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Textbook of Interventional Cardiovascular Pharmacology

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Textbook of Interventional Cardiovascular Pharmacology Nicholas N. Kipshidze FACC FESC FSCAI Professor of Medicine and Surgery Consultant Cardiologist Cardiovascular Research Foundation Director, Preclinical Research Lenox Hill Heart and Vascular Institute New York NY USA Director and Physician in Chief Central University Hospital Tblisi Georgia

Jawed Fareed PhD FACB Professor of Pathology and Pharmacology Director of Hemostasis and Thrombosis Research Laboratories and Department of Pathology Loyola University, Stritch School of Medicine Maywood IL USA

Jeffrey W. Moses MD FACC Professor of Medicine Director, Center for Interventional Vascular Therapy Director, Cardiac Catheterization Laboratories Columbia University Medical Center New York-Presbyterian Hospital New York NY USA

Patrick W. Serruys MD PhD FACC FESC Professor and Head Interventional Department Thoraxcenter Erasmus University Medical Center Rotterdam The Netherlands

Associate Editor:

Cathy Kennedy MLS Columbia University Medical Center New York NY USA

Forewords by Valentin Fuster MD PhD and Richard H Kennedy PhD

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© 2007 Informa UK Ltd First published in the United Kingdom in 2007 by Informa Healthcare, Telephone House, 69 -77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954. Tel: +44 (0)20 7017 5000 Fax: +44 (0)20 7017 6699 Website: www.informahealthcare.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A CIP record for this book is available from the British Library. Data available on application ISBN-10: 1 84184 438 1 ISBN-13: 978 184184 438 1 Distributed in North and South America by Taylor & Francis 6000 Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, USA Within Continental USA Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401 Outside Continental USA Tel: (561) 994 0555; Fax: (561) 361 6018 Email: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel: +44 (0)1264 332424 Email: [email protected] Cover design concept by Cathy Kennedy Cover image is the chemical and molecular structure of the anticoagulant heparin Back cover illustration: electron micrographs of drug distribution Composition by Egerton + Techset Printed and bound in India by Replika Press Pvt Ltd

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Contents

List of contributors

ix

Foreword

Valentin Fuster

xvii

Foreword

Richard H. Kennedy

xix

Preface

xxi

Acknowledgments Color plate Part I

xxiii xxv–xxxii

Systemic and Endoluminal Therapy

1

An overview of hemostasis and thrombosis Walter Jeske, Debra A. Hoppensteadt, Asad Shaikh, Jeanine M. Walenga, Mamdouh Bakhos, and Jawed Fareed

1

2

Principles of antiplatelet therapy Raul Altman, Alejandra Scazziota, and María de Lourdes Herrera

31

3

Glycoprotein IIb/IIIa inhibitors Sanjay Kaul

41

4

Adenosine diphosphate receptor inhibitors Michel E. Bertrand

59

5

Phosphodiesterase inhibitors: dipyridamole and cilostazol James J. Ferguson

69

6

Heparin, low molecular weight heparin Raphaelle Dumaine and Gilles Montalescot

79

7

Direct thrombin inhibition in percutaneous coronary intervention Derek P. Chew, Sam J. Lehman, and Harvey D. White

85

8

Clinical application of direct antithrombin inhibitors in acute coronary syndrome Shunji Suzuki, Hikari Watanabe, Takefumi Matsuo, and Masanori Osakabe

93

9

Oral antithrombin drugs Brigitte Kaiser

109

10

Rationale for direct factor Xa inhibitors in acute coronary syndromes Volker Laux and Markus Hinder

119

11

Combined anticoagulant and antiplatelet therapy Harry I. Messmore, Erwin Coyne, Meghan Businaro, Omer Iqbal, William Wehrmacher, and Walter Jeske

127

12

Fibrinolytic therapy Freek W. A. Verheugt

135

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13

Resistance to antiplatelet drugs Paul A. Gurbel and Udaya S. Tantry

139

14

Lipid-lowering agents Andrew M. Tonkin and Omar Farouque

155

15

Improving the diagnosis and management of high blood pressure in the cardiac patient Clarence E. Grim

171

16

Homocysteine regulators Torfi F. Jonasson and Hans Ohlin

177

17

Role of systemic antirestenotic drugs and results of current clinical trials Ron Waksman

185

18

Role of systemic antineoplastic drugs in the treatment of restenosis after percutaneous stent implantation Alfredo E. Rodriguez

195

19

Antioxidants Umberto Cornelli

211

20

Iron chelation: deferoxamine and beyond Valeri S. Chekanov

241

Part II

Local Therapy

21

Stent-mediated local drug delivery Yanming Huang, Lan Wang, and Ivan De Scheerder

22

The application of controlled drug delivery principles to the development of drug-eluting stents Kalpana R. Kamath, Kathleen M. Miller, and James J. Barry

249

267

23

Brachytherapy Ravi K. Ramana, Ferdinand Leya, and Bruce Lewis

279

24

Polymers and drug-eluting stents Robert Falotico and Jonathon Zhao

289

25

Utilization of antiproliferative and antimigratory compounds for the prevention of restenosis Kalpana R. Kamath and James J. Barry

299

26

Anti-inflammatory drugs, sirolimus, and inhibition of target of rapamycin and its effect on vascular diseases Steven J. Adelman

315

27

Anti-migratory drugs and mechanisms of action Ivan De Scheerder, Xiaoshun Liu, and Yanming Huang

325

28

Antiangiogenetic drugs—mechanisms of action Christodoulos Stefanadis, and Konstantinos Toutouzas

339

29

Vasculoprotective approach for restenosis Nicholas Kipshidze, Jean-François Tanguay, Alexandre C. Abizaid, and Antonio Colombo

347

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Contents

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30

Vascular endothelial growth factor Neil Swanson and Anthony Gershlick

355

31

Gene therapy: role in myocardial protection Alok S. Pachori, Luis G. Melo, and Victor J. Dzau

363

32

Antisense approach Patrick Iversen and Martin B Leon

371

33

Principles of photodynamic treatment Thomas L. Wenger and Nicholas H. G Yeo

381

Part III

Cell Therapy and Therapeutic Angiogenesis

34

Angiogenesis and myogenesis Shaker A. Mousa

393

35

Growth factor therapy Munir Boodhwani, Joanna J. Wykrzykowska, and Roger J. Laham

407

36

Cell transplantation for cardiovascular repair Doris A. Taylor, Harald Ott, and Patrick Serruys

419

37

Clinical trials in cellular therapy Joanna J. Wykrzykowska, Munir Boodhwani, and Roger J. Laham

439

Part IV

Adjunctive Pharmacotherapy

38

The heart failure patient Basil S. Lewis and Mihai Gheorghiade

451

39

The acute coronary syndrome patient John F. Moran

465

40

Cardiovascular interventional pharmacology in the diabetic patient Mitchell D. Weinberg and George D. Dangas

473

41

Atrial fibrillation during catheterization Yves L. E. Van Belle, M. F. Scholten, and Luc J. Jordaens

483

42

Contrast-induced nephropathy after percutaneous coronary interventions Ioannis Iakovou

493

43

Erectile dysfunction Graham Jackson

503

44

Peripheral arterial disease Zoran Lasic and Michael R. Jaff

515

45

Pharmacotherapy peri-percutaneous coronary intervention Waqas Ullah, Rakesh Sharma, and Carlo Di Mario

525

46

Pharmacologic management of patients with CTO interventions David R. Holmes, Jr

537

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47

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Contents

Newer pharmacologic approaches targeting receptors and genes Omer M. Iqbal, Debra Hoppensteadt, and Jawed Fareed

Part V

543

Noncoronary Interventions

48

Carotid artery stenting Amir Halkin, Sriram S. Iyer, Gary S. Roubin, and Jiri Vitek

555

49

Anticoagulants in peripheral vascular interventions Rajesh M. Dave, Azim Shaikh, and Mubin Syed

569

50

Repair of AAAs Alexandra A. MacLean and Barry T. Katzen

583

51

Interventions for structural heart disease Ralph Hein, Neil Wilson, and Horst Sievert

593

52

Pharmacological use of ethanol for myocardial septal ablation George Dangas, Edwin Lee, and Jeffrey W. Moses

603

Epilogue: Anticoagulant management of patients undergoing interventional procedures Jawed Fareed

613

Appendix A

619

Appendix B

623

Index

627

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Contributors

Alexandre C. Abizaid MD PhD

Mehgan Businaro

Institute Dante Pazzanese of Cardiology Sa~o Paulo Brazil

Midwest University Downers Grove IL USA

Steven J. Adelman PhD

Valeri S. Chekanov MD PhD

Nano Medical, Inc. Doylestown PA USA

Heart Care Associates Milwaukee Heart Institute Milwaukee WI USA

Raul Altman MD PhD

Derek P. Chew MBBS MPH FCSANZ

Centro de Trombosis de Buenos Aires Buenos Aires Argentina

Green Lane Cardiovascular Research Unit Flinders University and Medical Centre Adelaide Australia

James J. Barry PhD Boston Scientific Corporation Corporate Research and Advanced Technology Department Natick MA USA

Michel E. Bertrand MD FRCP FACC FAHA

Antonio Colombo EMO Centro Luore Columbus and San Ran Raffaele Hospital Milan Italy

Umberto Cornelli MD PhD

Lille Heart Institute Lille France

President, European Society of Biological Nutrition Loyola University Medical School Chicago IL USA

Rodger L. Bick MD PhD FACP

Erwin Coyne

Clinical Professor of Medicine University of Texas Southwestern Medical Center Director, Thrombosis Hemostasis and Vascular Medicine Clinical Center Dallas TX USA

Hines Veteran Affairs Hospital Hines IL USA

Munir Boodhwani BIDMC/Harvard Medical School Boston MA USA

George D. Dangas MD PhD Department of Medicine Columbia University Medical Center Program Director, Interventional Cardiology New York-Presbyterian Hospital New York NY USA

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Rajesh M. Dave MD

Mihai Gheorghiade MD FACC

Associate Cardiologists Harrisburg PA USA

Feinberg School of Medicine Northwestern University Chicago IL USA

Raphaelle Dumaine MD Institut de Cardiologie Pitié-Salpeˆtriére University Hospital Paris France

Victor J. Dzau MD Professor of Medicine Duke University Medical Center Durham NC USA

Clarence Grim BS MS MD Clinical Professor of Medicine and Epidemiology Shared Care Research, Education and Consulting Inc. Milwaukee WI USA

Paul A. Gurbel MD

Cordis Corporation Warren NJ USA

Director, Sinai Center for Thrombosis Research Sinai Hospital of Balimore Associate Professor of Medicine Department of Medicine John Hopkins University Baltimore MD USA

Jawed Fareed PhD

Amir Halkin MD

Department of Pathology Loyola University Stritch School of Medicine Maywood IL USA

Lenox Hill Heart and Vascular Institute New York NY USA

Omar Farouque MBBS (Hons) PhD FRACP FACC

Centro de Trombosis de Buenos Aires Buenos Aires Argentina

Robert Falotico

Interventional Cardiologist Department of Cardiology Austin Health Melbourne Australia

James J. Ferguson MD

María de Lourdes Herrera

Ralph Hein MD Cardiovascular Center Frankfurt Frankfurt Germany

Cardiology Research Bayler College of Medicine The University of Texas Health Care Center Houston USA

