cholesterol-lowering intervention. For younger adults, beginning from age 20 years for both men and women, testing for lipids and lipoproteins was recommended, with drug therapy mainly limited to those with LDL-cholesterol concentrations of 190 mg/dl or greater. For African Americans, it was recognized that the relative excess of high blood pressure and left ventricular hypertrophy (LVH) may not be accounted for adequately by the Framingham risk score, which does not include LVH as a predictor. Regardless of this limitation, the ATP III guidelines were treated as equally applicable to African Americans and Whites. For the remaining groups, accuracy of Framingham risk predictions has been questioned and some special considerations may apply—especially for South Asians, with a relatively high prevalence of CHD at earlier ages than Whites—but these and other differences were judged to be insufficient to warrant separate algorithms for cholesterol management for any of these groups.

Women An AHA Guideline for primary and secondary CVD prevention in women, published in 2007, updated an evidence-based review reported in 2004 and a still earlier guide from 1997.18 The most recent report was based on 246 accepted articles in which women were included—RCTs, large prospective cohort studies, and surrogate endpoint studies. Women were to be classified as “high risk,” “at risk,” or “optimal risk.” Lifetime risk rather than short-term (10-year) risk was emphasized, on grounds of overall high CVD risk in women and an otherwise unduly narrow focus on only 10-year risk. The Framingham risk score was less heavily relied on by this review group than by others, on three bases in the group’s assessment: omission of family history; understatement of risk in women with subclinical disease; and unreliability as a predictor in non-White populations. Twenty-eight clinical recommendations were presented, with the corresponding classification and level of evidence for each, in the areas of lifestyle interventions, major risk-factor interventions, preventive drug interventions, and Class III interventions (“not useful or effective” or “may be harmful”). Use of aspirin for primary prevention of heart disease was one of few examples of differences in recommendations between women and men: Its use was not recommended to prevent MI in women 65 years of age or in women aged 65 years if blood pressure was not controlled or risks outweighed benefits. A detailed algorithm outlined the process of stratification on presence or absence of high risk (presence of CVD or a global 10-year risk 20%). Lifestyle recommendations applied to all women regardless of risk level. Those classified as high risk and having a recent CVD event would be referred for rehabilitation. Research was proposed on several topics including the impact of the guidelines and effectiveness of their implementation in various settings.

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The Elderly An AHA Scientific Statement addressed secondary prevention of CHD in the elderly, especially persons 75 years of age.19 (No reference was made to primary prevention in this group. But, while obstructive coronary artery disease is found at autopsy in 70% to 80% in elderly men and 50% in elderly women—half of elderly women and one in four elderly men might still be candidates for primary prevention.) Recommendations in this report addressed clinical intervention for management of hypertension, abnormal blood lipids, obesity, diabetes, psychosocial factors, physical inactivity, and cardiac rehabilitation. Unlike the more formal evidence synthesis and evaluation that underlies the previously discussed recommendations, this report was based on expert opinion, with no attempt to rate the evidence or recommendations. Children and Adolescents Recommendations for CVD prevention at the individual level in childhood and adolescence have been published by AHA, NHLBI, and others over the past 20 years. Reports specific to one risk factor—such as blood pressure, cholesterol, smoking, or obesity—

Table 20-5 Cardiovascular Health Schedule Birth • Family history for early coronary heart disease, hyperlipidemia → if positive, introduce risk factors; parental referral • Start growth chart • Parental smoking history → smoking cessation referral 0–2 Years • Update family history, growth chart • With introduction of solids, begin teaching about healthy diet (nutritionally adequate, low in salt, low in saturated fats) • Recommend healthy snacks as finger foods • Change to whole milk from formula or breast feeding at approximately 1 year of age 2–6 Years • Update family history, growth chart → review growth charta with family (concept of weight for height) • Introduce prudent diet ( 30% of calories from fat) • Change to low-fat milk • Start blood pressure chart at approximately 3 years of age;b review for concept of lower salt intake • Encourage active parent-child play

are addressed in Part III, presented previously. Perhaps the first recommendations for comprehensive clinical preventive measures against CVD in childhood appeared in a Special Report of the AHA in 1992.20 This report incorporated guidelines for a “cardiovascular health schedule” and accompanying action by healthcare providers for all children—irrespective of individual risk—from birth to ages over 10 years, presumably to age 17 or 18 (Table 20-5). At birth, the schedule called for ascertainment of the family history of early CHD or hyperlipidemia. Because this is a dynamic characteristic of the family history, it was to be updated throughout childhood. According to this schedule, the child’s growth chart would be initiated at birth and updated periodically. The parental smoking history would also be ascertained at this time, with referral for smoking cessation if positive for either parent. From birth to 2 years of age, dietary recommendations were the focus of intervention. Foods would be introduced to establish a dietary pattern free of high fat and salt content, and whole milk would be substituted for breast milk beginning at age 1 year. At ages 2 to 6 years, the growth chart was to be reviewed to introduce to parents the concept of the child’s

• Lipid determination in children with positive family history or with parental cholesterol 240 mg/dl (obtain parental lipid levels if necessary) → if abnormal, initiate nutrition counseling 6–10 Years • Update family history, blood pressure and growth charts • Complete cardiovascular health profile with child; determine family history, smoking history, blood pressure percentile, weight for height, fingerstick cholesterol, and level of activity and fitness • Reinforce prudent diet • Begin active antismoking counseling • Introduce fitness for health → life sport activities for child and family • Discuss role of watching television in sedentary lifestyle and obesity 10 Years • Update family history, blood pressure and growth charts annually • Review prudent diet, risks of smoking, fitness benefits whenever possible • Consider lipid profile in all patients • Final review of personal cardiovascular health status

If weight 120% of normal for height, diagnosis of obesity should be considered and the subject addressed with child and family. If three consecutive interval blood pressure measurements exceed the 90th percentile and blood pressure is not explained by height or weight, diagnosis of hypertension should be made and appropriate evaluation considered.

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Source: Reprinted with permission from Circulation, Vol 85, p 1648, Copyright 1992, American Heart Association.

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weight in relation to height. The “prudent diet” would be introduced, with the goals of less than 30% of calories from fat and replacement of whole milk by low-fat milk. Active parent-child play would be encouraged to involve mutual participation in physical activity. Monitoring of blood pressure would be undertaken from age 3 years, with intervention if readings were persistently high and advice for all children to maintain low salt intake. Blood lipids would be evaluated for those children whose family history indicated early CHD or hypercholesterolemia and then dietary advice would be provided if indicated. (Parental lipid levels were to be determined if necessary.) At ages 6 to 10 years, in addition to updating the assessments of family history, blood pressure, and growth, the cardiovascular profile would be completed. This included the parent’s smoking history, weight for height, finger-stick cholesterol determination, and level of physical fitness and activity. Counseling was to be provided on diet, physical activity, tobacco, and the role of television watching in leading to sedentary habits and obesity. Continuing from age 10, annual updates of family history, growth charts, and blood pressure were recommended. Counseling on the prudent diet, risks of smoking, and benefits of fitness would occur “whenever possible.” Laboratory determination of the lipid profile would be considered in all patients. The “final review” of cardiovascular health status presumed a child’s valedictory physician visit for a precollege or preemployment final examination. Throughout this period, reliance on reference charts for blood pressure measurements would continue. A decade later, AHA recommendations for CVD prevention in children and adolescents adopted the concept of identifying high-risk individuals.21 Guidelines in this 2003 update presented health promotion goals for all children and adolescents with respect to diet, smoking, and physical activity. Individual assessment was proposed for risk stratification with respect to lipids and lipoproteins, blood pressure, and body size. Goals were specified for each of several risk factors—blood cholesterol, other lipids and lipoproteins, blood pressure, weight, diabetes, and cigarette smoking. For the child or adolescent whose assessment indicated that he or she was not at goal for a given risk factor, specific interventions were recommended with the intent to reach that goal. Evidence was cited in general support of those recommendations and included studies of pathology of atherosclerosis in the young and the impact of risk factors in this period of life; prevalence in youth of obesity and type 2 diabetes; tracking of risk factors from childhood into adult life; acquisition of risk be-

haviors in childhood; and intervention trials (four being listed) on dietary lowering of cholesterol, smoking prevention, and influencing school meal service and physical education. No formal assessment of this evidence was presented, and as in the case of recommendations in the elderly, noted previously, the recommendations were based on expert opinion regarding the available science. Further examples of organizations whose interest focuses on specific population groups in connection with CVD prevention include the American Diabetes Association and National Kidney Foundation, among others. A Note on Risk Scores Defining a high-risk stratum of the population for multifactor intervention, by addressing some equivalent of “total CVD risk,” is fundamental to current clinical guidelines for CVD.2 Clearly, risk stratification of individuals by use of predictive models derived from prospective epidemiologic studies has become a widely accepted convention. But this approach is not without shortcomings, and a number of concerns about cardiovascular risk scoring warrant comment. The most prominent issues are the wide range of predictive performance between models or across populations; limited predictive accuracy specifically for persons at intermediate risk, for women, and for lower socioeconomic strata of a population; resulting misclassification of individuals as being eligible or ineligible for intervention; and the narrow sense of “risk” when only fatal events, only CHD, or only “hard CHD” is the predicted outcome. A brief historical account of efforts to estimate absolute risk of cardiovascular events began with an AHA committee report in 1973.22 Data from the Framingham Heart Study have been used for this purpose to the present, and advances in analytic methods have yielded improved risk estimates. Availability of data from several other cohort studies, often pooled for increased generality and power of estimation, has broadened interest in application of this approach to European and other populations. Organizations developing guidelines increasingly rely on new prediction models. In 2003, a systematic review of risk prediction tools (tables and charts) used by clinicians described 16 of them based on the Framingham model alone.23 In addition, six studies were summarized in which one or more of these tools was compared with use of the full Framingham equation. In 2005, at least six epidemiologic data sets from studies other than the Framingham Heart Study were in use for building risk scores (continuous estimates of risk) and charts

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(simplified categorical representations of risk as in Figures 20-1 and 20-2). Giampaoli and colleagues noted that risk predicted in a single population varied widely with use of different models.24 This point was further emphasized by Brindle and others.25 They used recent Framingham models to predict CHD or CVD in 27 study populations representing more than 71,000 participants. Across these 27 studies, predicted-to-observed ratios for combined fatal and nonfatal CHD events ranged from underprediction (relative risk 0.43) to overprediction (relative risk 2.87). Overprediction was greatest in low-risk populations, and underprediction was greatest in high-risk populations. A similar, though less marked, gradient was found for prediction of combined fatal and nonfatal CVD. The suggested consequence of these systematic variations was that in low-risk populations, overestimation of risk would lead to unnecessary treatment for many, whereas the opposite would be true in high-risk populations. These investigators also sought evidence on effectiveness of use of these predictive tools in physician practice but found few relevant trials and no supportive data. Further studies have assessed performance of multiple predictive models in specific populations and concluded, for example, that the risk equations derived from a set of 11 Italian cohorts in the CUORE Study performed better for the Italian population than those from either the Framingham or PROCAM (Münster, Germany) Studies.26 Similarly, neither of these risk functions performed acceptably for the lowrisk populations of Belgium or France.27 Attention has focused on ways to improve risk scoring and its application in diverse populations. D’Agostino and others evaluated applicability of the sex-specific Framingham coronary heart disease prediction scores in multiple ethnic groups—US Blacks, Whites, and Native Americans, and in Hispanic and Japanese American men.28 They found good performance of the scores for Blacks and Whites and, after recalibration for population-specific risk factor distributions and coronary heart disease mortality rates, acceptable applicability for the other groups as well. Ridker and others proposed inclusion of additional risk markers to improve prediction among women, by using data from the Women’s Health Initiative study to derive and test two models.29 The best-fitting model included diabetes determined by HbA1c, systolic blood pressure, current smoking, three lipoprotein measures, and high-sensitivity CRP. They reported improved performance of these models over the original one with reclassification of 40–50% of women into higher- or lower-risk cate-

gories. Thompson and others proposed use of coronary artery calcium scoring, high-sensitivity CRP, heart rate recovery, and exercise tolerance during exercise stress testing to improve stratification of intermediate-risk patients, but without incorporating these measures in the Framingham Risk Score.30 Brindle and others, noted previously, and TunstallPedoe and colleagues argued for taking social deprivation into account in improving the performance of cardiovascular risk scoring.25,31 The case was made that populations, or within-population strata, at highest risk are those with greatest social deprivation; if risk were systematically underestimated, these populations would be undertreated and the disparity in health associated with poverty would be widened, counter to widely advocated health policy. Grundy called attention to the scope of defined outcomes to be predicted, suggesting that restriction to hard CHD is unduly narrow relative to a broader category of atherosclerotic cardiovascular disease (ASCVD) (acute coronary syndromes, coronary artery procedures, coronary deaths, and fatal and nonfatal strokes).32 In his view, social and economic costs of ASCVD, beyond hard CHD and fatal CVD events alone, were increasingly recognized. Therefore, prevention of CVD more generally should be considered in risk prediction. In further work on risk scores, D’Agostino and colleagues developed a general sexspecific cardiovascular risk profile intended for use in primary care to estimate risk of coronary heart disease, cerebrovascular diseases, peripheral vascular disease, and heart failure, both separately and as a combined outcome.33 In Grundy’s view, strata of lower to moderate, moderately high or intermediate, and high risk should be retained, being defined by scores of 10%, 10–20%, and 20% 10-year risk, respectively. This approach was proposed by Hense as well.22 He also urged improved calibration of risk functions to regional or local populations and, in view of the necessary cautions about the current status of risk estimation, suggested that risk communication with patients may be the most effective use of these tools in CVD prevention. (Readers interested in calculating their own risk score may do so by going to http://hp2010.nhlbihin.net/atpiii/evalData.asp.)34 Further, in an earlier report, Grundy and others had drawn an important distinction between longterm and short-term prevention, in the context of global risk assessment.35 Ten-year risk is typically low in younger adults, who are therefore less likely than older people to be considered eligible for drug therapy to manage risk factors. But from a longerterm perspective, documentation of low risk may be important for patient education, much as Hense later

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suggested.22 Although less attention has been given to this aspect of risk assessment, it has potential to stimulate nonpharmacologic preventive measures that maintain low risk, or reduce risk, throughout adult life. Grundy also called for periodic risk assessment in early adulthood and early middle age as a measure to reduce long-term risk. Implicitly the results could reinforce successful preservation of low risk or identify early adverse changes that might still be reversed with lifestyle changes alone. In summary, risk prediction to support clinical CVD prevention is under active development, with several fundamental questions being addressed in the current research. Substantial progress over the past decade has set the stage for new integrated CVD prevention guidelines anticipated from NHLBI in the near future.

COMMUNITY GUIDELINES The following discussion turns from high-risk, individual-level guidelines to those for communityor population-wide implementation. Diet, physical activity, and tobacco have long been the focus of CVD prevention at the population level. These are the keys to prevention and control of obesity, adverse blood lipid profiles, high blood pressure, and glucose intolerance, insulin resistance, and diabetes. Part III indicates the potential for population-wide measures to reduce incidence and prevalence of specific risk factors and mitigate their contributions to risks of atherosclerotic and hypertensive diseases. Similarly, as noted in Chapter 19, the Guide to Community Preventive Services presents recommendations for intervention on several specific conditions, some of which are directly related to CVD prevention, but it does not currently provide comprehensive recommendations for prevention of CHD or stroke.36 This gap is addressed in a 2003 AHA Scientific Statement, American Heart Association Guide for Improving Cardiovascular Health at the Community Level.37 This report, cited in Chapter 18, underscored the potential link between community-level intervention and recommendations in four previous AHA or AHA/ACC clinical prevention guidelines:37, p 645 This Guide differs from these four clinical guidelines because it provides a comprehensive approach to reducing the burden of cardiovascular diseases (CVD) through improving the local policies and environment as a means to promote cardiovascular health. Changes toward a healthier environment could be expected to en-

hance the clinically oriented guidelines because both the primary and secondary prevention guidelines recommend that healthcare providers encourage behavior change in individual patients. Improvements in facilities and resources in the places where people work and live should enhance the achievement of many goals, including: cessation of tobacco use and avoidance of environmental tobacco smoke; reduction in dietary saturated fat, cholesterol, sodium, and calories; increased plant-based food intake; increased physical activity; access to preventive healthcare services; and early recognition of symptoms of heart attack and stroke. Healthcare providers and their patients have better opportunities for successfully implementing the clinical guidelines when they live in such communities. The Guide was developed on the basis of expert opinion, an extensive body of scientific literature, and an evolving policy framework supporting community intervention (see Policy, as follows). Its recommendations were presented under six broad strategies: Assessment, Education, Community Organization and Partnering, Assuring Personal Health Services, Environmental Change, and Policy Change. Education was further categorized as General Health Education, School and Youth Education, Work Site Education, and Healthcare Facility Education. These six strategies, 19 goals, and 59 recommendations for comprehensive community intervention are of sufficient interest to warrant reproducing them in full (Table 20-6). Recognizable in this Guide are the core functions public health—assessment, policy development, and assurance—as well as the fundamental public health goal “to prevent the onset of risk factors in the first place, referred to as ‘primordial prevention’ or health promotion.” 37, p 645 How to implement this Guide was addressed in a subsequent AHA Scientific Statement, Taking the Initiative, whose purpose was to enable communities and local leaders to adopt the Guide, setting priorities on those recommendations that are most promising and amenable to action under local circumstances.38 This process would begin with community mobilization and would progress through assessment of local needs and resources and community-based planning to the stage of widespread and sustained implementation. Evaluation of the process and impact would then lead to further, continuing community efforts for improved cardiovascular health. Materials were identified and described regarding related guidelines, data sources, and tools for health promotion initiatives, partnership devel-

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Table 20-6

Guide to Improving Cardiovascular Health at the Community Level Strategies and Goals Recommendations Assessment Goal: All persons and communities should know that CVD and stroke are the leading causes of death and disability in men and women.

• Determine and make available data on the burden of CVD and stroke mortality at the local level (city or county). • Identify groups defined by sex, race/ethnicity, socioeconomic status, or geographic location that are at especially high risk of CVD and stroke within each community. • Assess the levels of major preventable causes of CVD and stroke in the community, including lifestyle behaviors (e.g., adverse nutrition, cigarette smoking, sedentary lifestyle) and risk factors (hypertension, atrial fibrillation, diabetes, elevated blood cholesterol, and obesity).

Education General Health Education Goal: All communities should provide information to their members about the burden, causes, and early symptoms of CVD and stroke.

• Mass media (television, radio, newspapers) should disseminate results of surveillance about the burden of CVD and stroke in the community. • Mass media and local media (e.g., pamphlets, brochures) should emphasize the importance of lifestyle behaviors and risk factors on cardiovascular health. • Public education campaigns should make the community aware of guidelines for primary and secondary prevention of CVD and stroke. • Mass and local media should emphasize the early warning signs of myocardial infarction and stroke. • Ongoing education programs should provide training of lay members in cardiopulmonary resuscitation. • All citizens should know how to access the emergency medical care system.

Goal: Communities should provide materials and programs to motivate and teach skills for changing risk behaviors that will target multiple population subgroups.

• A guide to community resources (services and programs) for prevention, diagnosis, and treatment of CVD and stroke should be available. • Communities should support and publicize research-based programs for CVD risk reduction that are targeted to key population subgroups, especially disadvantaged groups and people at all levels of readiness to change. • Communities should promote the use of web site programs for risk reduction by making web site access to such programs available in public libraries and schools. • Food advertising directed to youth should be limited to foods that meet health guidelines. • TV shows for children should promote physical activity during commercial breaks.

School and Youth Education Goal: All schools should have researchbased, comprehensive, and ageappropriate curricula about cardiovascular health and ways to improve health behaviors and reduce CVD risk.

• School curricula should include lessons about risk factors for CVD and stroke and the extent of heart disease and stroke in the community. • Research-based curricula about effective methods of changing health behaviors should be implemented. • Students should learn skills needed to achieve regular practice of healthful behaviors, and parents should learn how to support their children’s healthful behaviors. • Specific curricular materials for healthy nutrition and physical activity should be offered. • Physical education should be required at least three times a week in grades K–12, with an increasing emphasis on lifetime sports/activities. Implementation of research-based curricula is recommended. • Meals provided at schools should include alternatives conducive to cardiovascular health.

Goal: All schools should implement ageappropriate curricula on changing dietary, physical activity, and smoking behaviors.

Goal: All schools should provide teaching of early warning signs of myocardial infarction and stroke and appropriate initial steps of emergency care.

• Students should know how to activate the emergency medical system. • Cardiopulmonary resuscitation instruction should be provided to students at appropriate ages

continues

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Table 20-6

Guide to Improving Cardiovascular Health at the Community Level—continued Strategies and Goals Recommendations Work Site Education Goal: All work sites should provide materials and services to motivate and assist employees to adopt and maintain heart-healthy behaviors. Goal: All work sites should provide instruction in early warning signs of myocardial infarction and stroke and appropriate initial steps of emergency care.

• Work sites should promote increased physical activity in the day’s work (e.g., stair climbing). • Workers should have access to research-based effective materials and services to help them adopt and maintain heart-healthy behaviors. • Workers should know how to activate the emergency medical system. • Cardiopulmonary resuscitation instruction should be available to all workers.

Healthcare Facility Education Goal: All healthcare facilities should make available research-based, effective educational materials and programs about changing and maintaining risk factors/risk behaviors, ways to prevent CVD and stroke, and early warning signs of CVD and stroke.

• Print and other media should be available in healthcare facilities to describe CVD and stroke risk factors and their early warning signs. • Guides for primary and secondary prevention should be made available for all patients. • Educational materials should be modified to accommodate for limited literacy, cultural and language diversity, sex differences, and dissemination flexibility.

Source: Reprinted with permission from TA Pearson, TL Bazzarre, SR Daniels, et al., Circulation, Vol 107, © 2003 American Heart Association Inc., pp 648–649

opment and operation, evaluation, and education. Community-level indicators were listed for monitoring underlying social and environmental conditions, risk behaviors and biological risk factors, and CVD outcomes. Another sequel to the Guide illustrates targeting of intervention specifically to the school setting. Hayman and others, in Cardiovascular Health Promotion in the Schools, updated the guidelines for children and adolescents cited previously20,21 to place recommendations for school-based intervention in the context of community-level CVD prevention.39 Together, these several reports exemplify the community component of CVD prevention and highlight the importance of this public health component of preventive efforts, its complementary relation to clinical preventive guidelines, and the distinct character of community-wide intervention in contrast to physician- and patient-oriented recommendations.

PUBLIC POLICIES Background Policy interventions were discussed among other strategies of prevention in Chapter 18. Here, selected examples will illustrate policy for CVD prevention in the United States and its development to date on a

worldwide scale, especially as it relates to developing countries. The 1988 report, The Future of Public Health, identified three core functions of public health: assessment, policy development, and assurance. Policy development was characterized in this way:40, p 8 The Committee recommends that every public health agency exercise its responsibility to serve the public interest in the development of comprehensive public health policies by promoting use of the scientific knowledge base in decisionmaking about public health and by leading in developing public health policy. Agencies must take a strategic approach, developed on the basis of a positive appreciation for the democratic political process. Public policy in its fullest form influences whole populations or societies. However, multiple levels of society may be considered as potential beneficiaries of policy change. In their conceptualization of determinants of health, Dahlgren and Whitehead constructed the original version of Figure 18-3, now commonly referred to as the “socioecological model” of health.41 In parallel with the model, four levels of policy intervention were ordered from the outermost to the innermost regions of the model:41, p 12 Policy Level 1––aimed at structural changes

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Policy Level 2––aimed at improving living and working conditions through healthy public or business strategies Policy Level 3––aimed at strengthening social and community support Policy Level 4––aimed at influencing individual lifestyles and attitudes They noted that for any particular health policy goal, strategies could be devised at any of these four levels and emphasized the potential synergistic effect of multilevel policy interventions. Another kind of distinction has been drawn between two types of public health interventions, each of which would be included in Dahlgren’s and Whitehead’s four-level concept of policy:42, p 15 Policies, which include laws, regulations, and rules (both formal and informal). Environmental interventions, which include changes to the economic, social, or physical environments. Brownson and others concluded in a 2006 review that “a considerable body of evidence” shows effectiveness of environmental and policy interventions in risk-factor prevention (especially reduction in tobacco use). They admonished practitioners to “consider the power of environmental and policy approaches to set the stage for other interventions” before implementing individual-level chronic disease prevention programs.43, p 363 A further aspect of “policy instruments,” as termed by Gaziano and others and noted in Chapter 18, is their relative cost-effectiveness as a criterion of acceptability.44 The point was also made in Chapter 18 that the agent of policy interventions, although typically a governmental health agency, might in some instances—described as “whole-ofgovernment” interventions—involve a broad spectrum of interests well beyond the health sector alone.45 Taking these qualities together, ideal public policies for CVD prevention would be expected to have broad reach, multilevel components, multisector engagement, evidence of cost-effectiveness, and a facilitating effect in support of family or individuallevel interventions. The United States The Inter-Society Commission for Heart Disease Resources Early policy development for CVD prevention as a national-level governmental activity in the United States is illustrated by the reports of the Inter-Society Commission for Heart Disease Resources, published

in the 1970s.46 The Commission was created to fulfill congressional intent in establishing the Regional Medical Programs Service in 1965. It was charged to develop guidelines regarding “optimum medical resources” for prevention and treatment of cardiovascular diseases. With 29 participating organizations—chiefly representing national professional associations—and four federal agencies as advisory organizations, the Commission formed seven categorical and seven general study groups. Primary Prevention of the Atherosclerotic Diseases was a joint report of the Atherosclerosis Study Group (Jeremiah Stamler, Chair) and the Epidemiology Study Group (Abraham Lilienfeld, Chair). (The report on hypertension is noted in Chapter 12.) The report pointed to the need for a national commitment to primary prevention of CHD and other atherosclerotic diseases, outlined the rationale for prevention, and estimated the potential impact of primary prevention of CHD in terms of cases and deaths prevented among white males aged 35–64 years. The Commission called for “immediate and concurrent implementation” of its recommendations:47, p 44 The Commission recommends that a strategy of primary prevention of premature atherosclerotic diseases be adopted as long-term national policy for the United States and to implement this strategy that adequate resources of money and manpower be committed to accomplish: Changes in diet to prevent or control hyperlipidemia, obesity, hypertension and diabetes Elimination of cigarette smoking Pharmacologic control of elevated blood pressure. Further, among detailed recommendations within each of these three target areas, community prevention programs were proposed:47, p 50 “The Commission recommends that community programs be developed and expanded for the detection and treatment of persons of all ages who are very susceptible to premature atherosclerotic diseases due to combinations of the major risk factors.” Finally, the Commission addressed as a matter of national policy the relation between public health action and continuing research to resolve still unanswered questions:47, p 44 The Commission recommends that a Special Committee be established at a high level of the Federal Government to develop coordinated plans for large-scale, long-term trials to determine the effect of various interventions, particularly diet modification, on the rates of premature atherosclerotic diseases in the United

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States. . . . The public health importance of CHD makes it mandatory to conduct such trials. . . . At times urgent public health decisions must be made on the soundest evaluation and best judgment of available incomplete evidence. The report thus contemplated immediate public health measures to address diet, smoking, and blood pressure, concurrent with a program of major trials to strengthen evidence supporting primary prevention of the atherosclerotic diseases. How directly this recommendation contributed to the subsequent large-scale trials in the United States is difficult to judge, but the conceptual foundation for prevention policy was clearly evident from the date of this report. Healthy People 2010 Following shortly on the work of the Inter-Society Commission was the federal-level Healthy People initiative, described in Chapter 18. Reference to reducing death rates from heart attacks and strokes as a subgoal and high blood pressure control as a target for preventive health services was present in the 1979 Surgeon General’s Report.48 However, it was not until release of Healthy People 2010 early in the year 2000 that heart disease and stroke became a distinct focus area.49 Focus Area 12 in Healthy People 2010 can be seen as a policy statement for CVD prevention. It directs the two co-lead agencies of the Department of Health and Human Services, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH), to lead the nation’s efforts toward achievement of the four-part goal, discussed in Chapter 18: prevention of risk factors, detection and treatment of risk factors, early identification and treatment of heart attacks and strokes, and prevention of recurrent cardiovascular events. One policy implication for heart disease and stroke prevention is the implied requirement for intervention in each of these goal areas that span the full range of approaches indicated in Figure 18-12. A second policy implication is reflected in the objectives and targets for improving cardiovascular health. Sixteen measurable objectives are included that address blood pressure, cholesterol, heart disease, and stroke. Forty-six related objectives are presented under other behavioral or disease conditions within Healthy People 2010. Baseline data for each objective are taken from the most recent sources as of 2000, and targets are set usually as a percentage change from baseline by 2010. For several objectives, baseline data are given specifically for one or more population subgroups, variously by race and ethnicity, gender, education level, family in-

come level, disability status, presence or absence of diabetes, or urban or rural residence. Sometimes marked disparities in disease burden are evident in the baseline data, but the target levels are generally set at the same level for all groups. This reflects the overarching goal to eliminate disparities in health, a major policy provision of Healthy People 2010. It also implies especially intensified intervention for groups at a relative health disadvantage at baseline. An example is the target to bring African Americans and non-Hispanic Whites to the same greatly reduced prevalence of high blood pressure, in the face of a wide disparity in this condition. The National Forum for Heart Disease and Stroke Prevention Following its mandate under Healthy People 2010, the CDC brought a number of partner organizations and individual leaders together to develop a long-range strategic plan. The result was A Public Health Action Plan to Prevent Heart Disease and Stroke, released in 2003 and updated in 2008.50,51 The Plan itself comprised 24 recommendations and nearly 70 proposed action steps in seven thematic areas of communication, public health leadership, policy implementation, capacity development, monitoring and evaluation, prevention research, and regional and global collaboration. A new national organization was established to put the Plan to work, the National Forum for Heart Disease and Stroke Prevention. For each thematic area, an Implementation Group was established— including the Action Priorities group for policy implementation and the Policy Research group for fostering research on scientific bases for policy development and implementation. In accordance with their respective missions, these groups are expected to advance development and translation into action of public health policies for heart disease and stroke prevention:51, pp 50,64 Action Priorities Implementation Group: To identify effective policies in cardiovascular health promotion and cardiovascular disease prevention at the national, state, and local levels to ensure effective public health action against heart disease and stroke. Policy Research Implementation Group: To develop a comprehensive policy research agenda, foster translating this research into practice, and investigate relevant economic models. A third group, on Regional and Global Collaboration, searched for an authoritative statement of US policy regarding global dimensions of CVD prevention. Finding none, the group proposed and the National Forum adopted a Policy Framework Statement for Regional and Global Partnerships.52 The

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statement is consonant with CDC’s Global Health Promotion Goal and Global Health Diplomacy Goal,53 and it proposes as core values that “Health is a fundamental right of all the world’s people” and that “Everyone should have a fair and equitable opportunity to attain his/her full health potential.” Guiding principles address solidarity, community participation, accountability, sustainability, advocacy, and promotion of programs and actions meeting cardiovascular health needs. Implementation strategies support and promote tobacco control, healthier foods, everyday physical activity, and essential drugs, lifestyle counseling, and basic services, as needed—both to control risk factors prior to CVD onset and during acute CVD events and to prevent recurrence or progression of CVD through long-term management. State Policies In the United States, legal authority for public health resides primarily in the states. Accordingly, policies bearing on cardiovascular health at the state level are of particular interest. However, taking an inventory of health policies for 50 states and the District of Columbia in a comprehensive way is a complex task. The National Council of State Legislatures, for example, maintains a database of state laws, but health is only one of 20 topic areas, public health is one of 10 health subtopics, and only laws related to heart attacks, cardiac arrest, and defibrillators are currently included [http://www.ncsl.org/programs/health/aed .htm, accessed April 18, 2008].54 To address this interest, the Division for Heart Disease and Stroke Prevention at CDC hosts the HDSP Policy Project interactive Web site that lists 207 state-level policies that were in force at any time between 1978 (earliest date searched) and 2005.55 Users can search and study these policies, assisted by an annotated bibliography and spreadsheet display of policy details (state, bill number, status, year passed, topic area, policy abstract, and pdf file name of the policy). In addition, the site offers a mapping function that permits display of states with specified policies, a guide to policy making, and a handbook on policy assessment. These materials are available at www .cdc.gov/dhdsp/dhdspleg56 and at the Division Web site, www.cdc.gov/dhdsp.57 Worldwide/Developing Countries The World Health Organization (WHO) in 1955 convened a Study Group on Atherosclerosis and Ischaemic Heart Disease “to discuss the present status of knowledge of the etiology and pathogenesis of these diseases and to advise the Organization on

means of furthering knowledge which might lead to effective preventive programmes.”58, p 3 The focus of the Study Group’s report was research needs throughout the world. Annex 2 to the report commented on the state of knowledge regarding prevention: “Various preventive measures for the avoidance of ischaemic heart disease have been suggested but, as the Group’s report points out, adequate evidence does not yet exist to give scientific support to the premise that application of specific measures will prevent or delay the onset of manifest ischaemic heart disease.”58, p 37 No global policy for prevention was yet available. Stamler traced policy development for CVD prevention through the 1960s and 1970s.59 He cited several prominent landmarks in the United States indicating participation by multiple government agencies and nongovernmental organizations. Those reports addressed prevention of CVD either very broadly or in terms specific to nutrition or smoking. Additional policy reports were published in this period by Scandinavian countries, Germany, Australia, New Zealand, the United Kingdom, WHO, and the International Society and Federation of Cardiology. Clearly, wider recognition of the problem and the potential for prevention were emerging. In the 1980s, three prominent reports from WHO Expert Committees addressed prevention of CHD. The 29th World Health Assembly in 1976 had called for preparation of a long-term WHO program to promote research on CVD prevention and coordinate international cooperation in the cardiovascular area. WHO Member States were urged to implement prevention programs. That action led to convening the first of these three Expert Committees in late 1981. The resulting report, Prevention of Coronary Heart Disease, appeared in 1982.60 It adopted the dual population-wide and high-risk strategies and incorporated primordial prevention as the strategic foundation for developing countries. The report suggested that primordial prevention should be closely linked with primary healthcare resources, whose strengthening was already being advocated by WHO. Community Prevention and Control of Cardiovascular Diseases followed in 1986.61 This Expert Committee Report embraced the recommendations of the 1982 report, addressed means of implementation at the community level, and presented a model regional plan for CVD prevention. Prevention in Childhood and Youth of Adult Cardiovascular Diseases: Time for Action resulted from an Expert Committee meeting in 1988 and appeared in 1990.62 The focus was on early intervention to avert both the risk factors themselves and

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later complications of advanced atherosclerosis and hypertension, as well as other major cardiovascular conditions:62, p 83 It is therefore recommended that countries develop and pursue a comprehensive population strategy for the primary prevention of these diseases as part of their long-term national health development plan. This strategy should emphasize primary prevention beginning in early childhood and youth, in order to avoid the emergence of the established major risk factors for adult CVD and prevent their persistence on a mass scale in the community. Through improved nutrition (including reduced salt intake), increased physical activity, and elimination of smoking, risk factors including overweight and obesity would be prevented. Health promotion activities in schools and community organizations were seen as fundamental to this effort. These examples illustrate the seminal work of the WHO CVD Unit throughout its existence from 1960 until the mid-1990s. Subsequently, WHO has addressed CVD prevention mainly in conjunction with other chronic, or noncommunicable, diseases, and often with special reference to developing countries.

WHO Global Strategy on Diet, Physical Activity and Health Reflecting this broader context, the 2004 WHO report, Global Strategy on Diet, Physical Activity and Health discussed the global burden of these conditions and two main risk factors, diet and physical activity.63 It presented the challenge and opportunity for preventing these conditions, provided explicit goals and objectives, and outlined evidence, principles, and responsibilities for action. It described the roles of Member States, WHO, international partners, civil society and nongovernmental organizations, and the private sector. In particular, Member States were asked to develop national strategies, policies, and action plans; address national food and agricultural policies; engage multisectoral partners and especially schools; consult with policy stakeholders; link with health services; and invest in surveillance, research, and evaluation. Policy for CVD prevention now concerns a broad spectrum of issues, engages multiple sectors of society, and has potential impact on a wide range of health outcomes. (The landmark global treaty on tobacco, the Framework Convention on Tobacco Control, is discussed in Chapter 14, “Smoking and Other Tobacco Use.”)

Disease Control Priorities in Developing Countries Finally, in the global perspective, the World Bank report Disease Control Priorities in Developing Countries first appeared in 1993.64 Efficacy and cost of both community-based and clinic-based preventive strategies for CVD were reviewed. The second edition of this report similarly addressed both “population” and “personal” interventions.65 In the former category were policy-level interventions that included legislation to substitute trans-fat with polyunsaturated fat, reduce salt content of the diet, increase tobacco price, and implement nonprice interventions against tobacco use. Extensive detail on the rationale and projected cost and impact of these interventions was provided in discussion of priority setting for health interventions in low- and middleincome countries.

CURRENT ISSUES Current issues in this area concern, first, the extent to which existing recommendations, guidelines, and policies are actually implemented and their impact is evaluated and, second, the need for further research to identify and overcome barriers to advances in policy development and implementation. Effective action in both respects is required to assure that the intended benefits of CVD prevention are realized for the whole population, including individuals at high risk. The implementation and impact of clinical guidelines have been assessed in numerous studies, among them three sequential surveys of patients in preventive cardiology practices in Europe.66,67 The first survey, in 1995–1996, included more than 3500 patients in 9 countries; the second, in 1999–2000, included nearly 4000 patients in 15 countries. Need for improved lifestyle factors and use of recommended treatments were documented at the baseline survey and comparisons were made on the basis of the second one. Smoking and obesity had both increased in the interval; prevalence of high blood pressure showed no improvement, but total cholesterol concentrations were reduced and several medications were increased in use. The third survey was launched in 2006, but results were still awaited.67 The principal findings of this and similar reports are that clinical recommendations and guidelines are insufficient in themselves to change practice. Increasing adoption of performance measures to guide monitoring, evaluation, and in some circumstances reimbursement for clinical services may accelerate this

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process. Although population-wide policies for CVD prevention have less often been evaluated for their adoption and impact, a widely held view is that they, too, are seldom implemented on a scale and with sustained support to achieve the intended benefit to the population. The following chapters address what has been learned from experience with intervention, what are currently proposed strategies for more effective action, and what broad research agenda can guide further development, implementation, and evaluation of recommendations, guidelines, and policies for CVD prevention. REFERENCES 1. White PD, Wright IS, Sprague HB, et al. A Statement on Arteriosclerosis: Main Cause of “Heart Attacks” and “Strokes.” New York: National Health Education Committee, Inc; 1959. 2. Smith SC Jr, Jackson R, Pearson TA, et al. Principles for national and regional guidelines on cardiovascular disease prevention. A scientific statement from the World Heart and Stroke Forum. Circulation. 2004;109:3 3112–3121. 3. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. Current clinical practice guidelines and reports. Available at: http://www.nhlbi.nih.gov/guidelines/current/ htm. Accessed April 8, 2008. 4. American Heart Association. Prevention. Available at: http://www.americanheart.org/ presenter.jhtml?identifier=3004572. Accessed April 8, 2008. 5. US Department of Health and Human Services. Agency for Healthcare Research and Quality. US Preventive Services Task Force. The Guide to Clinical Preventive Services 2006. Recommendations of the US Preventive Services Task Force. AHRQ Publication No. 06-0588. Washington, DC: Agency for Healthcare Research and Quality; 2006. Available at: http://www .ahrq.gov/clinic/uspstf/uspstbac.htm. Accessed October 14, 2007. 6. US Department of Health and Human Services, National Institutes of Health, National Heart,

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heart disease risk functions applicable to different European populations? European Heart J. 2003;24:1903–1911. 28. D’Agostino Sr RB, Grundy S, Sullivan LM, et al. Validation of the Framingham coronary heart disease prediction scores. Results of a multiple ethnic groups investigation. J American Med Assoc. 2001;286:180–187. 29. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women. The Reynolds Risk Score. J American Med Assoc. 2007;297:611–619. 30. Thompson JB, Rivera JJ, Blumenthal RS, Danyi P. Primary prevention or patients with intermediate Framingham scores. Current Cardiol Reports. 2006;8:261–266. 31. Tunstall-Pedoe H, Woodward M, for the SIGN Group on Risk Estimation. By neglecting deprivation, cardiovascular risk scoring will exacerbate social gradients in disease. Heart. 2006;92:307–310. 32. Grundy SM. The changing face of cardiovascular risk. J American College of Cardiol. 2005; 46:173–175. 33. D’Agostino Sr RB, Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for use in primary care. The Framingham Heart Study. Circulation. 2008;117:743–753. 34. US Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 10-year risk calculator results. Available at: http:// hp2010.nhlbihin.net/atpiii/evalData.asp. Accessed July 6, 2007. 35. Grundy SM, Pasternak R, Greenland P, Smith S Jr, Fuster V. Asessment of cardiovascular risk by use of multiple-risk-factor assessment equations. A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation. 1999;100:1481–1492.

36. Guide to Community Preventive Services. The Community Guide. Available at: http://www .thecommunityguide.org/index.html. Accessed September 25, 2007. 37. Pearson TA, Bazzarre TL, Daniels SR, et al. American Heart Association guide for improving cardiovascular health at the community level: a statement for public health practitioners, healthcare providers, and health policy makers from the American Heart Association Expert Panel on Population and Prevention Science. Circulation. 2003;107:645–651. 38. Veazie MA, Galloway JM, Matson-Koffman D, et al. Taking the initiative. Implementing the American Heart Association guide for improving cardiovascular health at the community level. Circulation. 205;112:2538–2554. 39. Hayman LL, Williams CL, Daniels SR, et al. Cardiovascular health promotion in the schools. A statement for health and education professionals and child health advocates from the Committee on Atherosclerosis, Hypertension, and Obesity in Youth (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2266–2275. 40. Committee for the Study of the Future of Public Health. The Future of Public Health. Washington, DC: Division of Health Care Services, Institute of Medicine. National Academy Press; 1988. 41. Dahlgren G, Whitehead M. Policies and Strategies to Promote Social Equity in Health. Stockholm: Institute for the Futures Studies; 1991. 42. Association of State and Territorial Directors of Health Promotion and Public Health Education, Centers for Disease Control and Prevention. Policy and Environmental Change. New Directions in Public Health. Final Report. Atlanta, GA: United States Department of Health and Human Services, Centers for Disease Control and Prevention; 2001. 43. Brownson RC, Haire-Joshu D, Luke DA. Shaping the context of health: a review of environmental and policy approaches in the prevention of chronic diseases. Ann Rev Public Health. 2006;27:341–370.

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44. Jamison DT, Breman JG, Measham AR et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006.

52. National Forum for Heart Disease and Stroke Prevention. Policy Framework. Statement for Regional and Global Partnerships. Available at: http://www.nationalforum.org. Accessed May 8, 2008.

45. Leeder S, Raymond S, Greenberg H. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries. New York: The Trustees of Columbia University in the City of New York; 2004.

53. US Department of Health and Human Services, Centers for Disease Control and Prevention. Healthy People in a Healthy World. A Snapshot of CDC Efforts. http://intranet.cdc.gov/ cogh/goals/pdf. Accessed May 13, 2008.

46. Wright IS, Frederickson DT, eds. Cardiovascular Diseases. Guidelines for Prevention and Care. Reports of the Inter-Society Commission. Washington, DC: US Government Printing Office; 1973.

54. National Conference of State Legislatures. Health Program. State Laws on Heart Attacks, Cardiac Arrests, & Defibrillators. Encouraging or requiring community access and use. http:// www.ncsl.org/programs/health/aed.htm. Accessed April 18, 2008.

47. Stamler J, Lilienfeld AM, Chairmen. Primary prevention of the atherosclerotic diseases. In: Wright IS, Frederickson DT, eds. Cardiovascular Diseases. Guidelines for Prevention and Care. Reports of the Inter-Society Commission. Washington, DC: US Government Printing Office; 1973:11–58. 48. US Department of Health, Education, and Welfare. Healthy People. The Surgeon General’s Report on Health Promotion and Disease Prevention. Public Health Service, Office of the Assistant Secretary for Health and Surgeon General. DHEW (PHS) Publication No. 79-55071. Washington, DC: US Government Printing Office; 1979. 49. US Department of Health and Human Services. Healthy People 2010. 2nd ed. With Understanding and Improving Health and Objectives for Improving Health. 2 vols. Washington, DC: US Government Printing Office; 2000. 50. US Department of Health and Human Services. A Public Health Action Plan to Prevent Heart Disease and Stroke. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. 51. US Department of Health and Human Services. Update to a Public Health Action Plan to Prevent Heart Disease and Stroke. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2008.

55. Ford Lattimore B, O’Neil S, Besculides M. Tools for developing, implementing, and evaluating state policy. Prev Chron Dis. 2008;5(2). http://www.cdc.gov/pcd/issues/2008/apr/07_02 10.htm. Accessed 13 May 2008. 56. US Department of Health and Human Services, Centers for Disease Control and Prevention. Division for Heart Disease and Stroke Prevention. Heart Disease and Stroke Prevention Legislative Database. Available at: www.cdc .gov/dhdsp/dhdspleg. Accessed April 18, 2008. 57. US Department of Health and Human Services, Centers for Disease Control and Prevention. Division for Heart Disease and Stroke Prevention. Available at: http://www.cdc.gov/ dhdsp. Accessed April 18, 2008. 58. World Health Organization. Study Group on Atherosclerosis and Ischaemic Heart Disease. World Health Organization Technical Report Series No. 117. Geneva: World Health Organization; 1957. 59. Stamler J. Primary prevention of coronary heart disease: the last 20 years. Am J Cardiol. 1981;47:722–735. 60. World Health Organization Expert Committee. Prevention of Coronary Heart Disease. Technical Report Series 679. Geneva: World Health Organization; 1982.

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61. World Health Organization Expert Committee. Community Prevention and Control of Cardiovascular Diseases. WHO Technical Report Series 732. Geneva: World Health Organization; 1986. 62. World Health Organization Expert Committee. Prevention in Childhood and Youth of Adult Cardiovascular Diseases: Time for Action. WHO Technical Report Series 792. Geneva: World Health Organization; 1990. 63. World Health Organization. Global Strategy on Diet, Physical Activity and Health. Geneva: World Health Organization; 2004. 64. Jamison DT, Mosely WH, Measham AR, Bobadilla JL, eds. Disease Control Priorities in Developing Countries. Oxford (England): Oxford University Press; 1993.

65. Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006. 66. EUROASPIRE I and II Group. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. Lancet. 2001;357:995–1001. 67. European Society of Cardiology. Scheduled and Ongoing Surveys. Euroaspire III Euro Heart Survey on Secondary and Primary Prevention of Coronary Heart Disease. Available at: http://www.escardio.org/knowledge/ ehs/survey/scheduled-surveys/Euroaspire_III .htm. Accessed January 15, 2008.

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C H A P T E R

21 The Case for Prevention factors fail to account sufficiently for causation; interventions to change them are of unknown or uncertain effectiveness; and more immediate public health priorities already consume the available resources. Gaps in evidence are sometimes cited to question whether public health action is justified until further research has been completed. Current issues regarding the case for CVD and chronic disease prevention are, first, to communicate the urgency, potential for prevention, and consequences of inaction to reach the key audiences effectively—the public at large, local, national and global leaders in health and other sectors and policy-makers at all levels; and, second, to take action on the basis of current knowledge.

SUMMARY What is the case for full-scale implementation of public health approaches to cardiovascular disease (CVD) prevention on local, national, and global levels? Arguments specific to CHD, stroke, or other cardiovascular conditions, or CVD more generally, are complemented by those embracing a broader set of major chronic or noncommunicable diseases, including cancer and chronic respiratory diseases as well as CVDrelated conditions. Chronic disease prevention is therefore directly germane to CVD prevention, especially in the arena of national, regional, and global health policy. Several elements of the case for CVD prevention are: First, effectiveness of intervention has been reported from the experience of many clinical and community trials. Second, the growing burden of CVD risk factors for populations throughout the world can be described on the basis of a large body of epidemiologic data. Third, current economic assessments regarding CVD address both the impact of disease and disability and the cost-effectiveness of particular interventions, with special reference to low- and middle-income countries. Fourth, explanation of recent trends in CVD mortality and projections of the future course of the epidemic are now available through several approaches to statistical modeling. Fifth, a number of visionary statements express reasoned expectations of what public health might achieve through effective CVD or chronic disease prevention on a global scale but also propose means to attain such alternative futures. What counter-arguments are raised against largescale public health efforts in CVD prevention? Prominent themes include claims that established risk

INTRODUCTION As concepts of prevention have evolved and understanding of risk factors has grown over the past several decades, the accumulating evidence has been assembled, evaluated, and translated into recommendations, guidelines, and policies for CVD prevention at both individual and population levels. Despite limited implementation of clinical guidelines as discussed in Chapter 20, important progress in CVD prevention has been made over these several decades, accompanied by marked declines in agestandardized CVD mortality in many industrialized countries. However, burdens of CVD are substantial and increasing in low- and middle-income countries, and progress has slowed or reversed in others. These observations add urgency to the fact that strategies of prevention are having much less than their full potential public health impact. In terms of the three

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CHAPTER 21 THE CASE FOR PREVENTION

core functions of public health, assessment and policy development in CVD prevention have advanced substantially, but assurance lags far behind.1 The concepts, strategies, and goals of CVD prevention extend across the full spectrum, illustrated in Figure 18-1, from preventing risk factors to detecting and managing risk, responding to acute events, and reducing risk of recurrent CVD events for those who survive a first event. Public health aspects of prevention across this spectrum range from policy and environmental change to foster maintaining low risk to supporting community and clinical approaches to reduce risk for those in need; to increase public awareness of signs and symptoms of impending CVD events, use of appropriate emergency medical services, and availability of qualified hospital emergency departments; and to assure access to long-term care for rehabilitation, risk reduction, and end-of-life care. The whole array of approaches to intervention is of public health concern. However, those furthest “upstream” are most prominently dependent on public health action. Public health is therefore especially focused on interventions with the earliest potential impact and broadest reach— those aimed at both prevention of risk factors in the first place and detection and treatment of risk factors prior to first CVD events—or, simply, primary prevention. From this perspective, although public health must in principle advocate and pursue a comprehen-

sive strategic approach to CVD prevention, primary prevention is the focus of the present chapter. To put the case for CVD prevention in context, it is important to embrace the other chronic diseases that are of major public health concern and that are likely to be impacted by the same policy interventions. Thus the World Health Organization (WHO) brings together, under the rubric of chronic diseases, heart disease, stroke, cancer, chronic respiratory diseases, and diabetes.2 WHO’s 2005 report, Preventing Chronic Diseases: A Vital Investment, was the forerunner of two series of reports in The Lancet, one appearing in 2005 and the other in 2007, that contribute substantially to the case for preventing chronic diseases—and prominently including CVD.3 Credit for the mounting impetus behind chronic disease prevention as a global health priority is also due to the Disease Control Priorities in Developing Countries Project and the Global Burden of Disease Study.4,5 These and other sources regarding chronic disease prevention are noted here as they bear on the case for CVD prevention. It has long been recognized that factors contributing to cardiovascular risk are related to several other chronic conditions as well. It is therefore expected that effective intervention, through whatever means, will confer multiple benefits. This point was illustrated by Shigan as in Figure 21-1.6 (The original figure has been modified here to include links from ex-

Smoking

Coronary heart disease

Diet

Stroke

Excessive alcohol consumption

Diabetes

Physical inactivity

Lung cancer

Environmental pollution

Chronic bronchitis

Raised blood pressure

Liver cirrhosis

Hyperlipidemia

Gallbladder disease

Blood glucose

Peptic ulcer

Figure 21-1 Risk Factors and Non-Communicable Diseases—Main Links. Source: Reprinted with permission from E Shigan, World Statistics Quarterly, Vol 41, p 268, © 1988, World.

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cessive alcohol consumption to stroke and from hyperlipidemia to CHD, which were absent in the original. A connection from physical inactivity to diabetes could be added as well.) On the basis of this scheme, strategies that combine efforts to improve all eight factors would be expected to have significant impact not only on CHD and stroke but also on diabetes, lung cancer, chronic bronchitis, liver cirrhosis, gallbladder disease, and peptic ulcer. Even this extended list, however, fails to recognize the role of high blood pressure on heart failure, dementia, and other cardiovascular outcomes of growing importance. These are the main points in the case for CVD prevention: • Experience with multifactor primary prevention has accrued from a large number of studies in the United States and much of the world. What can be learned from this body of work is the cornerstone of the case for prevention. Widespread interest in community approaches suggests increasing readiness over the past decade to take further action. Lessons of experience indicate foremost a need to implement the most promising and comprehensive interventions, in multiple populations, on a large enough scale and with sufficient duration to permit rigorous evaluation. This would offer the greatest opportunity to identify intervention approaches with potential for widespread dissemination and adaptation to local needs and resources. • The fact of global occurrence of CVD on an epidemic level calls for application of current knowledge on a corresponding scale. The burden of risk is global in extent, and every region of the world is experiencing CVD on an epidemic scale. Distributions of particular risk factors vary among populations as do, therefore, their relative and respective populationattributable fractions for CHD and stroke. But the same factors are accountable everywhere. • At a macroeconomic level, CVD and other chronic diseases demand a level of attention and urgency of action that have been seriously underappreciated until quite recently. The economic and social impact of lost productivity, especially—but not exclusively—in low- and middle-income countries, would seem to compel action, the cost of continued inaction being unacceptable from the perspective of public health accountability. On the basis of costeffectiveness analysis, substantial progress could be made by implementing presently affordable preventive measures today.

• Modeling contributes importantly to explanation, description, and prediction of past, present, and future occurrence of CVD and other chronic diseases. Extending beyond the sometimes quite limited observations available, modeling offers insights that can influence decision making about health policy in positive ways. For example, reduction of population-wide risk factors has contributed to approximately half of the gain in coronary heart disease (CHD) mortality in high-income countries in recent decades. This strategy is projected to make continuing major contributions in low- and middleincome countries in the future. Wider interest in modeling can also stimulate strengthening of data sources for future analyses. • The visions expressed in several published statements from responsible organizations represent judgments that go beyond systematic review of evidence on a specific intervention. They reflect not only a sense of what such evidence says, but what it means in terms of societal interests and values. That such belief in the potential for CVD prevention is expressed strongly by many authoritative sources contributes significantly to the case for prevention. • That counter-arguments regarding the case for CVD prevention continue to be raised should not be surprising, given competing interests, priorities, or interpretations of the evidence. Weighed against the elements of the argument in favor of CVD prevention, however, they are not persuasive to many in positions of accountability for the public’s health.

EXPERIENCE WITH MULTIFACTOR PRIMARY PREVENTION The view that the major CVD risk factors and their underlying behavior patterns should be considered together rather than separately is well established. This is reflected in the recent practice of estimating absolute 10-year risk of CHD or stroke for individual patients from multivariate risk models, as discussed in Chapter 20. But already by the early 1970s, the potential for multifactor interventions was a topic of research interest. For example, one proposal for a multifactor trial in the United States was to assess independent and joint contributions of behavior changes in diet, physical activity, and smoking habits in primary prevention of CHD. However, the proposed trial, dubbed “Jumbo” by its designers, was considered by the government to be prohibitively

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expensive and was never implemented. Instead, such single-factor treatment trials as the Coronary Primary Prevention Trial of cholesterol reduction and Hypertension Detection and Follow-up Program (see Chapters 11 and 12, respectively) were undertaken. The joint impact of such measures for singlerisk-factor change would remain unknown until multifactor trials could be accomplished, however. The need for this evidence became compelling. Studies were initiated that represented both the high-risk strategy and the population strategy of prevention. Clinical trials were undertaken in groups selected for having already-established risk factors, for whom intervention would be applied individually, with spouses, or in groups. Community intervention trials tested population-wide interventions, especially those involving community organization and education, sometimes including risk-factor screening with targeted intervention for high-risk individuals.7 (Multifactor trials of secondary prevention were also conducted and showed benefit among persons with recognized CHD, but the present focus is on primary prevention.) The ultimate goal of these studies was to test the degree to which multifactor intervention could reduce the frequency of CHD. Adults were therefore the principal target for assessing effectiveness of both clinical and community interventions. However, studies in school-age populations were also initiated, usually separately, often with change in risk-factor levels as the primary outcome. As intermediate objectives, most of these studies also assessed success in delivery of interventions and ability to bring about relevant behavior change. It was expected that the lessons learned would guide further development of policies and practices for CVD prevention and strengthen the scientific basis for their implementation. Several examples illustrate the methods and results of such multifactor intervention trials. Intervention in Individuals The Multiple Risk Factor Intervention Trial (MRFIT) It was recommended in 1971 that a trial be undertaken of the combined effects of intervention to reduce high total cholesterol, high blood pressure, and smoking among high-risk men.8 Independent effects of the interventions could not be evaluated statistically, as Jumbo would have allowed, but study size and cost would be acceptable with the proposed design. High risk was defined in relation to a three-variable risk score from the Framingham Study based on the targeted risk factors. Initially the scores at or above the 85th percentile defined eligibility, but to increase the

average risk level of participants, this was raised to the 90th percentile after one-third of the screening had been completed. Men aged 35–57 years were invited to participate. Persons with sustained qualifying riskfactor levels after the third visit were randomly allocated to intervention (special intervention, SI) or control (usual care, UC). The UC group members were expected to receive risk-factor intervention as customarily delivered by their own sources of medical care. The SI group members received interventions for their respective risk factors, beginning with intensive group counseling and reinforced with individual counseling and therapy by a multidisciplinary team throughout the course of the trial. The primary end point of the trial was CHD mortality. As a result of screening 361,662 men in 22 clinical centers, 12,866 men were randomized into the trial. Results reported at the planned close of the intervention period were based on an average followup of 7.0 years.9 Cumulative coronary mortality was 17.9/1000 in SI and 19.3/1000 in UC, a nonsignificant difference of 7.1% with a 90% confidence interval of 15% to 25%. A difference of 26.6% had been projected in the design. Total mortality was slightly greater in SI than UC (41.2 versus 40.4/1000). Failure of intervention to bring about the expected relative reduction in CHD mortality was due, in part, to unexpected improvement in risk factors in UC and occurrence of only approximately two-thirds of the expected coronary mortality in this group. A consequence was to make the difference between groups more difficult to detect. In addition, relatively adverse experience of some participants receiving antihypertensive drug therapy offset the benefits of reductions in cholesterol concentration and smoking in participants without hypertension. This may have resulted from an anomalous deficit of deaths among UC hypertensives. Through continuing mortality follow-up of study participants after the close of the intervention period, MRFIT extended the analysis of intervention effects through 10.5 years and 16 years in subsequent reports.10,11 Ultimately, after 16 years, total deaths had reached three times the number in the initial analysis, with total mortality 5.7% less in SI than in UC (Table 21-1). For fatal acute myocardial infarction the SI-UC difference, 20.4%, was statistically significant. Because risk-factor status was not being monitored in most centers in the posttrial period, interpretation of this result is unclear. However, during the intervention period, fewer nonfatal coronary events had occurred in SI. On this basis, it was predicted that mortality would be reduced in SI subsequently, and the 16-year findings confirmed this prediction. These later results

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Table 21-1

Cause of Death for MRFIT SI and UC Men Through December 1990 Cause of Death ICD-9 Code No. SI, n UC, n All cardiovascular 390–459 507 550 Acute myocardial infarction 410 185 232 Other ischemic (coronary) heart disease 411–414, 429.2‡ 185 185 Cardiac dysrhythmias 427 15 21 Hypertensive heart disease 402 10 12 Other hypertensive 401, 403–405 6 2 Cerebrovascular 430–438 46 44 Other cardiovascular disease ... 60 54 All noncardiovascular 483 499 Neoplastic 140–239 316 321 Lip, oral cavity, and pharynx 140–149 5 12 Digestive organs and peritoneum 150–159 73 88 Colorectal 153–154 28 33 Other gastrointestinal 150–152, 155–159 45 55 Respiratory and intrathoracic organs 160–165 141 122 Lung 162 135 117 Other neoplasms ... 97 99 Respiratory 460–519 25 31 Digestive system 520–579 40 33 Accidents, suicides, and homicides 800–999 55 58 Other non-cardiovascular disease ... 47 56 Cause unknown (death certificate not found) ... 1 1 Total ... 991 1050

Relative Difference, % 7.9 20.4† 0.1 29.0 17.2 ... 5.2 11.0 3.3 1.8 ... 17.2 15.2 18.5 15.2 15.0 2.3 19.2 21.0 5.1 15.9 ... 5.7

*(RR–1) 100%, where the RR (relative risk) is estimated from the proportional-hazards regression model. † p .02; p .05 for all other relative differences. Relative difference is not given if there were 10 deaths in either the SI or UC. ‡ In ICD-9, No. 429.2 is cardiovascular disease, unspecified; in ICD-8 this is coded to coronary heart disease No. 412.4 Source: Reprinted with permission from MO Kjelsberg, MRFIT trial, Circulation, Vol 94, p 948, © American Heart Association.

were taken as evidence that all three interventions, targeting cholesterol, blood pressure, and smoking, conferred benefit that might continue to favor SI over still-longer follow-up. Other Multifactor Primary Prevention Trials in Individuals Three other clinical trials of multifactor intervention were reviewed in the 16-year MRFIT report, studies in Oslo (Norway), Göteborg (Sweden), and Helsinki (Finland), whose results appeared from 1980 through 1995. The Oslo Study included 1232 men aged 40–49 years at entry and free of cardiovascular symptoms and diabetes.12 Cholesterol concentrations were quite high, from 290 to 379 mg/dl, or the coronary risk score was in the upper 25% without high blood pressure; 80% of the men were smokers. Aggressive advice was provided on smoking cessation and dietary change to reduce fat and cholesterol and increase polyunsaturated fats in the diet for men randomized to intervention. At 5 years, several CHD endpoints were significantly less frequent in the intervention

group. After an additional 2.5 years of follow-up, without intervention, risk-factor levels converged between groups: prior smokers in the intervention group relapsed, but prior controls reduced their cholesterol levels. Reported mortality differences remained significant. The Multifactor Primary Prevention Trial (Göteborg, Sweden) sampled men aged 47–55 years, with approximately 10,000 participants in intervention and in each of two control groups.13 In the intervention group, all men were screened to identify those at high risk, for whom intervention was directly implemented. Criteria for high-risk status included quite high levels of blood pressure or cholesterol concentration and smoking of at least 15 cigarettes per day. One of the two control groups was sampled (2% at baseline, 11% at 4 years, and 20% at 10 years) for risk-factor assessment without intervention, and the second control group was not screened at all but only monitored to ascertain occurrence of endpoint events. Reductions in risk factors were closely parallel between intervention and control groups, and mortality after 11.8 years follow-up was not appreciably

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different between groups. Within the intervention group, there were nonparticipants whose mortality was notably higher than that for participants. Given that only the highest-risk individuals were targeted for intervention and many events arise from more moderate levels of risk in the population, intervention may not have reached a sufficiently broad segment of the population to attain the intended effect. The Helsinki Multifactorial Primary Prevention Trial enrolled more than 1200 business executives, approximately 40–55 years of age at randomization in 1974, in a trial of dietary and hygienic measures and drugs to lower cholesterol concentrations or blood pressure.14 The control group participants were untreated by the investigators. After five years of initial follow-up, total risk showed a net reduction of 46% in the intervention group. Strokes were significantly less frequent but coronary events were more frequent in the intervention group. The first posttrial followup was completed 5 years later, in 1985, and the second after another 5 years, or 15 years after randomization. The intervention group experienced significantly higher mortality for cardiac events and accidents and for all causes together. The use of multiple and changing drugs for therapy throughout the trial period complicated attempts to explain the findings, although particular drugs were implicated by the authors. Regardless, the mortality outcome remained clearly negative. These and other studies through 2001 were described in a Cochrane meta-analysis published by Ebrahim and colleagues in 2006, an update of a 1995 review.15 The intent was to aggregate studies of counseling or education, with or without drug therapy, to reduce more than one CVD risk factor in a general population, occupational group, or high-risk group. (Curiously, the Hypertension Detection and Followup Program was included, although it was specifically targeted to reduce high blood pressure; attention to other risk factors was only incidental in keeping with usual standards of care.) Each of 39 studies was described, allowing the reader to assess the body of work available at the time. Of the 39 selected studies, only 10 reported total or CHD mortality outcomes. The studies ranged widely in size and varied in other aspects of design as well. Overall, they showed significant reductions in blood pressure, blood cholesterol, and smoking, but no significant reductions in total or CHD mortality. The authors concluded:15, p 1 The pooled effects suggest multiple risk factor intervention has no effect on mortality. However, a small, but potentially important, benefit of treatment (about a 10% reduction in CHD mortality)

may have been missed. . . . Interventions using personal or family counseling and education with or without pharmacological treatments appear to be more effective at achieving risk factor reduction and consequent reductions in mortality in high risk hypertensive populations. The evidence suggests that such interventions have limited utility in the general population. It is important to emphasize that the interventions reviewed here were primarily physician advice, not necessarily including either intensive lifestyle intervention nor medication. The general conclusions should be interpreted accordingly. A contrasting view of multifactor intervention in individuals was presented in 2003 by Wald and Law.16 They presented meta-analyses of single-factor interventions targeting LDL-cholesterol, blood pressure, serum homocysteine, or platelet function to suggest the potential benefit of a combination pharmacological intervention. They proposed use of a combination “Polypill” as a “strategy to reduce cardiovascular disease by more than 80%. . . . This strategy would be suitable for people with known cardiovascular disease and for everyone over a specified age (say 55), without requiring risk factor measurement.”16, p 1 The pill would contain a statin, three blood pressurelowering drugs at half standard dose, folic acid, and aspirin. One of their premises in arguing for a pharmacologic approach was their view that, although Western diet and lifestyle underlie the causal risk factors for preventable CVD, changes in these conditions could not be achieved in the short term. Further, they argued, CVD occurs to a greater extent among those at moderate rather than extreme risk; risk is strongly predicted by age; risk factors apart from age contribute little to improving prediction of events; and CVD risk is reduced in proportion to reduction in a given risk factor regardless of the starting level. They concluded:16, p 5 It is time to discard the view that risk factors need to be measured and treated individually if found to be “abnormal”. Instead it should be recognised that in Western society the risk factors are high in us all, so everyone is at risk; that the diseases they cause are common and often fatal; and that there is much to gain and little to lose by the widespread use of these drugs. No other preventive method would have so great an impact on public health in the Western world. Extensive comment, pro and con, followed immediately after the Wald and Law publication. An

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Internet search reveals continuing interest in development and testing of various multidrug formulations as of mid-2008. (Available at www.medscape .com/viewarticle/575014. Accessed 8 May 2008.)17 Intervention in Communities In contrast to the foregoing examples, in which intervention was directed to individuals at high risk of coronary and other cardiovascular events, other multifactor intervention studies were designed to mobilize community-wide action and thereby modify knowledge, attitudes, and behavior related to the major risk factors. In some instances, risk-factor detection was included, with reinforcement of local health services to improve risk-factor treatment and control, but educational and other community strategies remained the central aspect of these programs. Six studies are summarized in Tables 21-2 and 21-3 and are further described as follows.18 Five of these were prospective studies, each with one or more intervention and control communities; the sixth study was a retrospective analysis of changes in CVD mortality concurrent with preventive programs reaching defined target populations. These programs used various intervention strategies, but the majority had several elements in common. Coupled with the differences among population settings, calendar periods, and other aspects of program design and implementation, variation in intervention content would be expected to yield differences in outcomes. Two programs used professional nursing staff and primary care integration; all included community organization, mass media, schools, groceries and restaurants, and group education. The North Karelia Project Among the earliest community intervention trials was the North Karelia Project, undertaken in 1972 in view of the exceptionally high mortality from coronary heart disease in Eastern Finland in the late 1960s.19 Recognition of the magnitude of the problem had led to recruitment of two cohorts, in East and West Finland, into the Seven Countries Study more than a decade earlier. A comprehensive review of the extraordinary 20-year North Karelia Project and its local, national, and international impact was published in 1995.20 One intervention area, North Karelia (population 210,000), was compared with one reference area, Kuopio (population 250,000). Multiple programs were implemented in North Karelia with the aim of reducing blood cholesterol concentration, controlling high blood pressure, and achieving smoking cessation for as many persons as possible in this target population. Risk-factor distributions in both com-

munities were assessed by cross-sectional surveys in independently drawn random samples, including men and women aged 30–59 years in each population. The surveys were conducted every 5 years from 1972 to 1992. In 1982 a third area, southwestern Finland, was added for further comparison of data in the last three surveys. Mortality was monitored from 1969 through 1992. Evaluation of the impact of intervention in North Karelia is complicated by large concurrent changes in risk factors and coronary mortality in the reference area.21 Risk-factor changes from 1972 to 1992 were substantial in North Karelia: Cholesterol concentration decreased by 13% for men and 18% for women, diastolic blood pressure decreased by 9% for men and 13% for women, and smoking decreased from 53% to 37% for men (but increased from 11% to 20% for women) (Table 21-4). But only during the first five years of the program were changes in these risk factors greater in North Karelia than in Kuopio. They were similar thereafter, and coronary mortality decreased 50% in Finland as a whole from 1970 to 1992. These circumstances, in addition to the sample size of only one intervention unit and one reference or control unit (despite the later addition of a second control area), limited the ability to evaluate program effects. One approach to analysis of risk factor and mortality change was to estimate the relation between each risk factor and coronary mortality within the Kuopio population and then to predict the mortality at each survey year on the basis of the risk-factor levels in the population at that time. The predicted mortality, taking into account smoking, blood pressure, and cholesterol concentration, was then compared with the observed mortality from 1972 to 1992 for men and women aged 35–64 years in Finland. These results are shown in Figure 21-2 for men and Figure 21-3 for women. A marked decline in coronary mortality was predicted throughout the period. For men, the observed decline was close to the prediction until 1985, when it began to exceed the prediction. For women, the decline exceeded the prediction throughout the entire period. Further analysis demonstrated that from 1972 through 1987, for both men and women, the observed and predicted trends were consistent, and it was concluded that the decline in mortality could be explained by the risk-factor changes over the same period. The interventions are not the only plausible explanation of these mortality changes, given that there were risk-factor changes in the reference area. Implementation of a number of prevention activities nationally during the course of intervention in North Karelia may have affected this target area as well as

Northern California

1972–1975

1980–1986

1981–1988

Stanford 3-CP (16)

Stanford 5-CP (17)

Minnesota (18) Minnesota, North and South Dakota

1 similar town

3 similar cities

3 similar cities

About 75,000 per city

Small: 25–40,000 Medium: 75–80,000 Metro: 80–115,000

2 cities

3 cities, small, large, metro

Comparison Community Similar region and Finland

12–15,000 per town

Population 180,000 in region

Improved risk factor knowledge, saturated fat intake, cigarette consumption, plasma cholesterol and blood pressure control, and projected cardiovascular risk by 15% to 20%. Mass media more cost-effective. Sustained improvements in blood pressure but not in physical activity. No reductions in cardiovascular morbidity or mortality. Higher education exposure scores and favorable risk factor changes. No reductions in cardiovascular morbidity or mortality.

Mass media only vs. mass media plus individual attention to high-risk individuals.

Mass media only. No individualized interventions.

Face-to-face communications, public events, TV

Prospective controlled


Unique Focus Indigenous impetus. Community ownership. Integration with health care. Sustained focus on risk factors among individuals.


Study Design Prospective controlled

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3 towns

Intervention Community North Karelia

Associated Outcomes Relative to Comparison Populations Improved risk factors. Reduced cardiovascular and cancer deaths.

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Northern California

Location Rural Finland

Years 1972–1997

Features and Outcomes of Six Major Community CVD Prevention Trials

626

Trial/Reference North Karelia (14)

Table 21-2

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Franklin County

Rural Maine

1974–Present

Franklin, Maine (26)

Retrospective ecologic observation

Adjacent, similar counties and state

40,000 in county

Integration of public health, medical care and community resources. Risk factor counseling, tracking and follow-up over time by 1-on-1 nurse encounters.

Community organization, campaigns; screening, counseling and referral.

Reduced: total, cardiovascular and cancer mortality; cardiovascular and “preventable” hospitalizations and hospital charges; and smoking rates. Dosedependent impact of nurse encounters on death rates.

Transient improvements in risk factors and risk ratio for projected cardiovascular disease rates. No reductions in cardiovascular morbidity or mortality.

Source: Reprinted with permission from PA Ades, TE Kottke, N Houston Miller, et al., Journal of the American College of Cardiology, Vol 40, © 2002 American College of Cardiology Foundation, p 618.


1 nearby similar city

70,000 in city

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CVD cardiovascular disease.

1 city

Southern New England

1984–1991

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Pawtucket (19)

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Table 21-3

Intervention Strategies of Six Major Community CVD Prevention Trials Strategies North Stanford Stanford Karelia 3-Community 5-Cities Minnesota Community organization Mass media Environmental modifications 0 0 Community groups 0 Schools Worksites 0 Groceries and restaurants Medical settings 0 Professional education 0 Health agencies collaboration 0 Train local personnel 0 Lay volunteer emphasis 0 0 0 Self-management focus 0 Group education Risk factor screening 0 Individual counseling 0 Referral for medical care 0 0 Client risk factor tracking 0 0 Active client follow-up 0 0 Professional nursing staff 0 0 0 Primary medical care integration 0 0 0

Franklin Maine 0

Pawtucket Print only 0 0 0 0

CVD cardiovascular disease “” indicates characteristic present, but does not imply equivalent intensity of intervention components. Source: Reprinted with permission from PA Ades, TE Kottke, N Houston Miller, et al., Journal of the American College of Cardiology, Vol 40, © 2002 American College of Cardiology Foundation, p 619.

other regions, independently of the planned local programs. Nonetheless, this program contributed importantly to development and implementation of community intervention strategies. It is widely regarded as pioneering work in the field providing tested models for programs applied throughout Finland and elsewhere.

Table 21-4

Community Intervention in the United States The six studies summarized in Tables 21-2 and 21-3 include five conducted in the United States: the threeand five-city phases of the Stanford Heart Disease Prevention Program, the Minnesota and Pawtucket (Rhode Island) Heart Health Programs, and the Franklin Cardiovascular Health Program in Franklin

Mean (Standard Error) Level of Coronary Risk Factors in Subjects in Finland, by Year and Sex 1972 1977 1982 1987 1992

Risk Factors Men Cholesterol (mmol/l) Diastolic blood pressure (mm Hg) Smoking (% of study population who were smokers) Women Cholesterol (mmol/l) Diastolic blood pressure (mm Hg) Smoking (% of study population who were smokers)

6·78 (0·02) 92·8 (0·18) 53 (0·8)

6·55 (0·02) 91·0 (0·18) 47 (0·8)

6·28 (0·02) 87·8 (0·26) 42 (1·0)

6·23 (0·03) 88·4 (0·28) 39 (1·2)

5·90 (0·03) 84·2 (0·37) 37 (1·5)

6·72 (0·02) 91·8 (0·19) 11 (0·5)

6·36 (0·02) 87·6 (0·17) 12 (0·5)

6·10 (0·03) 84·6 (0·25) 16 (0·8)

5·94 (0·03) 83·5 (0·26) 16 (0·9)

5·54 (0·03) 79·6 (0·33) 20 (1·1)

Source: Reprinted with permission from E Vartiainen et al., Changes in Risk Factors Explain Changes in Mortality from Ischemic Heart Disease in Finland, British Medical Journal, Vol 309, pp 24–27, © 1994, BMJ Publishing Group.

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0

Smoking

Decline in Mortality (%)

10 Blood Pressure

20

Cholesterol

30

Predicted (all risk factors)

40

50

Observed (all risk factors) 60 1972 74

76

78 80

82 Year

84

86

88

90

92

Figure 21-2 Observed and Predicted Decline in Mortality from Ischemic Heart Disease in Men Aged 35–64 in Finland. Source: Reprinted with permission from E Vartiainen et al., Changes in Risk Factors Explain Changes in Mortality from Ischemic Heart Disease in Finland, British Medical Journal, Vol 309, p 25, © 1994, BMJ Publishing Group.

220

Smoking

Decline in Mortality (%)

0

Blood Pressure

20

Cholesterol 40

Predicted (all risk factors)

60

Observed (all risk factors) 80 1972 74

76

78

80

82 Year

84

86

88

90

92

Figure 21-3 Observed and Predicted Decline in Mortality from Ischemic Heart Disease in Women Aged 35–64 in Finland. Source: Reprinted with permission from E Vartiainen et al., Changes in Risk Factors Explain Changes in Mortality from Ischemic Heart Disease in Finland, British Medical Journal, Vol 309, p 25, © 1994, BMJ Publishing Group.

County, Maine. Joint analysis of the Five-City Stanford Program and Minnesota and Pawtucket Heart Health Programs demonstrated the aggregate intervention effects on smoking, systolic and diastolic blood pressure, cholesterol, body mass index, and estimated 10-year risk of CHD mortality (Table 21-5).22 Findings of the Franklin study are described separately. Stanford. Concurrent with initiation of the North Karelia Project, and with close collaboration between the two responsible research groups, the Stanford Three-City Study began in northern California.23 The strategy was to implement community-wide health education in two communities, with supplemental individual counseling for a sample of high-risk individuals identified in one of them; the third community would serve as the control. The initial results after 2 years of intervention suggested that community-wide health education had substantial impact, with an overall reduction in a multivariate risk score of 23–28% in treatment compared with control communities. This favorable early experience led to a second study, the Stanford Five-City Project, based on newly selected communities.7,24 Two communities received a 5-year intervention program based on social-learning theory, a communication-behavior change model, community-organization principles, and social-marketing methods. In addition to continuous education programs, several short-term campaigns were also conducted in the two intervention communities. Two of the remaining communities served as observed controls and the third was subject only to monitoring of event rates as an unobserved control. Stroke and CHD were the primary end points, and change in blood cholesterol concentration, blood pressure, smoking prevalence, body weight, resting pulse rate, and knowledge of risk factors were intermediate end points. The program used several approaches to bring about riskfactor change (Table 24-3). Evaluation of risk-factor change was conducted both in cohorts and in independent cross-sectional samples in four of the study communities. Most risk factors improved from baseline, to a greater extent in the treatment communities. The overall multivariate risk score, based on a model for 12-year coronary event rates in the Framingham Study, was predicted to show a net reduction of 20% in treatment communities. For all-cause mortality, significant decreases in risk score of 16% and 14% were observed at the third and fourth cohort examinations, respectively; coronary event risks were correspondingly reduced 17% and 16% in the cohort evaluation. Minnesota. In 1980, a six-community intervention trial began in the upper Midwest of the United States, the Minnesota Heart Health Program.25 Three pairs of communities were matched on population size, type (from small to urban), and distance from

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Table 21-5

Cardiovascular Risk Factor Trends in Women and Men Aged 25–64 in the Stanford Five-City Study, Minnesota Heart Health Study, and Pawtucket Heart Health Study, Combined, Adjusted for Age and Education, 1978–1990 Results Expressed as Net Average Annual Change in Treatment Communities Minus Control Communities* Linear Trend in Tests of Net Intervention Linear Trend in Tests of Net Intervention Risk Factor Women (per Year) Effect in Women Men (per Year) Effect in Men Current smoking, % 0.30 0.42 p 0.48 0.31 0.51 p 0.54 Systolic blood pressure, 0.31 0.22 p 0.17 0.10 0.24 p 0.68 mm Hg Diastolic blood pressure, 0.23 0.16 p 0.15 0.09 0.23 p 0.68 mm Hg Cholesterol, mg/dl 0.70 0.48 p 0.15 0.23 0.51 p 0.66 Body mass index, kg/m2 0.06 0.05 p 0.19 0.03 0.04 p 0.46 Log10 estimated 10-year 0.001 0.003 p 0.85 0.001 0.002 p 0.64 coronary heart disease mortality risk *Estimate standard error, from mixed-model analysis of variance with pooled error term. Source: Data from MA Winkleby, HA Feldman, DM Murray, Journal of Clinical Epidemiology, Vol 50, © 1997 Elsevier Science, Inc., pp 651–652.

metropolitan Minneapolis–St. Paul. One community of each pair received a multicomponent education program and the other served as a control. The program was described as a high-intensity campaign that included risk-factor screening, education and intervention programs, involvement of most primary care physicians and many other health professionals in training activities, changes in community organization and environment conducive to heart health, and participation by youth in school-based health promotion programs. An intervention program of 5 or 6 years’ duration was projected to reduce population mean values for blood cholesterol concentration by 7 mg/dl, blood pressure by 2 mm Hg, and cigarette smoking by 3% and to increase energy expenditure in physical activity by 50 kcal/day. In the final analysis of event rates, for neither stroke nor CHD was there a significant difference in rates between intervention and control communities.26 Pawtucket. The third major multifactor community intervention trial of cardiovascular disease prevention in the United States was the Pawtucket (Rhode Island) Heart Health Program, in which one intervention and one control community were enrolled.27 The aim was to evaluate the impact on single risk factors and projected CVD rates on the basis of a composite risk score for persons aged 35–64 years in the Framingham Heart Study. Low-cost approaches to community behavior change and environmental changes conducive to the desired behaviors were implemented from 1984 to 1991. Heart health curricula in schools from grades one to high school were included. As in the Stanford and Minnesota programs, both cross-sectional and cohort examinations

were conducted for evaluation, beginning with preintervention assessment in 1981. Overall, the changes observed were generally favorable but modest, and they were similar between intervention and comparison communities. This outcome was attributed to the relatively small proportion of total media messages affecting health-related behavior represented by the program, in contrast with the total environment of advertising, marketplace displays, and countless inputs from other sources. Table 21-5 showed for women and for men in the age range from age 25 to 64 years the results of change in single risk factors (cigarette smoking, blood pressure, total cholesterol concentration, and body mass index) and in the composite coronary heart disease mortality risk score, for the three studies combined. Overall, 9 of 12 comparisons were favorable in direction, showing greater change in the intervention communities (five for women and four for men), but none of these results was statistically significant. Franklin Cardiovascular Health Program. Retrospective evaluation of trends in CVD and total death rates in Franklin County, Maine, in comparison with statewide rates from 1974–1994, suggested lower mortality during periods of intensified community-wide prevention programs (Figure 21-4).28 The intervention, staffed by professional nurses, comprised education, screening, counseling, referral, tracking, and follow-up, all integrated with primary care. The key indicator of program activity was the annual number of program encounters related to high blood pressure (1974–1985) or cholesterol and high blood pressure control together (1986–1994). Encounters due to these programs fluctuated in fre-

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1.16 Relative Death Rates

1.1

Total Death Relative Rates

1.06 Maine

1 0.96 0.9 0.86 Franklin

0.8

Encounters per Year

0.76 3000

Annual Encounters per 10,000 Franklin Population

2400 2000 1600 1000

Growth

Decline

Growth

HBP

Decline

CHOL

600 1.15 Relative Death Rates

1.1 1.05 1

Heart Death Relative Rates Maine

0.95 0.9 0.85 0.8 0.75

96

94

19

92

19

90

19

88

19

86

19

19

82

19

80

19

78

19

76

19

74

19

19

84

Franklin

0.7

Figure 21-4 Age-Adjusted Total and Heart Disease Death Rates for Franklin County and Maine, 1960–1994, with Study Periods and Franklin Program Phases. Source: Reprinted with permission from NB Record, DE Harris, SS Record, et al., American Journal of Preventive Medicine, Vol 19, © 2000 American Journal of Preventive Medicine.

quency over time with changing funding levels. During periods of increasing frequency of such encounters, death rates from heart disease or CHD decreased relative to statewide rates. A statistically significant inverse correlation was found between encounters and death rates over the total period of analysis. Community Trials in Europe Communities are definable in other than geographic terms, and employment communities or worksites have also been used for multifactorial cardiovascular

risk reduction programs. A major example of this approach is the European Collaborative Trial of Multifactorial Prevention of Coronary Heart Disease, conducted in 80 factories in Belgium, Italy, Poland, and the United Kingdom.29 The intent was to assess the degree to which educational efforts, undertaken at modest cost, could bring about risk-factor change and thereby reduce incidence and mortality from CHD. Within each country, factories or other large occupational units were matched as pairs and randomly allocated to intervention or control. In intervention factories, all men aged 50–69 years underwent risk-factor screening. This was followed for the higher-risk men—those in the upper 10–20% of risk in accordance with a simple risk function—by treatment or advice for lowering cholesterol, smoking cessation, daily physical exercise, weight reduction, and blood pressure-lowering drug therapy. Less intensive education was provided to the remaining men. In the control factories, only a 10% random sample of men were examined for risk-factor status, leaving 90% unaffected or even unaware of the trial. Follow-up for risk-factor change occurred in independent samples of men in the intervention factories, and the 10% sample in control factories underwent a repeat examination. Morbidity and mortality data were obtained through continuous monitoring of the study sites. Recruitment into the trial in the four countries took place in the early 1970s, and 60,881 men were entered. Results were presented in 1986, with extension of the analysis and some corrections appearing in 1987.30,31 After adjustment for baseline differences in risk factors within each pair of intervention and control factories, risk-factor change in intervention factories relative to control factories was found to be significantly associated with reduction in 6-year incidence of fatal coronary heart disease, total coronary heart disease, and total mortality. The actual reduction in coronary disease incidence was only 62% of the amount predicted from the observed risk-factor changes, and pooled results for the whole trial (in contrast to comparisons within countryspecific pairs) were not significant by two-tailed statistical tests; outcomes were least favorable in the United Kingdom factories and most favorable in Belgium, where exceptionally large reductions in risk factors were observed early in the trial during the most intensive intervention.32 German Cardiovascular Prevention Study. This study illustrates a different design, with outcomes in selected intervention regions compared against samples of the total national population as the control.33 In six regions of former West Germany, a 7-year

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program was implemented to achieve reductions in smoking prevalence and body mass index. From 1985 to 1991, significant net reductions were found between intervention communities and control samples for systolic and diastolic blood pressure and total cholesterol concentration. Concentration of HDLcholesterol increased initially and then declined, and the overall net decrease was not significant. Overall, change in body mass index showed no net difference between groups. Results over the full intervention period were similar for women and men, with somewhat greater net decreases in blood pressure for women. Northern Sweden. The Västerbotten Intervention Program, located in a rural area of Northern Sweden, combined multiple interventions strategies: health surveys for persons at ages 30, 40, 50, or 60 years; media programs and health counseling; worksite and school programs; food labeling and cooking activities; cultural programs; and group and public meetings. Integration with primary care was a prominent feature.34,35 The study used multiple cross-sectional surveys of the intervention area and periodic surveys of the neighboring MONICA Project reference area to monitor program impact. Reductions in risk of CHD death within the intervention and the control regions after 10 years of observation were estimated from the North Karelia risk model (Table 21-6). The crude or unadjusted risk reduction was 34% in the intervention area and 9% in the reference area; differences between areas were roughly similar by age and sex. By education, however, strikingly more favorable changes occurred for the lowest stratum, with 33% improvement in the intervention area and 15% increase in the reference area over the study period. These findings were taken to indicate that this community-wide intervention did not widen but rather narrowed the gap in CHD risk between lower and higher social strata. Concern that intervention will inevitably widen health disparities because of differential access and benefit across socioeconomic strata is belied by this experience. Community Intervention in Developing Countries In addressing evidence for community intervention in low- and middle-income countries, Gaziano and colleagues cited reports from China, Mauritius, Poland, and South Africa.36 Only one of these—the Coronary Risk Factor Study (CORIS) in the Cape Province of South Africa—was designed to compare intervention and control communities, but the others deserve brief mention.37 In the Noncommunicable Disease Intervention Areas in Tianjin, China, high blood pressure was ad-

dressed through efforts to reduce salt intake and body weight and increase antihypertensive therapy for persons with high blood pressure.38 These efforts were undertaken in the context of major policy changes regarding organization of primary care throughout the municipality of Tianjin.39 They were monitored by introduction of cross-sectional surveys of CVD risk factors and, separately, of salt intake between 1989 and 1996. Prevalence of hypertension declined over this period especially among persons aged 45–64 years; overweight and obesity decreased overall but increased in younger adults; and salt intake (12 g/day) was unchanged.38 In Mauritius, a multicomponent primary prevention program was evaluated by pre- and postintervention surveys conducted in 1987 and 1992.40 The program comprised mass media, fiscal measures, legislation, and health education activities in schools, workplaces, and communities to promote improved nutrition and physical activity, smoking cessation, and reduced alcohol intake. Statistically significant decreases in prevalence of hypertension, serum total cholesterol concentration, cigarette smoking, and heavy alcohol consumption were observed. Leisure time physical activity increased. Population distributions of blood pressure, cholesterol, and a composite risk-factor score improved, although prevalence of overweight or obesity increased. Especially noteworthy was a marked reduction in mean serum total cholesterol concentration, by approximately 0.80 mmol (32 mg/dl), a decrease attributed to nationwide substitution of soy oil for palm oil as the principal cooking oil.41 In Poland, consumer subsidies for purchase of animal products were withdrawn, resulting in a marked reduction in use of such foods, concurrent increase in fresh fruit and vegetable intake, and aggressive marketing of (low trans-fat) margarine.42 Subsequently, from 1991–1994, exceptionally sharp declines in mortality from ischemic heart disease ( 25%) were observed and have been described as greater than any previously known decline in CVD in peacetime. Stroke rates also declined in this short period ( 10%). Subsequent analysis of food availability data for Poland, as well as trends in medical care, smoking, alcohol consumption, and stress, has been taken as supporting the argument for abrupt change in nutrition as the most plausible explanation of the decline in CVD mortality.43 CORIS compared three Afrikaner communities in the Cape Province of South Africa—one community receiving low-intensity intervention (mass media only), one receiving high-intensity intervention (adding individual-level intervention for persons at

6.46 2.34 4.40

7.98 2.61 5.30 5.46 2.47 8.60

Age-and-education-adjusted All Women Men 3.49 1.66 5.50

5.32 2.56 4.00

3.49 1.65 5.26 0.67 5.89 3.37

4.28 1.67 6.73

6.43 2.12 4.37

33 2 24 36 33 36

4.28 1.62 6.85 0.81 7.51 4.28

34 33 36 30 38 37

4.39 1.78 7.01

7.33 2.27 4.80

4.30 1.71 6.97 0.76 7.48 4.23

Source: Reprinted with permission from L Weinhall, G Hellsten, K Boman, et al., Scandinavian Journal of Public Health, Vol 29, © Taylor and Francis 2001, p 65.

a

Risk equation for men: IHD 1/(1 e12.73 0.108 age 0.806 smoking 0.021 diastolic blood pressure 0.384 total cholesterol). Risk equation for women: IHD 1/(1 e14.90 0.104 age 1.240 smoking 0.0306 diastolic blood pressure 0.365 total cholesterol).