Markus Hinder MD

Anthony Gershlick

Division of Cardiovascular Diseases and Internal Medicine Mayo Clinic Rochester MN USA

Cardiology Clinical Sciences Department Glenfield Hospital Leicester UK

Sanofi-Aventis, Science & Medical Affairs Frankfurt Germany

David R. Holmes, Jr MD

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Debra Hoppensteadt PhD

Walter Jeske

Department of Pathology Loyola University Stritch School of Medicine Maywood IL USA

Cardiovascular Institute Loyola University Medical Center Maywood IL USA

Yanming Huang MD PhD

Torfi F. Jonasson MD PhD

Departments of Cardiology and Cell Biology The Cleveland Clinic Foundation Cleveland OH USA

Dept of Cardiology University Hospital of Iceland Reykjavik Iceland

Ioannis Iakovou MD Department of Cardiology Army Hospital of Thessaloniki and Blue Cross Heart Centre Thessaloniki Greece

Omer M. Iqbal MD FACC Department of Pathology Loyola University Stritch School of Medicine Maywood IL USA

Patrick Iversen PhD AVI-BioPharma Corvallis OR USA

Sriram S. Iyer MD Lenox Hill Hospital New York NY USA

Graham Jackson FRCP Guys & St. Thomas Hospital Cardiology Department London UK

Michael R. Jaff DO FACP FACC Assistant Professor of Medicine Harvard Medical School Director, Vascular Medicine Massachusetts General Hospital Boston MA USA

Luc J. Jordaens Erasmus University Thoraxcenter Rotterdam The Netherlands

Brigitte Kaiser MD PhD Friedrich Schiller University Jena Faculty of Medicine Institute for Vascular Medicine Jena Germany

Kalpana R. Kamath PhD Boston Scientific Corporation Corporate Research and Advanced Technology Department Natick MA USA

Barry T. Katzen MD Founder and Medical Director Baptist Cardiac and Vascular Institute Miami FL USA

Sanjay Kaul MD Director, Vascular Physiology and Thrombosis Laboratory Division of Cardiology Cedars-Sinai Medical Center Professor, David Geffen School of Medicine UCLA Los Angeles CA USA

xi

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Nicholas N. Kipshidze MD PhD FACC, FESC

Bruce E. Lewis MD

Cardiovascular Research Foundation New York NY USA

Division of Cardiology Loyola University Medical Center Maywood IL USA

Roger J. Laham MD BIDMC/Harvard Medical School Boston MA USA

Zoran Lasic MD FACC Department of Interventional Cardiology Lenox Hill Hospital New York NY USA

Volker Laux PhD Thrombosis Research Department Bayer Healthcare AC Wuppertal Germany

Edwin Lee MD PhD Fellow in Cardiology Albert Einstein College of Medicine Montefiore Medical Center Bronx NY USA

Ferdinand Leya MD Division of Cardiology Loyola University Medical Center Maywood IL USA

Xiaoshun Liu MD PhD Department of Cardiology University Hospital Leuven Belgium

Alexandra A. MacLean MD Assistant Professor of Surgery Department of Surgery New York Hospital, Queens Flushing NY USA

Carlo Di Mario MD PhD FACC, FESC

Flinders University and Medical Centre Adelaide Australia

Department of Cardiology Royal Brompton Hospital London UK

Martin B. Leon MD FACC

Takefumi Matsuo MD

Cardiovascular Research Foundation, Center for Interventional Vascular Therapy Columbia University Medical Center New York NY USA

Hyogo Prefectural Awaji Hospital Hyogo-ken Japan

Sam J. Lehman MBBS

Basil S. Lewis MD FRCP FACC Department of Cardiovascular Medicine Lady Davis Carmel Medical Center Haifa Israel

Luis G. Melo PhD Associate Professor of Physiology Department of Physiology College of Medicine Queen’s University Kingston, Ontario Canada

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Harry L. Messmore MD

Harald Ott MD

Cancer Center Loyola University Medical Center Maywood IL USA

Scientific Director Center for Cardiovascular Repair University of Minnesota Minneapolis MN USA

Kathleen M. Miller PhD Boston Scientific Corporation Corporate Research and Advanced Technology Department Natick MA USA

Alok S. Pachori PhD

Gilles Montalescot MD FESC

Ravi K. Ramana DO

Institut de Cardiologie Pitie-Salpetriere University Hospital Paris France

Division of Cardiology Loyola University Medical Center Maywood IL USA

John F. Moran MD Professor of Medicine Loyola University Stritch School of Medicine Maywood IL USA

Jeffrey W. Moses MD Professor of Medicine Director, Center for Interventional Vascular Therapy Director, Cardiac Catheterization Laboratories Columbia University Medical Center New York-Presbyterian Hospital New York NY USA

xiii

Instructor in Medicine Duke University Medical Center Durham NC USA

Alfredo E. Rodriguez MD PhD FACC FSCAI Otamendi Hospital - Cardiac Unit Buenos Aires Argentina

Gary S. Roubin MD PhD Lenox Hill Hospital New York NY USA

Alejandra Scazziota PhD Centro de Trombosis de Buenos Aires Buenos Aires Argentina

Shaker A. Mousa PhD MBA FACC FACB

Ivan De Scheerder MD PhD

Pharmaceutical Research Institute Albany College of Pharmacy Albany NY USA

Global Medical Services Keeromstraat Herent Belgium

Hans Ohlin MD PhD

M. F. Scholten

Department of Cardiology University Hospital Lund Lund Sweden

Erasmus University Thoraxcenter Rotterdam The Netherlands

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Patrick Serruys MD PhD

Jean-François Tanguay MD

Thoraxcenter Erasmus University Medical Center Rotterdam The Netherlands

Department of Medicine Montreal Heart Institute Montreal Quebec Canada

Azim Shaikh MD

Udaya S. Tantry PhD

Dayton Interventional Radiology Kettering OH USA

Sinai Center for Thrombosis Research Sinai Hospital of Baltimore Baltimore MD USA

Rakesh Sharma MRCP PhD Department of Cardiology Royal Brompton Hospital London UK

Horst Sievert MD Professor of Medicine Cardiovascular Center Frankfurt Germany

Doris A. Taylor PhD Scientific Director Center for Cardiovascular Repair University of Minnesota Minneapolis MN USA

Andrew M. Tonkin MBBS MD FRACP

Professor of Cardiology Athens Medical School Paleo Psychico Athens Greece

Head, Cardiovascular Research Unit Department of Epidemiology and Preventive Medicine Monash University Central and Eastern Clinical School Alfred Hospital Melbourne Australia

Shunji Suzuki MD

Konstantinos Toutouzas MD PhD

HIT Information Center Hyogo-ken Japan

Athens Medical School Athens Greece

Neil Swanson

Waqas Ullah MBBS

Cardiology Clinical Sciences Department Glenfield Hospital Leicester UK

Department of Cardiology Royal Brompton Hospital London UK

Mubin Syed MD

Yves L. E. van Belle

Clinical Associate Professor of Radiology Wright State University School of Medicine Dayton OH USA

Erasmus University Thoraxcenter Rotterdam The Netherlands

Christodoulos Stefanadis MD PhD

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Freek W. A. Verheugt MD

Thomas L. Wenger MD FACC

Professor of Cardiology University Medical Center St. Radboud Nijmegen The Netherlands

President Wenger Consulting Durham NC USA

Jiri Vitek

Harvey D. White DSc FCSANZ

Lenox Hill Hospital New York USA

Ron Waksman MD Washington Hospital Center Washington DC USA

Director of Coronary Care Unit Green Lane Cardiovascular Unit Auckland City Hospital Auckland New Zealand

Neil Wilson MD

Professor, Thoracic and Cardiovascular Surgery Loyola University Stritch School of Medicine Maywood IL USA

Cardiovascular Center Frankfurt Germany Department of Paediatric Cardiology John Radcliffe Hospital Oxford UK

Lan Wang MD

Joanna J. Wykrzykowska MD

Jeanine Walenga PhD

Institute of Pathology Casewestern Reserve University Cleveland OH USA

Hikari Watanabe

BIDMC/Harvard Medical School Boston MA USA

Nicholas H. G. Yeo

Mitsubishi Pharma Corporation Tokyo Japan

Chief Executive Officer Vascular Reconditioning, Inc. Snoqualmie WA USA

William Wehrmacher

Jonathon Zhao

Cancer Center Loyola University Medical Center Maywood IL USA

Mitchell D. Weinberg MD New York-Presbyterian Hospital Columbia University Medical Center New York NY USA

Cordis Corporation Warren NJ USA

Geert Grooteplein Zuid Nijmegen The Netherlands

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Foreword I am pleased to write this introduction for the Textbook of Interventional Cardiovascular Pharmacology. This definitive international textbook on cardiovascular pharmacology for interventional procedures incorporates contributions from world opinion leaders and a transatlantic perspective. This textbook is a first of its kind for practicing interventional cardiologists, cardiologists, and pharmacologists. Edited by Nicholas Kipshidze, Jawed Fareed, Jeffrey Moses, and Patrick Serruys, the Textbook of Interventional Cardiovascular Pharmacology is an outstanding text that focuses primarily on currently used pharmacologic agents, interventional approaches, and the delivery techniques available for treatment of cardiovascular diseases. In looking forward, the book also covers the exciting potential of various experimental drug therapies such as angiogenetic agents to treat the ischemic heart and limb, cardiovascular cell transplantation to treat the underlying injuries associated with cardiac and vascular disease, and the promising results of clinical trials in these rapidly moving fields. To this end the editors have assembled an impressive roster of international contributors who are all active in the field of interventional cardiology and write from a hands-on perspective. They have analyzed an enormous range of various cardiovascular pharmacological therapies in superbly illustrated and clearly focused chapters. The book is comprised of five sections with part I covering systemic and endoluminal therapy with an incisive overview of hemostasis and thrombosis; part II covers local therapy with several chapters devoted to drug-eluting stents and restenosis therapies; part III covers cell therapy and therapeutic angiogenesis and includes chapters on cell transplantation and clinical trials in cellular therapy; part IV covers adjunctive pharmacotherapy with chapters devoted to various patient populations including those with heart failure, diabetes, atrial fibrillation, peripheral artery disease,

acute coronary syndrome, and chronic total occlusions; and part V covers non coronary interventions such as carotid artery stenting, repair of abdominal aortic aneurysms, and alcohol septal ablation. The text is written with best clinical practice in mind yet provides much information that is translational in nature. The final chapter is an epilogue that provides an objective opinion on current drug development in vascular medicine and interventions. In addition, there is a handy drug table comparing the pharmacokinetics of the various anticoagulants used in cardiovascular medicine. Perhaps for the next edition the editors will include a separate section on imaging since it is a very important development in this decade and promises to stimulate the interest of all concerned and interested in cardiovascular disease, from those in basic science, to those in the interventional and pharmacological fields and to those interested in clinical trials and outcomes. In summary Nicholas Kipshidze, Jawed Fareed, Jeffrey Moses, and Patrick Serruys have put together an outstanding textbook covering a broad range of topics in cardiovascular pharmacology. I would recommend this book to anyone working in the field of cardiovascular disease, clinical research, and pharmacology.

Valentin Fuster MD PhD Director, Zena and Michael A. Wiener Cardiovascular Institute and the Marie-Josee and Henry R. Kravis Center for Cardiovascular Health The Mount Sinai Medical Center Professor of Medicine, Mount Sinai School of Medicine New York NY USA Past President, American Heart Association Immediate Past President, World Heart Federation

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Foreword The Textbook of Interventional Cardiovascular Pharmacology is an excellent up-to-date text that focuses on agents, interventional approaches, and delivery techniques that are available for treatment of, and to some extent prevention of, disease states arising from vascular and intravascular pathologies. Part I focuses on hemostasis and thrombosis, including chapters on available anticoagulant, antiplatelet, and fibrinolytic therapies. Also covered in this section are anti-restenotic drugs and approaches at minimizing proliferative and atherosclerotic processes. The second section, on local therapy, includes chapters on drugeluting stents, antiproliferative and antimigratory drugs, and use of growth factor, gene therapy, antisense, and photodynamic approaches. Part III examines current knowledge regarding cell therapy approaches for cardiovascular repair. Part IV addresses use of adjunctive pharmacotherapy in a number of patient populations, such as those with heart failure, diabetes, peripheral artery disease, and erectile dysfunction, and the final section discusses non-coronary interventions and structural diseases of the heart. Each chapter in this work provides a thorough evaluation and concise presentation that highlights both

recent advances in the field as well as the current overall understanding of the topic. Although written with the best clinical practice in mind, the text provides a wealth of information that is truly translational in nature, bridging pathogenesis and mechanism of action with therapeutic approach. I commend the editors for developing the vision of such a text, and congratulate each of the authors for the depth and clarity of their presentation. I would recommend this text to anyone working in the field of vascular and intravascular disease. Basic, clinical, and translational scientists, practicing clinicians, and clinical and research trainees can all benefit from the information included in indivi-dual chapters as well as from the overall scope and breadth of knowledge presented. Richard H. Kennedy, PhD Senior Associate Dean for Research Professor of Physiology and Pharmacology Loyola University Stritch School of Medicine Chicago IL USA

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Preface The last quarter of a century has seen dramatic developments in the management of cardiovascular diseases. Besides the pioneering developments in the medical management of cardiovascular disorders the field of interventional cardiology has also emerged as a major discipline with a huge impact on the clinical management of acute coronary syndrome, chronic coronary artery disease, congestive heart failure, and peripheral vascular and valvular diseases. Percutaneous interventions necessitated the development of newer agents and drugs for the imaging, anticoagulation, vascular tone control, and post-interventional proliferative control processes. Drug coating of mechanical devices posed yet another challenge in addressing the safety issues related to these modified devices. The last decade has witnessed a major breakthrough in the use of mechanical support devices such as stents and newer drugs, which has revolutionized the field of interventional cardiology. Moreover, novel uses of drugs, such as drug-coated stents and grafts have emerged. While conventional drugs, such as aspirin, heparin, and clopidrogel, are commonly used in the short-and long-term treatment of patients who have undergone interventions, many newer drugs and drug combinations have been developed. The molecular and cellular understanding of the pathogenesis of cardiovascular diseases, in particular acute coronary syndromes, and the use of interventional procedures in their management has identified several newer targets to optimize clinical management of patients undergoing these procedures. In the area of newer drugs developed in conjunction with interventional procedures, progress has been remarkable and there has been an influx of massive information on their pharmacology and toxicology. Recognizing the importance of this developing area and its impact on interventional cardiology practice, the Editors identified the need of a comprehensive reference book covering this topic. Having such information in one volume is projected to meet the need of practicing interventional cardiologists to obtain objective knowledge of the newer drugs used in interventional cardiology. It is hoped that this book will

provide a comprehensive coverage of pharmacologic agents which are currently used and for those that are in clinical trials and will soon become available for clinical use. The use of drugs for the acute and extended indications in this area is in transition. The recommendations from peer groups undergo periodic revisions due to the introduction of newer devices and/or newer drugs. Thus, it provides a moving target to develop guidelines. This book is intended to provide some of the fundamental knowledge as a foundation to appreciate the ongoing developments in the area of interventional sciences. This book is comprised of over fifty chapters, each of which is written by an expert in the assigned topic. Assembling a multi-authored specialized pharmacology book is a major challenge for both the authors and the editors. Because of the influx of newer information, differing opinions, data interpretation and regulatory positions, the authors are challenged to provide the most practical, unbiased and helpful information on specific topics. The editors are grateful to the authors contributing to this book for their excellent and objective manuscripts which are written in an integrated fashion to provide an updated and comprehensive account of different drugs and devices. This book is divided into five parts comprised of systemic and endoluminal therapy, local therapy, therapeutic angiogenesis, adjunctive pharmacotherapy and non-coronary interventions. The first chapter is on hemostasis and thrombosis and is included since many of the new drugs target the components of the hemostatic system including cellular sites and receptors on platelets, endothelial cells, white cells and blood proteins. The last chapter is written as an epilogue to provide an objective opinion on current drug development in vascular medicine and interventions. It is hoped that the individual chapters included will provide updated references to practicing clinicians and those who are involved in the development of newer drugs. This book is also intended to serve as a comprehensive reference and a practical guide in the application of drugs and devices used for primary

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Preface

coronary angioplasty, coronary thrombolysis and the correction in ST segment elevation in acute coronary syndrome. Specialized topics such as drug coated stents, molecular therapies, cellular therapies, newer pharmacologic approaches and specific topics on non-coronary interventions are also reported. It is hoped that this book will be periodically

updated to reflect the ongoing developments in this fast moving area.

Nicholas Kipshidze Jawed Fareed Jeffrey Moses Patrick Serruys

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Acknowledgments The editors are tremendously grateful to all of the contributing authors, who have voluntarily provided their expert chapters. The editors are also grateful to Ms. Cathy Kennedy, Associate Editor, who has been extremely helpful throughout this project and without whose help it

would have been difficult to publish this book. The publishers, in particular Mr. Oliver Walter, development editor and Mr. Alan Burgess, commissioning editor are to be thanked for their commitment and support in publishing this timely book on interventional pharmacology.

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Mechanism of Thrombogenesis

Prekallikrein·HMWK Protease Network in Coagulation, Fibrinolysis and Kallikrein-Kinin Systems

Kallikrein HMWK Bradykinin

TFPI

TFPI

TFPI

5-HT

Peroxide radicals

XII

AT-III

XIIa

HMWK·XI

s-TM

XIa

PF4

C5a

TAT

F1.2

TXs FPA

TAFI

IX

ProteinS VAPC

VIII

IXa

X

Xa

Protein C

V Va

VI I

Endothelin

sc-uPA

VIIIa

TF VIIa

LTs

P-AP PAI-1

Selectins TF Integrins

TFPI

II

XIII

tc-uPA

IIa

Plasminogen tPA

XIIIa HC-II

Fibrinogen

PAI

Fibrin

X-Fibrin Plasmin

FDPs

Figure 1.1 The primary hemostatic response. (See p. 2.)

Figure 1.2 The coagulation cascade. (See p. 2.)

Injured Vessel Wall

Anticoagulant and Antithrombotic Drugs Thrombin and Xa Inhibitor

Platelet Inhibitors

s

HEPARIN Recombinant TFPI agents Fibrinolytic modulators HIRUDIN TAFI LMWH PAI-1 inhibitor Peptidomimetics Factor XIIIa inhibitor Di-, tripeptides and peptidomimetics HIRULOG

Oligopeptides

Thrombin

PAR1, PAR4 c Se

ret

Collagen

GPIb/IX/V

Activated Platelet

TxA2

vWF

Activated GPIIb/IIIa Receptor Fibrinogen vWF

Heterotypic Aggregation With Leukocytes

1. Adhesion

PGI2, NO, EctoADPase Activity

Inflammation and Increased Thrombin Generation

Antithrombotic Factors

3. Aggregation

Thrombotic Events Myocardial Infarction

ReoPro and YM 337

Figure 13.1 Role of platelet activation and aggregation in cardiovascular diseases. (See p. 140.)

Current anticoagulant and anti-thrombotic drugs (See p. 20.)

Carboxyl Inactive Metabolite

Hydrolysis 85% Clopidogrel Bisulfate/ Prasugrel

15%

Intestinal Absorption

CYP3A4 Conversion

ADP

COX-1 Specific Methods

TxA 2 Collagen Thrombin

ADP, Collagen, Thrombin

P2Y1 Gg

Receptor G

PL Release

Platelet Activation

Rho Kinase

Shape Change

AA

X COX-1

TxA2 lat Ib/ ele III tAaA c gg tiv re at ga io tio n, n

X

G12

Granule Secretion

ASA

P2Y12

Gi

Ca++ Mobilization

– Pl3K

Adenylyl Cyclase cAMP

? RAP-1b Akt

VASP-P

P-selectin and CD40L Expression, Platelet-Leukocyte Aggregation

3. ADP-Induced Platelet Aggregation - LTA (PRP) - TEG (Whole Blood) 4. P2Y12 Reactivity Ratio - Flow cytometry VASP-P levels 5. P-selectin, activated PAC-1 expression and PLAs folllowing ex-vivo ADP stimulation- Flow Cytometry 6. Point-of-Care Methods - Thrombelastography, PFA-100 and VerifyNow P2Y12 with ADP as agonist

ADP

The Relevant Pathway to Measure Platelet Aspirin Responsiveness

Laboratory Evaluation of Clopidogrel Responsiveness

1. Plasma unchanged dopidogrel. active and inactive metabolites of dopidogrel Active Thiol - LC-MS/MS assay Metabolite AZD-6140, 2. Hepatic CYP3A4 activity Cangrelor - Erythromycin breath test-

12

Gg

1. AA-Induced Platelet Aggregation - LTA(PRP) - TEG (Whole Blood) 2. TxB2 Metabolite - Plasma - PRP (AA-Induced) TxA2 - Urine Receptor 3. Verify Now (AA-induced) 4. Flow Cytometry AA-induced G P-selectin, PAC-1 P PI

1. LTA- ADP and Collagen- Induced 2. PFA-100

P2Y11 P2Y12

ion ”Autocrine and Paracrine Effect” TP

CD40L P-selectin

Peptidomimetics

Figure 1.3

COX-1 Non-Specific Non-Specific Methods

2. Activation Shape Change Granule Secretion

Secondary Agonists ADP

ule an Gr Ca++ Activation Mobilization

GPIa/IIa GP VI

Ticlopidine, Clopidogrel

Cyclic Peptides

Prothrombotic Factors

Primary Agonists

TF

CO G AX-1 P c In IIb tiv d /II at ep Ia ion en Re o de ce f nt pt or

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GPllb/llla Activation, Platelet Aggregation

Figure 13.2

Figure 13.3

Mechanism of action of aspirin and laboratory evaluation of aspirin responsiveness. (See p. 141.)

Mechanism of action of clopidogrel and laboratory evaluation of clopidogrel nonresponsiveness. (See p. 145.)

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Drug concentration

Toxic concentration

Therapeutic window

Traditional Controlled Delivery Dosing

Sub-optimal concentration Dose

Dose

Dose (CDD)

Dose (Traditional)

Figure 22.1

Time

Traditional drug delivery

Drug levels in the blood with traditional drug delivery and controlled-delivery dosing. (See p. 268.)

Controlled delivery dosing

Figure 22.3 Effect of animal model and implant site on biologic response to polyurethane stents. (See p. 272.)