4.33 1.90 6.63

4.11 1.77 6.31 0.65 7.60 4.25

5.28 2.45 8.16 0.95 9.51 5.38

4.25 1.77 6.66

7.34 2.32 4.94

3.91 1.55 6.39 0.68 6.76 3.83

1 6 1

15 9 13

9 4 7 16 10 11

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Crude All Women Men 30–40 years 50–60 years Age-adjusteda Education Low Medium/high Education-adjusted

Trend for Estimated CHD Mortality Risk (%) in Intervention and Reference Areas. The Risk Estimationa is Based on Data from North Karelia, Finland. Unadjusted, Age-Adjusted, Education-Adjusted, and Joint Age-and-Education-Adjusted Estimates Shown Separately. All Adjustments According to the Distribution in the Reference Area in 1986 Intervention Area Reference Area Estimated Estimated Estimated Risk Estimated Estimated Estimated Risk Risk Risk Risk Difference Risk Risk Risk Difference 1985–87 (I) 1988–91 (II) 1992–94 (III) I–III (%) 1986 (I) 1990 (II) 1994 (III) I–III (%)

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Table 21-6

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high CVD risk), and one isolated community serving as control.37 Extensive intervention included many of the features described for the North Karelia and United States studies, described previously. Evaluation of the program was performed through pre- and postintervention surveys bracketing a 4-year intervention period. Significant net reductions were found in blood pressure, smoking, and a simple risk score based on the observed ranks in levels of risk factors— systolic blood pressure, total cholesterol/HDLcholesterol ratio, and tobacco consumption. Little difference was observed between outcomes of lowand high-intensity intervention, suggesting that the low-intensity approach was nearly as effective as the alternative, at one-fourth the cost. Intervention in Youth In addition to trials of interventions to reduce single risk factors during childhood and adolescence, addressed in Part III as preceded, multifactor interventions have been conducted in school-age populations since the 1980s. An early example of such a study is the evaluation of the Know Your Body Program, a school-based health education program for children at several grade levels.44–46 This program was in part a major descriptive epidemiologic study based on school examinations conducted in several countries. In addition, random assignment among six New York school districts, children in fourth grade (approximately 9 years old) in 11 schools received a curriculum beginning in grade four and continuing through grade nine, addressing nutrition, physical fitness, and cigarette smoking prevention. Those in 11 other schools served as controls. The impact of intervention was evaluated in two settings in or near New York City at 1, 3, and 5 years from initiation. After 1 year, diastolic blood pressure and serum thiocyanate (a marker of smoking) were significantly lower in intervention than control schools, although ponderosity index (an index of overweight or obesity) was greater.44 At 3 years, or at average ages of approximately 12 years, further evaluation was restricted to four of the six districts, as two had withdrawn because the curriculum was judged to require too much class time.45 Diastolic blood pressure and plasma total cholesterol concentration were significantly reduced in intervention relative to control schools, and trends for dietary practices and cigarette smoking were also favorable. At the 5-year evaluation, students in 22 elementary schools in Bronx, New York, who had been in the fourth grade in 1980, were added.46 Cholesterol concentration was reduced further in intervention than control

schools in Westchester but not in the Bronx. Trends were favorable for dietary intake of fat and knowledge of the risk factors in both study areas. It was concluded that educational programs could have favorable, though small, effects on cholesterol concentration in children and that there were no effects on blood pressure, body mass, or physical fitness. On the basis of the Know Your Body experience and others through the 1980s, a major new multicenter school-based intervention program was undertaken in the United States, known initially as the Children’s Activity Trial for Cardiovascular Health, more recently as the Coordinated Approach to Child Health (CATCH, in either case).47 Baseline assessment in 1991 was followed by 3 years of intervention and postintervention assessment in 1994. Participants were 5106 students in third grade at entry who attended one of 56 intervention or 40 control schools in California, Louisiana, Minnesota, and Texas. Intervention was designed to improve school food service and physical education programs and included classroom health curricula; half of the intervention schools also received a family education program. Outcomes were evaluated at two levels: at the school level, change in fat content of school lunches and the amount of moderate-to-vigorous physical activity in physical education programs, and at the individual level, dietary and activity patterns and change in serum cholesterol concentration. The results at the school level were significantly favorable. The relative decrease in fat content of lunch menus is shown in Table 21-7. Moderate-to-vigorous physical activity was also improved significantly in intervention as compared with control schools. Changes in self-reported dietary and activity behaviors were also significantly more favorable among intervention than control children, but changes in cholesterol concentration and other physiologic characteristics did not differ between groups of children. It was judged that the dietary changes were insufficient to produce a detectable change in cholesterol concentration, especially in view of pubertal influences on total cholesterol concentration. However, ability to modify the school environment and curriculum in favorable ways appeared to be well established. The CATCH program has become widely disseminated in the United States and now reaches several other countries as well. Some Implications of Experience with Multifactor Intervention A much wider representation of experience in community intervention can be found in Worldwide

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Table 21-7

School Lunch Menu Analysis at Three Time Points, 1991 Through 1994, Child and Adolescent Trial for Cardiovascular Health Intervention (I) and Control (C) Groups Value Measured Group Baseline Interim Follow-Up Total energy content, MJ C 2.97 (0.04) 3.04 (0.04) 3.12 (0.04) I 3.01 (0.04) 2.93 (0.04) 2.86 (0.04) p .05 p .001 Energy from total fat, % C 38.9 (0.5) 36.2 (0.5) 36.2 (0.5) I 38.7 (0.4) 32.5 (0.4) 31.9 (0.4) p .001 p .001 Energy from saturated fat, % C 15.1 (0.3) 13.6 (0.3) 13.7 (0.3) I 14.8 (0.2) 12.1 (0.2) 12.0 (0.2) p .02 p .007 Cholesterol content, mg C 80.3 (2.4) 75.2 (2.4) 83.2 (2.4) I 77.7 (2.0) 72.3 (2.0) 74.9 (2.0) p .95 p .17 Sodium content, mg/MJ C 386 (7) 415 (7) 421 (7) I 377 (6) 401 (6) 423 (6) p .64 p .34 Potassium content, mg/MJ C 325 (5) 333 (5) 327 (5) I 331 (4) 350 (4) 357 (4) p .18 p .004 Note: Data for baseline, interim, and follow-up are adjusted means (SE) from repeated-measures analysis of variance, adjusted for site and school random effect. P values compare C with I, adjusting for baseline difference. The school family intervention group did not differ from the school-only group for any endpoint (P .20). 1 MJ 239 kcal. 1 mg/MJ 4.184 mg/1000 kcal. Source: Reprinted with permission from RV Luepker et al., Journal of the American Medical Association, Vol 275, No 10, p 772, © 1996, American Medical Association.

Efforts to Improve Heart Health—the supplement to the report of the Second International Heart Health Conference, The Catalonia Declaration. Investing in Heart Health.48 This resource identified more than 75 heart health programs in Africa, the Americas, Asia, Australia, and Europe, 25 of them being multifactor community programs. References are provided for each program and contact information is given for members of each of six international Heart Health Networks, including the extensive Countrywide Integrated Noncommunicable Diseases Intervention (CINDI) Network. The outcomes of intervention to prevent CHD in various settings (geographic communities, worksites, schools, religious organizations, and medical care organizations), although mixed, have identified components of intervention that appear to have contributed importantly to reductions in risk. The morbidity and mortality outcomes that were positive were taken as reinforcing the possibility of benefit from intervention, but these studies have often presented challenges in design, conduct, and analysis. Statistical power may be seriously limited by study of only a small number of units of observation in the usual community comparison design, and strong, sometimes overriding, favorable secular trends in risk factors and event rates in control communities.

The expectations of favorable outcomes that would demonstrate reduced mortality were high as the formal trials were initiated. For those who were most optimistic about CVD prevention, the positive results stood out regarding both disease outcomes and intermediate behavioral or risk-factor effects. Findings after extended postintervention follow-up in some trials support the view, suggested in many reports, that appropriate evaluation requires longer than usual observation and perhaps more sustained and broadbased intervention than was planned at the outset of these studies. One commentary on “great expectations” contrasted the worlds of community interventions and advertising.49 The implication of that essay was that the likely impact of some public health interventions may be important but too small, at least for the relative investment made and under the conditions of study, to meet conventional criteria for statistical significance. But in the context of advertising, small effects, even if achieved through sometimes very large investments, are considered highly successful. The advice was not to abandon appropriate statistical standards but to ensure that assumptions about effect sizes and other design considerations are more realistic, and therefore more conservative. For example, much larger sample sizes should be provided.

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These and other issues in design and interpretation of community intervention trials were reviewed in the mid-1990s to update a 1978 symposium on community trials in CHD.50 The theme was that the preceding 15 years or more of experience provided a solid foundation for future community trials. Another review based on the Stanford, Minnesota, and Pawtucket studies proposed broader intervention approaches to include public policy initiatives.51 Complementary small-scale studies would target especially low-income groups and others not yet reached effectively by preventive measures. Outcomes of value for further research would include not only biomedical but also behavioral and attitudinal changes and qualitative assessments of programs. In his essay on the “tribulations of trials,” Susser considered community trials in the context of social movements and policy change.52 His conclusions suggested that the scope of experimental evaluation is unlikely ever to match the larger forces operating on the phenomena of interest. Understanding the social and policy milieu of communities in which interventions are to be evaluated is essential for appropriate choices of time, place, and characteristics of the target population, intervention strategies, and outcomes for evaluation. Overall, experience with multifactor primary prevention has accrued from a large number of studies in the United States and other countries. Widespread interest especially in community approaches suggests an increasing level of readiness over the past decade to take further action. Lessons of experience indicate foremost a need to implement the most promising and comprehensive interventions, in multiple populations, on a large enough scale and with sufficient duration to permit rigorous evaluation. This would offer the greatest opportunity to identify intervention approaches with potential for widespread dissemination and adaptation to local needs and resources. In his personal synthesis of this experience, Farquhar concluded that behavior can be influenced by community intervention; research is needed on options in the mix and sequencing of components in an intervention program; and environmental change (in the sense of the policy setting in which intervention occurs) must be incorporated for effective community change. Further, “The greatest unmet need is now for dissemination research and concurrent international technology transfer of the vast number of lessons learned and the many widely accepted practice principles of community-based interventions” (J Farquhar, personal communication, 1997).

THE BURDEN OF RISK Global Presence of Increased CVD Risk A vast body of evidence identifies the main determinants of CVD, including the major established risk factors, as presented in Part III. Essential to the case for CVD prevention is the knowledge that these risks are widespread on a national and global scale; they themselves constitute a public health challenge of huge proportions; and they underlie large disparities in health within and among populations. Further, individuals whose risk remains low experience better health throughout adult life, and this more favorable course is becoming well documented. Together, this knowledge from epidemiologic experience strongly supports public health strategies for both prevention of risk in the first place and reduction of risk when this becomes necessary. To demonstrate the magnitude and variation in CHD risk among adults in the United States, Ford and others presented estimates of 10-year risk for CHD based on data from the Third National Health and Nutrition Examination Survey, 1988–1994 (NHANES III) (Table 21-8).53 The risk model of the National Cholesterol Education Program’s Adult Treatment Panel III guidelines was applied to riskfactor assessments for more than 11,000 persons aged 20–79 years examined in NHANES III. Persons with CHD or a CHD risk equivalent (diabetes, peripheral vascular disease, or stroke) were excluded from analysis. Risk factors included in the model were age, total cholesterol, HDL cholesterol, systolic blood pressure, hypertension treatment, and current smoking. The outcome was CHD defined as self-reported heart attack or angina pectoris. Risks of 10% or greater of having a first CHD event within 10 years were present in 18.4% of the total population. (The proportion was 27.4% if those with CHD or CHD equivalent were included.) When extrapolated from the survey sample to the total population, 18.4% corresponds to 27 million persons. These risks increased sharply with age but were already greater than 10% of persons aged 40–49 years, increasing to more than 29% at age 50–59 years, more than 45% at age 60–69 years, and more than 65% at age 70–79 years. Risks were greater for men than for women by several times at all but the oldest age (only by two times at age 70–79 years) and differed significantly by race or ethnicity among women, being greater for African Americans and Mexican Americans than for Whites. Global Burden of Disease and Risk Factors drew upon several thousand data sources worldwide to

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Table 21-8

Age-Specific and Age-Adjusted Distribution of Risk for Coronary Heart Disease Among United States Adults Age 20 Years Without Self-Reported Coronary Heart Disease or a Coronary Heart Disease Equivalent,* National Health and Nutrition Examination Survey III, 1988 to 1994 10-Year Risk for Coronary Heart Disease 10% to 20%, 10%, % (SE) 20%, % (SE) n Weighted, n % (SE) p† 11,611 138,463,213 81.7(0.5) 15.5 (0.5) 2.9 (0.2) — 0.001 5,481 67,159,469 66.0 (0.6) 28.7 (0.8) 5.3 (0.4) 6,130 71,303,744 94.8 (0.3) 4.3 (0.3) 0.9 (0.1)

Total Gender Men Women Age (yrs) Total 20–29 30–39 40–49 50–59 60–69 70–79 Men 20–29 30–39 40–49 50–59 60–69 70–79 Women 20–29 30–39 40–49 50–59 60–69 70–79 Race or ethnicity Total White African American Mexican American Other Men White African American Mexican American Other Women White African American Mexican American Other

0.001 2,951 2,778 2,022 1,345 1,486 1,029

34,410,851 36,429,134 27,827,102 17,152,023 13,884,733 8,759,370

99.9 (0.1) 95.7 (0.8) 89.7 (0.8) 70.9 (1.7) 55.0 (1.2) 34.5 (1.6)

0.1 (0.1)‡ 3.7 (0.8) 8.5 (0.8) 25.3 (1.7) 40.1 (1.3) 51.5 (1.5)

0.0 (0.0) 0.6 (0.2)‡ 1.8 (0.5) 3.8 (0.6) 5.0 (0.6) 14.0 (1.4)

1,388 1,256 988 614 767 468

17,394,942 18,193,189 13,843,244 8,120,105 6,101,047 3,506,943

99.8 (0.2) 91.4 (1.5) 80.2 (1.7) 40.6 (2.4) 8.4 (1.4) 2.5 (0.7)

0.2 (0.2)‡ 7.4 (1.6) 16.2 (1.6) 52.0 (2.6) 80.8 (1.7) 75.5 (2.4)

0.0 (0.0) 1.2 (0.4) 3.6 (0.9) 7.4 (1.3) 10.8 (1.4) 22.0 (2.5)

1,563 1,522 1,034 731 719 561

17,015,909 18,235,945 13,983,858 9,031,919 7,783,687 5,252,426

100.0 (0.0) 99.9 (0.1) 99.1 (0.4) 98.2 (0.6) 91.5 (1.2) 55.9 (2.5)

0.0 (0.0) 0.1 (0.1)† 0.8 (0.4)† 1.4 (0.5)† 8.2 (1.2) 35.5 (2.1)

0.0 (0.0) 0.0 (0.0) 0.1 (0.0)‡ 0.4 (0.2)‡ 0.3 (0.2)‡ 8.6 (1.5)

4,573 3,290 3,249 499

106,562,092 13,978,761 6,937,452 10,984,907

81.6 (0.5) 80.5 (0.6) 80.6 (0.8) 83.1 (1.4)

15.6(0.5) 16.1 (0.6) 16.7 (0.7) 14.0 (2.0)

2.8 (0.3) 3.5 (0.3) 2.8 (0.3) 2.9 (1.2)‡

2,077 1,527 1,658 219

51,612,956 6,480,578 3,727,827 5,338,108

65.6 (0.8) 66.0 (1.3) 67.0 (1.1) 69.7 (2.4)

29.2 (0.8) 28.2 (1.2) 28.2 (1.2) 24.0 (3.6)

5.2 (0.4) 5.8 (0.6) 4.8 (0.5) 6.3 (2.7)‡

2,496 1,763 1,591 280

54,949,136 7,498,183 3,209,625 5,646,799

95.1 (0.3) 92.7 (0.6) 94.3 (0.7) 94.5 (1.1)

4.1 (0.3) 5.8 (0.6) 5.1 (0.7) 5.2 (1.1)

0.8 (0.1) 1.5 (0.3) 0.6 (0.3)‡ 0.3 (0.2)‡

0.001

0.001

0.289

0.275

0.002

*Self-reported myocardial infarction, angina pectoris, history of stroke, peripheral vascular disease, or diabetes mellitus; †p value is for chi-square test for unadjusted results and for Cochran-Mantel-Haenszel chi-square test for age-adjusted data; ‡estimate may be unstable and should be interpreted cautiously. Source: Reprinted with permission from ES Ford, WH Giles, AH Mokdad, Journal of the American College of Cardiology, Vol 43, © 2004 American College of Cardiology Foundation, p 1793.

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assess the contribution of common risk factors to death and disability as of 2001.54 Several of these findings are discussed in Part III. Taking together the category of “nutrition-related” risk factors (high blood pressure, high cholesterol, overweight and obesity, and low fruit and vegetable intake) and physical activity, and adding smoking, some 23 million deaths and 320 million disability-adjusted life years lost (DALYs) were attributed to these factors worldwide— 5 million deaths and 62 million DALYs in high-income and 18 million deaths and 263 million DALYs in low- and middle-income countries. For putting the distribution of estimated CVD risk in this global perspective, risk prediction charts from the WHO provide risk estimates for 14 subregions of the world defined by geography and pattern of mortality (A, very low child, very low adult mortality; B, low child, low adult mortality; C, low child, high adult mortality; D, high child, high adult mortality; and E, high child, very high adult mortality).55,56 Factors included in the risk models used were age, sex, smoking, blood pressure, blood cholesterol, and presence of diabetes. The CVD outcome to be predicted comprised acute coronary, cerebrovascular, or peripheral vascular events. Results are summarized in Table 21-9 for one selected age group of men and women across these regions. For reference, illustrative countries in Americas A, Europe A, and Western Pacific A, respectively, are the United States, the United Kingdom, and Japan. The estimates indicate the worldwide presence of risks of these CVD outcomes within 10 years of

Table 21-9

Proportion of the Population at 10% or Greater Total CVD Risk at Ages 50–59 Years, by Sex, by WHO Subregion Subregion Men (%) Women (%) Africa D 13.8 16.7 Africa E 13.6 16.7 Americas A 30.7 13.9 Americas B 22.8 14.4 Americas D 10.1 9.9 Eastern Mediterranean B 16.1 18.3 Eastern Mediterranean D 17.9 15.6 Europe A 17.4 5.5 Europe B 23.5 16.1 Europe C 30.3 20.9 South-East Asia B 14.2 10.6 South-East Asia C 17.0 15.4 Western Pacific A 16.1 8.1 Western Pacific B 16.0 8.6 Source: Data from World Health Organization, Prevention of Cardiovascular Disease: Guidelines for Assessment and Management of Total Cardiovascular Risk, © World Health Organization pp 75–78.

10% or more for 10 to 30% of men and 5 to 20% of women at ages 50–59 years. Proportions at this level of risk are greater for men than for women in most, but not all populations. For men they are exceptionally high in Americas A and in Europe C (including the Russian Federation and other Central European countries and Central Asian Republics), where they are also high in women. Proportions are notably lower for men in Africa and for women in the Western Pacific as well as Americas D (certain countries in Central and South America) and Europe A. Differences in results for the United States in these two analyses at age 50–59 years are striking—10% or greater risks of CHD (heart attack or angina) were 59.4% for men and 1.8% for women in the first report. In the WHO report, corresponding risks of combined CVD outcomes were 30.7% for men and 13.9% for women. The difference in sex ratios of these outcomes (30-fold in one report and 2-fold in the other) is especially puzzling, even recognizing major differences in methods; reasons are not clear from information in the reports. The WHO report, based on one consistent approach across all populations, is especially valuable in permitting geographic comparisons and demonstrating the near ubiquitousness of risk. Discussion of the INTERHEART Study in Chapter 4 indicated the consistent association of several major risk factors with presence of CHD in every population in this multinational case control study (see Table 4-10).57 Even in Africa, where the proportion of men at increased risk appears lower than elsewhere in the WHO analysis, odds ratios for current/ former smoking, diabetes, hypertension, abdominal obesity, and elevated ApoB/ApoA-1 ratio were significant for Black, Colored, European, and other Africans with the sole exception of smoking for Blacks.58 The contribution of these factors to epidemic CVD, as measured by the corresponding population-attributable fractions, is virtually universal as is their importance for CVD prevention. As described by Rodgers and others:59, p 851 High blood pressure, cholesterol, and bodyweight are responsible for a large and increasing proportion of the global burden of disease. Although historically these risks have been regarded as “Western,” their impact is now recognized as global: they are already leading causes of disease in middle-income countries and of emerging importance in low-income countries. It has been noted earlier that what is now “emerging” is appreciation of longstanding developments in low- and middle-income countries, where death rates from CHD and stroke were already substantial, ac-

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cording to World Bank estimates for 1985; the impact of the major risk factors throughout the world has in fact been evident for more than two decades (see Chapter 1). The Importance of Low Risk In a number of reports, beginning in 1999, Stamler and colleagues have presented data on long-term health experience of persons whose major risk factors were assessed in middle age or earlier.60 Table 21-10 presents data from two cohorts: first, men aged 35–39 and 40–59 years screened for the Multiple Risk Factor Intervention Trial (MRFIT), and, second, men aged 18–39 years and both men and women aged 40–59 years at examination during the Chicago Heart Association Detection Project in Industry (CHA). “Low risk” was defined as serum cholesterol below 200 mg/dl, blood pressure 120/80 mm Hg, and not currently smoking. Persons with a history of diabetes or myocardial infarction were excluded; in three of the five cohorts, those with electrocardiographic abnormalities were excluded as well. The prevalence of low risk was low, from 5% to 10% across the several cohorts. Death rates (per 100,000) for CHD and for all CVD among those at low risk relative to others in the corresponding cohorts were determined after 16 and 22 years of follow-up in MRFIT and CHA, respectively. Being at low risk at the indicated ages was associated with only 8% to 23% of CHD mortality

and 15% to 28% of CVD mortality experienced by the remainder of the study population. The authors concluded that long-term reduction in mortality and increased life expectancy could be achieved for many more people if prevalence of low risk were increased. Prevalence of risk factors is low in early childhood and increases by early adulthood, continuing generally to do so throughout most of the remaining years of life. Preserving the low-risk that is characteristic of early childhood would contribute importantly to achieving greater prevalence of low risk in the early or middle adult years as found in the experience of MRFIT and CHA follow-up. Several further contributions to this topic have indicated that low risk at middle age is associated with favorable health-related quality of life at older ages and lower healthcare expenditures in later years, including the last year of life.61–62 Low risk is less prevalent in African Americans than Whites in the United States, and this difference in risk distribution accounts for the excess CVD incidence in African Americans.63 The new emphasis on low risk underscores the reality for many people, and the potential for many more, to preserve optimum cardiovascular health throughout their lives. Analysis of long-term outcomes among Framingham Heart Study participants with two or more examinations between ages 40 and 50 showed increased longevity and survival free of major co-morbid conditions up to age 85 on the basis of favorable risk-factor levels at middle age.64 In

Table 21-10

Mortality from Coronary Heart Disease and All Cardiovascular Diseases for Low-Risk Subcohorts and Others* Age-Adjusted RR (95% CI), Low-Risk Cohort† No. Low-Risk Subcohort Others Subcohorts vs Others Coronary Heart Disease Mortality‡ MRFIT men aged 35–39 y 72,144 11 (0.2) 735 (1.5) 0.14 (0.08–0.25) CHA men aged 18–39 y 10,025 1 (0.6) 126 (5.9) 0.08 (0.01–0.61) MRFIT men aged 40–57 y 270,671 126 (4.4) 9578 (19.9) 0.22 (0.18–0.26) CHA men aged 40–59 y 7490 6 (8.8) 516 (38.1) 0.23 (0.10–0.51) CHA women aged 40–59 y 6229 2 (3.5) 181 (14.5) 0.21 (0.05–0.84) MRFIT men aged 35–39 y CHA men aged 18–39 y MRFIT men aged 40–57 y CHA men aged 40–59 y CHA women aged 40–59 y

72,144 10,025 270,671 7490 6229

All Cardiovascular Disease Mortality‡ 16 (0.3) 1022 (2.1) 3 (1.4) 163 (7.7) 190 (6.7) 13247 (27.5) 10 (15.8) 714 (53.1) 4 (5.3) 281 (22.6)

0.15 (0.09–0.24) 0.20 (0.06–0.62) 0.24 (0.21–0.28) 0.28 (0.15–0.52) 0.27 (0.10–0.72)

*MRFIT indicates the Multiple Risk Factor Intervention Trial; CHA, Chicago Heart Association Detection Project in Industry; RR, relative risk; and CI, confidence interval. † Ages are baseline ages; follow-up averaged 16 years in the MRFIT study and 22 years in the CHA study. ‡ Data presented as no. of deaths (age-adjusted mortality rate per 10 000 person-years). Source: Reprinted with permission from Journal of the American Medical Association, Vol 282, J Stamler, R Stamler, JD Neaton, et al., p 2015, © 1999 American Medical Association.

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a further development of analytic methods, lifetime risk of CVD among Framingham participants up to age 95 years was greatest for persons with no risk factors, and increased with each additional risk factor, at age 50.65 Public health strategies to increase prevalence of low risk through middle age are strongly supported on the basis of such evidence. The burden of risk is global in extent, and no region of the world is free of CVD on an epidemic scale. Distributions of particular risk factors vary among populations as do, therefore, specific populationattributable fractions for CHD and stroke. But the same factors are accountable everywhere, at populationspecific levels, as demonstrated by the INTERHEART Study.57

ECONOMIC CONSIDERATIONS The cost of health care is a prominent concern at present in many, perhaps all, countries. Discussion of economics in connection with health is often limited to the cost of care and its implications. The United States is exceptional for its high rate of expenditure for health care. The costs of CVD in the United States were projected for 2008 as shown in Table 21-11.66 The total direct costs, inclusive of all services for all

Table 21-11

CVD, were estimated to be $296.4 billion, which is nearly $1000 per person per year for the entire population of slightly more than 300 million people. These costs are attributed separately to each of several (nonexclusive) categories of CVD. How to pay for needed care at the individual level is a prominent social and political issue at local, state, and national levels. The implications of cost for healthcare insurers is also a major concern.67 Further, the United States, especially in comparison with other countries, is not achieving a level of health commensurate with this extraordinary spending on health care. This observation adds further to the economic concern.68 This point is emphasized in an analysis of health system impact on “amenable mortality”—deaths attributed to conditions considered preventable or treatable through health care, including half of CHD deaths—among the United States and 18 peer countries.69 From 1997–1998 to 2002, CHD death rates declined in every country, by large margins in several of them; the decline was less for the United States than for all but two of these countries (Greece and Japan); and the rate was higher at the end of this period than in all but two others (Finland and Ireland). This was despite the United States being “the most prolific health spender.”69, p 58

Estimated Direct and Indirect Costs (in Billions of Dollars) of CVD and Stroke: United States: 2008 Hypertensive Heart Disease* CHD Stroke Disease HF Total CVD†

Direct costs Hospital Nursing home Physicians/other professionals Drugs/other Medical durables Home health care Total expenditures† Indirect costs Lost productivity/morbidity Lost productivity/mortality‡ Grand totals†

$99.3 $22.7 $22.8

$51.0 $11.9 $12.9

$18.9 $15.7 $3.6

$7.6 $4.6 $12.8

$18.8 $4.3 $2.3

$140.1 $46.6 $44.4

$21.0 $7.0 $172.8

$9.7 $2.1 $87.6

$1.3 $4.2 $43.7

$24.1 $2.2 $51.3

$3.1 $3.2 $31.7

$49.5 $15.8 $296.4

$23.1 $91.4 $287.3

$10.2 $58.6 $156.4

$6.7 $15.1 $65.5

$8.1 $10.0 $69.4

... $3.1 $34.8

$37.6 $114.5 $448.5

Ellipses (. . .) indicate data not available. *This category includes CHD, HF, part of hypertensive disease, cardiac dysrhythmias, rheumatic heart disease, cardiomyopathy, pulmonary heart disease, and other or ill-defined “heart” diseases. † Totals do not add up because of rounding and overlap. ‡ Lost future earnings of persons who will die in 2008, discounted at 3%. Sources: Direct costs: Extrapolation from 1995 cost estimates for CVD in Hodgson and Cohen1 to the 2008 national health expenditure projections by the Centers for Medicare and Medicaid Services;2 indirect morbidity costs extrapolated to 2008 from indirect cost estimates by disease in 1980 by Rice et al3 after application of a 1980 to 2008 inflation factor computed from mean earnings published by the US Census Bureau;4 indirect mortality costs estimated by multiplying the numbers of deaths by age, sex, and cause in 20045 (NCHS mortality statistics) times estimates of the present value of lifetime earnings for 2003 by age and sex (unpublished estimates) furnished by Rice, Max, Michel, and Sung (University of California, San Francisco, 2007). All estimates prepared by Thomas Thom, NHLBI. Reprinted with permission from American Heart Association. Heart Disease and Stroke Statistics—2008 Update. Dallas, Texas: American Heart Association; 2008. ©2008, American Heart Association.

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But the remainder of the table points to another aspect of economics of CVD—indirect costs due to lost productivity by those afflicted by these conditions. This is a result of disability or death within the working years. These costs add another $150 billion— or another $500 per person per year for the whole population. Although these numbers are especially large for the United States, the global dimensions of CVD make the economics of CVD and of chronic diseases more generally important everywhere, as suggested by Ebrahim:70, p 225 . . . the burden of disease attributable to chronic diseases is dominant and rising in low- and middle-income countries; these diseases hit younger people at the peak of their productive lives; health systems cannot be made for each disease but need to be integrated to meet all health needs; and, finally, there are cost-effective interventions available that, if implemented, would save lives, reduce suffering and poverty. Aspects of economics addressed by Ebrahim extend far beyond the cost of care and include the impact of CVD and other chronic diseases on economic productivity and development; adequacy of health systems to provide affordable, accessible, high-quality care; and cost-effectiveness of available population-wide interventions that could have broad societal impact. Evidence presented throughout this book indicates that developed or high-income countries must also confront these issues. The broader economic considerations regarding CVD prevention include the following points, presented in the 2007 series of reports by The Lancet on chronic diseases in low- and middle-income countries: In the 23 countries with the most reliable data, chronic diseases (predominantly CVD, diabetes, cancer, and chronic respiratory diseases) accounted for 50% of the total disease burden in 2005. Heart disease, stroke, and diabetes alone were projected to cost these countries $83 billion in lost economic productivity between 2006 and 2015. A newly articulated goal for global health is to accelerate reduction in chronic disease mortality by 2% per year in these countries, through available interventions over these same 10 years. Success in this effort would avert 24 million deaths and reduce economic loss by $8 billion.71 A further point favoring investment in prevention of cardiovascular diseases was made in A Race Against Time:72, p 1 “Investments in health not only reduce the burden of disease, but also stimulate economic growth, which in turn raises a society’s ability to invest in public health.” At another level, cost-effectiveness analysis of particular clinical and public health interventions is

used widely as an aid to decision making in allocating resources. The principles and methods of this approach are presented in detail elsewhere, as is a review of economic evaluations specific to primary prevention of CVD through 2005.73,74 That review found that few cost-effectiveness evaluations had extended beyond clinical studies of lipid-lowering drugs to address broader health promotion strategies; most were conducted in the United States or the United Kingdom; sponsorship was needed from government and not only from the drug industry for a more balanced research agenda; and evaluation methods tended to bias results in favor of treatment over prevention. In the interest of increasing access to methods of cost-effectiveness analysis for public health decision making, WHO has developed and utilized the WHOCHOICE (Choosing Interventions that are CostEffective) project.75 Rather than focusing on “technical efficiency,” regarding a particular intervention alone, WHO-CHOICE addresses “allocative efficiency,” or alternative uses of resources given a wide range of potentially available interventions benefitting different segments of the population. Cost-effectiveness has also been used to assess feasibility of certain interventions for primary prevention of chronic diseases, including CVD. Resulting evidence has been judged to support bringing three population-wide interventions to scale on a national level: price increases for tobacco products, reduction of salt intake, and a low-cost multidrug regimen for people at high risk of CVD ( 25% or 15% in 10 years).36 The first two interventions could avert 13.8 million deaths in these 23 countries over 10 years, at costs from less than US$0.40 to $1.00 per capita per year.76 The corresponding costs for a drug regimen comprising a statin, aspirin, and two blood pressurelowering medications for the benefit of a high-risk subgroup of the population would range from about US$0.40–$2.90 per capita per year across the 23 countries. This intervention was projected to avert 17.9 million deaths over the 10 years, or three-fourths of the goal of a 2% per year reduction in chronic disease mortality “with a moderate increase in health expenditure.”77, p 2054 (The latter point that projected savings will require an increase in initial investment is a key element in the economics of CVD prevention.) At a macroeconomic level, CVD and other chronic diseases demand a level of attention and urgency of action that have been seriously underappreciated until quite recently. The economic and social impact of lost productivity, especially—but not exclusively—in lowand middle-income countries, would seem to compel action, the cost of continued inaction being unacceptable. On the basis of cost-effectiveness analysis of

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available interventions, substantial progress could be made by implementing largely affordable preventive measures today.

MODELS FOR EXPLANATION AND PREDICTION Models extend information beyond direct observation to complex mathematical representations that can be explored in various ways. This permits analysis of the influence of multiple factors operating simultaneously on an outcome of interest. Also, the parameters of the model derived from one period of observation can be used to project the future course of events under varying assumptions about influential conditions. These uses of modeling are distinct in purpose from those for estimating absolute CVD risk, or evaluating cost-effectiveness of interventions. As discussed in Chapter 4, the unanticipated downturn in age-standardized CHD mortality in the United States that was recognized in the late 1970s stimulated major research projects on trends in occurrence of CVD. Much of this work was simply to compile the available observations for descriptive purposes or to implement new surveillance activities for better documentation of contemporary events. The most far-reaching initiative in this area was the WHO MONICA Project, discussed in Chapter 4 and elsewhere. Following up on the Decline Conference of 1978, the National Heart, Lung and Blood Institute convened a conference in 1986 on the influence of medical care on CHD mortality trends. The proceedings present an extensive body of work with contributions from both epidemiologists and cardiologists, with the overall conclusion that the downturn was real and continuing, and “the relative roles of diverse causal factors [were] being clarified.”78, p 270 Further insight was to await expanded use of modeling in this area. Explaining Secular Trends and Current Burdens Understanding the contributions of prevention versus treatment, or of behavioral versus medical interventions, was and is a matter of central importance for public health decision making and resource allocation. A still broader scope of analysis today includes influences of policy and systems change. No less important is projection into the future of the likely burden of CVD and other chronic diseases, under varying assumptions. For these purposes, numerous approaches to modeling have been developed. Some of these, including the Global Burden of Disease and IMPACT models discussed in Parts I and II, are described in Table 21-12.79 In their review of “CHD

policy models,” Unal and colleagues found wide variation among more than 40 such models in quality, utility, and other characteristics. They selected six of these as the principal current approaches. The IMPACT model developed by Capewell and others, discussed in Chapter 4, is illustrated in Figure 21-5.80 Results are shown from 10 studies in 6 countries, 5 of them based on the IMPACT model and 5 on other methods. The importance of these findings to the case for CVD prevention is in part the consistent result, in 8 of these 10 studies, that 50% or more of past declines in CHD mortality were attributable to population-wide risk-factor changes. Details of the analysis for the United States over the period 1980–2000 included a net contribution of 44% for risk-factor reduction, given a cumulative positive effect of 61% for reductions in total cholesterol, systolic blood pressure, smoking, and physical inactivity that was offset by 17% because of adverse changes in body mass index and diabetes. In addition to this explanatory insight, the magnitude of decreases in CHD mortality over this period demonstrates forcefully the combined influence of changes in environmental conditions in the broadest sense: age-adjusted CHD mortality per 100,000 declined from 1980 to 2000 from 542.9 to 266.8 for men and from 263.3 to 134.4 for women, resulting in 341,745 fewer CHD deaths in 2000 than if the 1980 rates had persisted. Some qualification of this success is needed, however. An analysis of CHD mortality in the United States from 1980 through 2002 was conducted for specific age-sex strata to identify calendar periods in which trends might have changed for each subgroup.81 For both men and women aged 35–54 years, marked slowing of the decline occurred between 1980–1990 and 1991–2002; for women, the rate appeared to have reversed and increased from 2000–2002. No modeling of determinants of these changes was presented, but knowledge of continuing uptake of effective treatments was taken to support the view that offsetting adverse changes in risk factors were the likely explanation of the overall decline. To characterize the current global burden of disease and risk factors, as of the year 2000, Ezzati and colleagues in the Comparative Risk Assessment Collaborative Group estimated the joint contribution of 20 risk factors to occurrence of 10 leading causes of disease, injuries, and combined causes of death separately for low- and high-mortality developing countries, developed countries, and the world.82 (Analogous estimates of the proportionate contributions of each risk factor to both mortality and burden [in DALYs] of ischemic heart disease and stroke by economic region were presented in Chapter 1 [Table 1-8].)

Smoking, cholesterol, systolic blood pressure

England and Wales, Up to 85 years. Men and women

Micro simulation

CHD Policy Analysis (Sanderson and Davies)

Smoking, cholesterol, hypertension, obesity, physical activity, alcohol Smoking, total cholesterol, DBP, glucose intolerance, age

Netherlands; Denmark, England Depending on the purpose aged 65

Smoking, total cholesterol, DBP and weight to estimate CHD risk using Framingham Equations

Canada, Adult men and women, age group not clear

Cell based

PREVENT (GunningScheppers)

USA, Men and women aged 35–84

Did not consider CHD disease categories but treatments can be considered for primary prevention Angina (stable and unstable). AMI, post MI, CABG, PTCA None

None

Angina, AMI, sudden death, post MI, CABG, PTCA Specific treatments considered in different studies eg statins, aspirin, beta-blockers etc

643

Deaths prevented, morbidity prevented, CHD & non-cardiac deaths, unstable angina admissions, investigations, angiograms, PTCA, CABG

One-way

One way, different scenarios

Number of deaths prevented, life years gained

Years of life saved, cost per life year saved, years of life without CHD symptoms

In the initial model none. Subsequently papers reported one way sensitivity analysis

Sensitivity Analysis

Number of deaths prevented, LYG, CHD incidence (number of arrests, angina, AMI), CHD prevalence, CHD mortality, cost per life year

Outcomes

No validation reported

Calibrated

Not checked

Model was calibrated using 1986 mortality data. Validity: Model estimates were compared with 1990 observed— 92–98% fit reported.

Validation

continues

Separate risk factor and treatment components. Future model may include secondary prevention treatments. No sensitivity analyses yet. Model fit appears better for men than women.

This model uses hypothetical cohorts of participants. In most of the papers, time and the specific population are not clear.

Mainly a primary prevention model. Developed and adopted in several different populations.

First policy model rather basic. Steadily refined since then. Many papers in high impact journals

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Life table analysis— Markov model from 1998 onwards

State transition Markov Model

CHD Policy Model (Weinstein and Goldman)

Risk Factors Included

Disease Groups & Treatments Included

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CHD Life Expectancy Model (Grover et al)

Type of Model

Model Setting & Study Population(s)

Summary of the Six Principal CHD Policy Models

Name of the Model (Author)

Table 21-12

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644 Malnutrition, poor water, unsafe sex, alcohol, tobacco, occupation, hypertension, physical activity, illicit drugs, and air pollution

Initially smoking, cholesterol, blood pressure—then also obesity, diabetes and physical activity and deprivation

None

This model is comprehensive and considers all principal CHD categories and over 20 specific CHD treatments

Disability adjusted life years (DALYs)

Deaths prevented or postponed, life years gained.

Sensitivity Analysis

Multi-way sensitivity analysisdiscounting and age weighting

Multi way sensitivity analysis using analysis of extremes method.

Source: Reprinted with permission B Unal, S Capewell, JA Critchley, Biomed Central Public Health, Vol 6, on the basis of Open Access, © 2006 Unal et al.

World divided into eight geographic regions M-F all ages

Scotland, England & Wales, New Zealand. Initially men and women aged 45–84. IMPACT Model for England and Wales includes 25–84

Outcomes

None

Estimated falls in CHD mortality were compared with observed falls over specific time period stratified by age and sex.

Validation

A comprehensive and global model for WHO strategies. Well documented and described. CHD is included, and modelled as caused by tobacco use, hypertension and physical inactivity, and reduced by alcohol. Data quality. Extremely variable depending on the region

Considers all major effective treatments available for CHD and all major risk factors. Data quality adequate, used trial and meta-analyses: National population statistics and results from representative studies

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Population attributable risk method

Spread-sheet

IMPACT (Capewell, Critchley and Unal)

Risk Factors Included

Disease Groups & Treatments Included

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Global Burden of Disease (Murray and Lopez)

Type of Model

Model Setting & Study Population(s)

Summary of the Six Principal CHD Policy Models—continued

Name of the Model (Author)

Table 21-12

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MODELS FOR EXPLANATION AND PREDICTION 645

Risk Factors

Treatments

Unexplained

United States, 1968–7614

40

54 6

New Zealand, 1974–8115*

40

60

46

Holland, 1978–8517

44 10

43

United States, 1980–9013

50 7

IMPACT Scotland, 1975–9418

35

55 10

IMPACT New Zealand, 1982–9319

35

60 5

IMPACT England and Wales, 1981–200020

37

IMPACT United States, 1980–2000 (this study)

52 11 47

44 9

24

Finland, 1972–9216

23

IMPACT Finland, 1982–9722

0

76 53

50 Decrease in Deaths (%)

24 100

Figure 21-5 Percentage of the Decrease in Deaths from Coronary Heart Disease Attributed to Treatments and Risk-Factor Changes in Our Study Population and in Other Populations. Source: Reprinted with permission from ES Ford, UA Ajani, JB Croft, et al., New England Journal of Medicine, Vol 356, © 2007 Massachusetts Medical Society, p 41.

The report addressed here extended this type of analysis to examine contributions of these risk factors to healthy life expectancy (HALE). The results showed that, beyond preventing CVD or chronic diseases alone, elimination of the 20 risk factors would increase healthy life expectancy globally and reduce differentials across regions and subregions; for example, removing risks associated with alcohol, tobacco, high blood pressure, and high cholesterol would contribute importantly to an 8- to 11-year increase in HALE in much of eastern and central Europe and the former Soviet Union. Of particular interest was development of models to account for the joint effects of coexisting risk factors, by considering separately their direct and mediated effects—for example, the effects of body mass index mediated through blood pressure or other factors as distinct from its direct effects. Effect modification, resulting from influence of one risk factor on another, was also estimated and taken into account. The results regarding the factors associated with ischemic heart disease and stroke for the world as a whole are shown in Table 21-13. Contributions to the global burden of disease attributed to these factors range from 1.3% for physical inactivity to 4.4% for high blood pressure, to which tobacco and alcohol were nearly equivalent.