Bare metal stent Low coat weight polymer-coated stent High coat weight polymer-coated stent

Inflammation score

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2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0

Figure 22.5

60 days porcine

Strut-associated inflammation in response to the polyethylene-co-vinyl acetate — poly-n-butyl methacrylate polymers in porcine and canine models at two months. (See p. 273.)

56 days canine

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Lumen area 12 10 8 mm2 6 4 2 0

(A)

Bare metal stent

(B)

SIBS-coated stent

Translute coated

Bare control

90 28 Days Days

Figure 22.8 Vascular compatibility of poly(styrene-b-isobutylene-b-styrene) (SIBS) as examined in the porcine coronary model. (See p. 274.)

Cryomicrotomed Stent

100µm

SIBS polymer

EHT=10.00w Signal A = SE1 WD = 11 mm

35% PTx

Paclitaxel release (µg/108 µg total loading)

25% PTx

8.8% PTx

0 0.2 0.4 0.6 0.8 1.00µm 0 0.2 0.4 0.6 0.8 1.00µm 0 0.2 0.4 0.6 0.8 1.00µm 0 0.2 0.4 0.6 0.8 1.00µm

80

35% PTx

70 25% PTx

60

8.8% PTx

50 40 30 20 10 0 0

2

4

6

8

10

12

14 16 18 Time (Days)

20

22

24

26

28

30

Figure 22.9 Atomic force microscopy images and drug release kinetics of the paclitaxel-poly(styrene-bisobutylene-b-styrene) polymer combination. (See p. 275.)

70%

Mean ± SD

Fast

Fast Release n=4

60%

% Cumulative release (average)

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50% Moderate

40% 30% 20%

Moderate Release Slow n = 12

10%

Figure 22.10 Vascular response to slow-, moderate-, and fast-release formulations of paclitaxel in the porcine coronary artery model. (See p. 275.)

Slow Release n = 12

0% 0

2

4

6

8

10

12

Time (days)

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Leukocyte infiltration SMC proliferation/migration

Diseased artery pre-stent Atherosclerotic Plaque with Resident Macros Media Mac L

Endothelium

Fibrinogen

(A)

SMCs

(D)

Macros

Growth factors (FGF, PDGF, IGF, TGF-β, VEGF)

Immediate post-stent

Neointimal growth

Endothelial denudation, platelet/fibrinogen deposition

Continued SMC proliferation and macro recruitment

(B)

(E)

Platelets/fibrinogen

Leukocyte recruitment

Restenotic lesion

Cytokine release

More ECM rich over time

Repaired endothelium

PSGL-1

Macros

(C)

Cytokines

Neutros

P-Selectin

Figure 25.1

(F)

Pathophysiology of restenosis (See p. 300.)

(MCP-1, IL-6, IL-8)

Diffusion

Pressure-driven

Double balloon (blue-environment, Cordia)

Mechanical

Porous balloon (Wolinsky, Bard/USCI)

Iontophoretic balloon (CorTrak) Microporous balloon Multichamber balloon, DispatchTM, SciMed)

Macroporous balloon Hydrogel balance (SliderTM with Hydrogel PlumTM Mansfield Boston Scientific)

Coated stent (Johnson & Johnson)

Needle catheter (BMT Ltd) Balloon with a balloon (Transport TM, Endosonics)

Channeled balloon (Mansfield Boston Scientific)

Figure 25.2 Types of catheter-based local delivery devices. (See p. 302.)

Infusion sleeve (LocalMed)

Cumulative proportion surviving

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1.0 0.9 0.8 0.7 0.6 0.5 0.4 Control 2.5 ug 10 ug

0.3 0.2 0

30

60

90 Time

120

150

180

xxviii

Figure 25.3 Event-free survival at six months in the ACTinomycin-eluting stent improves outcomes by reduction of neointimal hyperplasia trial of the actinomycin-eluting stent. (See p. 304.)

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Figure 25.6 The effects of paclitaxel on smooth muscle cell migration. (See p. 306.)

Figure 25.5 Effect of paclitaxel on smooth muscle cell morphology. (See p. 305.)

Figure 25.7

(A)

Number of cells migrated (% of control)

Immunofluorescence micrographs demonstrating the effect of 1.0 µmol/L paclitaxel on the distribution of the contractile filament smooth muscle α-actin and the intermediate filament vimentin in haSMCs. (See p. 307.)

Number of cells migrated (% of control)

1180 FM

150

100

*

##

*

50

*

0

100 nM Insulin 0.01 ng/ml SRL 0.1 ng/ml SRL 1 ng/ml SRL

+ – – –

+ + – –

+ – + –

+ – – +

– – – +

+ – – –

+ + – –

+ – + –

+ – – +

– – – +

(B)

Normal glucose SRL High glucose SRL

150

Normal glucose PTXL High glucose PTXL

100

*p 18 sacch. units)

LMWH

Xa

ANTITHROMBIN

>

Exosite 2

THROMBIN

ANTITHROMBIN

Figure 1 Mechanisms of action of unfractionated heparin and low molecular weight heparin. Abbreviations: LMWH, low molecular weight heparin; UFH, unfractionated heparin. Source: From Ref. 1.

Low molecular weight heparins Low molecular weight heparins in the setting of elective percutaneous coronary interventions

anticoagulant activity. Anticoagulant activity is assessed by ACT, which varies substantially in the presence of other comorbidities as well as with the devices used to measure ACT; higher ACT values (30–50 seconds) are observed using the Hemochron device than the HemoTec device (3). Procedural anticoagulation monitoring is thus highly dependent on the device used to guide heparin administration (Table 1). In addition to this variability in ACT results, the optimal range of target ACT remains uncertain. Results from retrospective studies suggest that higher ACT values may be associated with less ischemic complications, but the balance

Pilot studies When patients are not pretreated by any form of anticoagulation before reaching the catheter lab, rapid, effective, and predictable anticoagulation can be obtained with intravenous LMWH during PCI.

Table 1 Contemporary guidelines for unfractionated heparin use in patients undergoing percutaneous coronary intervention

IV bolus

No concomittant GP IIb-IIIa inhibitors use

Concomittant GP IIb-IIIa inhibitors use

60–100 IU/kg

50–70 IU/kg

(HemoTec®

ACT to achieve

device) 250–300 sec 300–350 sec (Hemochron® device)

Additional bolus if target ACT not achieved

2000—5000 IU

Sheath removal Abbreviations: ACT, activated clotting time; GP, glycoprotein; IV, intravascular. Source: From Ref. 3.

200 sec

When ACT 180 sec

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Low molecular weight heparins

In a preliminary study, Choussat et al. (7) included 242 consecutive patients to receive a single intravascular (IV) bolus of enoxaparin (0.5 mg/kg) during elective PCI. A peak anti-Xa of 0.5 IU/mL was obtained in 97.5% of the population (Fig. 2); this dose allowed immediate sheath removal when used alone and did not require dose adjustment when used with a glycoprotein (GP) IIb–IIIa inhibitor. This strategy has now been tested in multiple studies and in a meta-analysis of eight trials, making a randomized comparison between single bolus IV LMWH and UFH in PCI (8). There was a nonsignificant trend favoring LMWH with regard to both a combined efficacy [death/myocardial infarction (MI)/urgent revascularization] and hemorrhagic endpoints. When a further pooled analysis was performed, including data from all randomized trials and seven additional nonrandomized trials/registries, 3787 patients received LMWH and 978 received UFH, the composite efficacy endpoint occurred in 5.7% versus 7.5% (P = 0.03), major bleeding in 0.6% versus 1.8% (P = 0.0001), and all bleeding (major plus minor) in 3.7% versus 4.9% (P = 0.09) of patients who received LMWH and UFH, respectively (8). In this meta-analysis, the best outcome data were obtained with the 0.5 mg/kg IV dose. (A)

50

Number of patients, %

40

30

20

81

Comparison between low molecular weight heparin and unfractionated heparin in elective percutaneous coronary intervention These results were confirmed in the recent randomized STEEPLE trial. This study was a prospective, open-label, randomized trial including 3528 patients undergoing elective PCI. Patients were randomized to enoxaparin (0.5 or 0.75 mg/kg) or an ACT-adjusted UFH regimen, stratified by the operator’s choice of GP IIb–IIIa inhibitor use. The primary endpoint was the incidence of noncoronary artery bypass graft (CABG)-related major and minor bleeding. Enoxaparin 0.5 mg/kg was associated with a significant 31% reduction in the primary endpoint when compared with UFH (6.0% vs. 8.7%, P 0.014), and the 0.75 mg/kg dose was associated with a 24% reduction (6.6% vs. 8.7%, P 0.052) meeting the criteria for noninferiority. There was a significant 57% reduction in major bleeding in both enoxaparin groups when compared with UFH. The incidence of the quadruple endpoint of death/MI/urgent target revascularization/major bleeding at 30 days was similar among the three groups (7.2%, 7.9%, and 8.4% in the enoxaparin 0.5 mg/kg, enoxaparin 0.75 mg/kg, and UFH groups, respectively). The sheath was immediately removed from the femoral site without excessive bleeding in the 0.5 mg/kg group. Converse to UFH, the use of enoxaparin during PCI did not require anticoagulation monitoring, and there was no dose modification with concomitant GP IIb–IIIa receptor blockers administration (9).

10

40

Low molecular weight heparin in percutaneous coronary intervention for acute coronary syndrome

30

Preliminary studies

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6

Anti-Xa activity, IU/mL

(B)

Number of patients, %

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20

10 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Anti-Xa activity, IU/mL

Figure 2 Distribution of anti-Xa activity levels at the beginning (A) and end (B) of percutaneous coronary intervention after a single intravascular dose of enoxaparin 0.5 mg/kg. Source: From Ref. 7.

Current recommendations for antithrombin management of patients being treated with SC LMWH undergoing PCI suggest a transition to UFH with a bolus given immediately prior to intervention. In the setting of acute coronary syndromes (ACSs), this strategy demonstrated at least similar safety between UFH and enoxaparin, and similar or less ischemic events among patients treated with enoxaparin when compared with UFH-treated patients (10–12). However, in spite of its logic and convenience, there is little literature regarding LMWH administration during PCI instead of UFH, in order to avoid anticoagulation change when transferring the patient to the cath lab.

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Collet et al. examined the safety and efficacy of performing PCI in the setting of ACS on LMWH therapy without interruption of this treatment or additional anticoagulant therapy. The only rule was to perform PCI within eight hours of the last SC enoxaparin injection (when anti-Xa levels are close to the peak of activity). Four hundred and fifty-one consecutive patients with ACS received at least 48 hours of treatment with SC LMWH (enoxaparin 1 mg/kg/12 hours SC) in the coronary care unit, and 65% of the patients underwent coronary angiography within eight hours of the morning SC injection. PCI was performed in 28% of the patients, with no further enoxaparin and no UFH during PCI. Mean anti-Xa activity at the time of catheterization was in the therapeutic range (0.98 0.03 IU/mL) and 0.5 IU/mL in 97.6% patients. No in-hospital acute vessel closure or urgent revascularization following PCI was observed. Death/MI at 30 days occurred in 3.0% in the PCI group, but 6.2% in the whole population, and in 10.8% of patients not undergoing catheterization. The 30-day major-bleeding rates were similar: 0.8% in the PCI group and 1.3% in the group of patients managed medically (13). In the NICE-3 study (14), 661 ACS patients were treated with enoxaparin SC 1 mg/kg plus abciximab, eptifibatide, or tirofiban at standard doses. Two strategies were combined for the transition from the ward to the catheter laboratory: no interruption and no addition of enoxaparin for PCI within eight hours of the last SC injection and an additive IV bolus of 0.3 mg/kg when PCI was performed between 8 and 12 hours of the last SC injection. The major bleeding rate was 4.5% and the in-hospital death/MI/urgent target vessel revascularization rate was 5.7%.