To put these values in perspective, among all 20 leading risk factors only two accounted for a greater percentage of disease burden than did blood pressure— underweight in children (9.5%) and unsafe sex (6.3%). Even unsafe water, sanitation, and hygiene contributed just 3.7%, less than any one of the three leading CVD risk factors. Further, the definitions of the CVD risk factors should be understood clearly. The “theoretical minimum” for each factor is the reference value against which any higher level is considered to increase risk. For systolic blood pressure, for example, the reference value to identify increased risk is not a clinical cut-point, such as 160, 140, or even 120 mm Hg, but 115 mm Hg. The approach to this definition is described in Global Burden of Disease and Risk Factors as based on “the lowest levels at which meta-analyses of cohort studies have characterized dose-response relationships.”83, p 246 From this perspective, joint population-attributable fractions of the risk factors to worldwide burden and mortality from ischemic heart disease were estimated. The resulting values were 83% and 78%, respectively, after adjustment for mediated effects of the risk factors. Corresponding estimates for stroke were 70% and 60%. That is to say, if these several risks were eliminated, 83% of the CHD burden and 70% of the stroke burden would be averted. (These results

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Table 21-13

Risk Factors for Ischemic Heart Disease and Stroke: Definitions and Contributions to the Global Burden of Disease, 2000 Contribution to Global Burden of Risk Factor Exposure Variable (See Source for Details) Theoretical Minimum Disease (%) High blood pressure Usual systolic blood pressure 115 mm Hg (SD 6) 4.4 High cholesterol Usual total blood cholesterol 3.8 mmol/L (SD 0.6) 2.8 High BMI BMI (weight over height squared) 21 kg/m2 (SD 1) 2.3 Low fruit and vegetable Fruit and vegetable intake per day 600 g (SD 50)/day for adults 1.8 intake Physical inactivity Three categories of inactive, All having at least 2.5 h/week insufficiently active, and sufficiently of moderate-intensity activity active, taking into account discretionary or equivalent (4000 KJ/week) time, work, transport 1.3 Tobacco Current values of smoking impact ratio; No tobacco use 4.1 prevalence of oral tobacco use Alcohol Current alcohol consumption volumes No alcohol use 4.0 and patterns Source: Data from M Ezzati, S Vender Hoorn, A Rodgers, et al., The Lancet, Vol 362, © 2003, pp 273–274.

were similar but not identical to those shown in Table 1-8.) The general concordance of these and the INTERHEART Study findings is noteworthy. Predicting Future Burdens Before the 1990s, use of modeling for the purpose of predicting the course of the CVD epidemic or of chronic disease burdens was rare, even at a national level. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020, published in 1996, is a landmark.84 Cited widely in current discussions of health policy on global, regional, and national levels, it was not without its limitations as noted in the Foreword by Dr. Ralph H. Henderson, Assistant Director-General of the World Health Organization:85, pp xiii–xiv The findings published in the Global Burden of Disease and Injury Series provide a unique and comprehensive assessment of the health of populations as the world enters the third millennium. We also expect that the methods described in the various volumes in the series will stimulate Member States to improve the functioning and usefulness of their own health information systems. Nevertheless, it must be borne in mind that the results from an undertaking as ambitious as the Global Burden of Disease Study can only be approximate. The reliability of the data for certain diseases, and for some regions, is extremely poor, with only scattered information available in some cases. . . . The concept of the

DALY as used in this Study is still under development, and further work is needed to assess the relevance of the social values that have been incorporated in the calculation of DALYs, as well as their applicability in different sociocultural settings. In this regard, WHO and its partners are continuing their efforts to investigate burden-of-disease measurements and their use in health policy decision-making. Accordingly, an updated assembly of data and application of further-developed methods led to publication of Global Burden of Disease and Risk Factors in 2006, and a further search for data to update the more recent report is already in progress. Global projections from 1990 to 2020 showing ischemic heart disease and stroke to be the first and second leading causes of death called increased attention to the previously under-appreciated burden of CVD throughout the world.86 Whether the baseline or alternative scenarios—optimistic or pessimistic—were considered, CVD remained dominant; only the gross numbers of deaths were influenced by alternative assumptions. Further work in projecting future burdens of CVD and other chronic diseases is illustrated by A Race Against Time: The Challenge of Cardiovascular Disease in Developing Economies (2004) and by Dying Too Young: Addressing Premature Mortality and Ill Health Due to Non-Communicable Diseases and Injuries in the Russian Federation (2005).72,87 The first of these reports, described in Chapter 1, was published in response to the Millennium Development

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VISIONS OF SUCCESS IN CVD AND CHRONIC DISEASE PREVENTION 647

Goals, which omitted reference to chronic diseases. Race Against Time projected CVD burdens from 2000 to 2030, from a macroeconomic perspective. It focused on the narrow window of opportunity, within the next two decades or so, “to prevent the precursors and reverse the negative effects of CVD in developing countries” and thereby rescue the labor force—people of working age—from falling victim to CVD in great numbers, thereby crippling economic and social development in such countries as China, Brazil, India, Russia, and South Africa.72, p 84 The second report, in projecting demographic, economic, and health conditions in the Russian Federation, forecast continuation of a national decline already referred to as “devastation” without precedent among industrial nations.87 Population was shrinking, life expectancy was receding, and CVD mortality was the principal cause of death for working men and the population as a whole, with a rate more than three times that of the United States. However, the response to these projections was optimistic:87, p 100 Reducing NCDs and injury-related mortality rates among Russian working-age adults will have a major macroeconomic and poverty reduction impact, regardless of how this is measured. . . . The expected economic benefits are of a magnitude that easily outweighs the costs of health promotion and disease prevention programs. Given the significant positive effect on economic growth from investing in health [citation given], governmental intervention is urgently needed in Russia to develop healthenhancing policies and programs to address the alarmingly high rates among the working-age population. These efforts should be seen as key investments to help improve the general welfare of the population and secure sustainable economic growth in the future. Modeling contributes importantly to explanation, description, and prediction of past, present, and future occurrence of CVD and other chronic diseases. Extending beyond the sometimes quite limited direct observations available, modeling offers insights that can influence decision making about health policy in positive ways. At the same time, it can stimulate continuing efforts to strengthen data sources for future improvement in the models.

VISIONS OF SUCCESS IN CVD AND CHRONIC DISEASE PREVENTION The two reports discussed previously cited opportunities for prevention, and not only threats, in the

projected burdens of CVD and other chronic diseases. Costs of these conditions due to reduced economic productivity in low- and middle-income countries were seen as being so immense that their prevention would more than repay the foreseeable expenditures. Optimism was also evident in the more specific economic analyses regarding cost-effectiveness of feasible interventions, such as were reported in The Lancet’s 2007 series cited previously. In the United States, Europe, and on the global level, many examples can be found of visionary statements of what is achievable through CVD prevention, not only improving health itself but also enhancing societal well-being through greater health equity and social justice. Several examples can serve to illustrate this point: • At a national level in the United States, both federal and voluntary organizations set explicit goals for CVD prevention, decade by decade. The federal Department of Health and Human Services (DHHS) published Healthy People 2010 early in the year 2000 with its heart disease and stroke prevention goal, cited earlier: prevention of risk factors, detection and treatment of risk factors, early identification and treatment of heart attacks and strokes, and prevention of recurrent cardiovascular events.88 At the Centers for Disease Control and Prevention (CDC), the Division for Heart Disease and Stroke Prevention is the administrative locus for leadership in these efforts. The Division’s mission is “To provide public health leadership to improve cardiovascular health for all, reduce the burden, and eliminate disparities associated with heart disease and stroke” and thereby to achieve the vision of a world that is “Heart-Healthy and Stroke-Free.”89 The American Heart Association’s (AHA’s) mission is “Building healthier lives, free of cardiovascular diseases and stroke.”90 Both DHHS and AHA have set targets for reducing the burden of CVD by 2010. DHHS, through Healthy People 2010, provides multiple objectives by which to measure success nationally, and AHA’s goal for 2010 is “to reduce coronary heart disease, stroke and risk by 25%.” • A landmark joint policy statement by the American Cancer Society, American Diabetes Association, and American Heart Association in 2008 declared that optimum delivery of clinical preventive services could reduce myocardial infarction by 63% and strokes by 31%.91 Cost

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reduction and increased efficiency would be necessary to realize this full impact, however. • Responding to the “challenges to health and equity” confronting European countries, the WHO Regional Office for Europe (WHOEURO) published in 2006 Gaining Health: The European Strategy for the Prevention and Control of Noncommunicable Diseases.92 Underlying the Strategy are the following key statements:92, p 17 Vision—A health-promoting Europe free of preventable noncommunicable disease, premature death and avoidable disability. Goal—To avoid premature death and significantly reduce the disease burden from NCD by taking integrated action, improving the quality of life and making healthy life expectancy more equitable within and between Member States. Objectives—To take integrated action on risk factors and their underlying determinants across sectors. To strengthen health systems for improved prevention and control of NCD. • Preventing Chronic Disease: A Vital Investment: WHO Global Report, supported by the governments of Canada, Norway, and the United Kingdom, was released in 2005.2 The Report “makes the case for urgent action to halt and turn back the growing threat of chronic diseases; presents a state-of-the-art guide to effective and feasible interventions; provides practical suggestions for how countries can implement these interventions to respond successfully to the growing epidemics.”2, p xiv The chronic conditions addressed are heart disease and stroke (CVD), cancer, asthma and chronic obstructive pulmonary disease, and diabetes. The overview of the report succinctly summarizes the argument:2, p 1 The Problem: 80% of chronic disease deaths occur in low and middle income countries and these deaths occur in equal numbers among men and women. The threat is growing––the number of people, families, and communities afflicted is increasing. This growing threat is an under-appreciated cause of poverty and hinders the economic development of many countries.

The Solution: The chronic disease threat can be overcome using existing knowledge. The solutions are effective—and highly cost-effective. Comprehensive and integral action at country level, led by governments, is the means to achieve success. The Goal: An additional 2% reduction in chronic disease death rates worldwide, per year, over the next 10 years. This will prevent 36 million premature deaths by 2015. The scientific knowledge to achieve this goal already exists. • In 1992, the first of seven three-yearly International Heart Health Conferences took place in Victoria, British Columbia, Canada, and concluded with issuance of The Victoria Declaration on Heart Health.93 The document was foremost a call to action and policy framework that addressed action areas, population groups, risk-factor reduction, strategies, developingworld perspectives, a research agenda, and partnerships to include international agencies, governments, and many other players. The Declaration recognized that “both scientific knowledge and widely tested methods exist to prevent most cardiovascular disease” and called upon virtually all segments of society “to join forces in eliminating this modern epidemic by adopting new policies, making regulatory changes and implementing health promotion and disease prevention programs directed at entire populations.”93, p iv Further Declarations from subsequent conferences in the series addressed particular aspects of heart health promotion. The recommendations from the first six reports, issued from 1992 through 2001, were synthesized in the document, International Action on Cardiovascular Disease: A Platform for Success Based on International Cardiovascular Disease (CVD) Declarations, released in 2005. The report concluded:94, p 22 Cardiovascular disease (CVD) is a challenge of global proportions. It is largely preventable. Unfortunately, overall investment in CVD prevention has been insufficient to achieve optimal results. Applying the existing knowledge with the wisdom that has accumulated over the past twenty years could stem the epidemic of CVD around the world. A strong international effort could encourage, promote, and facilitate country-led initiatives.

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CURRENT ISSUES 649

International organizations have a critical role to play in harnessing globalization in the service of health. The visions expressed in these several examples represent judgments by prominent organizations and individuals that go beyond the systematic review of evidence on any specific intervention. They reflect not only a sense of what such evidence says but also what it means in terms of societal interests and values. That such belief in the potential for CVD prevention is expressed strongly by many authoritative sources contributes significantly to the case for prevention.

COUNTER-ARGUMENTS Contrary views mainly follow one of three lines of argument: (1) Knowledge of causation of CVD is inadequate, whether because conventional risk factors fail to account for a sufficient proportion of risk; they exclude more fundamental causes, such as social determinants; or they will be superseded by emerging or yet-to-be-discovered factors, including genetics, that will better identify true causation.95–97 (2) Populationlevel interventions to prevent CVD and other chronic diseases are ineffective; they are of insufficient priority to compete for resources against an unfinished agenda of communicable disease and other health needs; or they would widen disparities in health by inequitable impact, favoring the affluent and leaving the poor at even greater relative disadvantage than at present.15,98,99 (3) Further research is needed in order to know what interventions will work, how to tailor them to particular populations, and what they will save in terms of return on investment, prior to taking any public health action.100 A number of published commentaries respond specifically to these views, some of them being cited elsewhere in this or other chapters. Several, for example, address the “myth” that only 50% or less of heart disease and stroke is accounted for by the major established risk factors.100–103 Others emphasize the value of lessons learned from the experience of population-level interventions, including their successes and their limitations, and the need to focus especially on the most disadvantaged populations, eliminating disparities in CVD and other chronic diseases.7,72,104–106 Finally, the judgment that knowledge is sufficient to support local, national, and global public health efforts in this area is reflected in each of the visions highlighted previously and many others, expressed recently as the global challenge of the “know-do gap.”107–108

That counter-arguments regarding the case for CVD prevention continue to be raised should not be surprising, given competing interests, priorities, or interpretations of the evidence. Weighed against the elements of the argument in favor of CVD prevention, however, they are not persuasive to many in positions of accountability for the public’s health.

CURRENT ISSUES Current understanding of the public health importance and feasibility of preventing CVD and other chronic diseases is based on several fundamental considerations: knowledge of their causation; widespread experience in implementation and evaluation of multifactor CVD prevention programs; accumulated evidence of the increasing mortality and burden due to these diseases globally and their especially heavy toll on particular regions, countries, or populations; results of a variety of modeling approaches to explanation and prediction of secular trends in their occurrence and estimation of the fraction of disease attributable to each of several globally operating risk factors; the macroeconomic impact of these diseases on development, affecting the majority of the world’s population; the potential cost-effectiveness of selected policy and health system interventions; and visionary statements over many years by prominent organizations and individuals. Effective communication is called for to express: (1) the urgency of large-scale implementation of policies and programs for prevention; (2) the great potential impact of prevention; and (3) the consequences of failure to take sufficient and timely action in the interest of the public’s health. In the concluding report in The Lancet 2007 series on prevention of chronic diseases, Beaglehole and coauthors summarize findings presented in the series:109, p 2157 This Series of papers in The Lancet provides evidence that achievement of the global goal for the prevention and control of chronic diseases is both possible and realistic through available interventions. These papers lend support to the rapid scaling-up of efforts to prevent and control chronic disease in low-income and middle-income countries. We appreciate the complex nature of the health problems of national authorities in lowincome and middle-income countries because of competing priorities. We are also aware that the evidence for the actual effects of interventions on reducing the burden of disease within

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countries is more limited than is the broader evidence base for action. However, the totality of the evidence suggests that large economic and health gains can be achieved in low-income and middle-income countries through increased efforts to prevent and control chronic diseases. A current challenge is to take action based on this case for prevention of CVD and other chronic diseases––in the United States, in other high-income countries, and in the developing world.

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13. Wilhelmsen L, Berglund D, Elmfeldt D, et al. The multifactor primary prevention trial in Göteborg, Sweden. Eur Heart J. 1986;7: 279–288.

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14. Strandberg TE, Salomaa VV, Naukkarinen VA, et al. Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men. JAMA. 1991; 266:1225–1229.

5. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, eds. Global Burden of Disease and Risk Factors. Washington, DC: The International Bank for Reconstruction and Development/ The World Bank; 2006.

15. Ebrahim S, Beswick A, Burke M, Davey Smith G. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database Syst Rev. 2006, Issue 4. Art. No.:CD001561. doi: 10.1002/14651858 .CD001561.pub2.

6. Shigan EN. Integrated programme for noncommunicable diseases prevention and control (NCD). World Health Stat Q. 1988;41:267–273. 7. Farquhar JW, Fortmann SP. Community-based health promotion. In: Aherns W, Pigeot I, eds. Handbook of Epidemiology. Berlin: Springer 2005;1305–1323. 8. The Multiple Risk Factor Intervention Trial (MRFIT). A national study of primary prevention of coronary heart disease. JAMA. 1976; 235:825–827

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57. Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364;937–952.

66. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update. A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117: e1–e122.

58. Steyn K, Sliwa K, Hawken S, et al. Risk factors associated with myocardial infarction in Africa. The INTERHEART Africa Study. Circulation. 2005;112:3554–3561. 59. Rodgers A, Lawes CMM, Gaziano T, Vos T. The growing burden of risk from high blood pressure, cholesterol, and bodyweight. In: Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006:851–868. 60. Stamler J, Stamler R, Neaton JD, et al. Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy. Findings for 5 large cohorts of young adult and middle-aged men and women. JAMA. 1999;282:2012–2018. 61. Daviglus ML, Liu K, Pirzada A, et al. Favorable cardiovascular risk profile in middle age and health-related quality of life in older age. Arch Int Med. 2003;163:2460–2468. 62. Daviglus ML, Liu K, Pirzada A, et al. Cardiovascular risk profile earlier in life and Medicare costs in the last year of life. Arch Int Med. 2005;165:1028–1034. 63. Hozawa A, Folsom AR, Sharrett AR, Chambless LE. Absolute and attributable risks of cardiovascular disease incidence in relation to optimal and borderline risk factors. Comparison of African American with white subjects—Atherosclerosis Risk in Communities Study. Arch Int Med. 2007;167:573–579. 64. Terry DF, Pencina MJ, Vasan RS, et al. Cardiovascular risk factors predictive for survival and morbidity-free survival in the oldest-old Framingham Heart Study participants. J Am Geriatr Soc. 2005;53:1944–1950.

67. Trogdon JG, Finkelstein EA, Nwaise IA, Tangka FK, Orenstein D. The economic burden of chronic cardiovascular disease for major insurers. Health Prom Pract. 2007;8:234–242. 68. World Health Organization. The World Health Report 2000. Health Systems: Improving Performance. Geneva: World Health Organization; 2000. 69. Nolte E, McKee CM. Measuring the health of nations: updating an earlier analysis. Health Aff. 2008;27:58–71. 70. Ebrahm S. Chronic diseases and calls to action. Int J Epid. 2008;37:225–230. 71. Abegunde DO, Mathers CD, Adam T, Ortegon M, Strong K. Chronic diseases 1. The burden and costs of chronic diseases in low-income and middle-income countries. Lancet 2007; 370:1929–1938. 72. Leeder S, Raymond S, Greenberg H. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries. New York: The Trustees of Columbia University in the City of New York; 2004. 73. Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-Effectiveness in Health and Medicine. New York: Oxford University Press; 1996. 74. Schwappach DLB, Boluarte TA, Suhrcke M. The economics of primary prevention of cardiovascular disease—a systematic review of economic evaluations. Cost Eff Resour Alloc. 2007;5:5. doi:10.1186/1478-7547-5-5. Available at http://www.resource-allocation .com/content/5/1/5.

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75. Hutubessy R, Chisholm D, Edejer T T-T, WHOCHOICE. Generalized cost-effectiveness analysis for national-level priority-setting in the health sector. Cost Effect Resource Alloc. 2003;1:8. Available at http://www.resource -allocation.com/content/1/1/8. 76. Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic diseases 3. Chronic disease prevention: health effects and financial costs of strategies to reduce salt intake and control tobacco use. Lancet. 2007;370: 2044–2053. 77. Lim SS, Gaziano TA, Gakidou E, et al. Chronic diseases 4. Prevention of cardiovascular disease in high-risk individuals in low-income and middle-income countries: health effects and costs. Lancet. 2007;370;2054–2062. 78. Carleton RA. Trends and determinants of coronary heart disease mortality: future prospects and projections. In: Higgins MW, Luepker RV, eds. Trends in Coronary Heart Disease Mortality. The Influence of Medical Care. New York: Oxford University Press; 1988. 79. Unal B, Capewell S, Critchley JA. Coronary heart disease policy models: a systematic review. BMC Public Health. 2006;6:213. doi:10.1186/1471-2458-6-213. 80. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000. N Engl J Med. 2007;356: 33–43. 81. Ford ES, Capewell S. Coronary heart disease mortality among young adults in the U.S. from 1980 through 2002. Concealed leveling of mortality rates. J Am Coll Cardiol. 2007; 50:2128–2132. 82. Ezzati M, Vander Hoorn S, et al. Estimates of global and regional potential health gains from reducing multiple major risk factors. Lancet. 2003;362:271–280. 83. Mazzati E, Vander Hoorn S, Lopez AD, et al. Comparative quantification of mortality and burden of disease attributable to selected risk factors. In: AD Lopez, CD Mathers, M Ezzati, DT Jamison, CJL Murray, eds. Global Burden

of Disease and Risk Factors. Washington, DC: The International Bank for Reconstruction and Development/The World Bank; 2006:241–396. 84. Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston: The Harvard School of Public Health; 1996. 85. Henderson H. Foreword to the Global Burden of Disease and Injury Series. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston: The Harvard School of Public Health; 1996: xiii–xiv. 86. Murray CJL, Lopez AD. Alternative visions of the future: projecting mortality and disability, 1990–2020. In: Murray CJL, Lopez AD, eds. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to 2020. Boston: The Harvard School of Public Health; 1996. 87. The World Bank. Dying Too Young. Washington: Europe and Central Asia, Human Development Department, The World Bank; 2005. 88. US Department of Health and Human Services. Healthy People 2010. 2nd ed. With Understanding and Improving Health and Objectives for Improving Health. 2 vols. Washington, DC: US Government Printing Office; 2000. 89. Centers for Disease Control and Prevention. Division for Heart Disease and Stroke Prevention. Available at http://www.cdc.gov/ dhdsp/. Accessed July 6, 2008. 90. American Heart Association. American Heart Association Strategic Goals. Available at http://www.americanheart.org/presenter.jhtml? identifier=4429. Accessed February 11, 2008. 91. Kahn R, Robertson RM, Smith R, Eddy D. The impact of prevention on reducing the burden of cardiovascular disease. Circulation. 2008;118: 576–585.

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102. Stamler J. Low risk—and the “No More Than 50%” myth/dogma. Arch Int Med. 2007;167:537–538. 103. Canto JG, Iskandrian AE. Major risk factors for cardiovascular disease. Debunking the “Only 50%” myth. JAMA. 2003;290: 947–949. 104. Fries JF, Green LW, Levine S. Health promotion and the compression of morbidity. Lancet. 1989;1:481–483.

94. International Heart Health Society. International Action on Cardiovascular Disease: A Platform for Success. Vancouver: International Heart Health Society, 2005. Available at: www.internationalhearthealth .org. Accessed January 21, 2008.

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96. Link BG, Phelan J. Social conditions as fundamental causes of disease. J Health Soc Behav. 1995;36:80–94. 97. Davey Smith G, Ebrahim S, Lewis S, Hansell AL, Palmer LJ, Burton PR. Genetic epidemiology 7. Genetic epidemiology and public health: hope, hype, and future prospects. Lancet. 2005;366:1484–1498. 98. McCormick J, Skrabanek P. Coronary heart disease is not preventable by population interventions. Lancet. 1988;2:839–841. 99. Ebrahim S, Davey Smith G. Exporting failure? Coronary heart disease and stroke in developing countries. Int J Epid. 2001;30: 201–205. 100. Pearson TA. Cardiovascular disease in developing countries: myths, realities, and opportunities. Cardiovasc Drugs Ther. 1999;13: 95–104. 101. Magnus P, Beaglehole R. The real contribution of the major risk factors to the coronary epidemic: time to end the 50% myth. Arch Int Med. 2001;161:2657–2660.

107. The John E. Fogarty International Center. Pathways to Global Health Research. Strategic Plan 2008–2012. NIH Publication No. 08-6261. Bethesda: US Department of Health and Human Services, National Institutes of Health, The John E. Fogarty International Center, May 2008. 108. US Department of Health and Human Services. A Public Health Action Plan to Prevent Heart Disease and Stroke. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. 109. Beaglehole R, Ebrahim S, Reddy S, Voûte J, Leeder S on behalf of the Chronic Disease Action Group. Chronic Diseases 5. Prevention of chronic diseases: a call to action. Lancet. 2007;370:2152–2157.

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22 Taking Action their work for heart disease and stroke prevention, with demonstrated outcomes. Still, despite widely held agreement on needed action, built on a substantial evidence base, prevention policies are not being implemented to full effect at either population or individual levels. Several obstacles at both levels pose challenges for preventive action. Common to both levels and underlying a number of more specific obstacles are issues of economics; health system structure and function; and priorities for CVD and other chronic disease prevention, among other policies within and beyond the health sector. Three strategic priorities for achieving the goals of heart disease and stroke prevention are to strike a new balance in our investment in health; transform our public health agencies into effective instruments for leadership in health system change; and prevent the causes of CVD and other chronic diseases rather than wait to treat their consequences. A continuum of care is envisioned that can link public health and clinical practice within a coherent health system addressing the needs of both populations and patients. Opportunities for effective prevention of the cardiovascular diseases are great, even while further research continues that may still better inform future prevention policies and plans.

SUMMARY Calls to action for prevention of cardiovascular and other chronic diseases are increasingly common at national, regional, and global levels. They variously include broad statements of goals, proposed strategies for achieving such goals, or concrete action plans to be implemented by governments and other players. Examples are cited from the Americas (the United States, Canada, and the Pan American Health Organization (PAHO), Europe (the Russian Federation, Country-wide Integrated Noncommunicable Diseases Intervention [CINDI] Program, and the European Region of the World Health Organization [WHO]), South Asia (Pakistan and the South Asian Association for Regional Cooperation [SAARC]), and other regions as well as at the global level (Heart Health Networks, WHO, and the Disease Control Priorities in Developing Countries Project [DCP2]). As a case study of action plan initiation, implementation, and institutionalization, A Public Health Action Plan to Prevent Heart Disease and Stroke, developed by the US Centers for Disease Control and Prevention (CDC) in partnership with the American Heart Association (AHA), Association of State and Territorial Health Officials (ASTHO), and other partners, is examined in some detail. This example describes a process for moving from explicit national goals to responsive recommendations and proposed action steps to comprise a comprehensive public health strategy for CVD prevention. Further steps to prioritize actions, establish means of their implementation, and accomplish the indicated tasks are also outlined. An action plan can be developed and can guide interested organizations and agencies in

INTRODUCTION: CALLS TO ACTION Parallel developments along multiple lines—knowledge of causation, concepts of prevention, assessments of evidence, and guidelines for clinical and public health practice—culminate in a strong case for prevention. If the force of argument supporting public

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health intervention to prevent cardiovascular and other chronic diseases is sufficient, effective action should be expected to follow. Accordingly, calls to action have been presented by many authoritative organizations and agencies. Some of these are found in the visionary statements illustrated in the preceding chapter. Building on precedents beginning decades ago, recent calls to action in CVD prevention have become more frequent, more comprehensive, and more prominent. For example, in the United States, the sense of urgency about chronic disease prevention led to development of an innovative partnership among three leading national voluntary organizations, the American Cancer Society, American Diabetes Association, and American Heart Association. This new collaboration and a common agenda were announced simultaneously in the principal journals of the three organizations in 2004:1, p 3244 Current approaches to health promotion and prevention of cardiovascular disease, cancer, and diabetes do not approach the potential of the existing state of knowledge. A concerted effort to increase application of public health and clinical interventions of known efficacy to reduce prevalence of tobacco use, poor diet, and insufficient physical activity––the major risk factors for these diseases––and to increase utilization of screening tests for their early detection could substantially reduce the human and economic cost of these diseases. Numerous national, regional, and global initiatives with similar missions have emerged over the past decade or more from governmental agencies and nongovernmental organizations alike. Calls for action have become commonplace, perhaps to excess, as suggested by Ebrahim in a recent editorial in which he notes, “The real challenge for any call to action is to develop and implement a plan for achieving its goals.”2, p 227 A call to action may in itself be a meaningful act of communication, as it conveys the urgency of current conditions, potential impact of intervention, and cost of inaction, yet it may fall short of actual plans for any direct health intervention. Effective response to a call to action requires taking action, which is presumed to have greatest likelihood of impact when based on explicit goals, strategies, and plans. The emergence of well-articulated responses to calls for prevention of cardiovascular and other chronic diseases is illustrated through an overview of examples from North American, European, South Asian, and other regional and global efforts. One example serves as a case study: A Public Health Action

Plan to Prevent Heart Disease and Stroke, first published in the United States in 2003.3

OVERVIEW: GOALS, STRATEGIES, AND ACTION PLANS Americas In the United States, nongovernmental and governmental bodies have gone varying distances along the path to a fully explicit action plan for CVD prevention. The American Heart Association (AHA), for example, has as its mission “Building healthier lives, free of cardiovascular disease and stroke.”4 (www.american heart.org; accessed February 11, 2008) AHA adopted strategic goals for the current decade in order, by 2010, “to reduce coronary heart disease, stroke, and risk by 25 percent.” The goal statement includes indicators of progress related to reduced coronary heart disease and stroke mortality, prevalence of smoking, high blood cholesterol, physical inactivity and uncontrolled high blood pressure, and limited growth of overweight and diabetes. Strategies are outlined by which to meet the targets for these indicators in four areas— knowledge, revenue generation, evaluation, and capacity building. Consistent with its mission and goals, AHA also published its Guide for Improving Cardiovascular Health at the Community Level and the sequel, Taking the Initiative, reviewed in Chapter 20.5,6 Although these documents stop short of proposing specific tasks, timelines, or accountability for achievement of goals and objectives, together they clearly anticipate that responsive action will occur. Coalitions of other nongovernmental organizations have also been established in the United States to address chronic disease prevention generally, such as the Partnership to Fight Chronic Disease, Partnership for Prevention, and Trust for America’s Health7–9 (www.fightchronicdisease.org, www.prevent.org, www.healthyamericans.org; accessed September 21, 2008). In some instances, such Web sites provide opportunities for action by interested visitors, although systematic action plans are not presented. The leading example of explicit goals, strategies, and action plans in the United States is A Public Health Action Plan to Prevent Heart Disease and Stroke.3 This is a comprehensive strategic plan that derived from national goals presented in Healthy People 2010 and that included recommendations, action steps, and a mechanism for long-term implementation, the National Forum for Heart Disease and Stroke Prevention. This plan will be examined in some detail as a case study as follows.

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In Canada, leadership in CVD prevention was represented early by the Canadian Heart Health Initiative, a federal-provincial partnership designed to implement and evaluate community interventions to reduce the burden and risk of CVD across Canada10,11 (www.pac-aspc.gc.ca/ccdpc-cpcmc/cindi/ pdf/chhi-eval_e.pdf; accessed September 21, 2008). Begun in 1986 with a five-phase 18-year plan, the program provided experience in integrated CVD prevention and “healthy living promotion” on which future community-based interventions for chronic disease prevention could be based. After this demonstration program and the series of heart health conferences cited previously, it was recognized that there was “no over-arching pan-Canadian strategy for heart health, nor . . . clear collaborative leadership or a coordinating mechanism to guide such a strategy”12, p 16-1 (www .chhs-scsc.ca; accessed September 21, 2008) With completion planned in late 2008, the direction of the Canadian Heart Health Strategy-Action Plan (CHHS-AP) can be anticipated from its statement of purpose and objectives:12, p 20–21 1. to develop a collaborative and inclusive Canadian Heart Health Strategy and Action Plan that will engage stakeholders with a commitment to improving cardiovascular health for Canadians Output: a comprehensive Canadian strategy document for a collaborative approach to cardiovascular health Output: a business plan to guide and support implementation of the Strategy 2. to agree on six to eight Theme Working Group topics (areas of emphasis) and related strategic priorities on the basis of the best evidence available Output: identification of five or six strategic priorities and related recommendations for action for each identified Theme Working Group Output: development of innovative knowledge synthesis, exchange and translation practices (appropriate for a range of populations, including those who are underserved) to promote the implementation of recommended policies and programs developed by each Theme Working Group 3. to develop a plan for a system (and related components) for a comprehensive and coordinated approach to cardiovascular health surveillance for Canada Output: a five-year staged plan for cardiovascular health surveillance, including key indicators

4. to propose a five-year monitoring and evaluation protocol to document the impact of the Strategy and suggest improvements Output: a document outlining realistic formative and summative approaches to monitoring and evaluation using a range of quantitative and qualitative strategies This Canadian initiative will thus present a true national strategy and action plan for cardiovascular health, combining key elements of collaboration, comprehensiveness, planned resources for implementation, recommended actions in identified priority areas, plans for monitoring and evaluation, and a supporting surveillance system. More broadly for the region, a Health Agenda for the Americas, 2008–2017 was presented by the Ministers of Health of the Americas in 2007.13 (Available at www.paho.org, accessed June 30, 2008.) The document includes a declaration regarding commitment to a broad health agenda and principles, followed by a situation analysis and review of regional health trends. Chronic diseases are recognized as dominant causes of morbidity and mortality throughout the region. The health agenda addresses strengthening the national health authorities, tackling health determinants, increasing social protection and access to quality health services, diminishing health inequalities among countries and inequities within them, reducing the risk and burden of disease, strengthening the management and development of health workers, harnessing knowledge, science, and technology, and strengthening health security (preparing, for example, for natural disasters or pandemic influenza). Regarding risk and burden of disease:13, p 18 Specific actions should be initiated to control diabetes, cardiovascular and cerebrovascular diseases, as well as types of cancer with the greatest incidence, as well as hypertension, dyslipidemia, obesity, and physical inactivity. . . . The health authority should be highly active in promoting healthy lifestyles and environments. Changes in behavior will only be sustained if they are accompanied by environmental, institutional, and policy changes that truly allow people to choose lifestyles that involve healthy eating habits, physical activity, and not smoking. Collaboration with industry, the media, and other strategic partners is needed to produce and market healthier foods, and with the education sector so that schools set an example of good dietary practices and promote healthy habits.

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The agenda, though far-reaching in scope, gives less direct guidance to action in the cardiovascular or chronic disease areas than, for example, the US and Canadian strategies. However, the fundamental concepts have much in common: expectation of shared impact across several chronic conditions, need for multisector approaches, and emphasis on diet, physical activity, and tobacco. Europe In Europe, at the national level, a very recent example is the document Strategy for the Prevention and Control of Noncommunicable Diseases and Injuries in the Russian Federation.14 This report was released by the Ministry of Health and Social Development of the Russian Federation and the State Research Center for Preventive Medicine, a World Health Organization (WHO) Collaborating Center on Development and Implementation of Noncommunicable Disease Prevention Policy and Programs:14, p 3 The purpose of the Strategy is to create an intersectoral system aimed at preventing the development and progression of NCDs and injuries in Russia by means of integrated measures that promote a healthier lifestyle, adjust the risk factors on which these diseases are based, enhance the effectiveness of treatment so as to improve the quality of and prolong people’s lives and increase the country’s work force and economic capacity. The main objectives of the Strategy are: • to upgrade the priority of preventing NCDs and Is in the programs of national action aimed at strengthening and preserving the health of the population; • to develop a system of interagency and interregional cooperation and partnership on matters of improving health and preventing NCDs and Is; • to determine and create an effective infrastructure for improving health and preventing NCDs and Is; • to propose resources for increasing, and ways of distributing, resources, such a professionals, equipment and funds allocated for health promotion and prevention and monitoring of NCDs and Is; • to define the role of the Strategy for the Prevention of NCDs and Is in the implementation of top-priority national health projects.

This document is aimed above all at decisionmakers: members of the RF Government and the government administration, members of the parliament, to the heads and staff members of the Russian Health Ministry and other ministries and agencies, to the heads of federal districts and regions, the heads of the public-health system in the regions, and to all who may participate in developing and implementing programs to prevent NCDs and Is in Russia. This report illustrates the approach of linking cardiovascular diseases, which account for more than 50% of all deaths in the Russian Federation, with other chronic diseases (together, NCDs) and injuries (Is), another major cause of death and disability. Emphasis is placed on implementation of programs that are nationwide, appropriate in content, and of sufficient size, duration, and intensity to be effective. Healthy lifestyles are to be promoted beginning in childhood and extending throughout life, both preserving physical and mental health and providing health care when needed. The strategy also addresses issues of according priority for prevention of these conditions within the national agenda, the need for cooperation across levels of government, and adequacy of infrastructure and resources. Although it focuses on decision makers throughout government, it also recognizes “all of those who may participate” as a potentially broader constituency for preventing NCDs and Is in Russia. Seven action areas are identified: developing policies and funding sources; improving legislative and regulatory frameworks; strengthening the public health system; training of professionals; educating the public; creating a system for monitoring NCDs, Is, and risk factors; and developing international cooperation. For implementation of the Strategy, specific decisions are required of governmental and parliamentary levels and the level of the Russian Health Ministry. Multinational and regional strategies and action plans have been proposed in Europe at least from the mid-1990s. A decade earlier, in 1986, WHO had established the Country-wide Integrated Noncommunicable Diseases Intervention (CINDI) Program as part of the Health for All by the Year 2000 program of the European Region of WHO.15 As a network of 24 countries primarily in Europe, the CINDI Program developed in 1995 a CINDI-EUROHEALTH Action Plan for NCD prevention and control.16 Priorities for action within the CINDI agenda were: policy development; multiple-risk reduction intervention through primary care and community intervention; enhancing prevention in primary care; children, youth, and families; worksites; and training. Experience based on the multinational character of the CINDI network

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led to recognition that intervention of any type at a local level would require adaptation to local infrastructure, priorities, and capacities. Accordingly, an action plan for the region should be considered as a framework within which countries could implement specific relevant activities. The CINDI-EUROHEALTH Action Plan was the forerunner of a document published in 2006, Gaining Health: The European Strategy for the Prevention and Control of Noncommunicable Diseases.17 The document begins by presenting the challenges to health and equity and to societies and health systems resulting from the burden of NCDs across the 52 member states of the European Region—accounting for 77% of DALYs and 86% of all deaths. Discussion follows of potential gains in health through effective strategies of prevention and a statement of vision and principles to guide strategic planning. The vision is that of “A health-promoting Europe free of preventable noncommunicable disease, premature death and avoidable disability”; the two objectives of the strategy are “To take integrated action on risk factors and their underlying determinants across sectors” and “To strengthen health systems for improved prevention and control of NCD.”17, p 17 Several key messages underlie the proposed actions for European states and may be taken to reflect the prevailing view of personal and societal roles in health:17, p 17 1. Prevention throughout life is effective and must be regarded as an investment in health and development. 2. Society should create health-supporting environments, thereby also making healthy choices easier choices. 3. Health and medical services should be fit for purpose, responding to the present disease burden and increasing opportunities for health promotion. 4. People should be empowered to promote their own health, interact effectively with health services and be active partners in managing disease. 5. Universal access to health promotion, disease prevention and health services is central to achieving equity in health. 6. Governments at all levels have the responsibility to build healthy public policies and ensure action across all the sectors concerned. The European Strategy is rooted in a composite framework that joins the Bangkok Charter for Health Promotion in a Globalized World and WHO Health

Systems Framework to inform six action areas: advocacy, knowledge, regulation and financing, capacities, community support, and health service delivery (Figure 22-1). It also recognizes an array of existing WHO strategies and action plans in areas relevant to NCD prevention. Nine such strategies are indicated as contributing to the specifics of the six lines of action, making the NCD strategy both comprehensive and consistent with previously defined, but independent, approaches (Figure 22-2). The Strategy presents altogether some 80 examples of specific actions under the six headings shown in the figures. The actions are “primarily directed at ministries of health and public health policy-makers, although other stakeholders such as nongovernmental organizations, private sector and community groups will recognize examples of relevance for their own work.”17, p 21 The concluding section, addressing the way forward, outlines areas of support to Member States that could be provided by WHO. These areas are, broadly, strengthening international, bilateral, and multilateral cooperation; facilitation of information exchange, technical cooperation, and capacity-building; and research, monitoring, and surveillance. The Strategy was endorsed by the WHO Regional Committee for Europe in September 2006. South Asia Pakistan’s public-private health partnership, Heartfile, took leadership in developing the National Action Plan for Prevention and Control of NonCommunicable Diseases and Health Promotion in Pakistan.18 This very substantial initiative was published in 2004 with joint sponsorship of the Ministry of Health, Government of Pakistan; WHO, Pakistan Office; and Heartfile. Following discussion of underlying concepts and principles, the document comprises several self-contained sections, first addressing action areas common to multiple NCDs, then specifically cardiovascular diseases, diabetes, tobacco use, chronic respiratory diseases, cancer, injuries, and mental illnesses. Each section concludes with its own action agenda, such as that for cardiovascular diseases reproduced here (Table 22-1). This 18-point agenda emphasizes eight priority items that concern surveillance, communications on physical activity and diet, population-level interventions, nutrition policy, environmental requirements for physical activity, religious support for physical activity among women, and health system capacity for CVD prevention and control. Key to the Plan is an “Integrated Framework for Action” that addresses systematically the elements of implementation and evaluation in three areas integrated across all disease outcomes:

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BANGKOK CHARTER FOR HEALTH PROMOTION

HEALTH SYSTEMS FRAMEWORK

Advocate for health based on human rights and solidarity

Stewardship and governance: influencing, formulating and implementing policy

Invest in sustainable policies, actions and infrastructure to address the determinants of health Build capacity for policy development, leadership, health promotion practice, knowledge transfer and research, and health literacy

Health financing: raising revenues, pooling funds and purchasing services

Regulate and legislate to ensure a high level of protection from harm and enable opportunity for health and well-being for all people

Resource generation: creating human resources, infrastructure and consumables

Partner and build alliances with public, private, nongovernmental and international organizations and civil society to create sustainable actions

Service delivery: efficiently producing high quality and accessible personal and non-personal services

ADVOCACY KNOWLEDGE REGULATION AND FINANCING CAPACITIES COMMUNITY SUPPORT HEALTH SERVICE DELIVERY

Figure 22-1 A Composite Framework for Action on NCD. Source: Reprinted with permission from WHO Regional Office for Europe, Gaining Health: The European Strategy for the Prevention and Control of Noncommunicable Diseases, WHO Regional Office for Europe, © World Health Organization 2006, p 18.

surveillance, an integrated behavioral change communication strategy, and an integrated reorientation of health services. The breadth of proposed actions has much in common with guidelines and policies for prevention reviewed in previous chapters, and it reflects a common perspective with advocates for CVD prevention elsewhere. A second initiative in the region was published in 2002 jointly by Heartfile and the South Asian Association for Regional Cooperation (SAARC), which links Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka to address issues of common concern to countries throughout South Asia (www.saarc-sec.org; accessed January 21, 2008).19 Preventing Coronary Heart Disease in South Asia: SAARC Cardiac Society Guidelines and Recommendations is more than a clinical guideline.20 It provides a broad contextual framework for addressing CVD prevention in the region and policy and program recommendations for public health as well as clinical practice. The document addresses the partic-

ular situation of south Asian populations with respect to demographics, economics, healthcare resources, and epidemiologic considerations. Analogous to the European Strategy, this report anticipates action tailored to the circumstances of each member country. Other Regional and Global Initiatives Heart Health Networks The need for action to promote heart health at community and national levels has been expressed continuously in the successive Declarations issued by the International Heart Health Society at its conferences from 1992 through 2004 and summarized in the document International Action on Cardiovascular Diseases: A Platform for Success.21 (Available at www.internationalhearthealth.org.) Action recommendations in this synthesis of previous Declarations were directed to:21, pp 23–24

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GLOBAL STRATEGY FOR PREVENTION AND CONTROL OF NONCOMMUNICABLE DISEASES 2000 HELSINKI DECLARATION & MENTAL HEALTH ACTION PLAN 2005 EUROPEAN STRATEGY FOR TOBACCO CONTROL 2002 EUROPEAN ACTION PLAN FOR FOOD AND NUTRITION POLICY 2000 EUROPEAN STRATEGY FOR CHILD AND ADOLESCENT HEALTH AND DEVELOPMENT 2005 EUROPEAN FRAMEWORK FOR ALCOHOL POLICY 2005 EUROPEAN ALCOHOL ACTION PLAN 2000 – 2005 STOCKHOLM DECLARATION ON YOUNG PEOPLE AND ALCOHOL 2001

ADVOCACY KNOWLEDGE REGULATION AND FINANCING CAPACITIES COMMUNITY SUPPORT HEALTH SERVICE DELIVERY

A C T I O N S

CHILDREN’S ENVIRONMENT AND HEALTH ACTION PLAN FOR EUROPE 2004 GLOBAL STRATEGY ON INFANT AND YOUNG CHILD FEEDING 2002 GLOBAL STRATEGY ON DIET, PHYSICAL ACTIVITY AND HEALTH 2004

Figure 22-2 A Comprehensive Action-Oriented Approach. Source: Reprinted with permission from WHO Regional Office for Europe, Gaining Health: The European Strategy for the Prevention and Control of Noncommunicable Diseases, WHO Regional Office for Europe, © World Health Organization 2006, p 19.

WHO, World Heart Federation and the International Heart Health Society and the US Centers for Disease Control and Prevention: Undertake a leadership role in facilitating international collaboration and communication among all countries and international organizations. International organizations and countries’ internal infrastructures: Adopt and promote of the 5 core values of the European Region of WHO as the foundation of CVD prevention and control programs; implement public policies across ministries to address social and behavioral determinants of CVD; develop strategies with the private sector to take economic and health effects of globalization in to account; recognize and create policy based on economic benefits of primary prevention of CVD; collaborate to address inequities between developed and developing countries, the rich and poor within countries, and genders at all ages.

Countries’ internal infrastructures: Facilitate effective collaboration between government, non-governmental organizations, the private sector, community groups, and partners outside the health sector to assure systematic and strategic planning, development, implementation and evaluation of CVD prevention programs. Governments: Invest in international CVD coalitions; create a balanced, coordinated and comprehensive prevention and treatment health system that is founded on the five health goals of the Declarations; includes CVD in an allNCD program; adds CVD prevention and control elements to existing programs; provides a comprehensive set of strategies including programs and services, public policies, community action, research and surveillance, and training of health service providers and other professionals; disseminates and implements effective prevention strategies; and invests adequate

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Table 22-1

Cardiovascular Diseases—Action Agenda

• Integrate surveillance of cardiovascular risk factors with a population-based NCD surveillance system; develop and validate tools of assessment for the Pakistani population. Integrate public health programme monitoring and evaluation with NCD surveillance.† • Promote physical activity and a healthy diet as a cultural norm as part of the NCD behavioural change communication strategy. Create awareness about the risks of CVD and its mitigates, prevention of RF and RHD and screening approaches.† • Promote strategies for mitigation of cardiovascular risks through population-level approaches.† • Revisit health policy on diet and nutrition to expand its current focus on under-nutrition.† • Develop a nutrition and physical activity policy seeking guidance from the WHO Global Strategy on Diet and Physical Activity.† • Develop policies and strategies to limit the production of, and access to, ghee as a medium for cooking. • Develop agricultural and fiscal policies that increase the demand for, and make healthy food more accessible. • Create an enabling physical and social environment for physical activity.† • Generate support from religious leaders to endorse the need for participation of women in physical activity.† • Enforce effective legislation to stipulate standards for urban planning. • Utilize available open spaces for physical activity where feasible and appropriate. • Integrate concerted primary and secondary prevention programmes into health services as part of a comprehensive and sustainable, scientifically valid, culturally appropriate and resource-sensitive CME programme for all categories of healthcare providers. • Promote screening for raised blood pressure at the population level. Promote high-risk screening for dyslipidaemia and diabetes in high-risk groups only. • Focus attention on improving the quality of prevention programmes within primary and basic health sites. • Ensure availability of aspirin, beta blockers, thiazides, ACE inhibitors, statins and penicillin at all levels of healthcare. • Conduct clinical end-point trials in the native Pakistani setting to define cost-effective therapeutic strategies for primary and secondary prevention of CVDs. • Build capacity of health systems in support of CVD prevention and control.† • Build a coalition or network of organizations at the national, provincial and local levels facilitated by federal and provincial health services to add momentum to CVD prevention and control as part of a comprehensive NCD prevention effort. †

Priority Action Areas. Priorities within other Action Areas will be determined subsequently.

Source: Reprinted with permission from Ministry of Health, Government of Pakistan; the World Health Organization, Pakistan Office; Heartfile, National Action Plan for Prevention and Control of Non-Communicable Diseases and Health Promotion in Pakistan, © Tripartite Collaboration on NCDs in Pakistan 2004, p 42.

resources in public health and primary health care while balancing attention to specialty care. Government and other research bodies: Fund interdisciplinary CVD research with a focus on CVD prevention policies. Here, then, is a consolidated call to action with a charge to international, national, and internal domestic organizations and agencies to undertake the essential tasks of a global movement for CVD prevention. Following the second International Heart Health Conference, in Barcelona in 1995, a supplemental report was published in 1997, Worldwide Efforts to Improve Heart Health.15 This report compiled information regarding a great many local and national programs and included six international heart health networks—in addition to the Canadian Heart Health Initiative and CINDI Program noted previously, these were networks in francophone countries, Chinese language countries and areas, the South Asian Heart Health Network, and the globally constituted

InterHealth organization. This report provides general descriptions of program activities in each instance, but it does not offer details of action plans guiding these efforts. This information may be available through identified contacts for leaders and members of each program. The World Heart Federation has called attention to work of the newly established African Heart Network, founded in 2001, whose members represent Cameroon, Democratic Republic of Congo, Ghana, Ivory Coast, Kenya, Mozambique, Nigeria, Rwanda, South Africa, Sudan, and Tunisia (www.world-heartfederation.org; accessed January 21, 2008).22 Its principal focus is on tobacco control. The World Health Organization (WHO) in 2005 published Cardiovascular Disease Prevention and Control: Translating Evidence into Action.23 This report described activities undertaken in keeping with the global strategy for NCD prevention and control endorsed by the World Health Assembly in 2000. Three areas of emphasis for country-based activities

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were CVD risk reduction and secondary prevention of heart attacks and strokes, as well as secondary prevention of rheumatic heart disease. The report centered on two focal areas: scaling up secondary prevention through implementation of the WHOPREMISE (Prevention of Recurrences of Myocardial Infarction and StrokE) project and the CVD-Risk Management Project, an integrated approach to primary prevention of CVD in high-risk populations. More recently, the World Health Assembly in April 2008 received a report, Prevention and Control of Noncommunicable Diseases: Implementation of the Global Strategy, that presented a draft action plan based on broad input from Member States and other interested parties.24 The purpose of the plan is:24, pp 3–4 • mapping the emerging epidemics of noncommunicable diseases and analysing their social, economic, behavioural and political determinants as the basis for providing guidance on the policy, programmatic, legislative and financial measures that are needed to support and monitor the prevention and control of noncommunicable diseases; • reducing the level of exposure of individuals and populations to the common modifiable risk factors for noncommunicable diseases–– namely, tobacco use, unhealthy diet and physical inactivity, and the harmful use of tobacco––and their determinants, while at the same time strengthening the capacity of individuals and populations to make healthier choices and follow lifestyle patterns that foster good health; and • strengthening health care for people with noncommunicable diseases by developing evidence-based norms, standards and guidelines for cost-effective interventions and by reorienting health systems to respond to the need for effective management of diseases of a chronic nature. Objectives of the plan are to raise priority of NCD prevention and integrate efforts across government departments; strengthen national policies and plans; reduce the risk factors common to multiple chronic diseases; promote research on NCD prevention and control; promote partnerships; and monitor NCDs and their determinants in order to evaluate progress at national, regional, and global levels. Further calls to action on a global scale, with special reference to low- and middle-income countries, are found, for example, in work from the Disease Control Priorities Project (DCP2), such as its

publication Priorities in Health, discussed in previous chapters.25 Here, cost-effectiveness of strategies to address the cluster of CVD, diabetes, high blood pressure, cholesterol, and body weight is addressed under the broad categories of lifestyle and medical interventions. Its “blueprint for action” acknowledges the limited specificity of proposals for action presented on a global level. “Even though the selection and design of interventions is not something that can be characterized in a single universal plan, some common features do emerge from DCP2.”25, p 180 These features, seemingly calling for action at global, regional, and national levels, address delivery and availability for everyone of cost-effective interventions; adequacy of public financing; a higher level of international financial and technical assistance; multisector collaboration; strengthened health systems; and building the knowledge base in basic and applied sciences and management. Similarly aimed at the global level, A Race Against Time concludes by stating that action is needed on a wide range of fronts to combat CVD effectively. These actions include:26, pp 85–87 Putting CVD in the developing world on the international health and development agenda . . . Deeper documentation of the prevalence and costs of CVD . . . Developing partnerships at the macroeconomic level with national governments in key developing countries . . . Train the trainer initiatives in health education . . . Undertaking trial treatment and prevention interventions . . . Longer term research and interventions . . . This agenda is seen as a basis for confidence that CVD control can be advanced in developing countries and as a framework for collaboration around the world.

CASE STUDY: A PUBLIC HEALTH ACTION PLAN TO PREVENT HEART DISEASE AND STROKE The preceding examples attest to the breadth of concern about epidemic CVD at national, regional, and global levels and the growing number of calls for action to intervene. It remains to consider one example more closely with respect to its initiation, implementation, and institutionalization, as it may guide future

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action for CVD prevention at local, state, and national levels in the United States and elsewhere: A Public Health Action Plan to Prevent Heart Disease and Stroke.3 Background The Action Plan was created during 2002 and released by the Secretary of the US Department of Health and Human Services (DHHS) in April 2003. The background of its development was reviewed on the occasion of its first 5-yearly update presented in March 2008.27,28 In 1994, in the absence of federal funding to states in support of CVD prevention, the Centers for Disease Control and Prevention (CDC) and National Heart, Lung and Blood Institute (NHLBI) supported a steering committee to develop a document, Preventing Death and Disability from Cardiovascular Diseases: A State-Based Plan for Action.29 This report called for federal support for much-needed efforts to address the documented CVD burden in the states and presented outlines of a plan that could bring about the needed improvements. Subsequently, in 1998, the US Congress appropriated funds enabling CDC to initiate “a comprehensive cardiovascular program, with particular emphasis on risk factors and the promotion of healthy behaviors.”30 A key further development setting the stage for the Action Plan was release in January 2000 of Healthy People 2010, presenting the nation’s goals for improving health throughout the new decade.31 In view of its responsibility for the just-established state CVD prevention program, CDC was designated with the National Institutes of Health (NIH) as “co-lead agency” within DHHS to work for progress toward achieving the national goal for heart disease and stroke prevention. This new role and accountability, adding to CDC’s vision for future growth of the state program, provided the impetus to develop a longrange strategic plan for public health efforts in this area. Its purpose would be “To chart a course for the Centers for Disease Control and Prevention (CDC) and collaborating public health agencies, with all interested partners and the public at large, to help in promoting achievement of national goals for preventing heart disease and stroke over the next two decades––through 2020 and beyond.”3, p 1 Initiation Preparation for the planning process began in January 2000 and continued to mid-2001. Leadership came from CDC and co-lead partners, the American Heart Association (AHA) and the Association of State and Territorial Health Officials (ASTHO). The conceptual foundation of the Action Plan would be the goal for

heart disease and stroke prevention presented in Healthy People 2010.31 This goal could be considered in four complementary parts: prevention of risk factors, detection and treatment of risk factors, early identification and treatment of heart attacks and strokes, and prevention of recurrent cardiovascular events. A comprehensive public health strategy would be expected to address each of these four goals and the needs and opportunities for effective prevention under each of them. A second underlying element of the plan would be a limited set of focus areas within which recommendations could be developed. A panel of experts, each with some 12–15 members representing major partner organizations, state and local health agencies, and other interested parties, would be appointed for this purpose. Their work would be guided by a working group similarly composed. The five designated panels and the respective topical areas or “essential components” of the plan were described in the Action Plan:3, pp 7–8 Taking action––Translating current knowledge into effective public health action (Expert Panel A). Strengthening capacity––Transforming public health agencies with new competencies and resources and expanding partnerships to mount and sustain such action (Expert Panel B). Evaluating impact––Systematically monitoring and evaluating the health impact of interventions to identify and rapidly disseminate those most effective (Expert Panel C). Advancing policy––Defining the most critical policy issues and pursuing the needed prevention research to resolve them and expedite policy development (Expert Panel D). Engaging in regional and global partnerships––Multiplying resources and capitalizing on shared experience with others throughout the global community who are addressing similar challenges (Expert Panel E). Each group met on two occasions at two-month intervals between January and May 2002 to define their areas more fully and develop recommendations, proposed action steps, and expected outcomes of these activities. These draft recommendations were compiled by the Working Group, which identified two cross-cutting topics, or “fundamental requirements,” to be recognized in addition to the five essential components: effective communication and public health leadership, partnership, and organization. In September 2002, in order to engage a broader constituency in support of the plan, poten-

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tially interested organizations and agencies were invited to participate in a National Forum for Heart Disease and Stroke Prevention. Nearly 70 organizations were represented by 120 attendees, who reviewed the draft recommendations and provided extensive input, leading to completion of the draft report in December 2002. The Action Plan is presented in four sections, following an executive summary: (1) Heart Disease and Stroke Prevention: Time for Action; (2) A Comprehensive Public Health Strategy and the Five Essential Components of the Plan: Platform for Action; (3) Recommendations: A Call to Action; and (4) Implementation: Mobilizing for Action. The conceptual foundation of the plan is represented in a detailed graphic, Strategic Framework for a Comprehensive Public Health Strategy to Prevent Heart Disease and Stroke (see Figure 18-9). The core of the plan is its 22 final recommendations, each with three to four proposed action steps and their expected outcomes. The recommendations can be expressed in summary form under each of the two fundamental requirements and five essential components, as follows:3, pp 8–11 Effective communication: Communicate to the public at large and to policy makers the urgent need and unprecedented opportunity to prevent heart disease and stroke in order to establish widespread awareness and concern about these conditions, as well as confidence in the ability to prevent and control them. Public health leadership, partnership, and organization: Transform the nation’s public health infrastructure to provide leadership and to develop and maintain effective partnerships and collaborations for the action needed. Taking action: Develop policies for preventing heart disease and stroke at national, state, and local levels to assure effective public health action, including new knowledge on the efficacy and safety of therapies to reduce risk factors. Implement intervention programs in a timely manner and on a sufficient scale to permit rigorous evaluation and the rapid replication and dissemination of those most effective. Promote cardiovascular health and prevent heart disease and stroke through interventions in multiple settings, for all ages groups, and for the whole population, especially high-risk groups. Strengthening capacity: Strengthen public health agencies to assure that they develop and maintain sufficient capacities and competencies, including their laboratories. Create opportunities for training, offer model standards for preventing chronic diseases, and

make consultation and technical support continuously available to public health agencies, including their laboratories. Monitoring and evaluation: Define criteria and standards for population-wide health data sources. Expand these sources as needed to assure adequate long-term monitoring of population measures related to heart disease and stroke. Upgrade and expand health data sources to allow systematic monitoring and evaluation of policy and program interventions. Advancing policy: Emphasize the critical roles of atherosclerosis and high blood pressure, which are the dominant conditions underlying heart disease and stroke, within a broad prevention research agenda. Develop innovative ways to monitor and evaluate policies and programs, especially for policy and environmental change and population-wide health promotion. Engaging in regional and global collaboration: Reap the full benefit of shared knowledge and experience from regional and global partners through information exchange in the area of heart disease and stroke prevention. Work with regional and global partners to develop prevention policies, formulate strategies for use of global media for health communications, and assess the impact of globalization on cardiovascular health. The Action Plan as released in April 2003 represented a substantial advance from the statement of goals in Healthy People 2010 by proposing specific recommendations and a wide range of supporting action steps to promote cardiovascular health and prevent heart disease and stroke. Broad participation in the process represented national, state, and local government, national and international organizations, academia, health professional organizations, community interests, and others. Thorough review and approval across the many agencies within DHHS and introductory messages from the Secretary and from directors of CDC and NIH gave high-level authority to the plan. (It should be noted that the Action Plan did not include specific attention to policies to improve healthcare quality, such as pay for performance and health information technology. These and more recent developments require consideration at the interface between public health goals and delivery of clinical services.) To put the plan into action, two major further steps were required: first, to implement the plan and, second, to institutionalize it.

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Implementation A strength of the plan, given the purpose of setting an agenda for two decades or more, is the number and scope of its 22 recommendations and some 70 proposed action steps. It became apparent soon after its release that this strength was also a liability, in that direction and focus were needed to begin implementation. Setting priorities was undertaken with participation from the Working Group and many of the participants in the National Forum meeting of 2002.32 For accomplishing this, a systematic review and prioritization of all proposed action steps was undertaken. In a second meeting of the National Forum, in April 2004, eight “concrete tasks” were adopted, one in each of six of the recommendation areas, and two in the seventh. For each of the priorities, a task group was based on the original Expert Panels

and was charged to complete the planning process and carry out each of the priorities. The product at this stage was a charge to each Task Group presenting the originally proposed action step, specific task, and expected outcome, with the supporting rationale and statement, “What success will look like.” Figure 22-3 represents by example the charge to the Monitoring and Evaluation: Surveillance Task Group. With this charge, related guidance, and some limited staff support, the group undertook the task and published its review and recommendations for strengthening CVD surveillance at national, state, and local levels as an AHA Scientific Statement in January 2007.33 Work is in progress to implement the recommendations, beginning with establishment of a national CVD surveillance unit within the Epidemiology and Surveillance Branch,

Monitoring and Evaluation: Surveillance Task Group Action:

Task:

Outcome:

Bring key partners and stakeholders together to address gaps in heart disease and strokerelated data systems Identify data requirements and gaps and propose remedies to insure optimum data collection, management, and reporting Presentation of proposals for improved heart disease and stroke-related health data systems

Rationale This task is intended to advance implementation of the Action Plan by addressing the need for improved cardiovascular health data systems. Such improvements are needed both to monitor more adequately the burden and disparities attributable to heart disease and stroke in the population as a whole and to create the potential for evaluating the impact of preventive programs and policies at the level of communities or larger units of observation.

What success will look like Proposals for improved data systems will include an inventory of the relevant existing data sources (e.g., those relating to cardiovascular events and conditions, risk factors, behaviors, underlying determinants, and current practices, programs, and policies) and their principal collective strengths and limitations; a listing of the most critical data elements that are lacking (e.g., incidence of heart disease and stroke, incidence of risk factors, estimates based on adequate sample sizes for population subgroups, etc.); and a proposed approach to filling these gaps (e.g., by strengthening existing systems or creating new ones (e.g., building in longitudinal components of NHANES, BRFSS, or YRBS, * increasing sample sizes in existing surveys, or establishing comprehensive surveillance of quality of life, events, risk factors, treatments, and other elements, in multiple sentinel communities). Additional considerations include estimated resource requirements (e.g., budget, personnel, training) for effective implementation and utilization of the enhanced data systems that are proposed. Finally, strategies to achieve implementation of the needed improvements should be addressed.

*NHANES, National Health and Nutrition Examination Survey; BRFSS. Behavioral Risk Factor Surveillance System; YRBS, Youth Risk Behavior Survey

Figure 22-3 Monitoring and Evaluation: Surveillance Task Group.

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Division for Heart Disease and Stroke Prevention, CDC. This illustration demonstrates how implementation can proceed through successive steps from a plan into a completed action. Institutionalization The second step to move the Action Plan forward was to institutionalize a means of long-term implementation. The National Forum appeared to be the most appropriate vehicle, with major support for its operation continuing to be provided by CDC. Rather than formalize its organization a priori, the National Forum evolved as functioning of the task groups developed and elements of a formal structure emerged from that experience. The Forum meets annually near the anniversary date of release of the Action Plan and in 2006 adopted an organizational plan illustrated in Figure 22-4. The foundation of the National Forum rests on the seven Implementation Groups (formerly task groups), with their respective Chairs serving as members of its governing body, the Coordinating Board. Additional members represent lead organizations and others with delegates elected by the full membership. Resource and Membership committees provide supporting functions, and a Leadership Council is planned for appointment in due course. The Action Plan recommendations were reviewed and reaffirmed by the National Forum in 2008, at the 5-year anniversary of their original publication.28

The Forum remains to date a voluntary membership organization operating under agreed principles and by-laws rather than as a legal entity. Its Vision is “Working together for a heart-healthy and stroke-free world”; its Mission is “To provide leadership and encourage collaboration among organizations committed to heart disease and stroke prevention.” A schematic view of the function of the Forum and its seven Implementation Groups in relation to the four goals for heart disease and stroke prevention is presented in Figure 22-5. One can consider, for example, the distinct communication functions and tasks required to serve each of the four goals or, alternatively, how each of the Implementation Groups can serve differently to achieve progress under goal 1 or any of the other three goals. With full future development of its membership, the National Forum for Heart Disease and Stroke Prevention may include the broad array of organizations and agencies whose collective interests align with each of the Implementation Groups and each of the four goals of prevention. By then, the agenda anticipated by the Action Plan will have reached the stage of full implementation.

OBSTACLES TO TAKING ACTION Action plans, policies, guidelines, and recommendations for CVD prevention are being implemented to varying degrees. The major declines in CHD death

National Forum for Heart Disease and Stroke Prevention Leadership Council Resource Committee

Coordinating Board Executive Committee

Membership Committee

Action Priorities Group Monitoring and Evaluation Group

Organizational Capacity Group

Regional and Global Collaboration Group

Communications Group

Policy Research Group Public Health Leadership and Partnership Group

Figure 22-4 National Forum for Heart Disease and Stroke Prevention.

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The Goals of Prevention Prevention of risk factors

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The scope of CVD prevention: 7 action areas ⫻4 goals

Figure 22-5 The Scope of CVD Prevention: 7 Action Areas 4 Goals.

rates in the United States and several other countries have been attributed about equally to populationwide shifts in risk-factor distributions and to application of treatment of persons with CVD. Both of these effects indicate real impacts of prevention. Yet strategies of prevention are underutilized. Prevention lags, from the United States and other industrial nations that are far along in experience of epidemic CVD to the low- and middle-income countries where the epidemic, though long-established, is only recently recognized. What impedes full implementation of existing knowledge about the urgency of the problem, the great potential of prevention, and the cost of inaction? It appears that obstacles remain that must be surmounted if taking action is to become fully effective. The goal of prevention of the atherosclerotic and hypertensive cardiovascular diseases globally is to reduce the morbidity, mortality, disparities, and costs— both social and economic—of these conditions. In the United States, the national goal for heart disease and stroke prevention spans the course of CVD from prevention of risk factors to prevention of recurrent cardiovascular events.31 The central issues in prevention of atherosclerotic and hypertensive diseases concern not the scientific basis for sound recommendations nor the availability of policy statements and guidelines at both community- or population-wide and high-risk levels, but rather the actual implementation of these by the organizations, agencies, or health professionals on whom implementation de-

pends. The apparent obstacles include divergent opinions, competing interests, issues of population diversity and heterogeneity, limitations of the policy framework, and failure to commit needed resources. Population-Wide and Community Intervention Divergent Opinions. Opponents of community- or population-wide intervention strategies can cite conflicts of opinion found in the scientific literature. However, these are perhaps among the least important obstacles to effective prevention. For example, Oliver’s feature article in Circulation in the mid-1980s protested: “Cardiologists and physicians throughout the world are being persuaded by health educationalists, and some epidemiologists who have also assumed this role, that the only really effective way to prevent coronary heart disease (CHD) is to endorse and promulgate changes in lifestyle of the public at large. . . . Much of the faith in the value of changing lifestyles is little more than wishful thinking.”34, p 1 Oliver mischaracterized the epidemiologic or “health educationalist” approach as exclusively populationwide in its strategy and advocated instead a focus on prevention of precipitating conditions immediately preceding acute coronary events, an approach that is of theoretical interest but has limited applicability. He further argued against continued investment in large-scale trials of population-wide interventions, although he identified such trials as the only source of convincing evidence of the effectiveness of preventive measures.

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Rose emphasized the view that only those interventions that tended to restore “biological normality,” such as improved dietary balance, increased physical activity, and cessation of smoking, could be strongly advocated as elements of population-wide interventions in the absence of extensive experimental evidence of safety as well as effectiveness.35 Rose also addressed what he characterized as the “prevention paradox”:35, p 1850 We arrive at what we might call the prevention paradox—“a measure that brings large benefits to the community offers little to each participating individual.” It implies that we should not expect too much from individual health education. People will not be motivated to any great extent to take our advice, because there is little in it for each of them, particularly in the short and medium term. Change in behaviour has to be for some the larger and more immediate reward. From these comments, it seems the “educationalists” and epidemiologists cannot fairly be charged with lack of circumspection about the nature of appropriate population interventions or with altogether unrealistic views of what may be achieved. Waiting to rely on intervention among persons already experiencing acute coronary events or their immediate precipitating conditions ignores both the high proportion of persons dying early in the course of the initial event and the inability to reverse entirely the high risk of recurrence and death among those who survive. For these reasons and because of the increasing evidence of the effectiveness of population interventions, these strategies remain widely advocated despite the opinions illustrated here. Competing Interests. In some areas central to policy development and implementation, competing interests exert strong influence. For example, James and Ralph noted in discussion of strategies for dietary change at the national level, with particular reference to the United Kingdom, “We are now in a position where the public health priorities are clear, but where the food policies of the government and of the farming and food industries are geared to completely different goals.”36, pp 524–528 The theme of the review was that “informed choice” as the sole determinant of individual action concerning diet is illusory in view of the many pressures on consumers that result in “the consumer’s dilemma”—the inability to make an informed “free” choice. The authors rejected as inappropriate the argument that governmental nutrition policy concerning health should be limited to a role of providing infor-

mation. Governmental policy development is needed that includes food protection, agricultural strategies, nutrition education, and food labeling, among other components. According to James and Ralph, “Analyses of different policies suggest that health issues are readily squeezed out of discussion by economic and vested interests unless able promoters of the health issues are involved in the discussions.”36, p 537 A specific example is the conflict between salt manufacturers and governmental policies in the United Kingdom, illustrated in Chapter 8 by reference to a revealing set of papers and commentaries that appeared in the British Medical Journal in May 1996.37 Population Diversity and Heterogeneity. Populations are diverse in many respects that may be potentially relevant to population-wide intervention. However, the nature and extent of such diversity and the need to tailor prevention policies for different groups are less clear. In the United States, development of culturally sensitive intervention programs has long been advocated. The Stanford Five City Project provided information on responsiveness to community-wide intervention, as measured by change in a composite, multivariate risk score for all-cause mortality among several subgroups of the population.38 The authors concluded that specific interventions should be developed for different age, socioeconomic, and cultural subgroups. On the international level, Janus and colleagues addressed the impact of modernization in Asia and its implications for the occurrence of CHD in that region.39 Population diversity with respect to coronary heart disease and its risk factors was illustrated by examples from Taiwan, the Philippines, Malaysia, Indonesia, and India. The premise of the review was that thorough knowledge of a region is required for development of acceptable and effective prevention programs, and the conclusion was that “a single prevention strategy for all of Asia may be inappropriate.”39, p 2671 In particular, it was suggested that recommendations developed in Europe, North America, or Australia might require substantial modification for different Asian countries. Importantly, however, “broader statements on exercise, obesity, smoking, and diet and on the prevention and control of diabetes and hypertension might be appropriate.”39, p 2673 Findings of the INTERHEART Study offer increased confidence that the causal factors are much the same across a very wide range of populations and support this latter view.40 Moreover, it would be contrary to principles of public health and public policy to focus on differences among specific groups or individuals to the neglect of common characteristics that call for and justify broad and inclusive intervention strategies. Within any population, how-

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ever, the details of intervention must nevertheless take local contextual factors into account. An extreme proposition is that lipid-lowering therapy should be individualized on the basis of genetic heterogeneity. A requirement that treatment be based on individual pretreatment genetic typing could undermine public health recommendations altogether.41 If individual-level genetic assessment were needed to evaluate potential risks and benefits of interventions, little might remain of population-wide recommendations. The effect would be a conceptual atomization of populations as mere aggregates of individuals for whom no common action could be proposed. Some vigilance may be required to protect the public’s health and public health policy from this reductionist view. Limited Scope of the Policy Framework for Intervention. Prevention policy for the atherosclerotic and hypertensive diseases is well established on the basis of scientific knowledge that was available 40 years ago and that has been greatly strengthened since then. At the broadest levels, however, as suggested by James’s observations concerning food and nutrition policy, the framework is incomplete because many large societal questions have not yet been resolved. Therefore consistency of policies across the spectrum from land use and food production to recommended dietary behaviors of individuals has not yet been attained. The unusual case of Poland’s removal of tax subsidies for animal products in the national food supply and ensuing sharp decline in CHD mortality was noted in Chapter 21. Similarly, Roemer’s review of tobacco legislation in developing countries suggests important gaps and implies that these will remain in any particular country until national data are available to provide the needed justification.42 Thus despite much support for existing policies, further policy development is needed to enhance the implementation of currently proposed interventions. Failure to Commit Needed Resources. Resource limitations are another obstacle to effective action. It might be assumed that this would be a less serious factor in the United States than elsewhere. But in 1997 the National Center for Chronic Disease Prevention and Health Promotion, CDC, reported the following:43, p 12 [T]he nation’s public health system framework is severely underdeveloped to address the tremendous burden of chronic disease. . . . Coordinated and comprehensive national chronic disease prevention efforts have not been nearly adequately or systematically applied.

Seven years ago, in 1989, only $245 million— less than 3%—of the $9.5 billion spent by state health agencies was directed toward the prevention and control of chronic disease. Of the 48,000 full-time employees in state health agencies that year, only 2% were employed in chronic disease programs. In 1996, the very small percentage of resources reflected in these numbers remains essentially unchanged. Without strong, well-coordinated state-based programs aimed at chronic disease and supported by essential national elements, state and local health departments, and indeed, this nation, cannot hope to address the current burden of chronic disease, and efforts will increasingly fall short as the population ages. To the extent that investment in cardiovascular disease prevention elsewhere is proportionately less than that in the United States, significant challenges remain to approach the minimum resource requirements for effective public health action. Adding to the discussion of resources is the matter of costs of intervention. Two contributions illustrate current views on this issue. As reviewed in Chapter 21 cost-effectiveness analysis identifies two populationwide interventions (increasing taxes on tobacco products and reducing sodium content of manufactured foods) and one high-risk level intervention (combination low-dose medication to reduce risk factors in high-risk individuals) as practical for implementation in low- and middle-income countries.44 Trust for America’s Health, a nongovernmental organization supporting disease prevention policies, estimates that (available at www.healthyamericans .org; accessed September 1, 2008):9, p 3 an investment of $10 per person per year in proven community-based disease prevention programs could yield net savings of more than $2.8 billion annually in health care costs in one to 2 years, more than $16 billion annually within 5 years, and nearly $18 billion annually in 10 to 20 years (in 2004 dollars). With this level of investment, the country could recoup nearly $1 over and above the cost of the program for every $1 invested in the first one to 2 years of these programs, a return on investment (ROI) of 0.96. Within 5 years, the ROI could rise to 5.6 for every $1 invested and rise to 6.2 within 10 to 20 years. This return on investment represents medical cost savings only and does not include the significant gains that could be achieved in worker productivity, re-

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duced absenteeism at work and school, and enhanced quality of life. Individual and High-Risk Intervention Many obstacles operate at the individual or high-risk level, as at the population level, to impede implementation of prevention policy. They have much in common with those discussed previously. Divergent Opinions. The idea that health promotion in clinical practice is unethical was advanced in The Lancet by McCormick in the mid-1990s. His commentary was in opposition to an announced policy for general practice in the United Kingdom that proposed attention to blood pressure, smoking, body mass index, alcohol consumption, family history, diet, and physical activity.45 His premise was that this activity constituted unsolicited intrusion into the lives of patients and lacked necessary support of “conclusive evidence that screening can alter the natural history of disease in a significant proportion of those screened,”45, p 390 a criterion attributed to Cochrane and Holland. He concluded, “Health promotion as encouraged by [the recommendations being addressed] falls far short of meeting the ethical imperatives for screening procedures, and moreover diminishes health and wastes recourse [sic]. General practitioners would do better to encourage people to live lives of modified hedonism, so that they may enjoy, to the full, the only life that they are likely to have.”45, p 391 This laissez-faire recommendation, of course, also lacks conclusive evidence. Limited Influence of Guidelines. The concern that published guidelines for preventive services often have less than intended impact was a special focus of the 1995 Bethesda Conference report and has been addressed extensively elsewhere.46,47 Four types of barriers were identified in that report, related to the patient, the physician, healthcare settings, and the community or society at large. These included, among others, lack of knowledge and motivation, lack of access to care, cultural and social factors, lack of policies and standards, and lack of reimbursement. Questions of Cost. Increasingly, in the present US healthcare situation and elsewhere, evaluation of procedures in terms of cost has intensified. The example of cholesterol lowering has been addressed in numerous reports, one of which illustrates the point:48, pp 329–330 Although preventive care is intuitively appealing and is often advocated as a means to reduce health care costs, formal economic analyses demonstrate that, similar to most preventive

care, cholesterol lowering for primary coronary prevention does not “pay for itself.” Nonetheless, most analyses suggest that drug treatment for young and middle-aged men with moderate-to-severe elevations of serum cholesterol ( 240 mg/dl) and multiple other risk factors for CHD has a cost-effectiveness ratio below $40,000 per year of life saved—similar to federally funded programs such as outpatient hemodialysis and many other widely practiced medical interventions. . . . The appropriateness of cholesterol reduction for other populations, including young men with isolated mild hypercholesterolemia, women, and the elderly is less certain, however. A more recent analysis of clinical interventions came to a similar conclusion:49, p 576 Aggressive application of nationally recommended prevention activities could prevent a high proportion of the CAD [coronary artery disease] events and strokes that are otherwise expected to occur in adults in the United States today. However, as they are currently delivered, most of the prevention activities will substantially increase costs. If preventive strategies are to achieve their full potential, ways must be found to reduce the costs and deliver preventive activities more efficiently. The dependence of these estimates on the costs of lipid-lowering agents has been emphasized.50 The tendency to identify intervention to lower cholesterol with use of drugs often clouds the question of whether intervention is justified in terms of cost or potential risks of side effects. Until more extensive experience is accumulated to indicate that substantial reductions in cholesterol concentration can be achieved even in high-risk persons by nonpharmacologic means, this issue will probably remain an obstacle to policies for intervention in high-risk persons except, perhaps, those with already-manifest coronary heart disease.

CURRENT ISSUES Economics, health systems, and policy priorities are central issues in determining what action will be taken to prevent CVD and other chronic diseases. Current discussions about global health commonly focus on one or more of these issues. Similarly, they were recognized in the Action Plan in 2003 as three “strategic imperatives,” to be addressed in order for the plan to be fully implemented:3

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1. strike a new balance in our investment in health, by putting prevention first; 2. transform our public health agencies into effective instruments for policy and environmental change, supporting the entire range of public health approaches for heart disease and stroke prevention; and 3. prevent the causes of heart disease and stroke––no longer waiting to treat the causes or their consequences, while their prevention was possible. More recent reflection on these issues suggests some refinements in thinking about the strategic imperatives. Both Healthy People 2010 and the Action Plan point to four levels of prevention. They reach from the “upstream” prevention of risk factors to detection and treatment of risk factors, early identifica-

tion and treatment of heart attacks and strokes, and the furthest “downstream” prevention of recurrent CVD events among those who have survived a first one. They represent a “continuum of care” that extends from populations to patients, from the broadest population-wide prevention-oriented policies and programs to the most individualized practices and rescue victims of CVD. This view of a continuum is intended to demonstrate the nexus linking public policy, public health, and community interventions on the one hand with health care, management guidelines, and clinical practice on the other. Figure 22-6 completes the representation of the “action framework” by incorporating this fundamental aspect. From this perspective the issues of economics, health systems, and policy priorities can be revisited. “Putting prevention first” in the context of investment in health is a strategy for sharpening the fo-

Action Framework for a Comprehensive Public Health Strategy To Prevent Heart Disease and Stroke A Vision of the Future Social and Environmental Conditions Favorable to Health

Behavioral Patterns Promote Health

Policy and Environmental Change

Behavior Change

‘upstream’

Few Events/ Only Rare Deaths

Low Population Risk

Continuum of care Risk Factor Detection and Control

Emergency Care/Acute Case Management

Intervention Approaches Unfavorable Social and Environmental Conditions

Adverse Behavioral Patterns

The Present Reality First Event/ Major Risk Sudden Factors Death

Full Functional Capacity/ Low Risk of Recurrence

Good Quality of Life Until Death

‘downstream’ Rehabilitation/ Long-term Case Management

End-ofLife Care

Fatal CVD Complications/Decompensation

Disability/ Risk of Recurrence

The Healthy People 2010 Goals Increase Quality and Years of Healthy Life Eliminate Disparities Goal 1

Prevention of risk factors

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Early identification and treatment of heart attacks and strokes

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Prevention of recurrent cardiovascular events

Figure 22-6 Action Framework for a Strategy to Prevent Heart Disease and Stroke. Source: Adapted from US Department of Health and Human Services. A Public Health Action Plan to Prevent Heart Disease and Stroke. p 6. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003.

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cus on prevention at all levels, but especially on prevention of the acute and irreversible coronary and cerebrovascular events with their toll of death, disability, disparities, and cost. Both detection and treatment of risk factors and prevention of risk factors have this potential, although having established risk factors and their accompanying pre- or subclinical consequences already entail disability, disparities, and cost. Prevention of risk factors in the first place is necessary to arrest the progression from optimum cardiovascular health into the state of increased risk and especially to protect future generations from following the course of past and present ones. This is the area where our under-investment in health is most critical. “Supporting the entire range of public health approaches for heart disease and stroke prevention” depends importantly on transforming our public health agencies. New capacities are needed for policy development and implementation and for effective leadership in creating and sustaining broad-based, multisector partnerships and collaborations for prevention of CVD and other chronic diseases. But pressures are intensifying, especially in the United States, for healthcare transformation in order to resolve problems of cost, insurance coverage, access, quality, and equity in the healthcare arena. From the perspective of the continuum of care, a focus on health care to the neglect of public health would be seriously incomplete. “Health system transformation” is therefore advocated by many as the needed focus. Progress would, in this view, extend beyond payment mechanisms that support the existing healthcare apparatus (not in the usual sense a “system” at present). Rather, it would incorporate the broader issues of prevention that put upstream strategies up front. Public health agencies and related organizations must engage effectively for health system transformation at this level to succeed. “No longer waiting to treat the causes or their consequences, while their prevention was possible” calls again for attention to prevention of the risk factors in the first place. A high priority is to preserve optimum cardiovascular health through effective upstream approaches—policy and environmental change and population-wide behavior change that promote health and protect from adverse influences. Prevention of risk factors must begin in childhood and adolescence (or even in utero) and continue throughout life to have fullest effect. An integrated strategy of investing in prevention, establishing a coherent health system, and focusing on promoting health as a first priority offers the best prospect for achieving the goals of preventing CVD and other chronic diseases.

A final consideration concerns monitoring and evaluation of cardiovascular health, at the population level, in order to know the extent to which the challenge of CVD prevention is being met: Is the plan being fully realized, with the expected impact on the health of the population? REFERENCES 1. Eyre H, Kahn R, Robertson RM, and the ACS/ ADA/AHA Collaborative Writing Committee. Preventing cancer, cardiovascular disease, and diabetes. A common agenda for the American Cancer Society, the American Diabetes Association, and the American Heart Association. Circulation. 2004;109:3244–3255. 2. Ebrahim S. Chronic diseases and calls to action. Int J Epid. 2008;37:225–230. 3. US Department of Health and Human Services. A Public Health Action Plan to Prevent Heart Disease and Stroke. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. 4. American Heart Association. American Heart Association strategic goals. Available at www.americanheart.org/presenter.jhtml? identifier=4429. Accessed February 11, 2008. 5. Pearson TA, Bazzarre TL, Daniels SR, et al. American Heart Association guide for improving cardiovascular health at the community level: a statement for public health practitioners, healthcare providers, and health policy makers from the American Heart Association Expert Panel on Population and Prevention Science. Circulation. 2003;107:645–651. 6. Veazie MA, Galloway JM, Matson-Koffman D, et al. Taking the initiative. Implementing the American Heart Association guide for improving cardiovascular health at the community level. Circulation. 205;112:2538–2554. 7. Partnership to Fight Chronic Disease. About the PFCD. Available at www.fightchronic disease.org/about/index.cfm. Accessed September 21, 2008. 8. Partnership for Prevention. Partnership news and updates. Available at www.prevent.org. Accessed September 21, 2008.

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9. Trust for America’s Health. Prevention for a Healthier America: Investments in Disease Prevention Yield Significant Savings, Stronger Communities. July 2008. Available at www.healthyamericans.org. Accessed September 21, 2008.

16. World Health Organization. Bridging the Health Gap in Europe. A Focus on Noncommunicable Disease Prevention and Control. The CINDI-EUROHEALTH Action Plan. Copenhagen (Denmark): WHO Regional Office for Europe; 1995.

10. Robinson K, Farmer T, Elliott SJ, Eyles J. From heart health promotion to chronic disease prevention: contributions of the Canadian Heart Health Initiative. Prev Chron Dis. 2007;4: A29. Available at www.cdc.gov/pcd/issues/ 2007/apr/06_0076.htm. Accessed September 21, 2008.

17. World Health Organization. Gaining Health: The European Strategy for the Prevention and Control of Noncommunicable Diseases. Copenhagen (Denmark): WHO Regional Office for Europe; 2006.

11. Blair L, MacLean D, National Evaluation Steering Group and Writing Group. Canadian Heart Health Initiative: Process Evaluation of the Demonstration Phase. Conference of Principal Investigators of Heart Health. Available at www.med.ca/chhdbc/. Accessed September 21, 2008. 12. Canadian Heart Health Strategy and Action Plan. About the CHS-AP. Available at www .chhs-scsc.ca/web/?page_id=16. Accessed September 21, 2008. 13. Ministers of Health of the Americas. Health Agenda for the Americas 2008–2017. Presented by the Ministers of Health of the Americas in Panama City, June 2007. Available at www.paho.org. Accessed September 1, 2008. 14. Ministry of Health and Social Development of the Russian Federation and State Research Center for Preventive Medicine. Strategy for the Prevention and Control of Noncommunicable Diseases and Injuries in the Russian Federation. Moscow, Russian Federation: Ministry of Health and Social Development of the Russian Federation and State Research Center for Preventive Medicine; 2008. 15. Grabowsky TA, Farquhar JW, Sunnarborg KR, Bales VS. Worldwide Efforts to Improve Heart Health: A Follow-up to the Catalonia Declaration––Selected Program Descriptions. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 1997.

18. National Action Plan for Prevention and Control of Non-Communicable Diseases and Health Promotion in Pakistan. Islamabad, Pakistan: tripartite collaboration of the Ministry of Health, Government of Pakistan; WHO, Pakistan office; and Heartfile; 2004. 19. South Asian Association for Regional Cooperation. A brief on SAARC. Available at www.saarc-sec.org/main.php?id=76. Accessed January 21, 2008. 20. Nishtar S. Preventing Coronary Heart Disease in South Asia. SAARC Cardiac Society Guidelines and Recommendations. Islamabad, Pakistan: SAARC Cardiac Society and Heartfile, 2002. 21. International Heart Health Society. International Action on Cardiovascular Disease: A Platform for Success. Vancouver: International Heart Health Society; 2005. 22. World Heart Federation. African Heart Network gathers and grows. Heart Beat; June 2007. Available at www.world-heartfederation.org/publications/heart-beate-newsletter. Accessed January 21, 2008. 23. World Health Organization. Cardiovascular Disease Prevention and Control. Translating Evidence into Action. Geneva: World Health Organization; 2005. 24. World Health Organization. Prevention and Control of Noncommunicable Diseases: Implementation of the Global Strategy. Report by the Secretariat. A61/8. Geneva: World Health Organization; 2008.

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25. Jamison DT, Breman JG, Measham AR, et al., eds. Priorities in Health. Washington DC: The World Bank; 2006. 26. Leeder S, Raymond S, Greenberg H. A Race Against Time: The Challenge of Cardiovascular Disease in Developing Countries. New York: The Trustees of Columbia University in the City of New York; 2004. 27. Labarthe DR. Heart-healthy and stroke-free, 2008. Prev Chron Dis. 2008;5(2). Available at: www.cdc.gov/pcd/issues/2008/apr/07_0259 .htm. Accessed May 1, 2008. 28. US Department of Health and Human Services. Update to a Public Health Action Plan to Prevent Heart Disease and Stroke. Atlanta, GA: Centers for Disease Control and Prevention; 2008. 29. CVD Plan Steering Committee. Preventing Death and Disability From Cardiovascular Diseases: A State-Based Plan for Action. Washington, DC: Association of State and Territorial Health Officials; 1994. 30. US House Committee on Appropriations. Conference report to accompany H.R. 2264. Making appropriations for the Departments of Labor, Health and Human Services, and Education, and related agencies for the fiscal year ending September 30, 1998, and for other purposes. (H. Rpt. 105-390.) Washington, DC: Government Printing Office; 1997. 31. US Department of Health and Human Services. Healthy People 2010. 2nd ed. With Understanding and Improving Health and Objectives for Improving Health. 2 vols. Washington, DC: US Government Printing Office; 2000. 32. Labarthe DR, Biggers A, Goff Jr DC, Houston M. Translating a plan into action. A Public Health Action Plan to Prevent Heart Disease and Stroke. Am J Prev Med. 2005;29(5S1): 146–151. 33. Goff Jr DC, Brass L, Braun LT, et al. Essential features of a surveillance system to support the prevention and management of heart disease and stroke. A Scientific Statement from the American Heart Association Councils on Epidemiology and Prevention, Stroke, and

Cardiovascular Nursing and the Interdisciplinary Working Groups on Quality of Care and Outcomes Research and Atherosclerotic Peripheral Vascular Disease. Circulation. 2007;115:127–155. 34. Oliver MF. Prevention of coronary heart disease—propaganda, promises, problems, and prospects. Circulation. 1986;73:1–8. 35. Rose G. Strategy of prevention: lessons from cardiovascular disease. BMJ. 1981;282: 1847–1851. 36. James WPT, Ralph A. National strategies for dietary change. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology: From Aetiology to Public Health. Oxford (England): Oxford Medical Publications; 1992:525–540. 37. Godlee F. The food industry fights for salt. BMJ. 1996;312:1239–1240. 38. Winkleby MA, Flora JA, Kraemer HC. A community-based heart disease intervention: predictors of change. Am J Public Health. 1994;84:767–772. 39. Janus ED, Postiglione A, Singh RB, Lewis B, Council on Arteriosclerosis of the International Society and Federation of Cardiology. The modernization of Asia: implications for coronary heart disease. Circulation. 1996;94: 2671–2673. 40. Yusuf S, Hawken S, Ôunpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364;937–952. 41. Omenn GS. Comment: genetics and public health. Am J Public Health. 1996;86: 1701–1704. 42. Roemer R. Legislative Action to Combat the World Smoking Epidemic. Geneva, Switzerland: World Health Organization; 1982. 43. Report of the National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention. Unrealized Prevention Opportunities: Reducing the Health and Economic Burden of

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Chronic Disease. Bethesda, MD: Public Health Service, US Department of Health and Human Services; 1997. 44. Gaziano TA, Galea G, Reddy KS. Chronic diseases 2. Scaling up interventions for chronic disease prevention: the evidence. Lancet. 2007;370:1939–1945. 45. McCormick J. Health promotion: the ethical dimension. Lancet. 1994;344:390–391. 46. Pearson TA, Fuster V. Executive summary. J Am Coll Cardiol. 1996;27:957–1047. 47. Pearson TA, McBride PE, Miller NH, Smith SC Jr. Task Force 8: organization of preventive cardiology service. J Am Coll Cardiol. 1996; 27:1039–1047.