Comparison between low molecular weight heparin and unfractionated heparin in percutaneous coronary intervention for acute coronary syndrome Several randomized clinical trials have compared the efficacy and safety of LMWH and UFH among initially medically managed patients presenting with ACS (15–18). Among those, enoxaparin was the only LMWH to demonstrate a significant and sustained benefit over UFH; in the metaanalysis of the thrombolysis in MI (TIMI) 11B and ESSENCE trials, enoxaparin was associated with a significant reduction of death and MI at 8, 14, and 43 days (OR 0.77, 95% CI: 0.62–0.95; OR 0.79, 95% CI: 0.65–0.96; and OR 0.82, 95% CI: 0.69–0.97, respectively) (19). More recently, safety and efficacy of these two antithrombin regimens have been compared among patients receiving upto-date antithrombotic regimens, with tirofiban [A to Z (11), ACUTE II (10)] or eptifibatide [INTERACT (12)], and among patients undergoing an early invasive strategy [SYNERGY (20)].

In the ACUTE II trial (10), 525 patients with non-STsegment elevation ACS and treated with tirofiban and aspirin were randomized to receive either UFH [5000 U bolus followed by an infusion of 1000 U/hour adjusted to a therapeutic activated partial thromboplastin time (aPTT), n 210] or enoxaparin (1.0 mg/kg SC injection every 12 hours, n 315) in a double-blind fashion during 24 to 96 hours. The primary safety endpoint of total bleeding incidence (TIMI major TIMI minor loss without any identified site) occurred among 4.8% versus 3.5% of patients receiving UFH versus enoxaparin (OR 1.4, 95% CI: 0.6–3.4). There was no difference in the incidence of death or MI between the UFH and enoxaparin groups (1.9% versus 2.5% and 7.1% versus 6.7%, respectively; P NS for both). However, refractory ischemia and rehospitalization due to unstable angina occurred more often in the UFH, respectively, P 0.05 for both). The A to Z trial (phase A) was an open-label randomized noninferiority trial comparing enoxaparin (n 2026) with weight- and aPTT-adjusted intravenous UFH (n 1961) in non-ST-segment elevation ACS receiving aspirin and tirofiban (11). The prespecified criterion for noninferiority was met for the primary efficacy endpoint of death/MI/refractory ischemia at seven days (9.4% in the UFH group versus 8.4% in the enoxaparin group, HR 0.88, 95% CI: 0.71–1.08). When stratifying patients according to prerandomization treatment, the authors observed a trend toward a lower incidence of the primary endpoint in the enoxaparin arm when no prior anticoagulant had been administered (HR 0.77, 95% CI: 0.53–1.11, P 0.38 for interaction). Enoxaparin was as safe as UFH regarding the incidence of TIMI minor or major bleeding (3.0% vs. 2.2%, P NS). The INTERACT trial was a randomized open-label trial comparing enoxaparin (n 380) with intravenous aPTTadjusted UFH (n 366) in high-risk non-ST-segment elevation ACS receiving aspirin and eptifibatide (12). The primary safety endpoint of major non-CABG-related bleeding at 96 hours occurred significantly less often among enoxaparin-treated patients (1.8% vs. 4.6%, P 0.03). Minor bleeding was more frequent in the enoxaparin group (30.3% vs. 20.8%, P 0.003). The primary efficacy outcome of ischemia detected by continuous ECG monitoring was significantly less frequent in the enoxaparin group during the initial (14.3% vs. 25.4%, P 0.0002) and subsequent (12.7% vs. 25.9%, P 0.0001) 48-hour monitoring periods. Finally, death or MI at 30 days occurred significantly less among enoxaparin-treated patients (5% vs. 9%, P 0.031). The Superior Yield of the New Strategy of Enoxaparin Revascularization and GP IIb/IIIa Inhibitors (SYNERGY) trial (20) was a randomized, open-label, international trial comparing enoxaparin and UFH among 10,027 high-risk patients with non-ST-segment elevation ACS to be treated with an intended early invasive strategy. The incidence of the composite primary efficacy endpoint (death/MI at 30 days) was similar in enoxaparin and UFH-treated patients (14.0% vs. 14.5%,

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References

respectively, OR 0.96; 95% CI: 0.86–1.06). There was no difference in the rate of ischemic events between the two groups during PCI. The primary safety outcome was major bleeding or stroke. There was no difference between the two groups with respect to stroke incidence; the incidence of major bleeding was modestly increased in the enoxaparin group when using the TIMI bleeding classification (9.1% vs. 7.6%, P 0.008) but not when using the GUSTO classification (2.7% vs. 2.2%, P 0.08). The need for transfusions was similar among the two groups (17.0% vs. 16.0%, P 0.16). When stratifying by prerandomization therapy, the benefit of enoxaparin was the highest among patients receiving either enoxaparin or no antithrombin therapy before randomization. The authors stated that “as a first-line agent in the absence of changing antithrombin therapy during treatment, enoxaparin appears to be superior to UFH without an increased bleeding risk” (20). Data from various trials are becoming integrated into current recommendations. A recent expert consensus concluded that substantial evidence exists that patients receiving SC LMWH in the management of ACS can safely undergo cardiac catheterization and PCI and that concerns about transition of medical to interventional management “should not impede the upstream use of LMWH” (21). It was furthermore concluded that LMWH and GP IIb–IIIa antagonists can be safely used in combination without any apparent increase in the risk of major bleeding (21). A pooled analysis was performed among 21,946 patients included in the six randomized trials comparing UFH and enoxaparin in the setting of non-ST-segment elevation ACS (22). Death at 30 days was similar for both antithrombin strategies (3.0% for both), but enoxaparin treatment was associated with lower incidence of death/MI at 30 days than UFH populations (10.1% vs. 11.0%; OR 0.91; 95% CI: 0.83–0.99; number needed to treat: 107). The benefit of enoxaparin was even higher among patients receiving no prerandomization antithrombin therapy (8.0% vs. 9.4%; OR 0.81; 95% CI: 0.70–0.94; number needed to treat: 72). No significant difference was found in blood transfusion (OR 1.01; 95% CI: 0.89–1.14) or major bleeding (OR 1.04; 95% CI: 0.83–1.30) at seven days after randomization. In all these trials, enoxaparin was administered at the dose of 1 mg/kg SC every 12 hours, in order to achieve therapeutic anti-Xa levels. This is of importance as it has been demonstrated that low anti-Xa activity (0.5 IU/mL) was an independent predictor of poor outcome among ACS patients; conversely, anti-Xa activity, within the target range of 0.5 to 1.2 IU/mL, is not related to bleeding events (23). Among patients with impaired creatinine clearance (chronic kidney disease in elderly patients), the therapeutic range is achieved safely by reducing enoxaparin dose (24). In ACS patients, LMWH has now been compared with newer anticoagulants such as direct thrombin inhibitors, such as bivalirudin [ACUITY trial (25)], and a pentasaccharide, such as fondaparinux [OASIS-5 and -6 trials (26,27)]. These new

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molecules appear to have similar efficacy as compared to enoxaparin and they may be safer with lower bleeding rates. The benefit and the indication of these newer and more costly anticoagulant agents in the catheterization laboratory remain to be determined.

Conclusion LMWH is a safe and efficient alternative to UFH during PCI. From a practical point of view, a unique IV dose of 0.5 mg/kg enoxaparin is convenient, simple, and does not need adjustment for IIb–IIIa antagonist use nor for renal function. In addition, this unique dose requires no anticoagulant monitoring and allows an early sheath removal. The convenience, safety, and efficacy of LMWHs have led many centers to use them as a standard of care for the treatment of ACS with or without ST-segment elevation, with no anticoagulant shift during PCI. Emerging evidence suggests that other alternatives to UFH may be found among other therapeutic classes such as direct thrombin inhibitors: bivalirudin appears to be atleast as safe and effective as UFH in the setting of elective as well as emergent PCI. Other anticoagulant agents such as factor Xa inhibitors (fondaparinux) may be of interest in these settings and the results of ongoing trials should bring more definitive conclusions.

References 1

2 3

4

5 6

7

8

Weitz JI, Buller HR. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation 2002; 105: 1004–1011. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688–698. Popma JJ, Ohman EM, Weitz J, et al. Antithrombotic therapy in patients undergoing percutaneous coronary intervention. Chest 2001; 119:321S–336S. Boccara A, Benamer H, Juliard JM, et al. A randomized trial of a fixed high dose vs a weight-adjusted low dose of intravenous heparin during coronary angioplasty. Eur Heart J 1997; 18:631–635. Koch KT, Piek JJ, de Winter RJ, et al. Safety of low dose heparin in elective coronary angioplasty. Heart 1997; 77:517–522. Kaluski E, Krakover R, Cotter G, et al. Minimal heparinization in coronary angioplasty–how much heparin is really warranted? Am J Cardiol 2000; 85:953–956. Choussat R, Montalescot G, Collet JP, et al. A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention. J Am Coll Cardiol 2002; 40:1943–1950. Borentain M, Montalescot G, Bouzamondo A, et al. Lowmolecular-weight heparin vs. unfractionated heparin in percutaneous coronary intervention: a combined analysis. Catheter Cardiovasc Interv 2005; 65:212–221.

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Montalescot G and the STEEPLE investigators. The STEEPLE study: safety and efficacy of intravenous enoxaparin in elective percutaneous coronary intervention: an international randomized evaluation. European Society of Cardiology 2005 Hotline session. Cohen M, Theroux P, Borzak S, et al. Randomized double-blind safety study of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes treated with tirofiban and aspirin: the ACUTE II study. The antithrombotic combination using tirofiban and enoxaparin. Am Heart J 2002; 144:470–477. Blazing MA, de Lemos JA, White HD, et al. Safety and efficacy of enoxaparin vs unfractionated heparin in patients with nonST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: a randomized controlled trial. JAMA 2004; 292:55–64. Goodman SG, Fitchett D, Armstrong PW, et al. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-STsegment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation 2003; 107:238–244. Collet JP, Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation 2001; 103:658–663. Ferguson JJ, Antman EM, Bates ER, et al. Combining enoxaparin and glycoprotein IIb/IIIa antagonists for the treatment of acute coronary syndromes: final results of the National Investigators Collaborating on Enoxaparin-3 (NICE-3) study. Am Heart J 2003; 146:628–634. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999; 100:1593–1601. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous enoxaparin in non-Q-wave coronary events study group. N Engl J Med 1997; 337:447–452. Klein W, Buchwald A, Hillis SE, et al. Comparison of lowmolecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable

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coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation 1997; 96:61–68. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome). Eur Heart J 1999; 20: 1553–1562. Antman EM, Cohen M, Radley D, et al. Assessment of the treatment effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction. TIMI 11B-ESSENCE meta–analysis. Circulation 1999; 100:1602–1608. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004; 292:45–54. Kereiakes DJ, Montalescot G, Antman EM, et al. Low-molecularweight heparin therapy for non-ST-elevation acute coronary syndromes and during percutaneous coronary intervention: an expert consensus. Am Heart J 2002; 144:615–624. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in nonST-Segment elevation acute coronary syndromes: a systematic overview. JAMA 2004; 292:89–96. Montalescot G, Collet JP, Tanguy ML, et al. Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin. Circulation 2004; 110:392–398. Collet JP, Montalescot G, Fine E, et al. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials. J Am Coll Cardiol 2003; 41:8–14. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J 2004; 148:764–775. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006; 354:1464–1476. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006; 295:1519–1530.