48. Cohen DJ, Goldman L, Weinstein MC. The cost-effectiveness of programs to lower serum cholesterol. In: Rifkind BM, ed. Lowering Cholesterol in High Risk Individuals and Populations. New York: Marcel Dekker, Inc.; 1995:311–336. 49. Kahn R, Robertson RM, Smith R, Eddy D. The impact of prevention on reducing the burden of cardiovascular disease. Circulation. 2008;118: 576–585. 50. Lloyd-Jones DM. Is an ounce of prevention worth a pound of cure? Or does it take 16 ounces of prevention (or more)? AHA Communities Learning Library, July 7, 2008. Available at http://pt.wkhealth.com/pt/re/aha/ addcontent. Accessed July 10, 2008.

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C H A P T E R

23 Epidemiology and a CVD Prevention Research Agenda dependent on collaboration with other disciplines today than previously. How should epidemiology be understood today in view of its expanding horizon, growing complexity, and potential for greater impact on population health? It has been suggested that “black box” epidemiology (focusing on specific risk factors in isolation) has given way to “Chinese box” epidemiology (putting specific observations into their hierarchical social context). But further reflection suggests still another developmental stage. First, from a global perspective on CVD and other chronic disease prevention, the classic epidemiologic dimensions of person, place, and time require consideration on a much larger than usual scale. An example of this view is the theory of epidemiologic transition, with its global reach over decades. Second, the recognized value of collaboration across scientific disciplines, communication between science and other societal interests, and partnerships extending beyond health to reach all sectors, call for consideration of “connectivity.” Effective connections of these kinds may require a new outlook and unfamiliar skills on the part of epidemiologists but can greatly enhance the relevance and impact of our work. The goals of epidemiologic research can be summarized as understanding causes, identifying means of prevention, and monitoring populations to assess the burden of disease and impact of interventions. Strategies of epidemiologic investigation afford a range of approaches, among them cross-sectional population surveys, retrospective and prospective analytic studies, and intervention trials. Other relevant strategies include surveillance, program evaluation, policy analysis, modeling, and economic analysis. Newer areas of

SUMMARY The scope and complexity of CVD epidemiology are increasing, for several reasons. First, although the population is its ultimate concern, its interests extend across the full spectrum of biomedical and community health research. Epidemiology necessarily connects with laboratory and clinical research disciplines in its wide-ranging pursuits, as evidenced in Part III on determinants of atherosclerotic and hypertensive diseases. Second, social determinants of health are receiving new emphasis as being fundamental to causation and prevention of adverse health conditions, especially as they afflict disadvantaged groups within society. This emphasis calls for epidemiologic research extending further into social and behavioral sciences, economics, public policy, and other related fields. Third, epidemiologic research, with surveillance and program evaluation, are required to fulfill the three core functions of public health: to assess the health status of communities and populations, develop policies that will foster conditions in which people can be healthy, and assure that these policies are being implemented with the intended benefits. These roles require collaboration between epidemiology and other disciplines concerned with population health and public health practice. Fourth, in parallel with public health action for CVD prevention at local, national, regional, and global levels, epidemiologic research and evaluation of programs and policies are needed at every level, from community health to global health. For these reasons, research in epidemiology and prevention of cardiovascular diseases—including surveillance and evaluation—is relevant on a wider scale and still more

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CHAPTER 23 EPIDEMIOLOGY AND A CVD PREVENTION RESEARCH AGENDA

implementation science and public health services and systems research are also applicable. Proposals for an epidemiologic research agenda in CVD prevention come from multiple sources, including the National Institutes of Health, the World Health Organization, the International Heart Health Society, and others. A Public Health Action Plan to Prevent Heart Disease and Stroke emphasizes the importance of research that provides evidence for policy and other public health decision making. Capacity to implement the research agenda and sustain the proposed research depends on sponsorship and funding, training, and institutionalization. These key elements of infrastructure depend, in turn, on effective efforts by those who recognize and value the potential contributions of cardiovascular epidemiology. In view of the large gap between the current level of research and the need, it has been suggested that a social movement is required to develop sufficient support for research to meet the global challenge of CVD and other chronic disease prevention. Epidemiology is an essential component of a larger scientific enterprise. Recognition of this could provide a frame of reference for epidemiology regarding its place among related disciplines. It might also help to shape the research agenda through which epidemiology can make its best contributions to advancing population health. In the present period, described elsewhere as “the -omics era,” this wider enterprise might be designated “populomics”—a term to represent what may be thought of as “integrative human ecology,” with population health as its focus and epidemiology as its core scientific discipline.

INTRODUCTION A challenge was posed to the field of epidemiology by Remington, in a symposium honoring the late Geoffrey Rose on his retirement in 1991:1, p 517 [A]s epidemiology passes from aetiological investigations through longitudinal studies to community intervention programmes and evaluative trials of CHD control programmes, it recapitulates the several stages en-compassed in this publication. The concern of this chapter is with the far end of that transition—the role of organized public health in applying the fruits of epidemiological investigation to cardiovascular disease prevention in the community. This transition from research to policy formation to application has received too little attention

among epidemiologists and, for that matter, among professional public health workers. Yet the transition itself has much to do with the uses of epidemiology in improving community health. Put another way, in the language of the Institute of Medicine report, the substance of public health is considered to be “organized community efforts aimed at the prevention of disease and promotion of health. (Public health) links many disciplines and rests upon the scientific core of epidemiology.” Practical application is the principal focus here. Substantial accountability rests with epidemiology to apply what decades of research have previously established, that the major cardiovascular diseases are largely preventable. As Remington emphasizes, the transition from research through policy formation to application has largely been neglected by epidemiologists. Within contemporary epidemiology as a whole, the scope of research interest has been considered previously as very broad, reaching from molecules to societies (see Figure 17-4). Much of current epidemiologic research concerns mechanisms of disease at the molecular level, and such research seems likely to continue. Remington’s observation implies different questions: What could epidemiologic research contribute to policy development? Is this occurring? What impact is policy development having on population health? These practical questions should be strongly influential in shaping a research agenda for CVD prevention. Such questions were anticipated when recommendations for research priorities were developed in the Public Health Action Plan to Prevent Heart Disease and Stroke.2 The charge to the Expert Panel on Advancing Policy was to consider issues in policy development, adoption, or implementation where epidemiologic research could potentially make a decisive contribution. The underlying premise was that in certain areas of CVD prevention progress might be impeded either by lack of a sufficient science base or by inadequate synthesis and communication of existing evidence. In the latter case, a renewed evaluation of pertinent evidence might suffice. But in the former case, one or more “critical investigations” should be devised with the intent to resolve the policy issue and promote action in accordance with the research findings. For example, such a critical investigation could address the lack of widespread adoption of communitywide interventions to prevent atherosclerotic and hypertensive diseases beginning in childhood, as called for in several published recommendations and guide-

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lines. The research approach would be to assess current policy statements and their scientific foundation; consider what impediments to action could be resolved with new research; plan and conduct the research; and communicate the findings to those positioned to mobilize the indicated action. The generic questions posed in the preceding extend beyond a narrow understanding of epidemiologic research to include both surveillance and program evaluation as well as other approaches. These latter activities are sometimes distinguished from research. A commonly cited definition of public health surveillance is “the ongoing systematic collection, analysis, and interpretation of outcome-specific data for use in the planning, implementation, and evaluation of public health practice.”3, p 1 Public health practitioners generally are said not to consider surveillance as research, on grounds that its purpose is to support taking public health actions rather than to acquire generalizable knowledge. This distinction exempts surveillance activities of official public health agencies from encumbering regulations that apply to research, such as informed consent of participants and institutional review board approval, so long as individually identifiable information is not collected.4 (see also 5) Program evaluation has been described as “a systematic way to improve and account for public health actions by involving procedures that are useful, feasible, ethical, and accurate” and as “an essential organizational practice in public health.”6, p 1 Further, “Evaluation is the only way to separate programs that promote health and prevent injury, disease, or disability from those that do not; it is a driving force for planning effective public health strategies, improving existing programs, and demonstrating the results of resource investments. Evaluation also focuses attention on the common purpose of public health programs and asks whether the magnitude of investment matches the tasks to be accomplished.”6, p 34 “Program” in this context refers to “any organized public health action.”6, p 3 Evaluation is sometimes distinguished from research by its purposes of assessing programs and supporting decision making rather than testing prior hypotheses. While recognizing these distinctions in the present discussion, epidemiologic research, surveillance, and program evaluation are considered together within a larger set of approaches to research in CVD prevention. All of these contribute to a potential research agenda with its principal purpose of providing evidence for policy development, while supporting the two other core public health functions, assessment and assurance.7

CONCEPTS OF EPIDEMIOLOGY The Array of Biomedical and Community Health Sciences A scientific discipline is characterized by the array of phenomena with which it is concerned. In his 1980 essay, “To Advance Epidemiology,” Stallones depicted the biomedical sciences as arrayed across a scale of biological organization, ranging from the phenomena of “submolecular particles” to those of whole societies and from the discipline of molecular biology to epidemiology (see Figure 17-4).8 While noting discontinuities along this spectrum due to specialization in science, Stallones observed that the true underlying continuity “should be an integrating force, not a divisive one, and ultimately the knowledge accrued by different subspecialties must all fit together without internal contradictions.”8, p 70 The sphere of interest of epidemiology was shown in his depiction to reach across four levels of organization, from individuals to families, communities, and societies. The individual, at the midpoint of the spectrum from particles to societies, was seen as the focal point for integration of all of the biomedical sciences, “and the totality of biomedical research should be coherent, with different disciplines sustaining and supporting each other.”7, p 70 Developments to the mid-1990s suggested some revisions to this scheme. For example, Rose argued persuasively for much greater prominence, indeed primacy, of the population level in thinking about the impact of preventive measures.9 Determinants of differences in rates of disease between populations are, under his argument, the foremost concern of public health. This is because the impact of interventions at the population level can be far broader than that of individual-level, patient-oriented interventions. Epidemiology that is limited to the individual level may be irrelevant to the larger forces of disease causation at the population level and therefore incapable of contributing to achievement of public health goals. It is true that population-wide and high-risk intervention strategies have been widely acknowledged as complementary. However, from the public health perspective, the population as a whole is the primary point of reference and the principal orientation of its core functions of assessment, policy development, and assurance. Consequently, adequacy of the term “biomedical” to represent the full array of health research has been questioned. The concern is that the essential contributions of research at the societal or community level may be undervalued in an era of exuberant expectations of laboratory research, for

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example, in genetics and molecular biology. Thus, in the report of the first 10 years’ experience in CDC’s Prevention Research Centers Program, the expression “biomedical and community health research” was proposed to connote the full research spectrum.10 From “Black Box” to “Chinese Boxes” A further development of the 1980s and 1990s was growing recognition of fragmentation among the health sciences, especially epidemiology. This development was cited by Susser and Susser in a two-part essay on the future of epidemiology.11,12 They argued that: (1) Epidemiology in previous eras was rooted in public health; (2) the latter half of the 20th century focused chiefly on individual risks, out of context of the population as a whole; and, therefore, (3) epidemiology had evolved to be out of touch with public health. They proposed a “different paradigm” that has close parallels with the thought of Stallones and Rose and with evolution of cardiovascular epidemiology in the most recent decades:12, pp 674, 677 Encompassing many levels of organization— molecular and societal as well as individual—this paradigm, termed Chinese boxes, aims to integrate more than a single level in design, analysis and interpretation. Such a paradigm could sustain and refine a public health-oriented epidemiology. But preventing a decline in this new era will require more than a cogent scientific paradigm. Attention will have to be paid to the social processes that foster a cohesive and humane discipline. . . . Without intense socialization and learning, we may well find—because of the natural momentum and narrow focus that specialization generates—that the links between the values of public health and its specialized disciplines dissolve as we watch. In this respect, epidemiology is most certainly at risk. The Chinese boxes symbolized for the Sussers an advance, or perhaps a recovery, from the “black box” paradigm of previous decades. In this period, the authors had seen a profusion of epidemiologic research on “decontextualized risk factors” that had concluded with finding associations between exposures and outcomes but failed to integrate these findings into a larger picture of social phenomena. The image of a multilevel hierarchy of different levels of organization, represented by nested Chinese boxes, conveys the idea of their proposed paradigm. In their concept, epidemiology could gain breadth by exploiting modern information systems to communicate within and across levels of organization. Greater depth could result from incorporating new biomedical techniques.

This view of epidemiology, consistent with the illustration in Figure 17-4, incorporates the multilevel concept common to the views of Stallones, Rose, and the Sussers. It also indicates a preeminent place for society as a whole and shows the territory of epidemiology extending across the whole array as a basic discipline of biomedical and community health research. Whether this is a sufficient representation of contemporary epidemiology will be considered further as follows.

GOALS Why Do Epidemiology? The goals of cardiovascular epidemiology and prevention can be characterized as understanding causes, identifying means of prevention, and monitoring populations to assess both the burden of cardiovascular diseases and the impact of interventions to control them. Common reference to “epidemiology and prevention” points to a dual role and emphasizes that “epidemiology” alone, without “prevention,” is incomplete. Much has been said in preceding chapters about engagement of epidemiology and epidemiologists in development of guidelines, recommendations, and policies for CVD prevention. These activities, and their extension into communication about, and advocacy for, needed interventions in the interest of public health, are essential aspects of epidemiology and prevention. Contributing critical evidence and translating evidence into effective public health strategies are defining roles for epidemiology and prevention. Ultimately, the goal of epidemiology and prevention is achievement of better population health through disease prevention and health promotion, based on sound, relevant science. Outcomes of Epidemiologic Research What the cardiovascular epidemiologist does through research can be seen in part as continually adding new increments to Stallones’s “n-dimensional complex” of accumulated evidence described in Chapter 17. For reasons discussed there, this pursuit has scientific and intellectual value, even elegance, in itself. It represents the purely scientific or theoretical aspect of epidemiology. But to draw also on the Stallones metaphor of “directed pathways” within the complex, results of epidemiologic research can have major practical utility. Through this applied aspect, epidemiology contributes more directly to improving population health. Meeting the global challenge of preventing cardiovascular diseases depends importantly on progress in applied epidemiology, embracing the broad concept

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of research that includes surveillance and evaluation. The outcomes of this research extend from immediate study findings to syntheses of evidence; from resulting recommendations, guidelines, or policies to implementation strategies; and from impact assessments to updated syntheses of the evidence, taking practice experience into account. Dissemination of policies and programs may follow, with further research regarding effectiveness of interventions when adapted for particular population settings. The outcomes of epidemiologic research are illustrated throughout the preceding chapters, whether describing the global distribution of the major atherosclerotic and hypertensive diseases, epidemiologic evidence regarding their determinants, or translation of this evidence into recommendations, guidelines, policies, and public health strategies and action plans.

STRATEGIES OF INVESTIGATION Overview Epidemiologists are well aware of the range of conventional approaches to investigation that includes cross-sectional population surveys, retrospective and prospective analytic studies, and intervention trials. Each is useful and necessary for addressing one or another type of epidemiologic question, as demonstrated abundantly throughout Parts I–III. Other approaches are also needed that are less often considered within the purview of epidemiology. Surveillance, program evaluation, and policy analysis are described more fully here, and brief mention of implementation science and public health services and systems research are noted as well. Modeling and economic analysis were discussed in Chapter 21. Surveillance As addressed here, surveillance is viewed as integral to the topic of research for CVD prevention and control. Within A Public Health Action Plan to Prevent Heart Disease and Stroke, a priority task has been to assess the strengths and limitations of existing surveillance systems in the United States and recommend changes as appropriate. The National Forum for Heart Disease and Stroke Prevention, through its Monitoring and Evaluation Implementation Group, commissioned such an assessment that resulted in a comprehensive report with nine key recommendations for improvement.13 National, state, and local surveillance systems are critically reviewed, including the National Health and Nutrition Examination Survey, Behavioral Risk Factor Surveillance System, Youth Risk Behavioral Surveillance System, National

Health Interview Survey, and several others. Overarching recommendations concerned establishment of a National Heart Disease and Stroke Surveillance Unit, making major CVD events reportable conditions; strengthening current data collection practices and linkages between data systems; validating data from self-reported sources; and adopting variable sampling fractions among specific geographic or other defined populations of high priority to permit more adequate representation. Complemented by recommendations specific to the four Healthy People 2010 goals for heart disease and stroke prevention, these provisions for improved surveillance at local, state, and national levels would contribute greatly to research in CVD epidemiology throughout the United States. Concurrently, improvements in cardiovascular surveillance in Europe have been proposed by the Section on Prevention and Health Policy, European Association for Cardiovascular Prevention and Rehabilitation (EACPR).14 The European Cardiovascular Indicators Surveillance Set (EUROCISS) comprises operations manuals for three areas— population-based registers of both acute myocardial infarction and stroke, and cardiovascular surveys. The context of this proposal was as follows:14, p S1 Europe is now facing the challenge to implement preventive actions, identify persons in need of treatment, apply the European Guidelines for CVD Prevention in Clinical Practice and verify improving effectiveness. The development, testing and implementation of effective surveillance systems for CVD will produce reliable and comparable indicators, thus enabling policy makers to trace differences within and between countries and to make better decisions on planning and evaluation of prevention programs, healthcare delivery, resource allocation, and research. WHO has been active as well in developing and implementing a strategy to strengthen and standardize population-level data collection supporting noncommunicable disease prevention efforts globally.15 The WHO STEPwise approach to Surveillance (STEPS) program proposes an incremental strategy for developing national surveillance incorporating questionnaires at step 1, adding physical measurements at step 2, and further adding biochemical measurements at step 3. Each step begins with core data elements, with expanded scope and further optional increments as resources permit. Emphasis here is on the critical need for good information as a basis for decision making. At the same time, availability of such data permits population-level research that is otherwise impossible.

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Program Evaluation Program evaluation, as defined previously, is recognizable at least implicitly in some or all of the research agendas described here. It was the subject of a 1995 monograph, Evaluating Community Efforts to Prevent Cardiovascular Diseases.16 That report noted the complexity of evaluating community programs conducted by multiple partner organizations and individuals, owing to the multifaceted activities often undertaken. The following core questions for evaluation were presented:16, p 14 • Was the community mobilized to reduce risks for CVD? • What changes in the community resulted from the initiative? • Is there a change in behavior related to risks for CVD? • Does the initiative have a community-level outcome related to risks for CVD? • Is community-level outcome related to changes facilitated by the initiative? The nature of these questions combines qualitative assessments of program processes with measures of community changes and outcomes that require attention to program design, data collection, and appropriate analysis and interpretation. These latter activities merge into research, making the distinction of program evaluation seem exaggerated. One approach to program evaluation that is widely used is the RE-AIM framework discussed in Chapter 19. A Public Health Action Plan to Prevent Heart Disease and Stroke includes a recommendation to elevate the prominence of program evaluation by convening a “watershed conference” calling attention to its methods, contributions, and the need for broader visibility and support of this critical public health function.2 Success would be seen in public health agencies attaining greater capacity for program evaluation, state and local public health agencies receiving needed assistance in planning for program evaluation, and a plan for meeting these requirements being in place. The proposed conference took place in late summer 2007, and a report of the proceedings is forthcoming. Policy Analysis Policy analysis in the present context concerns the relation between epidemiologic evidence and policy development—whether current policy is consistent with epidemiologic evidence, whether existing evidence is sufficient to support policy change, and whether identifiable gaps in evidence suggest that

new research is needed to advance the development and implementation of policy for CVD prevention. To take up the approach of policy analysis in this sense suggests considering types of issues that might constitute deterrents to policy development, adoption, and implementation—for example, issues surrounding primordial prevention, with respect to need, assets, costs, priorities, and impact: Is the policy needed? Evidence indicates that investment in primordial prevention is low; prevention can be effective; and risk factors and their consequences begin to develop early in life and progress with age, at differential rates such that some groups (such as African Americans) are at early and continuing disadvantage. Although these observations would support the need for the policy, some decision makers might require further evidence on one or another of these points or raise other questions about need. Potential research question: What proportion of the population is at low risk of CVD, who are they, and what interventions are effective in preserving low risk? What assets are required and available to implement the policy? Increased investment would require adequate infrastructure, access, and utilization to be effective. Research may be needed to determine whether these conditions are present or could be established and with what reach with respect to populations of special concern due to disparities. Potential research question: What conditions, behaviors, or practices are expected to change in consequence of increased investment in prevention, what is their nature and prevalence in the population and groups of special concern, and what specific interventions are known to be feasible for the target population? What are the costs of prevention? Alternative prevention scenarios, each with its evidence base, costs, and expected effectiveness would be desirable inputs to decision making on this policy. Potential research question: How much gain would be expected in what measures of health from a given increase in investment in primordial prevention, and for what segments of the population? How would other priorities be affected by this policy? Within the health arena, increased investment in primordial prevention might be instituted by containing cost increases or reducing some treatment expenditures. Or resources might be shifted from another sector. Potential research question: Would gains from increased support of prevention “upstream” be offset by reduced investment causing higher rates of disability or recurrence of CVD events “downstream”? Are there potential positive effects in other sectors from increased investment in prevention?

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What would be the expected impact of this policy on population health indicators, on what time scale? Potential research question: Can consequences of similar policies implemented elsewhere be applied, or can models of population impact under different policies be developed and evaluated? Implementation Research Less familiar than the foregoing approaches, “implementation research,” or “implementation science,” was described by staff of the Fogarty International Center, National Institutes of Health, as a tool in the Center’s efforts to strengthen health care especially in developing countries:17 Realizing the need for a quantitative, scientific framework to guide health-care scale-up in developing countries, researchers in health, engineering, and business are building interest in implementation science. Unlike routine applied (or operations) research, which may identify and address barriers related to performance of specific projects, implementation science creates generalizable knowledge that can be applied across settings and contexts to answer central questions. Why do established programs lose effectiveness over days, weeks, or months? Why do tested programs sometimes exhibit unintended effects when transferred to a new setting? How can multiple interventions be effectively packaged to capture cost efficiencies and to reduce the splintering of health systems into disease-specific programs? Answering questions like these will require analysis of biological, social, and environmental factors that impact implementation, both to develop and test communitywide, multisector interventions that are not testable in clinical settings, and to identify how proven clinical interventions should be modified to achieve sustained health improvements in the “real world.” Although this focus is on clinical settings, the questions posed imply that multiple disciplines are needed to address them and that policy and environmental considerations enter into the contemplated research and interpretation of its findings. Public Health Services and Systems Research “Public health services and systems research” is an emerging area of research that might be seen as the public health counterpart of health services research.18 It focuses on the working of the public health system, whereas traditional health services re-

search mainly concerns medical care delivery and financing. The relevance of public health services and systems research to CVD and other chronic disease prevention lies in the importance of upstream, system effects for achieving population-level impact on risk and disease:18, p 171 The continued development of this area is imperative if we are to have any possibility of success in rebuilding and modernizing our public health infrastructure and improving our nation’s health. It is difficult to change major disease indicators one person at a time. It is much more parsimonious to attack these problems on a population basis, where even modest changes can lead to major changes in the incidence of disease. The knowledge of how we build and design systems to provide population-based services efficiently and effectively is key to that effort. Research that answers questions focused on those efforts is vital to the nation’s health.

PROPOSED RESEARCH AGENDAS Proposals for an organized research agenda in various aspects of CVD prevention have been presented and updated from time to time over the past halfcentury by multiple organizations, agencies, and expert groups. The diversity of research topics reflected in several examples highlighted here illustrates the breadth and depth of CVD epidemiology and prevention as a research endeavor. National Heart, Lung and Blood Institute A comprehensive research agenda was presented more than a decade ago in the National Heart, Lung and Blood Institute (NHLBI) Report of the Task Force on Research in Epidemiology and Prevention of Cardiovascular Diseases.19 Its recommendations remain relevant today, more than a decade after its publication. The report addresses the challenge of cardiovascular disease prevention in these terms:19, pp xiv–xv [T]here are now unequaled opportunities for further reducing CVD within all segments of American society. The strategic key, and the greatest opportunity in preventing CVD, is to prevent the development of CVD risk in the first place. . . . The task force thus emphasizes a population-wide strategy aimed at modifying lifestyles and major CVD risk factors beginning in early childhood and continuing throughout

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the life-span. Pursuit of this strategy will involve observational and analytical studies, basic epidemiological research, randomized clinical trials, and demonstration projects essential to an effective CVD prevention effort. The great importance of this recommended focus of future research in epidemiology and prevention of cardiovascular diseases is that it makes explicit a fundamental shift from prevention of cardiovascular events to prevention of increased risk. Several implications of this concept have been discussed elsewhere.20 The chief emphasis is on the risk factors themselves as the outcome of concern. Their precursors (e.g., dietary imbalance, physical inactivity, and others) become the focus of intervention. The target population for research and demonstration projects begins with early childhood (or earlier) and extends throughout midadulthood—a stage of life in which a large proportion of the population may still exhibit desirable levels of blood lipids, blood pressure, and other risk factors and can still benefit from interventions to prevent the risk factors “in the first place.” Beyond this fundamental approach, the Task Force report proposed six specific priority areas for research (Table 23-1). The first priority expressed the overall goal of prevention of the risk factors. The second addressed control of already-existing risk factors—especially blood pressure, for which greater control should have been achieved through the existing population-wide measures. The third concerned the socioeconomic differences in cardiovascular disease occurrence throughout the United States. The fourth and fifth priorities related to intervention methods and strategies for population monitoring, beginning in youth and extending to whole populations.

Table 23-1

Priority Areas for Research

The priority areas—for both basic epidemiological research on causation and enhanced application of already available knowledge—are: • Prevention of adverse lifestyles and related risk factors • Control of high blood pressure and other established cardiovascular disease (CVD) risk factors • Reduction of CVD events, disability, and death associated with socioeconomic differences • Prevention of hypertension, dyslipidemia, smoking, and atherosclerosis beginning in youth • Improvement of populationwide prevention strategies • Clarification of the insulin-glucose-atherosclerosis association Source: Reprinted from National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

The sixth priority was to clarify the complex relationships among insulin and glucose regulation, atherosclerosis, and the other major risk factors. In each priority area, a number of more specific research questions were posed. Though proposed more than a decade ago, the areas of emphasis proposed by the Task Force remain valid today. Additional technical resources and developments are needed to support the research agenda proposed by the NHLBI Task Force.19 These include new biostatistical techniques to address complex issues including design and analysis of community trials; improved follow-up methods for population studies especially of low-income, unemployed, or highly mobile persons; enhanced standardization and certification procedures for epidemiologic data collection; long-term storage and utilization of biological samples from population studies; a funding mechanism for short-term pilot studies to explore new laboratory findings or for methodologic investigations; and improved methods for large-scale dietary assessment of populations, based on large samples and repeated comprehensive nutritional assessments. Apart from these methodologic approaches, five broad qualities or characteristics to be considered as criteria in setting research priorities were addressed in the NHLBI Task Force report (Table 23-2).19 First, research that has potential for application early in the processes of atherosclerosis and hypertension should be emphasized. Second, a population-wide focus should be an important criterion for selection of research questions and programs by the Institute in planning its research agenda. Third, specific population groups should be addressed for whom special disease burdens or obstacles to prevention are present. (This provision would reinforce inclusion of women and minorities in epidemiologic research and underscores the importance of populations experiencing health disparities.) Fourth, studies with potential to bridge gaps between laboratory or patient-oriented research and prevention in the community should receive high priority to accelerate translation of research at every level into public health practice. Fifth, studies with potential to build banks of information and materials should be considered especially valuable, since the need for large data sets is increasingly recognized, as is the utility of longterm follow-up of groups with good documentation of behaviors or risk factors prior to the onset of overt cardiovascular disease. Currently, it is the Division of Cardiovascular Sciences within NHLBI that supports populationbased research (as well as clinical studies) on cardiovascular and other diseases. The scope of the

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Table 23-2

Strategies for Research

The nation’s research program in epidemiology and prevention of cardiovascular disease (CVD) has the greatest promise of benefiting the public if it is continued and expanded to emphasize research that • Has potential for early application in CVD prevention (especially prevention of elevated risk factors) and for discovering other traits amenable to intervention early in the disease process • Focuses on the whole population, as well as on individuals at high risk, in seeking causes and means of prevention of high rates of disease • Embraces specific population groups whose social circumstances (eg, low socioeconomic status), behavioral patterns (eg, diet, smoking, and physical activity), or other characteristics (eg, age, sex, ethnicity, genetics) impose special burdens of disease or special challenges to prevention • Incorporates approaches and findings from laboratory and clinical science and from developing technologies (eg, noninvasive imaging of atherosclerotic lesions) which enhance the potential for population-based studies to accelerate the translation of laboratory, clinical, and epidemiological research results into public health applications • Builds banks of information and materials to support future studies (eg, from large-scale studies, participant rosters maintained to provide later follow-up data on lifestyle characteristics and risk factors for defined populations, frozen samples of serum or DNA and urine, registries of family sets for future studies of postulated genetic-environmental interactions) Source: Reprinted from National Heart, Blood and Lung Institute, National Institutes of Health, Bethesda, Maryland.

Division’s charge includes epidemiologic research to identify and describe risk factors and study influences on both these factors and disease outcomes; clinical trials of preventive measures; and studies of applied prevention and treatment strategies. Topics of research include genetic, behavioral, sociocultural, and environmental factors and temporal patterns in disease mortality, incidence, prevalence, and morbidity, based in part in ongoing multicenter population studies.21 (Available at www.nhlbi.nih.gov. Accessed December 26, 2009.) Fogarty International Center The Fogarty International Center is the principal component of NIH that addresses needs in global health research. In its strategic plan for 2008–2012, the Center set forth as its first two goals:22,23, pp 1–2 to mobilize the scientific community to address the growing epidemic of chronic, noncommu-

nicable diseases related to increased longevity and changing lifestyles in the developing world . . . [and] to foster implementation research training in order to help reduce the “know-do” gap, which prevents discoveries from being put into practice, particularly in resource-poor countries. The recently increased emphasis by the Center on chronic disease prevention and management is reflected in these goals, with both research and training components. The widely acknowledged failure to follow discovery by application of new knowledge, the “know-do” gap, is to be narrowed specifically through implementation research. The impact as described would be chiefly in the clinical arena, but populationlevel applications are readily identifiable. World Health Organization The World Health Organization (WHO) has addressed research needs in CVD and other chronic disease prevention for several decades, principally through a longstanding effort to convene expert groups by the former CVD Unit at Headquarters in Geneva. Typically such reports presented a review of current science as background to recommendations for policy and research, and several of them are cited in Parts I–III. Following dissolution of the Unit, with reorganization of activities in the area of noncommunicable diseases, a new sequence of reports began to appear. A Scientific Group report in 1994 on research priorities regarding CVD risk factors was followed closely by the more generic report, Investing in Health Research and Development. This was “a review of health needs and related priorities for research and development in the low-income and middle-income countries . . . intended as a resource to assist decision-making by governments, industry and other investors on the allocation of funds to, and within, health R&D.”24,25, p xxi Emphasis was placed on the need to obtain “reliable basic data on prevalence of and trends in noncommunicable diseases and risk factors”:25, p xxxvii Faced with rapidly growing burdens of noncommunicable diseases, low-income and middleincome countries should significantly increase their relevant strategic research in epidemiology, behavioural science and health policy with the aim of reliably monitoring the true prevalence and trends of these conditions in their populations, and understanding their determinants. Basic data on morbidity, mortality and disability are currently inadequate in many regions, as are data on the country-specific and

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region-specific levels and determinants of environmental and behavioural risk factors. Lowcost methods for collecting reliable data, such as the use of disease surveillance points, must therefore be developed. In contrast to the need for epidemiological and behavioural research, biomedical science relevant to these conditions is already comparatively well supported in the established market economies. However, genuine differences in the characteristics of environments and populations will occasionally require additional biomedical research in some regions—as, for example, in seeking explanations for the observed high risk in South Asians of diabetes and heart disease. . . . The development and evaluation of algorithms and policy instruments for the cost-effective prevention, diagnosis, treatment and rehabilitation of noncommunicable diseases is an immediate priority for support by governments and other investors. A later interest was to support the concept of “life course” research. This aspect of the WHO research agenda for NCD prevention is addressed in Life Course Perspectives on Coronary Heart Disease, Stroke, and Diabetes. The Evidence and Implications for Policy and Research, a WHO report on a 2001 expert consultation.26 The underlying concept is that, more than simple age-specific differences over the life span in manifestations of risk or disease, differences in the influence of health-related exposures characterize certain periods of life, specifically “critical periods” or “sensitive periods”:26, p 3 The term “critical period” implies exposures that must occur in some specified window(s) of time and often involve exposures that alter normal biological development. “Sensitive period” exposures refer to a broader class of influences that may have greater impact on later outcomes if they occur in certain periods than others. In empirical terms, both critical and sensitive period exposures imply time by exposure interactions. Implications of the life-course concept for research in CVD and NCD prevention are to specify several research questions under each of four headings: research on causes and interactions; trends analysis and surveillance; intervention research; and refinement of methodology. Both research topics and design approaches for each category are outlined in the report. At the conclusion of the consultation, it was judged that it represented “a vital starting point for harnessing the potential of the life course perspective to identify the most appropriate and effective prevention policies in different populations.”26, p 30

Most recently, in accordance with its Global Strategy for the Prevention and Control of Noncommunicable Diseases, WHO developed an action plan, adopted by the Sixty-First World Health Assembly in May, 2008, one of whose six objectives is “to promote research for the prevention and control of noncommunicable diseases”:27, pp 14–15 A coordinated agenda for noncommunicable disease research is an essential element in the effective prevention and control of noncommunicable diseases. In establishing such an agenda, the aim is to enhance international collaboration to promote and support the multidimensional and multisectoral research that is needed in order to generate or strengthen the evidence base for cost-effective prevention and control strategies. Priority areas include the analytical, health system, operational, economic and behavioural research that are required for programme implementation and evaluation. The plan calls for the Secretariat of WHO to take action by developing a prioritized research agenda for noncommunicable diseases that “should generate knowledge and help to translate knowledge into action through innovative approaches in the context of low- and middle-income countries.” It is worth considering which if any of the proposed items on the proposed agenda would not be relevant to highincome countries as well:27, pp 15–16 • the assessment and monitoring of the burden of noncommunicable diseases and its impact on socioeconomic development; • the monitoring of the impact of poverty and other indicators of socioeconomic disparity on the distribution of risk factors; • the assessment of national capacity for the prevention and control of noncommunicable diseases and the evaluation of approaches to fill existing gaps in capacity; • the evaluation of impact of community-based interventions on risk factor levels, and on morbidity and mortality associated with noncommunicable diseases in different populations; • the assessment of the cost-effectiveness of clinical and public-health interventions for improving health behaviours and health outcomes; • the evaluation of different strategies for early detection and screening of noncommunicable diseases in different populations, with an emphasis on cancers, diabetes, and hypertension; • the evaluation of interventions for secondary prevention on cardiovascular disease outcomes in different settings;

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• the study of the effectiveness of different organizational patterns in health-care institutions in improving health care for chronic conditions, with a special focus on primary health care; • the analysis of research on factors affecting consumer behaviour and dietary choices, including marketing; • the study of approaches for improving access to, and availability of, essential medicines, essential medical technologies and other central elements of health care; and of approaches for improving the development of affordable new drugs for neglected diseases like Chagas disease, and for rheumatic fever, together with vaccines like that against human papillomavirus; • the assessments of the role, efficacy, and safety of traditional medicines in the management of noncommunicable disease [2008–2009]. To implement this action, WHO convened an international meeting in August 2008 to discuss such a prioritized research agenda. Background papers were prepared to address both disease-specific and crosscutting topics. Closing remarks were presented by Richard Horton, Editor of The Lancet, and subsequently published by ProCor.28 (Available at www .procor.org/advocacy. Accessed October 19, 2008.) Reflecting on the proceedings of that meeting, Horton noted the uniqueness of WHO in its role and responsibility to foster research for prevention and control of noncommunicable diseases and the need for WHO to direct more of its resources to this area. He also posed the question how a social movement for research to improve human health is to be created. He suggested that the answer comes not from biomedical science, but from political science:28, p 3 We need to understand the politics of global health. We have to be opportunistic. Is the time right for us? Are the global conditions favorable for us to make progress? They are favorable, but we can make them even more favorable by doing great science, convening the right people at the right events, and through advocacy––all tied to institutional leadership, nationally and globally. International Heart Health Society As part of the International Heart Health Conference in Victoria, British Columbia, and subsequent Heart Health Conferences, calls for policy development and action by governmental and private organizations and agencies included recommended areas of research. For example, the International Heart Health Advisory

Committee included in its Catalonia Declaration, directed to governments throughout the world, several specific research emphases:29, p 79 Research agencies should allocate appropriate resources to accomplish the following: • Develop new methods and approaches that facilitate the dissemination and uptake of existing prevention knowledge and interventions by organizations concerned with heart health at all levels. • Carry out organizational and evaluative research studies to learn about the value and cost of alternative methods for organizing, financing, and managing heart health programmes, including options for private sector funding of the delivery of such programmes. • Implement systems for surveillance of risk factors and cardiovascular disease, particularly in sentinel populations, including young people and people undergoing rapid social and economic change. • Implement systems for monitoring and reporting progress and results of both planned and unplanned interventions. Public Health Action Plan As noted previously, development of a prevention research agenda for cardiovascular diseases is recommended in A Public Health Action Plan to Prevent Heart Disease and Stroke.2,30 From the perspective of the Action Plan, present knowledge must be put into immediate action to prevent cardiovascular diseases. The greatest opportunity at this stage of knowledge lies in development, adoption, and implementation of policies for cardiovascular health promotion and CVD prevention. Because policy and environmental change, system change, and population-wide behavior change have broadest reach, these populationlevel intervention approaches have high priority in a research agenda supporting public health action. A more favorable balance in research between “upstream” and “downstream” areas of the Action Framework is called for. Yet this need is not well recognized. For this reason, a newly articulated research agenda has been considered a high priority. How might such an agenda be framed? For undertaking this task, it appears necessary to focus initially on one selected policy issue, potentially devising in the process a method that might have general applicability in other policy areas. The desired outcome for the research agenda would be to determine whether one or more “critical investigations” could be devised to resolve a policy issue and

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enable policy development, adoption, and implementation to proceed. For illustration, a candidate focal issue might be the current low level of investment in prevention of cardiovascular and other chronic diseases in the United States, in relation to expenditures for treating these conditions. Proposals to increase investment in prevention have had little success. What are the principal obstacles to progress in this policy area, and are there questions that could be resolved through research? It is anticipated that the National Forum for Heart Disease and Stroke Prevention, as it matures, will develop a proposed research agenda, perhaps initially in the area of economics of prevention, utilizing the strategy of policy analysis outlined previously.

CAPACITY REQUIREMENTS The resource requirements for realizing the research potential in epidemiology and prevention of cardiovascular diseases include sponsorship and funding, training of investigators, and institutionalization. Underlying these capacities is the need for support of political leadership and government, the private sector, and society as a whole. Sponsorship and Funding In the United States, health-related research funding comes largely from the federal government and principally via the National Institutes of Health. The emphasis of this research is concentrated in the biomedical arena, as indicated by the themes of the NIH Roadmap: New Pathways to Discovery, Research Teams of the Future, and Reengineering the Biomedical Research Enterprise.31 Nonetheless, support for population studies and other work in cardiovascular epidemiology continues under the Division of Cardiovascular Sciences at NHLBI. (Available at www.nih.gov/nhlbi. Accessed December 26, 2009.) CDC’s Advancing the Nation’s Health: A Guide to Public Health Research Needs, 2006–2015 links research priorities to the agency’s overall strategic imperatives, among them public health research: “Research supports the scientific foundation of public health policies, programs, and practices [italics in original].”32, p 3 In the area of promoting health to reduce the burden of chronic diseases and disability, CDC’s research priorities include both age-specific goals and research across the life span to enable implementation of effective health promotion strategies and reduction of risk factors and chronic diseases, with special emphasis on disparities. Cross-cutting research priorities potentially relevant to CVD preven-

tion include social determinants of health; health systems; public health science, policy and practice; economics and public health; and others. There is close alignment between the CDC research agenda and the approach outlined previously. It is implemented in part through the Prevention Research Centers Program, linking CDC with multidisciplinary research groups chiefly in schools of public health throughout the United States.10,33 Over time, CDC could develop a greatly expanded extramural public health research enterprise and support a major prevention research agenda for CVD and other chronic diseases. A leading example of a national voluntary organization sponsoring cardiovascular research is the American Heart Association (AHA), whose Task Force on Strategic Research Direction reported in 2002 on identified priority topics in basic science, clinical science, and “population/outcomes/epidemiology/social science.”34, p 2632 Topics proposed by the latter group were: (1) methods to improve utilization and quality of preventive services and the role of the healthcare system and policies; (2) causes of disparities in risk in subpopulations; (3) understanding the relation of lifestyle and metabolic risk factors; (4) psychosocial risk factors; and (5) population genetics and pharmacogenetics. Topic (1) has the closest affinity with the policy-related research emphasized here, although it focuses on clinical preventive practice rather than the broader health system and population health. The AHA Task Force identified two topics for strategic research funding—obesity and other risk factors, and functional genomics and population genetics. These would be given special priority for funding within the overall research program. Of special interest is the mechanism proposed by the Task Force for implementing this new concept of strategic research priorities, by supporting small clusters or teams of investigators:34, p 2630 (a) Multidisciplinary composition––i.e., including intellectual support for all three domains of basic, clinical, and population science (including, as appropriate, bioinformatics and social sciences). The cluster of investigators would be expected to include competence in all three domains. (b) Focus on developing beginning investigators’ abilities in applying basic, clinical, and population science techniques to CVD and stroke problems. (c) Involvement of more than one institution. This might take the shape of the beginning investigator’s receiving training at one institution and bringing these techniques to another. Or it could involve formation of a

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research program cluster across two or more institutions. This outline of AHA’s new strategic research direction touches on integration across research domains and disciplines, training for multilevel capacities in new investigators, and multi-institutional collaboration. Training Personnel requirements in health research, especially in epidemiology and prevention, have been emphasized, for example, by the Pew Health Professions Commission.35 In its assessment Critical Challenges: Revitalizing the Health Professions for the TwentyFirst Century, the Commission concluded that “large numbers of health professionals will require retraining in disease prevention, clinical epidemiology, process and systems analysis and managerial epidemiology.”35, p 55 To provide adequate numbers of epidemiologists in cardiovascular disease prevention will require new and expanded training programs, including those with innovative approaches to interdisciplinary research and program development. Fields and topics to be represented in training programs might well include—in addition to epidemiology, biostatistics, and preventive cardiology—such areas as social and behavioral sciences; public health economics; policy development and implementation; and community organization and community participatory research. The NHLBI Task Force report addressed training requirements as well as research priorities.19 Training opportunities for physicians and other health professionals and researchers should be expanded, as these recommendations suggest. Access to both shortterm courses and academic degree programs is needed by large numbers of candidates to meet the current and growing demand for qualified investigators. Opportunities for acquiring and expanding knowledge and skills through web-based tools should be a prominent part of strategies for meeting long-term training needs. Institutionalization The institutional and organizational bases for the needed research depend, as do individual investigators, on continuity of funding for maintenance of key staff, facilities, and equipment to enable the development and implementation of research proposals. Institutionalization of field settings for research is critical for recruitment, training, advancement, and retention of qualified and experienced researchers. Although sponsorship and funding by central agencies is of course indispensable, stable settings in which

to conduct the funded research are equally so. Longterm research programs of the past, such as the Seven Countries Study and the WHO MONICA Project, have provided settings in which new investigators could enter the field, develop credentials and careers, and become leaders. There is need to organize research with such longterm stability in view. This issue is considered at local or national, regional, and global levels, in the Institute of Medicine report Control of Cardiovascular Diseases in Developing Countries. Research, Development, and Institutional Strengthening.36 Although presented in the context of developing countries, the outline of major research and development (R&D) functions seems universally applicable:36, p 61 The immediate goal for cardiovascular R&D is to enhance local capacity through education and training; development of networks where appropriate; and conduct of local research that is comparable with other centers and applicable internationally. For activities in CVD prevention and control to be successful, it is essential that nonhealth sectors––for example, education, agriculture, industry, and environment––are also included in development of the program. Potential partnerships should be identified and integrated into the action plan. The major functions to be undertaken at different levels are as follows: 1. Local or national: Develop and maintain the capacity and resources to plan, implement, and evaluate research and demonstration projects for CVD prevention. These should include: • community-based assessment of the CVD burden; • monitoring of and intervention in risk factors and their determinants; • testing clinical intervention (e.g., EVP [‘essential vascular package’ of effective, low-cost drugs] and algorithms for low-cost clinical care) and, where feasible, • investigating the local determinants of CVD risk. 2. Regional: Support local or national centers as they undertake their activities providing: • technical support; • communication and exchange of information; • funding support from regional and international donors; and

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• evaluation of the status of CVD prevention activities in the region. 3. Global: Support regional centers in the conduct of their activities: • maintenance of global data on CVD prevention and control programs; • dissemination of current data, protocols, guidelines, and literature on CVD prevention and control; and • convening of advisory groups to assess global needs, evaluate current activities, and recommend additional activities if they are needed. The report concluded that global leadership for R&D in CVD prevention and control should be assumed by WHO. Given assimilation of CVD into the noncommunicable disease agenda by WHO, and the current initiative to develop a comprehensive research agenda in this area, it will be of interest to see the outcome of this process and its applicability to CVD epidemiology and prevention throughout the world.

POPULOMICS: THE POPULATION CONTEXT OF RESEARCH ON HEALTH The current global context of epidemiology of CVD and other chronic diseases suggests that the concept of epidemiology represented in Figure 17-4 and described previously is no longer sufficient. For example, the regional and global scale of population health addressed by the Disease Control Priorities and Global Burden of Disease projects, ultimately concerning the whole of the world population, is far greater than implied by “societies” in the figure.37,38 The object of epidemiologic research has become all people in all places. The dimension of time has expanded with increasing attention to both historicalexplanatory and predictive models of long-term changes in population health. The theory of epidemiologic transition, for example, first published in 1971, gained more recent prominence with growth of interest in the increasing burden of CVD and other chronic diseases in the developing countries.39 Models of past and future trends in CHD mortality are further examples of contemporary epidemiologic research extending backward and forward over decades or longer. These several developments have greatly extended the classic dimensions of person, place, and time in cardiovascular epidemiology. The increasing need for interaction between epidemiology and other health science disciplines, as

well as engagement with sectors beyond biomedical and community health, is also increasingly apparent. This is especially so if epidemiology is to become more strongly oriented toward policy development and public health action. For example, interaction between CVD epidemiology and other social and behavioral sciences gains new importance if social determinants of health are to be addressed more prominently in the research agenda. Similarly, links between CVD and other chronic diseases suggest connections between the respective specialties concerned with these diseases and their causation and prevention. For epidemiology to contribute effectively to policy development, appreciation of other influences on health policy and decision making, including economics, politics, culture, special interests, and others, is required. The research agenda, proposed especially to identify and resolve barriers to policy development and implementation, should also recognize the importance of understanding these influences. The implied connectivity between epidemiology and the array of disciplines concerned with specific levels of biological organization, particular disease processes, and myriad external factors adds a new dimension to our concept of contemporary epidemiology. To put CVD epidemiology in its proper context today requires a holistic view of populations and health. There is an analogy in this circumstance between epidemiology and genetics, as each seeks a more integrated conceptualization of its larger purpose. According to Khoury and others, quoting Guttmacher and Collins, genetics is “the study of single genes and their effects,” whereas genomics is “the study of not just of [sic] single genes but of the functions of and interactions of all genes in the genome.”40, pp 7–8 Much as “genomics” serves the field of genetics as an all-encompassing concept, the term “populomics” would serve the study of population health. In what has been termed “the -omics era,” this is an appealing concept and may have considerable heuristic value.41 Populomics, then, represents a scientific domain that concerns population health and is global in scale, dynamic over long reaches of time, and inclusive of fundamental population processes and their interactions—anthropological, demographic, sociocultural, economic, environmental, and others. Populomics can be understood as an “integrative human ecology,” having population health as its focus and embracing all relevant disciplines, with epidemiology at its core. It is epidemiology transcending the “boxes.” This concept of epidemiology is represented in Figure 23-1.

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Contemporary Epidemiology as the Core Discipline of Populomics: Beyond the Box PERSON GLOBAL SOCIETIES COMMUNITES FAMILIES POPULATION

INDIVIDUALS

PLACE ORGANS

CELLS

MOLECULAR AND SUBMOLECULAR PARTICLES

Traditional Epidemiology Clinical Research Pathology, Physiology

TIME

Cell Biology Molecular Biology Contemporary Epidemiology

RELATED DISCIPLINES AND SECTORS

Figure 23-1 Contemporary Epidemiology as the Core Discipline of Populomics: Beyond the Box. Source: Adapted with permission from the Annual Review of Public Health, Vol 1, © 1980, by Annual Reviews, Inc.

CURRENT ISSUES 1. Will the call for a greatly expanded research enterprise to support CVD and other chronic disease prevention be heard by those in a position to provide sponsorship and funding? 2. Can a network of broad-based training programs for research and practice in CVD and other chronic disease prevention become established to strengthen local, national, regional, and global efforts and develop new leaders for today and the coming decades? 3. How shall institutionalization be accomplished to assure growth and sustainability of populomics and its core discipline of epidemiology, as it is applied to the challenge of preventing CVD and other chronic diseases at the population level and on a global scale? 4. What is the compelling research agenda, with what promise of success in leading to societal change for prevention of CVD and other chronic diseases, that will support the case and build on the success of 1, 2, and 3 above?

REFERENCES 1. Remington RD. Role of organized public health in cardiovascular disease prevention. In: Marmot M, Elliott P, eds. Coronary Heart Disease Epidemiology: From Aetiology to Public Health. Oxford (England): Oxford Medical Publications; 1992: 515–524. 2. US Department of Health and Human Services. A Public Health Action Plan to Prevent Heart Disease and Stroke. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; 2003. 3. Thacker SB. Historical development. In: Teutsch SM, Churchill RE, eds. Principles and Practice of Public Health Surveillance. 2nd ed. Oxford (UK): Oxford University Press; 2000. 4. Birkhead GS, Maylahn CM. State and local public health surveillance. In: Teutsch SM, Churchill RE, eds. Principles and Practice of Public Health Surveillance. 2nd ed. Oxford (UK): Oxford University Press; 2000.

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5. Teutsch SM, Churchill RE, eds. Principles and Practice of Public Health Surveillance. 2nd ed. Oxford (UK): Oxford University Press; 2000. 6. Centers for Disease Control and Prevention. Framework for program evaluation in public health. MMWR. 1999;48(No. RR-11):1–40. 7. Committee for the Study of the Future of Public Health. The Future of Public Health. Washington, DC: Division of Health Care Services, Institute of Medicine. National Academy Press; 1988. 8. Stallones RA. To advance epidemiology. Annu Rev Public Health. 1980;1:69–82. 9. Rose G. Sick individuals and sick populations. Int J Epidemiol. 1985;14:32–38. 10. Stoto MA, Green LW, Bailey LA, eds. Linking Research and Public Health Practice: A Review of CDC’s Program of Centers for Research and Demonstration of Health Promotion and Disease Prevention. Board on Health Promotion and Disease Prevention. Institute of Medicine. Washington, DC: National Academy Press; 1997. 11. Susser M, Susser E. Choosing a future for epidemiology: I. Eras and paradigms. Am J Public Health. 1996;86:668–673. 12. Susser M, Susser E. Choosing a future for epidemiology: II. From black box to Chinese boxes and eco-epidemiology. Am J Public Health. 1996;86:674–677. 13. Goff DC Jr, Brass L, Braun LT, et al. Essential features of a surveillance system to support the prevention and management of heart disease and stroke. A Scientific Statement from the American Heart Association Councils on Epidemiology and Prevention, Stroke, and Cardiovascular Nursing and the Interdisciplinary Working Groups on Quality of Care and Outcomes Research and Atherosclerotic Peripheral Vascular Disease. Circulation. 2207;115:127–155. 14. Giampaoli S, Capewell S, Shelley E, et al. Foreword. Eur J Cardiovasc Prev and Rehab. 2007;14(suppl 3):S1.

15. Bonita R, de Courten M, Dwyer T, Jamrozik K, Winkelmann R. Surveillance of Risk Factors for Noncommunicable Diseases: The WHO STEPwise approach. Summary. Geneva: World Health Organization; 2001. 16. Fawcett SB, Sterling TD, Paine-Andrews A, et al. Evaluating Community Efforts to Prevent Cardiovascular Diseases. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 1995. 17. Maden T, Hofman KJ, Kupfer L, Glass RI. Implementation science. Science. 2007;318: 1728–1729. 18. Scutchfield FD, Marks JS, Perez DJ, Mays GP. Public health services and systems research. Am J Prev Med. 2007;33:169–171. 19. National Heart, Lung and Blood Institute. Report of the Task Force on Research in Epidemiology and Prevention of Cardiovascular Diseases. Washington, DC: National Institutes of Health, Public Health Service, US Department of Health and Human Services; 1994. 20. Labarthe DR. Prevention of cardiovascular risk factors in the first place. J Epidemiol. 1997; 6(suppl):1–5. 21. National Heart, Lung and Blood Institute. About NHLBI. Division of Prevention and Population Sciences. Available at www.nhlbi .nih.gov/about/dpps/index.htm. Accessed October 19, 2008. 22. Fogarty International Center. Pathways to Global Health Research. Strategic Plan 2008–2012. NIH Publication No. 08-6261. Bethesda: US Department of Health and Human Services, National Institutes of Health; May 2008. 23. Fogarty International Center. Pathways to Global Health Research. Strategic Plan 2008–2012. Available at www.fic.nih.gov/ about/plan/strategicplan_08-12.htm. Accessed July 15, 2008. 24. Report of a WHO Scientific Group. Cardiovascular Disease Risk Factors: New Areas for

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Research. Geneva, Switzerland: World Health Organization; 1994. WHO Technical Report Series 841. 25. Ad Hoc Committee on Health Research Relating to Future Intervention Options. Report of the Ad Hoc Committee on Health Research Relating to Future Intervention Options: Investing in Health Research and Development. Geneva, Switzerland: World Health Organization; 1996. 26. Aboderin I, Kalache A, Ben-Shlomo Y, et al. Life Course Perspectives on Coronary Heart Disease, Stroke and Diabetes: Key Issues and Implications for Policy and Research. Geneva: World Health Organization; 2002. 27. World Health Organization. Prevention and control of noncommunicable diseases: implementation of the global strategy. Report by the Secretariat. A61/8 Sixty-First World Health Assembly. Geneva:World Health Organization; 2008. 28. Horton R. Commentary: An NCD research agenda for WHO. Available at www.procor .org/advocacy/advocacy_show.htm. Accessed October 19, 2008. 29. Advisory Board of the Second International Heart Health Conference. The Catalonia Declaration: Investing in Heart Health. Barcelona, Spain: Department of Health and Social Security, Autonomous Government of Catalonia; 1996. 30. US Department of Health and Human Services. Update to a Public Health Action Plan to Prevent Heart Disease and Stroke. Atlanta, GA: Centers for Diseases Control and Prevention; 2008. 31. Zerhouni E. The NIH roadmap. Science. 2003; 302:63–64, 72. 32. Centers for Disease Control and Prevention. Advancing the Nation’s Health: A Guide to Public Health Research Needs, 2006–2015. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention; December 2006.

33. Centers for Disease Control and Prevention. Prevention Research Centers (PRC). Available at www.cdc.gov/prc/. Accessed October 21, 2008. 34. Roberts R, Bonow RO, Loscalzo J, Mosca L. Report of the American Heart Association Task Force on Strategic Research Direction: Executive summary. Circulation. 2002;106: 2630–2632. 35. Critical Challenges: Revitalizing the Health Professions for the Twenty-First Century: The Third Report of the Pew Health Professions Commission. San Francisco, CA: Center for the Health Professions, University of California; 1995. 36. Howson CP, Reddy KS, Ryan TJ, Bale JR, eds. Control of Cardiovascular Diseases in Developing Countries. Research, Development, and Institutional Strengthening. Washington, DC: Institute of Medicine, National Academy Press; 1998. 37. Jamison DT, Breman JG, Measham AR, et al., eds. Disease Control Priorities in Developing Countries. 2nd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank; 2006. 38. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJL, eds. Global Burden of Disease and Risk Factors. Washington, DC: The International Bank for Reconstruction and Development/The World Bank; 2006. 39. Omran AR. The epidemiological transition: a theory of the epidemiology of population change. Milbank Q. 1971;49:509–538. 40. Khoury MJ, Little J, Burke W. Human genome epidemiology: scope and strategies. In: Khoury MJ, Little J, Burke W, eds. Human Genome Epidemiology. A Scientific Foundation for Using Genetic Information to Improve Health and Prevent Disease. Oxford (UK): Oxford University Press; 2004. 41. National Heart, Lung and Blood Institute. Working Group Summary: The Next Step. Population Studies in the “-OMIC” Age. Available at www.nhlbi.nih.gov/meetings/workshops/ population.htm. Accessed June 26, 2007.

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Index

AAA (Abdominal aortic aneurysm), 120–123 AACVPR (American Association of Cardiovascular and Pulmonary Rehabilitation), 599–600 Abdominal aortic aneurysm (AAA), 120–123 Abell-Kendall method, 273 ABI. See Ankle-brachial index (ABI) ACC. See American College of Cardiology (ACC) ACCORD (Action to Control Cardiovascular Risk in Diabetes) Trial, 384 ACPM (American College of Preventive Medicine), 553 ACS (Acute coronary syndrome), classification of, 64 ACS (American Cancer Society), 409, 523 Action plans, 657–675. See also A Public Health Action Plan to Prevent Heart Disease and Stroke (CDC) in Americas, 658–660 community/population-wide measures, 670–673 in Europe, 660–661 Heart Health Networks, 662–665 high-risk intervention, 673 individual intervention, 673 obstacles to, 669–673 population diversity and, 671–672 resource limitations and, 672–673 in South Asia, 661–662 strategic imperatives, 673–675 Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, 384 Active antiretroviral therapy (HAART), 481 Active living concept, 194 Active Living Policy and Environmental Studies, 194, 527 Acute coronary syndrome (ACS), classification of, 64 Acute ischemic heart disease, classification of, 64 Acute myocardial infarction case-fatality for, 72 classification of, 64

diabetes and, 377–378, 381 diet and, 180 risk factors of, 76–77 smokefree laws and, 422 Adolescents. see Children and adolescents Adulthood. See also Age atherosclerosis and, 49–54 health patterns of, 25 obesity in, 236, 239–241, 257–259 Advancing the Nation’s Health (CDC), 690 Aerobics Center Longitudinal Study, 207 Affluent society diet, 160–161, 164, 165 African Americans. see Race/ethnicity African Heart Network, 664 Age. see also specific age groups adjustment and standardization of, 23 ascertainment of, 23 atherosclerosis and, 48, 49–54 blood lipids and, 274 classification of, 22–23 congestive heart failure and, 126–127 coronary heart disease and, 81–82 fetal and neonatal period, 24 high blood pressure and, 317–318 and life stages, 22–26 modifiability of, 22 mortality patterns and, 19–24 population, age 65 and over, 26 and prevalence of risk factors, 12–13 stroke and, 105–107 Agency for Healthcare Research and Quality (AHRQ), 73 AHA. See American Heart Association (AHA) AIDS, 481 Air pollution, as risk factor, 522–525 Alcohol consumption, 431, 433–447 aortic aneurysms and, 122–123 blood pressure and, 343, 435 community/population-wide measures, 445–446 exdrinkers and risk, 434 genetic factors and, 435 HDL-cholesterol and, 152, 434–435 hemostasis and, 435–436 measurement methods, 433–434 myocardial infarction and, 151–152

697

population differences and, 441–444 population distribution and, 437–441 public health issues, 444–445, 447 race/ethnicity and, 437–440 sex and, 437–440, 443 Alcohol Policy Index, 445 ALLHAT (Antihypertensive and LipidLowering Heart Attack Trial), 348 Alliance for a Healthier Generation, 183 AMA (American Medical Association) Assessment and Management of Adult Obesity, 257 Amenable mortality, use of term, 640 American Academy of Pediatrics, 196, 273 American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), 599–600 American Cancer Society (ACS), 409, 523 American College of Cardiology (ACC) on congestive heart failure, 124–125, 127 on evidence-based decision making, 575–577 guidelines and policies, 596–597 on influenza vaccination, 481 on peripheral arterial disease, 118 American College of Preventive Medicine (ACPM), 553 American College of Sports Medicine, 192 American Heart Association (AHA) annual statistical updates, 66 Cardiovascular Diseases and Stroke in African-Americans and Other Racial Minorities in the United States, 29 Cardiovascular Health Promotion in the Schools, 609 childhood recommendations, 181, 182, 604–605, 609 Circulation, 12 Committee on Vascular Lesions report, 42 on community-based implementation of recommendations, 183 on congestive heart failure, 124–125, 127 Council on Arteriosclerosis, 42 Council on Epidemiology and Prevention, 63, 92 Criteria for Evaluation of Novel Markers of Cardiovascular Risk, 490–491 on diabetes and stroke, 381

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INDEX

(American Heart Association (AHA) cont’d) Diet and Lifestyle Recommendations Revision 2006, 180–181 on dietary recommendations, 180, 182 on drug therapy for high risk lipid levels, 296 on evidence-based decision making, 575–577 on food choice determinants, 169 Guide for Improving Cardiovascular Health at the Community Level, 607, 658 guidelines and policies, 596–597, 599–600, 603–607 on HIV/AIDS, 481 on inflammation, 488 on influenza vaccination, 481 on metabolic syndrome, 384 Methodology Manual for ACC/AHA Guideline Writing Committees, 575–577 on obesity, 253 on optimal dietary guidelines, 294 on peripheral arterial disease, 118 Population-Based Prevention of Obesity, 259 on prevention and control, 556–557 on prevention of heart failure, 131 Primary Prevention of Heart Failure, 131 Primary Prevention of Ischemic Stroke, 103 recommendations for women, 603 Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease, 143 Report of the Special Writing Group on Cardiovascular Disease in Women, 27 research agendas and, 690–691 scope of, 647–648, 658 on smoking, 414 Taking the Initiative, 607–609, 658 website, 12 American Journal of Clinical Nutrition, 167 American Journal of Preventive Medicine on active living, 194 on physical inactivity, 215 American Medical Association (AMA) Assessment and Management of Adult Obesity, 257 American Stroke Association (ASA), 596–597 Aneroid manometers, 316 Angina pectoris causal pathways, 544 classification of, 64 incidence of CHD, 70, 72–73 unstable angina, 61, 64, 452 Ankle-brachial index (ABI) age-adjusted prevalence of CVD and, 120 atherosclerosis and, 44 PAD assessment and, 114–118 Anthropometry methods, 229, 259 Antihypertensive and Lipid-Lowering Heart Attack Trial (ALLHAT), 348 Antioxidants, 481–485 Antiplatelet Trialists’ Collaboration, 474, 475 Antithrombotic Trialists’ (ATT) Collaboration, 474–475 Aortic aneurysms abdominal, 120–123

background of, 121 cardiovascular diseases and, 111–113, 120–123 classification of, 112 features of individual cases, 120–121 mortality patterns and, 121–122 risk factors of, 122–123 sex and, 121 smoking and, 122–123 surgical intervention and, 123 Appalachia, health patterns in, 30, 32 ARIC. See Atherosclerosis Risk in Communities Study (ARIC) Arrhythmias atrial fibrillation, 135–136 cardiovascular diseases and, 135–136 classification of, 111–113 ventricular, 135–136 Arteriosclerosis, mortality patterns and, 173 Arthogenisis, mechanisms of, 46–47 ASA (American Stroke Association), 596–597 Ashes to Ashes (Kluger), 396 Aspirin treatment, 474–475 Assessing Physical Fitness and Physical Activity in Population-Based Surveys (CDC, 1989), 194 Assessment and Management of Adult Obesity (AMA), 257 Association of State and Territorial Directors of Health Promotion and Public Health Education (ASTDHPPHE), 554–555 Association of State and Territorial Health Officials (ASTHO), 666 ATBC Study, 178, 485 Atherosclerosis, 41–55 blood lipids and, 275–277 causes of, 543–547 development of, schematic view, 44 genetic factors, 152–153 manifestations of, 43–45 measurement methods, 42–43 mechanisms of atherogenesis, 46–47 person, place, and time, 47–49 prevention and control, 54–55, 211 race/ethnicity and, 44–45, 47, 49, 51 sex and, 44, 47–49, 51–53 in specific life stages, 49–54 treatment of, 54 Atherosclerosis Risk in Communities Study (ARIC) on alcohol consumption, 436, 442–443 carotid ultrasonography in, 43 on hemostatic factors, 466, 472–473 on incidence of stroke, 96, 98 on neighborhood of residence, 525–526 scope of, 12, 26, 70 Atherosclerotic plaque, 41–42 Atkins Diet, 165, 179 Atlas of Heart Disease and Stroke Among American Indians and Alaska Natives (CDC), 94 Atlas of Stroke Hospitalizations Among Medicare Beneficiaries, 98 ATP III reports. see National Cholesterol Education Program (NCEP) Atrial fibrillation, 103–104, 111–112, 135–136, 597 ATT (Antithrombotic Trialists’) Collaboration, 474–475

Bacterial infections, 46–47, 480 Barker hypothesis, 518 Behavior. see Psychosocial factors; Type A behavior pattern Behavioral cardiology, 448 Behavioral Risk Factor Surveillance System (BRFSS) on blood pressure, 345 on diabetes/metabolic syndrome, 371–372 on fruit/vegetable consumption surveys, 170–171 on mortality rates, 66 scope of, 12 on stroke mortality patterns, 94, 98–99 Behavior change, use of term, 555, 560 Bell System Operating Companies study, 505 Best Practices for Comprehensive Tobacco Control Programs (CDC), 421 Binge drinking, 433, 437. see also Alcohol consumption Biomedical and community health research, 568–569 Birth weight, social factors and, 515–518 Black box epidemiology, 679, 682 Blood lipids. see also Genes and environment adverse profiles of, 269–304 atherosclerosis and, 275–277 biological mechanisms of, 275–276 community/population-wide measures, 299–301 concepts and definitions, 270–273 determinants of, 274–275 dietary imbalance and, 275 dietary trials, 294 drug trials, 294–296 early trials, 292–294 family history and, 274–275 genetic factors and, 153, 271–272, 274 HDL-cholesterol, 152, 270, 434–435 hypercholesterolemia, 153, 269, 274 LDL-cholesterol, 269, 273, 485 measurement methods, 273–274 population distribution and, 277–283 prevention and control, 292–299 public health issues, 290, 299–302 race/ethnicity and, 274, 277, 280 risk and individual differences, 285–290 risk and population differences, 283–285 secondary hyperlipidemia, 275–276 sex and, 274, 282, 286–290, 296 Blood pressure. see also High blood pressure (HBP) age and, 345 alcohol consumption and, 435 children/adolescents and, 318, 326–327, 329, 342 genes and environment, 153–154 genetic factors and, 153 migration and, 322 salt intake and, 319–321, 343 sex and, 597–599 studies on, 318 Blood Pressure Studies in Children (WHO), 342 Blood Pressure Study of the Society of Actuaries and Association of Life Insurance Medical Directors of America, 336–337

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Bloomberg Global Initiative to Reduce Tobacco Use, 423–424 BMA (British Medical Association), 232 Body composition, 166, 229, 231. see also Obesity Body mass index (BMI). see also Obesity associated disease risks, 227 birth weight and, 517–518 cardiovascular risk factors, 237 diabetes and, 368 formula for, 223 physical activity and, 208 as standard measure for obesity, 227–228 weight control and, 259 Bogalusa Heart Study on blood pressure, 318 on childhood atherosclerosis, 49–51, 54 on childhood obesity, 229, 234 diabetes/metabolic syndrome and, 369 Brain attacks. see Stroke (CVA) Brain Attack Surveillance in Corpus Christi (TX) Project, 93 BRFSS. See Behavioral Risk Factor Surveillance System (BRFSS) British Medical Association (BMA), 232 British Medical Journal on atherosclerosis, 535–536 on combination pharmacotherapy, 476 on sodium and HBP, 320 British Regional Heart Study on alcohol consumption, 434 on diabetes, 368 on metabolic syndrome, 378 on physical inactivity, 208 CAC (Coronary artery calcium) score, 43 CAD, use of term, 4 Calls to action. see Action plans Canadian Heart Health Initiative, 659 Candidate genes, 152, 542 CARDIA (Coronary Artery Risk Development in Young Adults Study), 12, 26, 54, 454–455 Cardiac rehabilitation programs, 213 Cardiomyopathies, 8, 124, 125, 381 Cardiovascular Disease Prevention and Control (WHO), 664–665 Cardiovascular diseases, major aortic aneurysms and, 111–113, 120–123 arrhythmias and, 135–136 atherosclerosis, 41–55 congestive heart disease, 58–83 congestive heart failure, 111–113, 123–132 peripheral arterial disease, 111–120 pulmonary embolism, 111–113, 132–135 related conditions, 111–136 stroke, 89–107 venous thromboembolism, 111–113, 132–135 Cardiovascular Diseases and Stroke in African-Americans and Other Racial Minorities in the United States (AHA), 29 Cardiovascular Health and Disease in Women report, 27 Cardiovascular Health Promotion in the Schools (AHA), 609 Cardiovascular Health Study (CHS), 12, 26, 44, 115

Cardiovascular Risk in Young Finns Study, 456 Cardiovascular Survey Methods (WHO), 63–64 Carotid artery, ultrasonography and, 43 Carotid IMT (CIMT), 43–44, 50 Case-control-family design, 145 Case-fatality for coronary heart disease, 71–72, 82–83, 105–107 definition, 65 hospitalization and, 127–130 for stroke, 91, 97–98 CATCH. See Coordinated Approach to Child Health (CATCH) Program Causal pie model, 540–541 Causal Thinking in the Health Sciences (Susser), 538 Causes, of cardiovascular diseases, 535–548 for atheroslcerotic diseases, 543–547 causal constructs, 540–543 causal judgment, 537–540 causal pathways, 544–546 causal thinking, 538–539 causes vs. mechanisms, 542–543 etiology vs. pathogenesis, 542–543 for hypertensive diseases, 543–547 from molecules to populations, 541–542 mutifactorial causation, 537–538 Present Reality continuum, 546–547 risk factors and, 543–544, 546 from single agent to n-dimensional complex, 540–541 CDP (Coronary Drug Project), 292 Centers for Disease Control and Prevention (CDC). See also National Center for Health Statistics (CDC); A Public Health Action Plan to Prevent Heart Disease and Stroke (CDC) Action Plan, 689–690 Advancing the Nation’s Health, 690 Atlas of Heart Disease and Stroke Among American Indians and Alaska Natives, 94 Best Practices for Comprehensive Tobacco Control Programs, 421 on combination pharmacotherapy, 476 HDSP Policy Project website, 612 Heart Disease and Stroke Prevention Division, 612, 647 on inflammation, 488 Lipid Standardization Program, 273 on mortality rates, 66 National Diabetes Fact Sheet website, 371 National Office of Genomics and Disease Prevention, 155 Preventing Death and Disability from Cardiovascular Diseases, 666 Racial and Ethnic Disparities in Heart Disease Among Women, 30–31 on resource limitations, 672 scope of, 647 surveillance systems, 12 Cerebral arteries, 89–90. see also Stroke Chagas disease, 124, 689 Chart Book (NHLBI), 70, 96 CHD. See Coronary heart disease (CHD) CHD, use of term, 4 CHF. See Congestive heart failure (CHF)

699

Chicago Heart Association Detection Project in Industry Study, 77, 246, 248 Chicago Peoples Gas Study, 375 Chicago Western Electric Company Study, 176, 435 Child and Adolescent Trial for Cardiovascular Health. see Coordinated Approach to Child Health (CATCH) Program Children and adolescents. See also Age AHA guidelines for, 181, 182, 604–605, 609 alcohol consumption and, 437 atherosclerosis and, 49–54 birth weight and, 515–518 blood lipids and, 261–262, 272–275, 282, 284, 296, 299 blood pressure and, 318, 326–327, 329, 342 developmental body fat changes, 225 diabetes/metabolic syndrome and, 361, 363, 369, 371–372, 374, 383 health patterns of, 24–25 infant death rates, 515 obesity in, 227–228, 234, 236, 237–238, 242, 256–257 physical activity recommendations, 183 physical inactivity and, 201–202, 208, 214–215 prevalence of risk factors, 12–13 prevention and control, 634 school meal choices, 169, 183 smoking and, 400–405, 417, 420–421 social factors and, 512–513, 515 study on marketing of food products to, 261 tracking of risk factors in, 228 Type A behavior pattern, 455 vulnerable developmental periods, 226–227 Chinese box epidemiology, 679, 682 Chlamydia pneumoniae, 46–47, 477–478 Cholesterol, dietary, 172–176, 237. see also Diet, effects of Chronic bronchitis, 131, 416 Chronic diseases, 620–621 Chronic heart failure. see Congestive heart failure (CHF) Chronic ischemic heart disease, classification of, 64 Chronic obstructive pulmonary disease (COPD), 131 Cigarette smoking. See Smoking, and other tobacco use Cigarette Wars (Tate), 396 CIMT (Carotid IMT), 43–44, 50 CINDI PROGRAM (Country-wide Integrated Noncommunicable Diseases Intervention/WHO), 660–661 Circulation (AHA), 12 Circulatory shock, 312 Coagulation factors, 465 Coagulation pathways, 466–470 Cochrane Collaboration, 574–575 Cochrane Database of Systematic Reviews, 575 Cochrane Handbook for Systematic Reviews of Interventions, 574–575 Coffee and tea, effects of, 178–179 Collaborative Lipoprotein Phenotyping Study, 433, 435

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Combination pharmacotherapy, 476, 624–625 Commission on Social Determinants of Health (CSDH), 504 COMMIT (Community Intervention Trial for Smoking Cessation), 420 Committee on Diet and Health, 181–182 Committee on Vascular Lesions report (AHA), 42 Common SNP, 145 Community Pathology Study (CPS), 52 Community Prevention and Control of Cardiovascular Diseases (WHO), 612 Community prevention strategies. see Population-wide prevention strategies; specific communities Community Preventive Services Task Force on diabetes, 384–385 Guide to Community Preventive Services, 570–571, 607 Comparative Risk Assessment Collaborative Group, 642, 645–646 Computed tomography, ultra-fast, 43–44, 54 Congestive heart failure (CHF) background of, 124 cardiovascular diseases and, 111–113, 123–132 classification of, 112 features of individual cases, 124 hospitalization and, 127–128 incidence of, 128–129 mortality patterns and, 125–128, 131 population studies, 124–125 prevalence, 129 prevention and control, 131 race/ethnicity and, 126, 129 right ventricular failure, 131 risk factors of, 129–130 sex and, 126, 129–130 trends and explanations, 130 Contemporary epidemiology scale, 542 Continuing Survey of Food Intakes by Individuals (CSFII), 170 Control of Cardiovascular Diseases in Developing Countries (IOM), 691–692 Coordinated Approach to Child Health (CATCH) Program, 183 on blood lipid control, 300 on physical inactivity, 214, 215–216 on school meals, 634 COPD (Chronic obstructive pulmonary disease), 131 CORIS (Coronary Risk Factor Study), 632, 634 Coronary arteries, 59–60 Coronary artery calcium (CAC) score, 43 Coronary Artery Risk Development in Young Adults Study (CARDIA), 12, 26, 54, 454–455 Coronary Drug Project (CDP), 292 Coronary heart disease (CHD), 59–83 acute myocardial infarction and, 72 air pollution and, 522–524 background of, 62–63 case-fatality and, 71–72, 82–83, 105–107 coronary arteries, 59–60 depression and, 459 diabetes/metabolic syndrome and, 375–378

diagnostic elements, 64 disability and, 73–74 disparities in, 74 family history and, 146 features of individual cases, 60–62 genetic complexity of, 143–144 hemostatic factors and, 473 incidence of, 67–72 mortality patterns, 66–67 occurrence rates, 65–74 population studies, 63–65 prevalence, 65–66, 72–73 race/ethnicity and, 66, 70–73, 77–78 risk factors, 74–79 sex and, 59, 67–68, 70–73, 77–78, 477 smoking and, 410, 413 sudden death and, 61, 67, 69 trends and explanations, 79–83 triggers, 79, 208 Coronary Risk Factor Study (CORIS), 632, 634 Correlations with vascular pathology, 24 Cost-Effectiveness in Health and Medicine, 583 Cotinine. See Smoking, and other tobacco use Council on Arteriosclerosis (AHA), 42 Council on Epidemiology and Prevention (AHA), 63, 92 Country-wide Integrated Noncommunicable Diseases Intervention (CINDI) Program (WHO), 660–661 CPS (Community Pathology Study), 52 C-reactive protein (CRP), 369, 474, 488–489 Criteria for Evaluation of Novel Markers of Cardiovascular Risk (AHA), 490–491 Critical Challenges (Pew Commission), 691 CSDH (Commission on Social Determinants of Health), 504 CSFII (Continuing Survey of Food Intakes by Individuals), 170 CT angiography, 43 CT scans, 43–44, 54 Cultural heritability, 142 CUORE Study, 606 Current issues alcohol consumption, 446–447 arrhythmias, 135–136 chronic heart failure, 123, 131–132 deep vein thrombosis, 134–135 hemostatic factors, 475 peripheral arterial disease, 118, 120 psychosocial factors, 464 pulmonary embolism, 134–135 CVA. See Stroke (CVA) CVD, use of term, 4 DALYs. See Disability-adjusted life years (DALYs) Da Qing IGT and Diabetes Study, 382 DASH Trial (Dietary Approaches to Stop Hypertension) blood pressure and, 321, 342, 343 coronary heart disease risk and, 179–180 optimal dietary pattern and, 163–164 DCCT (Diabetes Control and Complications Trial), 384

Deaths rates. see Mortality patterns Decision making. see Evidence-based decision making Decline Conference reports (NHLBI, 1978), 67, 79–80, 642 DECODE (Diabetes Epidemiology) Study Group, 375, 377–378 Deep vein thrombosis (DVT). see Venous thromboembolism (VTE) Depression, 456–460 Determinants, of cardiovascular diseases adverse blood lipid profile, 269–304 diabetes and metabolic syndrome, 361–388 dietary imbalance, 159–186 genes and environment, 141–156 high blood pressure, 311–352 obesity, 223–262 other personal factors, 431–491 physical activity, 191–217 smoking, 395–424 social and physical environment, 503–528 Determinants of Myocardial Infarction Onset Study, 179 Developing countries. see also Disease Control Priorities in Developing Countries Project (World Bank) community intervention, 632–634 mortality patterns in, 5–6 prevention and control, 561–563 DGA (Food Guide Pyramid), 163–164 Diabetes and metabolic syndrome, 361–388 asymptomatic hyperglycemia and, 375–377 biological mechanisms of, 368–369 blood insulin and, 377 body mass index and, 237 community/population-wide measures, 384–385 concepts and definitions, 363–366 coronary heart disease and, 375–378 determinants of, 367–368 diabetes control, 383–384 genetic factors and, 368 large/small vessel disease, 381–382 measurement methods, 366–367 metabolic syndrome, 363–366, 372–373, 384 population distribution and, 369–375 prevention and control, 382–387 public health issues, 374–375, 382, 385–386 race/ethnicity and, 369–374, 378 screening tests, 366–367, 387 stroke and, 378–381 Diabetes Control and Complications Trial (DCCT), 384 Diabetes in America study (1995), 377 Diabetes mellitus. see Diabetes and metabolic syndrome Diabetes Prevention Program (DPP), 382–383 Diabetes Self-Management Education (DSME), 383, 384–385 Diastolic pressure. see also High blood pressure (HBP) dysfunction of, 124 hypertension and, 313, 314–318 measurement methods, 317

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as risk factor, 74–75 stroke and, 101–102 Diet, effects of, 172–180 affluent society diet, 160–161, 164, 165 Atkins Diet, 165, 179 childhood recommendations, 181, 182 coffee and tea, 178–179 DASH Trial, 163–164, 179–180, 321, 342, 343 dietary cholesterol, 172–176 dietary fiber, 160–161, 163–165, 178, 506 fats and coronary heart disease, 173–176 fats and total cholesterol, 172 folate, 181, 432, 444, 487–488, 595 high blood pressure and, 319–322, 342, 343–344, 350–351 hunter-gatherer diet, 160–161 Mediterranean diet, 164, 175, 179 mortality patterns and, 179 nutrients and, 179–180 omega-3 fatty acids, 177–178 optimal dietary pattern, 180–182 Ornish Diet, 165, 179 popular diets, 164–165 public health issues, 184–185 saturated fat consumption, 161 Sugar Busters! diet, 165 TLC diet, 165 trans fatty acids, 176–177 Weight Watchers Diet, 165, 179 Zone Diet, 179 Diet, Nutrition and the Prevention of Chronic Diseases (WHO), 184 Diet and Health study (NRC) on alcohol consumption, 434, 437 on changes in dietary patterns, 161 on diet and chronic disease, 172 on dietary assessment methods, 166 on dietary fiber, 178 on high blood pressure, 319–320 on nutrients, 162–163 Diet and Lifestyle Recommendations Revision 2006 (AHA), 180–181 Dietary Assessment Resource Manual, 166 Dietary imbalance, 159–186 blood lipids and, 275 cardiovascular-related effects of diet, 172–180 changes in national dietary patterns, 161–162 community/population-wide measures, 182–184 concepts and definitions, 161–165 dietary composition, 164 dietary prescriptions, 165 evolution of eating patterns, 160–161 food choice determinants, 168–170 foods and, 163–164 measurement methods, 165–168 nutrients and, 162–165, 179–180 optimal dietary pattern, 180–182 popular diets and, 164–165 population distribution and, 170–172 prevention and control, 180–185 Dietary Intervention Study in Children (DISC), 296 Diet-Heart Feasibility Study, 172 Disability-adjusted life years (DALYs) alcohol consumption and, 445

blood lipids and, 290–291 blood pressure and, 338–340, 350 coronary heart disease and, 73–74 depression and, 460 diabetes and, 375–376 global projections for, 14–15, 638 obesity and, 233 physical inactivity and, 211 risk factors and, 16 smoking and, 413, 585 stroke and, 98–99, 107 DISC (Dietary Intervention Study in Children), 296 Disease Control Priorities in Developing Countries Project (World Bank) action plans, 665 on alcohol consumption, 444–446 on blood lipids, 301–302 on chronic diseases, 620 on depression, 460 on incidence of diabetes, 375 on obesity interventions, 261 on prevention and control, 561–562 scope of, 7, 613 on smoking, 403, 413 DPP (Diabetes Prevention Program), 382–383 DSME (Diabetes Self-Management Education), 383, 384–385 Dying Too Young (2005), 646–647 EACPR (European Association for Cardiovascular Prevention and Rehabilitation), 683 Eating pattern determinants, 168–170 EBM (Evidence-based medicine), use of term, 570 EBPH (Evidence-based public health), use of term, 570 ECG-LVH (Left ventricular hypertrophy), 129 Economic issues amenable mortality in U.S., 640 cost-effectiveness of intervention, 301–303, 385–388 cost-effectiveness of prevention, 640–642, 673 decision making and, 571, 583–587 in global public health efforts, 9–10, 385–387 income groups and, 13–14, 17 medical care costs in U.S., 13–14 prevention strategies and, 640–642 research funding, 690–691 Education levels, as risk factor, 27, 99, 506–509 Eight Americas project, 30–31, 33, 510 Elderly, 25–26, 345, 604. See also Age Emergency care/acute case management, use of term, 555–556, 560–561 Emphysema, 131 Ending the Tobacco Problem (2007), 415 End-of-life care, use of term, 556, 561 Endogenous tissue-type plasminogen activator (tPA), 474 Environment, use of term, 503 Environmental factors. see Genes and environment; Social and physical environment The Environment and Disease (Hill), 539–540

701

EPIC (European Prospective Investigation into Cancer and Nutrition), 179, 440–441 Epidemiologic transition theory public health issues and, 7–9, 32 westernization and, 503, 514 Epidemiology of Diabetes and Its Vascular Lesions, 362 Epigenetic epidemiology, 143 Epinephrine, 323 EROS (European Registers of Stroke) Collaboration, 97 ESC (European Society of Cardiology), 577, 597 Essential vascular package (EVP), 476 Estrogen. see Hormone replacement therapy (HRT) Ethnicity. see Race/ethnicity EURAMIC study, 177 European Association for Cardiovascular Prevention and Rehabilitation (EACPR), 683 European Atherosclerosis Society, 597 European Cardiovascular Indicators Surveillance Set (EUROCISS), 683 European Collaborative Trial of Multifactorial Prevention of Coronary Heart Disease, 631 European Prospective Investigation into Cancer and Nutrition (EPIC), 179, 440–441 European Registers of Stroke (EROS) Collaboration, 97 European Society of Cardiology (ESC), 577, 597 European Society of Hypertension, 597 Evaluating Community Efforts to Prevent Cardiovascular Diseases, 684 Evans County Study, 22 Evidence-based decision making, 567–587 ACC/AHA approach, 575–577 clinical intervention, 574–579 Cochrane Collaboration and, 574–575 community intervention, 579–583 economic evaluations and, 583–587 evaluation of evidence, 573–579 external validity, 573, 586 GCPS approach, 579–584 Levy’s arrow, 568–569 nature of evidence, 569–570 randomized controlled trials and, 572–573, 575–576 RE-AIM approach, 583, 585 study design algorithm, 580, 581 Evidence-based medicine (EBM), use of term, 570 Evidence-Based Public Health (2003), 569 Evidence-based public health (EBPH), use of term, 570 EVP (Essential vascular package), 476 Exdrinkers, risk factors of, 434. see also Alcohol consumption Exercise, 192–193, 213, 526–527. see also Physical inactivity Expert Panel on Guidelines for Use of Dietary Intake Data, 167 External validity, 573, 586 Familial aggregation, 24, 144 Familial concordance, 24 Familial risks, genes and environment, 142

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Family Blood Pressure Program, 153–154 My Family Health Portrait assessment tool, 150 Family history blood lipids and, 274–275 coronary heart disease and, 146–149 genes and environment and, 146–150 high blood pressure and, 318–319 high-risk families, 146–147 optimal dietary pattern and, 180 parental genetic influences, 149–150 FAO (Food and Agriculture Organization), 161–162, 175–176 Fat distribution, definition, 226 Fatness, definition, 225 Fats, dietary, 172–178. see also Diet, effects of FCTC (Framework Convention on Tobacco Control), 396, 423–424 FDA. See Food and Drug Administration, U.S. (FDA) Fetal and neonatal development, 24 Fetal origins hypothesis, 318 FHS. See Framingham Heart Study (FHS) Fiber, dietary effects of, 160–161, 163–165, 178, 506 recommendations on, 256, 294, 299, 385 Fibrinogen alcohol consumption and, 434–436 coronary events and, 472–473 genetic factors and, 471 insulin resistance and, 369 risk factors and, 470–471 smoking and, 414, 432 thrombosis and, 465–470 Fibrinolysis alcohol consumption and, 435–436 impairment of, 474 obesity and, 236 physical activity and, 196–197 thrombosis and, 400 Finnish Mental Hospital Study, 292–293 Fogarty International Center goals, 685, 687 Folate, 181, 432, 444, 487–488, 595 Food and Agriculture Organization (FAO), 161–162, 175–176 Food and Drug Administration, U.S. (FDA) dietary guidelines, 167 on tobacco regulation, 422 trans fat content labeling, 177 Food and Nutrition Board (IOM), 177 Food chain elements, 168 Food Guide Pyramid (DGA), 163–164 Foods. see also Diet, effects of; Dietary imbalance coffee and tea, 178–179 fish consumption, 177–178 Food Guide Pyramid, 163–164 Framework Convention on Tobacco Control (FCTC), 396, 423–424 Framingham Heart Study (FHS) on blood lipids, 286–290 on congestive heart failure, 128–130 on coronary heart disease, 81 on diabetes and stroke, 381 40 year follow-up, 124–125 on genetic factors in obesity, 230 on incidence of stroke, 96 population diversity of, 22

on risk factors, 16, 71, 77, 543 risk scores and, 606 scope of, 59, 62, 74 on stroke, 103–104 on sudden deaths, 126 website, 12 on weight and disease, 246 Franklin Cardiovascular Health Program, 626–628, 630–631 Fredrickson classification, of blood lipids, 271–272 Fundamentals of Genetic Epidemiology (Khoury), 142 The Future of Public Health report (1988), 551, 609–610 The Future of the Public’s Health in the 21st Century (IOM), 556–557 Gaining Health (WHO-EURO), 648, 661–663 GBDS (Global Burden of Disease Study), 459–460 GCPS. See Guide to Community Preventive Services (GCPS) Gender. see Sex General Accounting Office (GAO), on lipid measurement standards, 273 Genes and environment, 141–156. see also specific diseases blood lipids, 153, 271–272 blood pressure, 153–154 cardiovascular applications of genomic epidemiology, 152–155 cardiovascular diseases and, 143–144 epigenetic epidemiology, 143 familial risks, 142 family history and, 146–150 genetic complexity of coronary heart disease, 143 genetic epidemiological concepts, 144–145 genetic testing, 156 genome-wide association studies, 145, 152 interaction of, 150–152 linkage analysis, 144–145 population-based family designs, 145 public health issues, 155 research strategies and, 155 stroke, 154–155 Genetic Factors in Coronary Heart Disease (Goldbourt et al.), 152, 368 Genetics and Public Health in the 21st Century, 143 Genetic testing, 156 Genome-wide association (GWA) studies, 145, 152 Geographic information systems (GIS), 30, 525 Geography/place disparities in Appalachia, 30, 32 in eight Americas, 30–31, 33, 510 health patterns and, 29–31 German Cardiovascular Prevention Study, 631–632 GIS (Geographic information systems), 30, 525 Global Burden of Disease and Risk Factors Study (World Bank) on blood lipids, 290 on depression, 460

on diabetes, 382 on global burden of risk, 636, 638–639, 642 on limitations of death registrations, 65 on obesity, 253 on physical inactivity, 211 on public health issues by income/region, 13–14 on risk factors, 16 on smoking, 396 on stroke, 107 Global Burden of Disease Study (GBDS), 459–460 Globalization, social factors and, 503, 514 Global public health issues. see Public health issues; specific issues Global Strategy for the Prevention and Control of Noncommunicable Diseases (WHO), 688–689 Global Strategy on Diet, Physical Activity and Health (WHO), 184–185, 191, 192, 216, 613 Global Tobacco Epidemic, 2008 (WHO), 396, 415, 424 Global Youth Tobacco Survey (GYTS), 404, 405 Glucose metabolism. see Diabetes and metabolic syndrome GNP (Gross National Product), per capita food consumption and, 161–162 Greater Cincinnati/Northern Kentucky Stroke Study, 96 Guide for Improving Cardiovascular Health at the Community Level (AHA), 607, 658 Guidelines and policies, 591–614. see also specific organizations on children and adolescents, 604–605 clinical guidelines, 594–607 community guidelines, 607–609 current recommendations, 593 on developing country populations, 612–613 on elderly persons, 604 in Europe, 597–598 on groups of special concern, 600–605 history of, 592–593 individual total risk and, 601–603 policy models, 642–644 on prevention of CHD, 594–596 on prevention of ischemic stroke, 596–597 public policies, 609–613 risk scores and, 605–607 on secondary prevention, 600 on women’s health, 603 worldwide, 598–600 Guide to Community Preventive Services (GCPS) on evidence-based decision making, 570–571, 579–584 guidelines and policies, 607 GWA (Genome-wide association) studies, 145, 152 GYTS (Global Youth Tobacco Survey), 404, 405 HAART (Active antiretroviral therapy), 481 HALE (Healthy life expectancy), 645 Harvard Six Cities Study, 523