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7 Direct thrombin inhibition in percutaneous coronary intervention Derek P. Chew, Sam J. Lehman, and Harvey D. White

Introduction As a class of anticoagulants for the prevention of ischemic complications among patients undergoing percutaneous coronary intervention (PCI), the direct thrombin inhibitors have enjoyed a renewed interest, despite the fact that the development of these agents extends back over nearly two decades. These agents inhibit all the actions of thrombin by direct binding to this molecule, and in some cases, their action is limited by subsequent catalytic degradation by thrombin. Clinical evidence with these agents have been acquired in the context of balloon angioplasty as well as coronary stenting, across a spectrum of patient risk profiles and in conjunction with various antiplatelet agents, with the bulk of these data in the context of bivalirudin therapy. This chapter summarizes the basic physiology of thrombin and discusses each of the direct thrombin inhibitors with respect to their clinical pharmacology, indications, and clinical trial evidence in the context of PCI.

Thrombin physiology As a serine protease, thrombin has a central role in thrombus formation (Fig. 1) (1). Vascular injury and inflammation result in the expression of tissue factor on the surface of endothelial cells and inflammatory cells. Interaction between tissue factor and factor VII leads to the initiation of the coagulation cascade, hence promoting the generation of thrombin from prothrombin. As a key factor in thrombosis, thrombin is responsible for the conversion of fibrinogen to fibrin and activation of factors V, VIII, and X, in addition to promoting platelet activation (2). With a short circulating half-life, the role of thrombin is normally tightly controlled by negative

feedback mechanisms in the context of normal endothelium. These include the binding to thrombomodulin and protein C, which, in conjunction with protein S, inactivates the factors Va and VIIIa. In addition, this molecule promotes the release of tissue plasminogen activator. Thus, the effects of thrombin are usually confined to the local area of tissue injury. The direct effects of thrombin on cellular structures are increasingly being appreciated. Acting via the proteaseactivated receptor (PAR)-1, thrombin promotes expression of P-selectin and CD 40 ligand on the surface of the platelets, and stimulates the release of adenosine diphosphate (ADP), serotonin, and thromboxane A2, as well as increased expression and activation of glycoprotein (GP) ␣IIb/␤3 involved in fibrinogen and von Willebrand factor (vWF) binding and platelet aggregation (3,4). The effects on endothelial cells include the release of vWF and the upregulation of surface adhesion molecules enabling platelet and leukocyte adhesion. In response to thrombin, endothelial cells undergo conformational changes that allow transudation and edema formation. In the context of an intact endothelium, thrombin promotes vasodilation, but where the endothelium is denuded, local thrombin generation contributes to vasoconstriction. Evidence also suggests that thrombin promotes fibroblast cytokine production and is mitogenic (5). Hence, as a therapeutic target, thrombin has a critical role in orchestrating adverse local responses to balloon/stent local vascular injury. A schematic of the structure of the thrombin molecule is presented in Figure 2. The important binding sites on the surface of the thrombin molecule include the catalytic site and two exosites (anionic and apolar) or substrate recognition sites. Whereas the catalytic site is responsible for the serine protease activity, the separate substrate recognition sites are involved in the binding of heparin, fibrinogen, and thrombomodulin (6). These sites serve as targets for the direct thrombin inhibitors.

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Figure 1

Fibrinogen

COAGULATION

Protein S Activated Protein C Inactivate FVa FVllla Tissue Factor/FVa

Fibrin

Thrombomodulin

TxA2, ADP, Serotonin release CD40L, P-Serectin GPIIb/IIIa Expression

(PAR-1)

PROTHROMBIN

Shape change

The role of thrombin in vascular injury. Abbreviation: ADP, adenosine diphosphate.

PLATELET ACTIVATION FXa THROMBIN

FIXa

Monocyte

FVIIIa INFLAMMATORY CELL ACTIVATION Lymphocyte INCREASE ENDOTHELIAL PERMEABILITY

Neutrophil

Smooth Muscle Mitogenicity

Pharmacology Collectively, the direct thrombin inhibitors are prototypically represented by hirudin, the antithrombotic molecule found in the saliva of the medicinal leech (Hirudo medicinalis). This protein is a 65 amino acid molecule that forms a highly stable but noncovalent complex with thrombin (7). With two domains, the NH2-terminal core domain and the COOHterminal tail, the hirudin molecule inhibits the catalytic site and the anion-binding exosite in a two-step process. The first step is an ionic interaction that leads to a rearrangement of the thrombin–hirudin complex to form a tighter bond that is stoichiometrically 1:1 and irreversible. The apolar-binding site may also be involved in hirudin binding. This complex and

Bivalent Inhibitor

Exosite 1

Univalent Inhibitor Catalytic Site Exosite 2 Fibrin Binding

Fibrin

Figure 2 Thrombin-inhibitor pharmacology.

tight binding of hirudin to thrombin helps account for the highly specific effect of hirudin on thrombin, but none of the other serine proteases. As a group, the direct thrombin inhibitor molecules are small, in contrast to the indirect thrombin inhibitors, and consequently demonstrate greater efficacy for the inhibition of clot-bound thrombin, in addition to fluid-phase thrombin (8). Through recombinant DNA technology, recombinant hirudin (r-hirudin) has been produced in two forms, with and without sulfated Tyr63. In contrast to the naturally occurring molecule, the nonsulfated tyrosine appears to have a 10-fold lower affinity for thrombin. The interaction between hirudin and thrombin forms the template for understanding and categorizing the other direct thrombin inhibitors. In broad terms, these have been divided into univalent and bivalent molecules. The univalent molecules, such as dabigatran, argatroban, and melagatran (and the oral prodrug, ximelagatran), inhibit only the catalytic site. Therefore, these agents inactivate only fibrin-bound thrombin. Of note, argatroban binds to the apolar-binding site adjacent to the catalytic site and provides competitive inhibition. Although the inhibition of thrombin with these agents is potent, binding with these agents is less robust than that observed with hirudin. Hence, dissociation occurs leaving some active thrombin available. The bivalent molecules, the natural and r-hirudin and bivalirudin, bind to the catalytic site and at least one of the exosites. However, while the interaction between hirudin and thrombin is irreversible, the inhibition provided by bivalirudin is more transient, by nature of its structure (9). Bivalirudin is a synthetic 20 amino acid molecule. Its two domains, which block the anion-binding exosite and catalytic sites, are linked by four glycine spacers. In contrast to the larger hirudin amino acid chain, bivalirudin’s truncated structure leads to less avid ionic binding. In addition,

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Monitoring direct thrombin inhibitors

thrombin acts to cleave the bivalirudin molecule at the Arg-Pro bond of the NH2-terminal extension, which releases the thrombin active site for further thrombotic activity. Several other direct thrombin inhibitors have been developed in addition to those discussed, but so far these have not found a clinical role in the catheterization laboratory.

Pharmacokinetics An appreciation of the pharmacodynamic interactions between the various direct thrombin inhibitors provides an insight into the differences in pharmacokinetic behavior (10). All of these agents require parenteral administration with the exception of ximelagatran, which is converted to melagatran in the liver, and dabigatran. With the exception of argatroban, these agents are renally cleared, and clearance is attenuated in the setting of reduced renal function. In the setting of excessive dosing, these agents can be removed by hemofiltration. Argatroban’s main route of elimination is through hepatic metabolism and dose reduction in the setting of hepatic dysfunction is required. However, renal function also influences dosing (11). Bivalirudin also undergoes proteolysis within the plasma, thus contributing to its shorter half-life and relatively constant elimination characteristics even among patients with mild to moderate renal impairment. Nevertheless, dose attenuation is required among patients with creatinine clearance ⬍30 mL/min. A summary of the pharmacokinetic properties of these agents is presented in Table 1. No reversal agent has yet been developed for these agents, and in the context of active bleeding, nonspecific measures such as transfusion of blood productions, including fresh frozen plasma and local measures, are recommended. Hence, among patients undergoing PCI, the relatively short half-life of bivalirudin appears to be an advantage.

Table 1

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Monitoring direct thrombin inhibitors As opposed to the low molecular weight heparins, the direct thrombin inhibitors prolong the activated clotting time (ACT) and the activated partial thromboplastin time (APTT) (12). Studies with bivalirudin demonstrate that this occurs in a dose-dependent manner, and at the doses used within the clinical trials, the prolongation of ACT observed was generally greater than that observed with heparin and heparin/GP IIb/IIIa inhibition combinations. However, less apparent is the relationship between the ACT level and ischemic or bleeding outcomes. As opposed to heparin therapy (13), a relationship between actual levels of ACT achieved and bleeding outcomes has not been described, and of note, despite higher ACT levels achieved with this agent, bleeding rates have been consistently lower than that observed with unfractionated heparin-based strategies. Some evidence suggests that monitoring these agents with the ecarin clotting time (ECT) may be more appropriate. Measurements based on this test appear to better correlate with bivalirudin and hirudin levels (14). Whether levels based on this assay evolve to recommended targets for therapy remains to be established.

Indications and clinical evidence for the use of direct thrombin inhibitors in percutaneous coronary interventions Although the role of these agents in the management of patients presenting with acute coronary syndromes (ACS)

Thrombin-inhibition pharmacokinetics

Characteristics

Recombinant hirudins

Bivalirudin

Argatroban

Ximelagatran and melagatran

Dabigatran

Route of administration

Intravenous, subcutaneous

Intravenous

Intravenous

Intravenous and subcutaneous (melagatran), oral (ximelagatran)

Oral

Plasma half-life

Intravenous (60 min) Subcutaneous (120 min)

25 min

45 min

Intravenous and subcutaneous (2–3 hr), oral (3–5 hr)

12 hr

Main site of clearance

Kidney

Kidney, liver, and other sites

Liver

Kidney

Kidney

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remains contentious, the evidence in the setting of PCI is robust. The vast majority of these data are with bivalirudin, though consistent evidence also exists for some of the other direct thrombin inhibitors as subgroup analyses of ACS patients undergoing PCI (hirudin) and within special indications such as in the setting of heparin-induced thrombocytopenia syndrome (HITS) (argatroban).

16 14

10

OR 0.48 (0.29–0.73)

8 6

2

Initial studies of hirudin among patients undergoing PCI suggested an improvement in clinical outcomes (15,16). These initial reports lead to the conduct of the Hirudin in a European Trial Versus Heparin in the Prevention of Restenosis after PTCA (HELVETICA) trial that compared two dose regimens of hirudin with unfractionated heparin in patients with unstable angina in the context of balloon angioplasty (17). Randomization to intravenous hirudin was associated with a reduction in early cardiac events, but at seven-month follow-up (the primary endpoint), there was no difference in event-free survival or restenosis among the three treatment groups. In contrast to the observations with bivalirudin, a slight excess in bleeding was observed. Similarly, the angioplasty substudy among ST-elevation myocardial infarction (MI) patients of the Global Utilization of Strategies to Open Occluded Coronary Arteries IIb (GUSTO IIb) trial randomized 503 patients undergoing PCI to receive either hirudin or heparin (18). The primary endpoint of death, MI, or stroke at 30 days was reduced with hirudin by 23%, but this did not reach statistical significance. No excess in bleeding was observed. A nonrandomized analysis of all patients enrolled within GUSTO IIb (ST-elevation and non-ST-elevation) undergoing PCI while receiving treatment with either hirudin (n ⫽ 672) or heparin (n ⫽ 738) observed a reduction in 30 day MI (4.9% vs. 7.6%, P ⫽ 0.04) among the hirudin group (19). A nonsignificant excess in bleeding was observed. These data are consistent with a similar analysis from the OASIS-2 trial assessing the outcomes in 172 patients undergoing PCI within 72 hours of randomization (20). In this observational analysis, hirudin was associated with a lower rate of death or MI at 96 hours, (6.4% vs. 21.4%, OR 0.30; 95% CI: 0.36–0.81) and 35 days (6.4% vs. 22.9%, OR 0.25; 95% CI: 0.07–0.86). Hence, in meta-analysis of these data drawn from two PCI and nine ACS trials (n ⫽ 35,970), in conjunction with the data with bivalirudin and the univalent direct thrombin inhibitors, the direct thrombin inhibitors have been shown to be associated with lower rates of death or MI (OR 0.66; 95% CI: 0.48–0.91), in the context of PCI undertaken with 72 hours of randomization, with a reduction in bleeding driven by the benefits observed in the PCI trials (Fig. 3) (21). Attenuated benefit was observed when PCI was delayed after this time, with no benefit with these agents observed in the context of conservative management. Case reports also suggest that rhirudin (lepirudin) may be used in patients with HITS undergoing PCI (22).

DTI

12

4

Clinical evidence: hirudin

OR 0.66 (0.48–0.91)

UFH

OR 0.94 (0.86–1.03)

OR 0.55 (0.57–1.33)

OR 0.55 (0.21–1.48)

0 MI Pre-PCI

Death or MI MI On day of PCI post-PCI

Death or MI early PCI

Early PCI

Death or MI

Conservative treatment

Figure 3 DTI meta-analysis. Abbreviations: DTI, direct thrombin inhibition; MI, myocardial infarction; OR, odds ratio; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

Clinical evidence: argatroban To date, the role of argatroban in PCI has been inadequately studied. As an alternative to heparin among patients with HITS, a small case series suggests that this agent is safe (23,24). A small open labeled study of argatroban among patients treated with abciximab (n ⫽ 150) and eptifibatide (n ⫽ 2) suggests that the use of this agent in combination with GP IIb/IIIa inhibition is feasible (25). Definitive data demonstrating specific advantages over currently practiced strategies are still awaited.

Clinical evidence: bivalirudin The initial clinical trial evidence supporting the use of bivalirudin was observed in the Bivalirudin Angioplasty Trial (BAT) (26,27). This study predated the use of coronary stents, GP IIb/IIIa inhibition, and the routine use of thienopyridines. A total of 4312 patients presenting for urgent or elective angioplasty were randomized to bivalirudin 1 mg/kg bolus and 2.5 mg/kg/hr infusion or high-dose unfractionated heparin. A subgroup of 741 post-MI patients underwent stratified randomization. At seven days, bivalirudin was associated with a 22% reduction (6.2% vs. 7.9%, P ⫽ 0.039) in the incidence of death, MI, or urgent revascularization, a 62% reduction (3.9% vs. 9.7%, P ⬍ 0.001) in major bleeding events, and a 44% reduction in the combination of bleeding and ischemic events. The suppression of ischemic and bleeding events was more striking among the post-MI patients with the triple ischemic endpoint being reduced by 46% by 90 days [odds ratio (OR) 0.54; 95% CI: 36–0.81, P ⫽ 0.009].

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Special groups

With the emerging development of the GP IIb/IIIa inhibitors, two smaller pilot studies were conducted. The CACHET A/B/C studies with 208 patients examined the role of bivalirudin in the context of either routine or provisional use of abciximab. Although this study was small, a reduction in bleeding events, without an increase in ischemic events was observed. In contrast, the randomized evaluation of PCI linking angiomax to reduced clinical events (REPLACE)-1 study randomized 1056 PCI patients to either 0.75 mg/kg and 1.75 mg/kg/hr or heparin 60 to 70 U/kg with GP IIb/IIIa inhibition (either abciximab, eptifibatide, or tirofiban) either provisionally, routinely, or not at all at the discretion of the clinician (28). Approximately 76% and 85% of patients in this study received a GP IIb/IIIa inhibitor and stent, respectively. Despite the liberal use of GP IIb/IIIa inhibition, a nonsignificant benefit favoring the use of bivalirudin was observed at 48 hours in terms of both ischemic and bleeding complications. These studies formed the basis of the contemporary pivotal study, REPLACE-2. Published in 2003, the REPLACE-2 study enrolled 6010 patients undergoing elective or urgent PCI, randomizing them to bivalirudin (0.75 mg/kg and 1.75 mg/kg/hr IV) and provisional abciximab or eptifibatide versus the planned use of these agents and heparin (65 U/kg IV) in a double blind, double dummy manner (29). This study was designed as a noninferiority trial with respect to the commonly used “triple ischemic endpoint” of death, MI, or urgent revascularization by 30 days. In addition, noninferiority with respect to a “quadruple endpoint” of ischemia and bleeding was also examined. Mirroring the inclusion and exclusion criteria for the EPISTENT studies, (30) the major exclusions to this study were patients presenting with ST-elevation MI undergoing PCI for reperfusion, patients at significant risk of bleeding or those requiring dialysis. Consequently, approximately 50% of patients underwent PCI for an ACS, multivessel intervention was undertaken in ~15% of cases, and saphenous vein graft intervention occurred in 6% of patients. Provisional use of a GP IIb/IIIa inhibitor was permitted for a wide range of indications including coronary dissection, thrombus formation, unplanned stenting, slow flow, distal embolization, and ongoing clinical instability. GP IIb/IIIa inhibition was used in 7.5% of bivalirudin treated patients, and 5.2% of heparin/GP IIb/IIIa inhibition patients received provisional placebo (P ⫽ 0.002). Across the study, 86% of patients received pretreatment with a thienopyridine, and the vast majority of this was clopidogrel. Meeting the predefined noninferiority boundary, bivalirudin (and provisional GP IIb/IIIa inhibition) was associated with a nonsignificant excess in ischemic events (7.6% vs. 7.9%, OR 1.09; 95% CI: 0.90–1.32, P ⫽ 0.40). This difference was accounted for entirely by a small excess in CKMB-elevations 5 to 10 times the upper limit of normal, but in no other category. However, bleeding events were significantly reduced when evaluated by the thrombolysis in myocardial infarction (TIMI) criteria or the slightly broader protocol definition that included blood transfusion. Most of the bleeding benefit was evident as reduced

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vascular access site events. Although not designed to evaluate mortality at 12 months, a lower point estimate for mortality in favor of the bivalirudin arm (1.6% vs. 2.5%, P ⫽ 0.16) was reassuring in that the nonsignificant excess in MI was not associated with an excess in mortality (31). Hence in pooled analysis of the randomized clinical trial experience in PCI, including 11,638 patients (bivalirudin, 5861; heparin, 5777), bivalirudin was associated with a reduction in the incidence of death, MI, revascularization, and major bleeding (7.8% vs. 10.8%, P ⬍ 0.001) at 48 hours (32). Despite a very low event rate, a benefit in terms of mortality was observed (0.01% vs. 0.02%, P ⫽ 0.049), whereas reductions for major bleeding were substantial (2.7% vs. 5.8%, P ⬍ 0.001). Furthermore, given the lower overall costs of this agent and savings associated with reduced bleeding, the use of bivalirudin remains economically attractive (33). In the recent ACUITY trial in moderate and high-risk patients (n ⫽ 13,819) with ACS undergoing an invasive strategy, patients were randomized to five arms: unfractionated heparin or LMWH ⫹ upstream GPIIb/IIIa inhibitors, unfractionated heparin or LMWH ⫹ in lab GPIIb/IIIa inhibitors, bivalirudin ⫹ upstream GPIIb/IIIa inhibitors, bivalirudin ⫹ in lab GPIIb/IIIa inhibitors alone, bivalirudin alone. The primary endpoint was a composite of death, MI, or unplanned revascularization for ischemia plus major bleeding. The time from drug administration to angiogram was 5.3 hours. Fifty-six percent of patients underwent PCI, 32% had medical therapy, and 12% had surgery. The primary endpoint showed noninferiority for the net clinical outcome: 11.7% heparin ⫹ IIb/IIIa groups versus 11.8% bivalirudin ⫹ IIb/IIIa groups, P ⬍ 0.001. The ischemic composite was 7.3% versus 7.7%, P ⫽ 0.015, for noninferiority and major bleeding was 5.7% versus 5.3%, P ⬍ 0.001 for noninferiority. The results for bivalirudin group alone was 10.1% for the composite endpoint, P ⬍ 0.0001, 7.8% for the ischemic endpoint, P ⫽ 0.32, and 3.0% for major bleeding, P ⬍ 0.001 (all P-values for superiority). All causes of major bleeding were numerically lower with bivalirudin, except for intracranial hemorrhage, 0.07% versus 0.07%. Notably transfusions were less frequent with bivalirudin; 2.7% heparin ⫹ GP IIb/IIIa versus 1.6%, P ⬍ 0.001. Thus, the simpler regimen of bivalirudin alone resulted in significantly greater net clinical benefit (34).

Special groups Decreased renal function Among patients treated with direct thrombin inhibitors, several observational studies have sought to address known

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high-risk groups undergoing PCI. Although large-scale studies in ST-elevation MI are ongoing, observational data with bivalirudin suggest that the use of this agent is at least feasible, complementing the data with hirudin in the GUSTO IIb study (18,35). Both pooled analysis from the BAT, CACHET, and REPLACE-1 and an analysis from REPLACE-2 have demonstrated an increase in the risk of bleeding and ischemic events among patients with reduced renal function being treated with heparin and heparin/GP IIb/IIIa inhibition (36,37). In these analyses, the benefit of bivalirudin in relative terms was maintained, for both ischemic and bleeding events. Hence, in absolute terms, among patients with creatinine clearance ⬍60 mL/min, bivalirudin is associated with a greater absolute benefit.

Diabetes Patients with diabetes remain an important subgroup given the evidence supporting reduced revascularization and mortality associated with abciximab in these patients undergoing PCI (38). Compared with a strategy of heparin and GP IIb/IIIa inhibition, diabetic patients treated with bivalirudin experienced a numerically lower but nonsignificant late mortality at 12 months (2.3% vs. 3.9%, P ⫽ NS). No differences were observed with short-term bleeding and ischemic outcomes.

Heparin-induced thrombocytopenia syndrome Bivalirudin may also have a particular role among patients with HITS (39). Among 52 patients studied, clinical success defined as the absence of death, q-wave infarction, or emergent CABG was achieved in 96% of patients. No patients experienced thrombocytopenia (platelet count ⬍50 ⫻ 109/L), suggesting that bivalirudin is a safe alternative to indirect thrombin inhibition among this high-risk group.