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HBP. See High blood pressure (HBP) HDFP (Hypertension Detection and Follow-Up Program), 345–346, 348, 624 HDL-cholesterol. see also Blood lipids alcohol consumption and, 434–435 alcohol consumption and metabolism of, 152 coronary heart disease and, 270 Health, United States reports (CDC), 66, 238 Health Affairs, on race/ethnicity disparities, 28 Health Agenda for the Americas, 2008–2017, 659–660 Health and Human Services, U.S. (HHS). see also Healthy People 2010 (HHS) Physical Activity Guidelines for Americans, 192 Report of the Secretary’s Task Force on Black and Minority Health, 29 Health and Retirement Study, 208 The Health Consequences of Involuntary Exposure to Tobacco Smoke (2006), 396 Health educationalist approach, 670–671 Health family trees, 146 Health Professionals Follow-Up Study, 122–123, 178, 436–437, 444 Health promotion, 553, 673 Health-related quality of life (HRQoL), 73, 98–99 HealthStyles surveys, 150, 348 Healthy Eating Index (HEI), 170 Healthy life expectancy (HALE), 645 Healthy People 2010 (HHS) on blood pressure, 327 on diabetes, 372 goals of, 21, 561 guidelines and policies, 611 on heart disease, 127 on high cholesterol, 277 on levels of prevention, 674 physical activity and, 202 scope of, 647, 658, 666 on stages of prevention, 551 on stroke, 99 Healthy weight, definition, 228–229 Heart attacks. see Myocardial infarction Heart Disease and Stroke Prevention Division (CDC), 612, 647 Heart Disease and Stroke Statistics-2009 Update, 135 Heart failure. see Congestive heart failure (CHF) Heartfile, 661–662 Heart Health Network action plans, 662–665 Heart Outcomes Prevention Evaluation (HOPE), 485, 488 HEI (Healthy Eating Index), 170 Helicobacter pylori, 46–47 The Helsinki Multifactorial Primary Prevention Trial, 624 Hemostatic factors, 432, 464–475 alcohol consumption and, 435–436 coagulation factors, 465 coagulation pathways, 466–470 established risk factors and, 470–471 fibrinogen, 369, 414, 432, 434–436, 465–473 fibrinolysis and, 172, 196–197, 236, 400, 435–436, 472, 474

genetic factors and, 471 measurement methods, 465–466 menopause and, 472 population distribution and, 471–472 prevention and control, 474–475 risk factors and, 470–471 studies on, 472–474 theoretical schemes, 466 thrombolytic treatment, 475 Henle-Koch postulates, 539 Heredity. see Genes and environment Herpesvirus group, 46 HHS. See Health and Human Services, U.S. (HHS) High blood pressure (HBP) age and, 317–318 biological mechanisms of, 322–323 body mass index and, 237 classification of, 314–316 community/population-wide measures, 348–350 concepts and definitions, 312–316 as CVD determinant, 311–352 determinants of, 317–322 dietary issues and, 319–322, 342, 343–344, 350–351 family history and, 318–319 incidence of, 333–336 individual differences, 336–338 measurement methods, 316–317 population differences, 336 population distribution and, 323–336 prevention and control, 341–351 public health issues, 338–339, 350–351 race/ethnicity and, 317–318, 323–326, 336 sex and, 317–318 stroke and, 16, 103–104, 336–339 treatment algorithm, 344 High cholesterol, 153, 269, 274. see also Blood lipids High-risk families, 146–147. see also Family history HIV/AIDS, 432, 481 HMG CoA reductase, 294 Homocysteine Studies Collaboration (2002), 486–487 Honolulu Heart Program, 176, 434–435, 460–461 HOPE (Heart Outcomes Prevention Evaluation), 485, 488 Hormone replacement therapy (HRT), 432, 472, 476–479 Hostility and anger, 454–455. see also Type A behavior pattern HRQoL (Health-related quality of life), 73, 98–99 HRT (Hormone replacement therapy), 432, 472, 476–479 Human Body Composition, 225 Human Genome Epidemiology (Khoury et al.), 143 Human Genome Project, 156 Hunter-gatherer diet, 160–161 Hypercholesterolemia, 153, 269, 274. see also Blood lipids Hyperglycemia, 52, 361. see also Diabetes and metabolic syndrome Hyperhomocysteinemia, 432, 476, 485–488 Hyperlipidemia. see also Blood lipids

703

causal pathways, 544 Fredrickson classification of, 271–272 impaired fibrinolysis and, 472 prevention and control, 610, 620–621 screening tests, 384, 604 secondary, 275–276 Hypertension. see also High blood pressure (HBP) essential vs. secondary, 313–314 use of term, 54 Hypertension Control (WHO), 348–349 Hypertension Detection and Follow-Up Program (HDFP), 345–346, 348, 624 Hypertension Primer, 322–323 IAP (International Atherosclerosis Project), 47–49 ICD 10. See International Statistical Classification of Diseases and Related Health Problems (ICD 10) IHD, use of term, 4 IMPACT model, 81–82, 642 Implementation research, 685. see also Prevention research agendas IMT (Intimal-medial thickness), 43, 50 Incidence & Prevalence (NHLBI) on congestive heart failure, 128–129 on current studies, 69, 72 on incidence of stroke, 96 Income, mortality patterns and, 506–509 Indian Polycap Study (TIPS), 476 Indirect auscultatory method, 316 Infant death rates, social factors and, 515 Infection, as risk factor, 477–478, 480–481 Inflammation, as risk factor, 46, 488–489 Influenza vaccinations, 481 Institute of Medicine (IOM) on childhood obesity, 256–257, 262 on combination pharmacotherapy, 476 Control of Cardiovascular Diseases in Developing Countries, 691–692 Diet and Health report, 181 Ending the Tobacco Problem, 415 The Future of the Public’s Health in the 21st Century, 556–557 Preventing Childhood Obesity, 256–257 Progress in Preventing Childhood Obesity, 262 research agendas and, 691–692 Social-Ecological Framework, 557 on social environments, 504 on trans fatty acids, 177 Insulin-glucose regulation. see Diabetes and metabolic syndrome Insulin resistance, obesity and, 236 Insulin Resistance Atherosclerosis Study (IRAS), 369 INTERHEART Study on acute myocardial infarction, 76 on blood lipids, 290 on community intervention, 671 on dietary patterns, 180 on global burden of risk, 639, 640 on obesity, 250–252 on psychosocial factors, 462 on smoking, 410–413 INTERMAP study, 167, 321–322 Intermittent claudication, use of term, 114 International Action on Cardiovascular Disease, 648–649, 662–664

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International Atherosclerosis Project (IAP), 47–49 International Heart Health Society, 648, 662–664, 689 International Journal of Epidemiology, on genetic epidemiology, 143 International Obesity Task Force (IOTF), 243, 256, 261 International Physical Activity Questionnaire (IPAQ), 202–204 International Society of Hypertension, 351 International Statistical Classification of Diseases and Related Health Problems (ICD 10) atherosclerosis and, 44 circulatory system diseases, 4–5 classification of diabetes, 363 coronary heart disease and, 64 related conditions, 111–112 stroke and, 92–93 International Studies of Infarct Survival (ISIS) Study, 471 International Symposium on Moderate Drinking and Health, 445 International Textbook of Diabetes Mellitus, 363 International Union for Health Promotion and Education (IUHPE), 553 INTERSALT Study on alcohol consumption, 437, 440 on blood pressure, 317–318 on body mass index, 243 on sodium and HBP, 321 Inter-Society Commission for Heart Disease Resources guidelines and policies, 610–611 Primary Prevention of the Athersclerotic Diseases, 610 Intimal-medial thickness (IMT), 43, 50 Investing in Health Research and Development (WHO), 687–688 IOM. See Institute of Medicine (IOM) IOTF (International Obesity Task Force), 243, 256, 261 IPAQ (International Physical Activity Questionnaire), 202–204 IRAS (Insulin Resistance Atherosclerosis Study), 369 Ireland-Boston Study, 176 Ischemic heart disease alcohol consumption and, 444 diabetes and, 378 genetic factors, 153 obesity and, 254–255 physical inactivity and, 211 risk factors of, 16–17 ISIS (International Studies of Infarct Survival) Study, 471 IUHPE (International Union for Health Promotion and Education), 553 Jenkins Activity Survey (JAS), 454 Job strain, 455–458 Journal of Chronic Diseases, on HenleKoch postulates, 539 Justification for Use of Statins in Prevention (JUPITER), 489 Kenyan Luo Migrant Study, 520 Know Your Body Program, 634

Korotkov sounds, 316 Kuopio Ischemic Heart Disease Risk Factor Survey, 471 The Lancet on alcohol consumption, 444–445 on chronic diseases, 620, 641, 649–650 on genetic epidemiology, 144 on global public health impacts, 16 on health promotion in clinical practice, 673 The Lancet Neurology, on stroke, 107 Large-vessel PAD (LV-PAD), 114–115, 119 LDL-cholesterol, 269, 273, 485. see also Blood lipids Lectures on Angina Pectoris and Allied States (Osler), 62 Left ventricular hypertrophy (ECG-LVH), 129 Leisure time physical activity (LTPA), 193, 208 Levy’s arrow (research continuum), 568–569 Life Course Perspectives on Coronary Heart Disease, Stroke, and Diabetes (WHO), 688 Life course research, 688 Life-course view, on obesity, 230–232 Life expectancy at birth, 8–9 Lifestyle Modification for the Prevention and Treatment of Hypertension, 343 Linkage analysis, genes and environment, 144–145 Lipids. see Blood lipids Lipid Standardization Program (CDC), 273 Lipoprotein molecules, 270–271 London School of Hygiene questionnaire, 65, 114 Longitudinal Investigation of Thromboembolism Etiology, 132–133 LTPA (Leisure time physical activity), 193, 208 LV-PAD (Large-vessel PAD), 114–115, 119 Magnetic resonance imaging (MRI), 43, 92, 93–94 Marketing influences, on smoking behaviors, 398 Measurement methods. see specific methods and diseases Medical Expenditure Panel Survey (MEPS), 73, 98–100 Medical Nutrition Therapy (MNT), 383 Medicine and Science in Sports and Exercise, on assessment questionnaires, 194 Mediterranean diet, 164, 175, 179 MED PED program, 146, 274 Men. See Sex Menopause hemostatic factors and, 472 HRT and, 432, 472, 476–479 MEPS (Medical Expenditure Panel Survey), 73, 98–100 MESA (Multi-Ethnic Study of Atherosclerosis), 43, 232, 524 Metabolic syndrome (MetS). see Diabetes and metabolic syndrome

Methodology Manual for ACC/AHA Guideline Writing Committees, 575–577 Metropolitan Life Insurance Company, on desirable weight tables, 225 MetS (metabolic syndrome). see Diabetes and metabolic syndrome Mexican-Americans. see Race/ethnicity Microalbuminuria, 381 Migration blood pressure and, 322 social factors and, 513, 518–520 Minnesota Heart Health Program, 626–630 Minnesota Heart Survey, 64 Minnesota Leisure Time Physical Activity questionnaire, 206 Minnesota Multiphasic Personality Inventory (MMPI), 449, 454 MNT (Medical Nutrition Therapy), 383 Modified Framingham Stroke Risk Profile, 103 MONICA Project (WHO) on alcohol consumption, 151–152, 434, 435 on antioxidants, 481–482 on blood pressure, 330–333, 335 on coronary heart disease, 59, 82–83 diagnostic elements, 63–64 on global cholesterol levels, 281–282 population diversity of, 71–72 research agendas and, 691 on stroke, 92, 94–96, 98, 105–107 on worldwide mortality rates, 67–69, 94–96, 105–107 MONItoring Trends and Determinants in CArdiovascular Disease. see MONICA Project Mortality patterns. See also specific studies age and, 20–21, 23–24 aortic aneurysms and, 121–122 arteriosclerosis and, 173 congestive heart failure and, 125–128, 131 coronary heart disease and, 65–67 in developing countries, 5–6 diet and, 179 education and, 506–509 in eight Americas, 30–31, 33, 510 globally, 5–6 income and, 506–509 in industrial countries, 5–6 myocardial infarction and, 66 peripheral arterial disease and, 115 physical inactivity and, 209–211 stroke and, 91–96, 98–99, 104–107 subclinical disease and, 44–45 in U.S., 6–7, 12–13, 19–22, 66, 253, 510 venous thromboembolism and, 133–134 WHO data (1950–1987), 32, 34–35 in women, ages 35 and older, 31 World Bank estimates (1988–1998), 10–11 World Bank estimates (2001), 13–14 MPOWER Package (smoking prevention), 396, 415, 424 MRFIT. See Multiple Risk Factor Intervention Trial (MRFIT) MRI (Magnetic resonance imaging), 43, 92 stroke and, 93–94

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Multi-Ethnic Study of Atherosclerosis (MESA), 43, 232, 524 Multi-factor primary prevention, 621–636 intervention in communities, 625–634 intervention in individuals, 622–625 intervention in youth, 634 in North Karelia Project, 625–628 outcomes, 634–636 trials, 622–625 The Multifactor Primary Prevention Trial, 623–624 Multi-infarct dementia, 91 Multinational Study of Vascular Disease in Diabetics (WHO), 381 Multiple Risk Factor Intervention Trial (MRFIT) on blood lipids, 285–286 on coronary heart disease, 75–76 on diabetes, 378, 380 on dietary assessment methods, 167 intervention in individuals, 622–623 mortality patterns and, 639 on physical inactivity, 206–207 on smoking, 414 on stroke, 102–103 on Type A behavior pattern, 454 Muscatine Study, 54 Myocardial infarction. see also Atherosclerosis alcohol consumption and, 151–152, 435–436 atherosclerotic plaque and, 41–42 causal pathways, 544 classification of, 64 elderly survival of, 25–26 heart failure and, 124 high-risk families and, 146–149 job strain and, 456 mortality patterns and, 66 physical activity and, 208 rehabilitation with exercise, 213 thrombosis and, 62 National Action Plan for Prevention and Control of Non-Communicable Diseases and Health Promotion in Pakistan, 661–662, 664 National Bureau of Standards, 273 National Center for Health Statistics (CDC), 12 Assessing Physical Fitness and Physical Activity in Population-Based Surveys, 194 Health, United States reports, 66, 238 on stroke, 93–94 National Cholesterol Education Program (NCEP) on blood lipid control, 270, 294–295, 300–301, 303–304 on diabetes and coronary heart disease, 362 on global burden of risk, 636–638 guidelines and policies, 594–596, 600, 603 guidelines for children, 272–273 on HIV/AIDS, 481 on Therapeutic Lifestyle Changes, 165 National Cooperative Pooling Project, U.S. blood lipids and, 285, 287 population diversity and, 22 on risk factors, 74–76

on smoking, 407–409 on weight and disease, 245–246 National Council of State Legislatures, 612 National Diabetes Fact Sheet website (CDC), 371 National Forum for Heart Disease and Stroke Prevention, 611–612, 658, 668–670 National Health and Nutrition Examination Surveys (NHANES) on ABI categories, 115 on blood pressure, 317, 335–336, 348 on congestive heart failure, 126–127, 129 continuous data collection, 12 on diabetes, 361, 369–371 on global burden of risk, 636–638 on high blood pressure, 323–324 on incidence of stroke, 98 on metabolic syndrome, 372–373, 378 on modifiable dietary factors, 179 on mortality decline (II Study), 81 on mortality decline (I Study), 81 on nutrition, 170 on prehypertension, 314, 326 on prevalence of high cholesterol in U.S., 277–280 on pro-oxidants, 485 proposed goals of, 685–687 research agendas and, 685–687 on risk factors (III Study), 77 on smoking, 400, 401–403, 414 on sodium and HBP, 320 National Health Education Committee, Inc., A Statement on Arteriosclerosis, Main Cause of “Heart Attacks” and “Strokes,” 543 National Health Interview Survey (2004) on alcohol consumption, 437 on ischemic heart disease, 378 on prediabetes, 383 on race/ethnicity disparities, 28 on smoking, 400 National Health Service (UK), 294, 296 National Heart, Lung and Blood Institute (NHLBI), 12. see also National Cholesterol Education Program (NCEP) Cardiovascular Health and Disease in Women report, 27 Chart Book, 70, 96 on CRP, 488–489 Decline Conference reports (1978), 67, 79–80, 642 guidelines and policies, 594–596, 604 on heart failure mortality rates, 126 Incidence & Prevalence, 69, 72, 96, 128–129 on incidence of stroke, 96 research agendas and, 685–687, 691 Task Force on Research in Epidemiology and Prevention of Cardiovascular Diseases, 685–687 Working Group on Genome Wide Association in NHLBI Cohorts, 155 National High Blood Pressure Education Program, 326, 341–342 National Hospital Discharge Surveys, 377–378 National Human Genome Research Institute, 155 National Institutes of Health (NIH) as funding source, 690

705

on health disparities, 20 on obesity, 224, 225 on population diversity, 22 research agendas and, 685, 687 on smoking, 415 National Longitudinal Mortality Study (1979–1989), 29, 506–508 National Mortality and Morbidity Air Pollution Study (NMAPS), 523 National Mortality Follow-Back Survey (1986), 378 National Office of Genomics and Disease Prevention (CDC), 155 National Research Council (NRC). see Diet and Health study (NRC) National Survey on Drug Use and Health, 437 Nationwide Food Consumption Survey (NFCS), 170 NCEP. See National Cholesterol Education Program (NCEP) n-dimensional complex, 540–541, 682 Neighborhood characteristics, as risk factor, 524–527 NEMS-S (Nutrition Environment Measures Survey-Stores), 169 NHANES. See National Health and Nutrition Examination Surveys (NHANES) NHLBI. See National Heart, Lung and Blood Institute (NHLBI) Nicotine addiction, 396, 400. See also Smoking, and other tobacco use NIH. See National Institutes of Health (NIH) Ni-Hon-San Study, 62, 519 NMAPS (National Mortality and Morbidity Air Pollution Study), 523 Norepinephrine, 323 North Karelia Project, 625–628 Northwick Park Heart Study (NPHS), 471–472 Norwegian Adolescent Follow-Up Study, 248–249 Norwegian Vitamin (NORVIT) Trial, 488 Novel risk factors, 489–491 Nuclear lung scans, 134 Nurses Health Study on alcohol consumption, 436–437 on body mass index, 236 on smoking, 409 on smoking and BMI, 246–247 on trans fatty acids, 176 Nutrition Environment Measures SurveyStores (NEMS-S), 169 Obesity, 223–262 biological mechanisms of, 233–236 community/population-wide measures, 259–261 concepts and definitions, 224–229 determinants of, 229–232 genetic factors and, 230–231 measurement methods, 229 population distribution and, 236–244 prevention and control, 253–262, 572 public health issues, 241, 243–244, 253, 261–262 race/ethnicity and, 238, 241 risk factors of, 230 sex and, 243, 248–249

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(Obesity cont’d) studies on, 244–252 treatment algorithm, 257 validity of surveys and, 170 Obesity: Preventing and Managing the Global Epidemic (WHO), 259–261 Obesity Education Initiative, 226 Occupational stress, 455–458 Omega-3 fatty acids, 177–178. see also Diet, effects of Ontario Survey on the Prevalence and Control of Hypertension (2006), 332–333 Ornish Diet, 165, 179 The Oslo Study, 623 Overweight, definition, 225–227. see also Obesity Oxygen supply, 196–197 PAD. See Peripheral arterial disease (PAD) Palpitations. see Arrhythmias Partnership for Prevention, 658 Partnership to Fight Chronic Disease, 658 Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Study, 49–54, 249, 412–413 Paul Coverdell National Acute Stroke Registry, 93 Pawtucket Heart Health Program, 626–628, 630 PE. See Pulmonary embolism (PE) Peasant agriculturalist diet, 160–161 Pediatrics, on childhood obesity, 256 Perinatal Collaborative Project, 318 Peripheral arterial disease (PAD) ankle-brachial index, 120 ankle-brachial index and, 114–118 background of, 114 cardiovascular diseases and, 111–120 classification of, 112 hospitalization and, 112 mortality patterns and, 115 population studies, 114 race/ethnicity and, 115, 117–118 risk factors of, 115–119 sex and, 117–118 Person, place, and time factors atherosclerosis and, 47–49 health patterns and, 32–35 scales of time, 32 WHO data, 32, 34–35 Personal factors, in cardiovascular disease risk, 431–491 adverse psychosocial factors, 431–432, 447–464 alcohol consumption, 433–447 emerging factors, 476–491 hemostatic factors, 432, 464–475 Pew Health Professions Commission, 691 Physical activity, definition, 192 Physical Activity and Health, 191–192 Physical Activity and Public Health, 213 Physical Activity Guidelines for Americans (HHS, 2008) on physical inactivity, 192, 206, 212–213 physical inactivity and, 211 Physical environment. see Social and physical environment Physical fitness, definition, 193–194 Physical inactivity, 191–217 biological mechanisms of, 196–198

cardiovascular-related effects of, 204–211 community/population-wide measures, 214–216 concepts and definitions, 192–194 determinants of, 194, 196 measurement methods, 194 population distribution and, 197, 199–204 prevention and control, 211–217 public health issues, 211 race/ethnicity and, 197–202 sex and, 197–202, 207 social factors and, 526–527 Physicians Health Study, 435–436, 442, 474 PIOPED (Prospective Investigation of Pulmonary Embolism), 134 Policies. see Guidelines and policies; specific organizations Policy analysis, 684–685 Policy Framework Statement for Regional and Global Partnerships, 611–612 Polypills. see Combination pharmacotherapy Popular diets, 164–165 Population-based family designs, 145 Population-Based Prevention of Obesity (AHA), 259 Population-wide prevention strategies action plans, 670–673 alcohol consumption and, 445 blood lipids and, 299–301 community intervention in North Karelia, 625, 626–628 community intervention in U.S., 626–634 diabetes/metabolic syndrome and, 384–385 heart healthy nutrition and, 182–184 high blood pressure and, 348–350 physical inactivity and, 214–216 smoking and tobacco use, 419–422 walkability indexes, 216 Populomics, 680, 692–693 Prediabetes, use of term, 363, 368. see also Diabetes and metabolic syndrome Pregnancy, 230, 385, 423, 445, 578 Present Reality continuum, 546–547, 552, 560, 562 Preventing Childhood Obesity (IOM), 256–257 Preventing Chronic Diseases (WHO), 620 Preventing Coronary Heart Disease in South Asia (SAARC), 662 Preventing Death and Disability from Cardiovascular Diseases (CDC/HNLBI), 666 Preventing Tobacco Use Among Young People, 398 Prevention, evidence for, 619–650 counter-arguments, 621, 649 economic issues and, 640–642 future trends, 646–649 global burden of risk and, 636–640, 642–647 intervention in communities, 625, 628–634 intervention in individuals, 622–625 intervention in youth, 634 low risk populations and, 639–640

multi-factor primary prevention and, 621–636 policy models, 642–644 predictive models, 642–647 Prevention and Control of Noncommunicable Diseases, 665 Prevention Effectiveness, 583 Prevention in Childhood and Youth of Adult Cardiovascular Diseases (WHO), 301, 342, 423 Prevention of Cardiovascular diseases (WHO), 350 Prevention of Coronary Disease (WHO), 612 Prevention of Diabetes Mellitus (WHO), 363–364 The Prevention of Stroke (Gorelick and Alter), 92 Prevention research agendas, 679–693 capacity requirements, 690–692 CDC Action Plan, 689–690 concepts of epidemiology, 681–682 Fogarty International Center goals, 687 goals of, 682–683 implementation research, 685 institutionalization and, 691–692 International Heart Health Society, 689 NHLBI goals, 685–687, 691 outcomes, 682–683 personnel training, 691 policy analysis, 684–685 populomics, 692–693 program evaluations, 684 sponsorship and funding, 690–691 surveillance strategies, 683 systems research, 685 WHO goals, 687–689 Prevention strategies, 551–565 for atherosclerosis, 54–55 for blood lipids, 292–299 concepts and language of, 552–557 for congestive heart failure, 131 developing country perspective, 561–563 for diabetes/metabolic syndrome, 382–387 for dietary imbalance, 180–185 emergency care/acute case management, 555–556, 560 end-of-life care, 556, 561 in global public health, 15–17, 216–217 hemostatic factors and, 474–475 for high blood pressure, 341–351 high-risk approach, 563–564 intervention approaches, 560–561 lifestyle changes, 556 multi-factor intervention, 556 for obesity, 253–262, 572 outcomes, 557–560 pharmacotherapy, 556 for physical inactivity, 211–217 policy and environmental change, 560 psychosocial factors and, 462–464 public health framework, 557–558 rehabilitation/long-term case management, 556, 561 risk factor detection and control, 555, 560 settings of, 556–557 single-factor intervention, 556 for smoking, 414–424 Preventive Medicine on children’s physical activity, 192 on physical inactivity, 214

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Preventive Services Task Force (USPSTF) on adult obesity, 257–258 on behavioral counseling, 182, 213, 445 on blood lipids, 303–304 on blood pressure, 342 on childhood obesity, 256 on diabetes, 384 on evidence-based decision making, 577–578 on hemostatic factors, 474 on HRT, 477 on obesity, 118 on smoking, 417 Primary Prevention of Essential Hypertension (WHO), 341, 612–613 Primary Prevention of Heart Failure (AHA), 131 Primary Prevention of Ischemic Stroke (AHA), 103 Primary Prevention of the Athersclerotic Diseases, 610 Primordial prevention, 551, 554, 558–559 PROCAM Study, 606 Progress in Preventing Childhood Obesity (IOM), 262 Project HeartBeat!, 234, 236, 282, 284 Pro-oxidants, 485 Prospective Diabetes Study (UKPDS), 384 Prospective Investigation of Pulmonary Embolism (PIOPED), 134 Prospective Studies Collaboration, 101–103, 337–338 Psychosocial factors, 431–432, 447–464 depression, 456–460 favorable attributes, 452–453 measurement methods, 449 occupational stress, 455–458 prevention and control, 462–464 public health issues, 464 race/ethnicity and, 450 sex and, 450 social support, 460–462 stress research, 449–452 theoretical background of, 448–449 Type A behavior pattern, 453–455 A Public Health Action Plan to Prevent Heart Disease and Stroke (CDC) background of, 657, 665–666 components of, 666–667 implementation of, 668–669 institutionalization of, 669 research agendas and, 680, 683, 684, 689–690 scope of, 611 strategic imperatives, 658, 673–675 summary of determinants, 547 Public health issues, 3–35. see also Population-wide prevention strategies; Prevention strategies age and life stages, 22–26 blood lipids, 290, 299–302 cartography of, 29–30 diabetes/metabolic syndrome, 374–375, 382, 385–386 dietary patterns, 170, 184–185 disability-adjusted life years (DALYs), 14–15, 638 economic issues, 9–10, 385–387 epidemiologic transition theory, 7–9, 32, 503, 514

genes and environment, 155 geography and place of, 29–30 global concerns, 5–10, 14–15 health disparities, 20–22 high blood pressure, 338–339, 350–351 international classification, 4–5 International Physical Activity Questionnaire, 216–217 list of characteristics, 490 mortality patterns in U.S., 6–7, 12–13, 19–22, 30–31, 33 obesity, 241, 243–244, 253, 261–262 occurrence rates, 10–11 person, place, and time, 32–35 physical activity questionnaire, 202–204 prevention and control, 15–17, 216–217, 636–640, 642–647 psychosocial factors, 464 race/ethnicity and, 27–29 salt intake, 350–352 scope of, 3–5 sex and, 26–27 smoking, 403–404, 413–414, 422–424 treaties on, 396, 423–424 world income groups/regions, 13–14 years of life lost (YLL), 14–15, 73–74, 290–291 Public Health Strategies for Preventing and Controlling Overweight and Obesity in School and Worksite Settings, 261 Pulmonary embolism (PE), 111–113, 132–135. see also Venous thromboembolism (VTE) Quetelet’s index. see Body mass index (BMI) A Race Against Time study (2004) on chronic diseases, 16 on economic investment in prevention, 641 on future trends, 646–647 on government intervention, 562–563 on productive years of life lost, 15 Race/ethnicity alcohol consumption and, 437–440 ascertainment of, 28 atherosclerosis and, 44–45, 47, 49, 51 blood lipids and, 274, 277, 280 classification of, 27–28 congestive heart failure and, 126, 129 coronary heart disease and, 66, 70–73 diabetes/metabolic syndrome and, 369–374, 378 high blood pressure and, 317–318, 323–329, 336 modifiability of, 22 and morality patterns in U.S., 19–22 mortality patterns and, 20 obesity and, 238, 241 peripheral arterial disease and, 115, 117–118 physical inactivity and, 197–202 prevalence of risk factors and, 12–13 psychosocial factors and, 450 smoking and, 400, 406 stroke and, 89, 98–99 Racial and Ethnic Disparities in Heart Disease Among Women (CDC), 30–31

707

Randomized controlled trials (RCTs), 572–573, 575–576 RE-AIM approach, on evidence-based decision making, 583, 585 Recommendations. see Guidelines and policies; specific organizations Reducing Tobacco Use (2000), 417 Rehabilitation/long-term case management, use of term, 556, 561 Relative weight, measurement methods, 229 Relevance of Genetics and Genomics for Prevention and Treatment of Cardiovascular Disease, 143 Report of a Joint FAO/WHO Expert Consultation, 184 Report of the Secretary’s Task Force on Black and Minority Health (HHS), 29 Report of the Special Writing Group on Cardiovascular Disease in Women (AHA), 27 Report on Tobacco Control in India, 423 Research. see Prevention research agendas; specific organizations and studies Research-policy interface, 569 Response-to-injury hypothesis, 46 Rheumatic fever/heart disease, 4, 7–8, 30, 124, 665, 689 Rich diet, 160–161, 164, 165 Right ventricular failure, congestive heart failure and, 131 Risk factor, use of term, 489 Robert Wood Johnson Foundation, 194, 527 Robin Hood Index, 508 Rose questionnaire, 65, 114 Rotterdam Study, 122 SAARC (South Asian Association for Regional Cooperation), 662 Salt, Diet & Health, on high blood pressure, 319 Salt intake blood pressure and, 319–321, 343 global reduction strategies, 350–352 increases in, 170 mortality patterns and, 179 Schools. see also Population-wide prevention strategies Know Your Body Program, 634 meal choices, 169, 183, 634 smoking prevention programs, 420–421 Science on genetic testing, 156 on high-risk family factors, 146, 149 on physical inactivity, 217 Secondhand smoke exposure, 396–397. See also Smoking, and other tobacco use Sedentary lifestyle. see Physical inactivity Sensible Drinking report, 445, 446 Seven Countries Study, 62, 70–71 blood lipids and, 282–285 on blood pressure, 336 on dietary assessment methods, 166–167 on dietary cholesterol intake, 176 on fats and coronary heart disease, 174–175 obesity and, 244 physical activity and, 204–206 scope of, 59 on smoking, 404, 414 on trans fatty acids, 176–177

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INDEX

Sex alcohol consumption and, 437–440, 443 aortic aneurysms and, 121 ascertainment of, 26 atherosclerosis and, 44, 47–49, 51–53 blood lipids and, 274, 282, 286–290, 296 blood pressure and, 597–599 classification of, 26 congestive heart failure and, 126, 129–130 coronary heart disease and, 59, 67–68, 70–73, 77–78, 477 health patterns of, 26–27 high blood pressure and, 317–318 modifiability of, 22 and morality patterns in U.S., 19–22 mortality patterns and, 20 obesity and, 243, 248–249 peripheral arterial disease and, 117–118 physical activity and, 197–202, 207 psychosocial factors and, 450 public health issues and, 26–27 smoking and, 406 stroke and, 96 SHEP (Systolic Hypertension in the Elderly Program), 345 Silent infarction, definition, 61 Single-nucleotide polymorphism (SNP), 145 Skinfold thickness, 224 SMARTRAQ (Strategies for Metropolitan Atlanta’s Regional Transportation and Air Quality), 216 Smokefree laws, 422 Smoking, and other tobacco use aortic aneurysms and, 122 biological mechanisms of, 398–400 body mass index and, 237, 246–247 community/population-wide measures, 419–422 concepts and definitions, 396–397 coronary heart disease and, 75–76, 151 harm reduction and, 424 individual differences, 407–413 initiation stages, 398, 399 intervention options, 418 marketing and, 398 measurement methods, 397 other tobacco use and, 395–424 population differences, 404–407 population distribution and, 400–404 pregnancy and, 578 prevention and control, 414–424 public health issues, 403–404, 413–414, 422–424 race/ethnicity and, 400, 406 secondhand smoke, 397 sex and, 406 smokeless tobacco and, 396, 400 treatment algorithm, 419 Smoking and Health report, 539 SNP (Single-nucleotide polymorphism), 145 Social and physical environment, 503–528 birth weight and, 515–518 changes in social conditions, 512–522 diet/physical activity and, 525–526 economic development and, 514 globalization and, 514 infant death rates, 515

migration and, 513, 518–520 neighborhood characteristics, 524–527 particulate air pollution, 522–525 programming mechanism, 518 social change concepts, 512–513 social development and, 515–518 social status, 505–512 societal changes over time, 513–514 socioeconomic status and social change in U.S., 520–522 westernization of population groups, 503, 514 Social disadvantage, 509–512 Social-Ecological Framework (IOM), 557 Social environment. see Social and physical environment Social status, 505–512 disparities in health and, 510 income and education, 506–509 occupational class and, 505–507 Robin Hood Index, 508 social disadvantage and, 509–512 Social support, 460–462 Societal influences, on smoking behaviors, 398 Socioeconomic Inequalities in Health Working Group (EU), 506 Sodium intake. see Salt intake South Asian Association for Regional Cooperation (SAARC), 662 Standards for Medical Care in Diabetes2009, 383 Stanford Five-City Program, 72, 626–630, 671 Stanford Three-City Program, 626–629 A Statement on Arteriosclerosis, Main Cause of “Heart Attacks” and “Strokes,” 211, 543 State programs, (US), 554–555, 612, 666. see also Population-wide prevention strategies Statins, 294–296, 489 Status syndrome, 511–512 Strategies for Metropolitan Atlanta’s Regional Transportation and Air Quality (SMARTRAQ), 216 Strategies of prevention. see Prevention strategies Strategy for the Prevention and Control of Noncommunicable Diseases and Injuries in the Russian Federation, 660 The Strategy of Preventive Medicine (Rose), 552 Stress research, psychosocial factors and, 449–452 Stroke belt region, 92, 94, 105 Stroke (CVA), 89–107 background of, 91–92 body mass index and, 248, 250 case-fatality and, 91, 97–98 cerebral arteries, 89–90 diabetes/metabolic syndrome and, 378–381 diagnostic elements, 92 disability and, 98–100 disparities in, 99 features of individual cases, 90–91 genetic factors and, 154–155 high blood pressure and, 16, 17, 336–339 incidence of, 96–97

mortality patterns and, 91–96, 104–107 population studies, 92–93 prevalence, 98 race/ethnicity and, 89, 93–94, 98–99 risk factors of, 16–17, 101–104 sex and, 96 trends and explanations, 104–107 Sudden death, 65, 208 Sugar Busters! diet, 165 Surgeon General Reports, U.S. on health promotion and disease prevention, 553 on nutrition and health, 184 on smoking, 396, 398, 404, 411–412, 414, 417, 419, 422 Surveillance strategies, 683 Sydney Principles (IOTF), 261 Syndrome X, 364. see also Diabetes and metabolic syndrome Systolic Hypertension in the Elderly Program (SHEP), 345 Systolic pressure, 123–124, 316, 317. see also High blood pressure (HBP) TAAG (Trial of Activity for Adolescent Girls), 208 Taking action. see Action plans Taking the Initiative (AHA), 607–609, 658 Task Force on Community Preventive Services on evidence-based decision making, 579–584 on obesity, 261 on physical inactivity, 214 on school-based intervention programs, 183 Task Force on Research in Epidemiology and Prevention of Cardiovascular Diseases (NHLBI), 685–687 Tecumseh Study, 22 Therapeutic Lifestyle Changes (TLC) on blood lipid control, 299 blood pressure and, 342–348 diabetes/metabolic syndrome and, 382–383 TLC diet, 165 Thin-cap fibroatheroma, 42 Third Joint Task Force Recommendations (Europe), 597–598 Thrifty gene hypothesis, 367–368 Thrombolytic treatment, 475 TIA (Transient ischemic attack), 91, 92, 96 TIPS (Indian Polycap Study), 476 TLC. See Therapeutic Lifestyle Changes (TLC) TLC diet, 165 Tobacco use. See Smoking, and other tobacco use TOHP (Trials of Hypertension Prevention), 343 tPA antigen, 474 Tracking obesity and, 225, 228 of risk factors in childhood, 24 Trans fatty acids, 176–177. see also Diet, effects of Transient ischemic attack (TIA), 91, 92, 96 Treaties, on global health, 396, 423–424

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Treatment. see specific cardiovascular diseases Trial of Activity for Adolescent Girls (TAAG), 208 Trials of Hypertension Prevention (TOHP), 343 Triglycerides, classification of, 271. See also Blood lipids Trust for America’s Health, 658, 672–673 T2DM mellitus. see Diabetes and metabolic syndrome Type A behavior pattern, 453–455 development of concept, 453 hostility and anger, 454–455 initial findings, 453 modifiability of, 454 Western Collaborative Group Study results, 453–454 UCLA Health Forecasting Project, 241 Ultra-fast computed tomography (UFCT), 43–44, 54 Ultrasonography aortic aneurysms and, 121 on carotid arteries, 43 PAD assessment and, 114 United States. See also specific organizations and studies health related economic issues in, 13–14, 640 medical care costs (2009), 10 mortality patterns in, 6–7, 12–13, 19–22, 66, 253, 510 socioeconomic status and social change in, 520–522 Unnatural Causes: Is Inequality Making Us Sick? (film), 510 Unstable angina, 61, 64, 452 USPSTF. See Preventive Services Task Force (USPSTF) Västerbotten Intervention Program, 632–633 Venography, 134 Venous thromboembolism (VTE) background of, 132–133 cardiovascular diseases and, 111–113, 132–135 classification of, 112 features of individual cases, 132 mortality patterns and, 133–134 population studies, 133 risk factors of, 134 Ventricular arrhythmias, 135–136 Ventricular fibrillation (VF), 135 Ventricular tachycardia (VT), 135 VERB Campaign, 214–215 Veterans Administration, U.S., 345 The Victoria Declaration on Heart Health, 648 Viral infections, 46, 480 A Vital Investment (WHO), 648 Vitamin B complex, 485–487 Vitamin E, 481–482 VTE. See Venous thromboembolism (VTE)

Waist-hip ratio (WHR) diabetes and, 368, 372 measurement methods, 224, 229, 236, 244, 251 Walking, as exercise, 526–527 Web of causation, 540–541 Weight. see Obesity Weight Watchers Diet, 165, 179 Western Collaborative Group Study, 453–454 Western Diseases (Trowell and Burkitt), 514 Westernization, of population groups, 503, 514 WHA. See World Health Assembly (WHA) WHI. See Women’s Health Initiative (WHI) WHO. See World Health Organization (WHO) WHR. See Waist-hip ratio (WHR) William J. Clinton Foundation, 183 Women, AHA guidelines for, 603. see also Sex Women’s Health Initiative (WHI) on air pollution exposure, 523–524 on aspirin treatment, 475 on HRT, 476–477 risk scores and, 606 Women’s Health Study (WHS), 248, 488 Worcester DVT Study, 132–133 Work, stress and, 455–458 Working Group on Genome Wide Association in NHLBI Cohorts, 155 World Action on Salt & Health, 351 World Bank. See also Disease Control Priorities in Developing Countries Project (World Bank); Global Burden of Disease and Risk Factors Study (World Bank) on government intervention, 562 on mortality rates by region, 10–11, 13–14 on per capita food consumption, 161–162 World Health Assembly (WHA) on alcohol consumption, 444 on coronary heart disease, 301 on diabetes, 385 on dietary recommendations, 184–185 on physical inactivity, 192 on prevention and control, 664–665 on smoking, 423 World Health Organization (WHO). see also MONICA Project (WHO) on alcohol consumption, 445–446 atherosclerosis studies, 48–49 Blood Press Studies in Children, 342 on BMI, 226 on burden of risk, 638 Cardiovascular Disease Prevention and Control, 664–665 Cardiovascular Survey Methods, 63–64 CINDI Program, 660–661

709

Community Prevention and Control of Cardiovascular Diseases, 612 Diet, Nutrition and the Prevention of Chronic Diseases, 184 on estimated lost income, 10 on evidence-based decision making, 579–580 Gaining Health, 648, 661–663 Global Strategy for the Prevention and Control of Noncommunicable Diseases, 688–689 Global Strategy on Diet, Physical Activity and Health, 184–185, 191, 192, 216, 613 Global Tobacco Epidemic, 2008, 396, 415, 424 guidelines and policies, 598, 601–603, 612–613 Hypertension Control, 348–349 International Physical Activity Questionnaire, 202–204 Investing in Health Research and Development, 687–688 Life Course Perspectives on Coronary Heart Disease, Stroke, and Diabetes, 688 map of distribution of DALYs, 15 Multinational Study of Vascular Disease in Diabetics, 381 on obesity, 243–244, 259 Obesity: Preventing and Managing the Global Epidemic, 259–261 on physical inactivity, 216 Preventing Chronic Diseases, 620 Prevention in Childhood and Youth of Adult Cardiovascular Diseases, 301, 342, 423 Prevention of Cardiovascular Diseases, 350 Prevention of Coronary Disease, 612 Prevention of Diabetes Mellitus, 363–364 Primary Prevention of Essential Hypertension, 341, 612–613 research goals, 687–689 on smoking, 414–415 STEPS Stroke System, 97 Study Group Report, 25 Surveillance STEPS program, 683 A Vital Investment, 648 website, 15 World Health Report, 2004, 67–69 World Heart and Stroke Forum, 593 World Heart Federation, 593, 664 Worldwide Efforts to Improve Heart Health, 634–635, 664 Years of life lost (YLL), 14–15, 73–74, 290–291 Youth Media Campaign Longitudinal Survey, 215–216 Youth Risk Behavior Survey (YRBS), 171, 208, 400 Zone Diet, 179

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