Drug-eluting stents, brachytherapy, and peripheral intervention Several smaller studies have also explored the use of bivalirudin with drug-eluting stents, brachytherapy, and in peripheral intervention (40–42). Although lacking optimal comparative design, these studies appear to indicate a safety and efficacy profile comparable to that observed in the randomized clinical trials.

Combination therapies Direct thrombin inhibition provides theoretical advantages for combination pharmacotherapies in PCI. Providing potent inhibition of thrombin-induced platelet activation, synergistic effects with agents blocking the activation and aggregation of platelets can be expected. Furthermore, these agents have not been shown to induce platelet activation in the same manner that has been observed with heparin (43). Although the majority of evidence with bivalirudin has focused on its role as an alternative to heparin and GP IIb/IIIa inhibition, the combination of bivalirudin and GP IIb/IIIa inhibition in a planned and provisional strategy also appears to be safe (28). Although not a randomized comparison, patients in the REPLACE-1 study receiving both bivalirudin and GP IIb/IIIa inhibition experienced a nonsignificant excess in bleeding events compared with those receiving bivalirudin alone, and ischemic events were nonsignificantly lower than heparin/GP IIb/IIIa inhibition treated patients in this pilot study. Although associated with lower rates of ischemic events, pretreatment with clopidogrel in the REPLACE-2 study did not impact the relative risk of ischemic events or the benefit with respect to bleeding associated with bivalirudin compared with heparin and GP IIb/IIIa inhibition (44).

Applications to interventional cardiology: when and why Argatroban is indicated for HITS and bivalirudin is indicated for a wide range of clinical indications including patients undergoing elective PCI and those presenting with ACS. Specific evidence among patients undergoing catheter-based reperfusion for ST-elevation MI is currently lacking but is being addressed in ongoing trials. Bivalirudin has particular advantages among certain high-risk groups who are at increased risk of bleeding and ischemic events, such as the elderly, those presenting with anemia, and patients with moderate renal impairment. Evidence in the setting of more recent innovations in interventional practice such as drug-eluting stents, brachytherapy, and peripheral intervention do not suggest any variance with the benefit documented in clinical trials. The use of bivalirudin is cost-effective.

Conclusion The direct thrombin inhibitors have theoretical advantages over the indirect anticoagulants that include more predictable dose–responses, and efficacy against clot bound thrombin. With bivalirudin, clinical trials suggest superiority compared with heparin alone and comparable outcomes when

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References

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van den Bos AA, Deckers JW, Heyndrickx GR, et al. Safety and efficacy of recombinant hirudin (CGP 39 393) versus heparin in patients with stable angina undergoing coronary angioplasty. Circulation 1993; 88:2058–2066. Hafner G, Rupprecht HJ, Luz M, et al. Recombinant hirudin as a periprocedural antithrombotic in coronary angioplasty for unstable angina pectoris. Eur Heart J 1996; 17:1207–1215. Serruys PW, Herrman J-PR, Simon R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 333:757–763. The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1997; 336:1621–1628. Roe MT, Granger CB, Puma JA, et al. Comparison of benefits and complications of hirudin versus heparin for patients with acute coronary syndromes undergoing early percutaneous coronary intervention. Am J Cardiol 2001; 88:1403–1406. Mehta SR, Eikelboom JW, Rupprecht HJ, et al. Efficacy of hirudin in reducing cardiovascular events in patients with acute coronary syndrome undergoing early percutaneous coronary intervention. Eur Heart J 2002; 23:117–123. Sinnaeve PR, Simes J, Yusuf S, et al. Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention. Eur Heart J 2005; 26:2396–2403. Manfredi JA, Wall RP, Sane DC, et al. Lepirudin as a safe alternative for effective anticoagulation in patients with known heparin-induced thrombocytopenia undergoing percutaneous coronary intervention: case reports. Catheter Cardiovasc Interv 2001; 52:468–472. Matthai WH Jr. Use of argatroban during percutaneous coronary interventions in patients with heparin-induced thrombocytopenia. Semin Thromb Hemost 1999; 25(suppl 1):57–60. Lewis BE, Matthai WH Jr, Cohen M, et al. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Catheter Cardiovasc Interv 2002; 57:177–184. Jang IK, Lewis BE, Matthai WH Jr, et al. Argatroban anticoagulation in conjunction with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention: an open-label, nonrandomized pilot study. J Thromb Thrombolysis 2004; 18:31–37. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995; 333:764–769. Bittl JA, Chaitman BR, Feit F, et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142:952–959. Lincoff AM, Bittl JA, Kleiman NS, et al. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial). Am J Cardiol 2004; 93:1092–1096.

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Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289:853–863. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352:87–92. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004; 292:696–703. Ebrahimi R, Lincoff AM, Bittl JA, et al. Bivalirudin vs heparin in percutaneous coronary intervention: a pooled analysis. J Cardiovasc Pharmacol Ther 2005; 10:209–216. Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIa inhibition versus heparin with routine glycoprotein IIb/IIIa inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 2004; 44:1792–1800. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355: 2203–2216. Stella JF, Stella RE, Iaffaldano RA, et al. Anticoagulation with bivalirudin during percutaneous coronary intervention for STsegment elevation myocardial infarction. J Invasive Cardiol 2004; 16:451–454. Chew DP, Bhatt DL, Kimball W, et al. Bivalirudin provides increasing benefit with decreasing renal function: a meta-analysis of randomized trials. Am J Cardiol 2003; 92:919–923. Chew DP, Lincoff AM, Gurm H, et al. Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary

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intervention (a subanalysis of the REPLACE-2 trial). Am J Cardiol 2005; 95:581–585. Gurm HS, Sarembock IJ, Kereiakes DJ, et al. Use of bivalirudin during percutaneous coronary intervention in patients with diabetes mellitus: an analysis from the randomized evaluation in percutaneous coronary intervention linking angiomax to reduced clinical events (REPLACE)-2 trial. J Am Coll Cardiol 2005; 45:1932–1938. Mahaffey KW, Lewis BE, Wildermann NM, et al. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparininduced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol 2003; 15:611–616. Dangas G, Lasic Z, Mehran R, et al. Effectiveness of the concomitant use of bivalirudin and drug-eluting stents (from the prospective, multicenter BivAlirudin and Drug-Eluting STents [ADEST] study). Am J Cardiol 2005; 96:659–663. Allie DE, Hebert CJ, Lirtzman MD, et al. A safety and feasibility report of combined direct thrombin and GP IIb/IIIa inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention: treating critical limb ischemia like acute coronary syndrome. J Invasive Cardiol 2005; 17:427–432. Kuchulakanti P, Wolfram R, Torguson R, et al. Bivalirudin compared with IIb/IIIa inhibitors in patients with in-stent restenosis undergoing intracoronary brachytherapy. Cardiovasc Revasc Med 2005; 6:154–159. Keating FK, Dauerman HL, Whitaker DA, Sobel BE, Schneider DJ. Increased expression of platelet P-selectin and formation of platelet-leukocyte aggregates in blood from patients treated with unfractionated heparin plus eptifibatide compared with bivalirudin. Thromb Res 2006; 118:361–369. Saw J, Lincoff AM, Desmet W, et al. Lack of clopidogrel pretreatment effect on the relative efficacy of bivalirudin with provisional glycoprotein IIb/IIIa blockade compared to heparin with routine glycoprotein IIb/IIIa blockade: a REPLACE-2 substudy. J Am Coll Cardiol 2004; 44:1194–1199.

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8 Clinical application of direct antithrombin inhibitors in acute coronary syndrome Shunji Suzuki, Hikari Watanabe, Takefumi Matsuo, and Masanori Osakabe

Introduction Percutaneous coronary intervention (PCI) such as coronary angioplasty and stent implantation has become a worldwide routine strategy for coronary arterial occlusive diseases. Along with the recognition that thrombus formation is very likely to be involved in acute coronary syndrome (ACS), selection of the optimal anticoagulant is becoming essential to achieve reliable anticoagulation for successful PCI. Although unfractionated heparin (UFH) has long been used as the standard anticoagulant with great potency, there are some therapeutic dilemmas in its use. Given the availability of new anticoagulants and to address these clinical considerations, the choice of the anticoagulant should take into account the individual patient’s condition.

70 to 100 U/kg (50–70 U/kg if GPIIbIIIa receptor inhibitors is given) (1). Similar guidelines have been issued from the European Society of Cardiology (2). In a multicenter prospective study in Japan, patients underwent a successful PCI received UFH of 4980 ⫾ 1754 (mean ⫾ SD) U at an activated partial thromboplastin time (aPTT) ratio of 2.4 ⫾ 1.8 (mean ⫾ SD). Empirically, lower dose has been used in Japan (3). Despite the excellence of UFH as an anticoagulant, several problems occur during PCI. Following vascular injury by PCI which disrupts the endothelium and subendothelium, the resultant generation of thrombin may not be sufficiently minimized with UFH. Recently, the additional use of GPIIb/IIIa inhibitors for the purpose of suppressing platelet activation during PCI has in some situations been recommended to address this problem of UFH. For these reasons, it has not been concluded whether heparin is the optimal anticoagulant to support successful PCI (4).

Heparin The anticoagulant action of heparin was discovered by McLean in 1916, and it has since been the landmark anticoagulant therapy employed in clinical practice. The most common preparation of heparin is UFH (molecular weight: 5000 to 30,000 Da) which is a mixture of mucopolysaccharides derived from porcine intestinal mucosa. Among the various pathways affected by UFH, the main action is to accelerate the inhibitory effects of antithrombin on thrombin and factors Xa, Va, and VIIa. The American College of Cardiology and the American Heart Association recommend that UFH should be given during a PCI procedure to achieve an activated clotting time (ACT) of 250 to 350 seconds [200 seconds if glycoprotein (GP) IIbIIIa receptor inhibitor is given] with a weight-adjusted bolus dose,

Inter-individual difference in anticoagulation UFH acts directly on platelets to promote platelet aggregation and releases platelet factor 4 (PF4) from the endothelium. PF4 binds UFH and neutralizes its anticoagulant action (5). Furthermore, UFH induces the release of tissue factor pathway inhibitor (TFPI) from platelets and endothelial cells into the circulation. One of the major effects of UFH is the release of free-type TFPI, which strongly inhibits FVIIa tissue factor. Therefore, the anticoagulant actions of UFH vary depending on the individual patient and are influenced by the level of PF4, antithrombin, and histidine-rich GP.

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Clinical application of direct antithrombin inhibitors

No inhibition of fibrin/clot-bound thrombin Due to its large molecular size in comparison with direct thrombin inhibitors (DTIs), UFH is unable to penetrate into fibrin clot and to inhibit thrombin trapped in a clot. Hence, its anticoagulant activity is limited only to the inhibition of thrombin in the process of thrombi formation.

heparin + platelet factor (PF4) heparin-PF4 complex production of lgG antibody against the heparin-PF4 complex lgG antibody + heparin-PF4 complex lgG antibody-heparin-PF4 immunocomplex binding of the immunocomplex on platelet surface/endothelium

Heparin resistance The conventional dosing regime of UFH aims to maintain aPTT values within 1.5 to 2.5 times the baseline value. If aPTT 1.5-fold or above the baseline is not obtained when dosing with 35,000 U/day of UFH, this condition is regarded as heparin resistance. Heparin resistance presents in various clinical settings and, in particular, is closely associated with decreased antithrombin-III (AT-III). Since UFH accelerates its antithrombin action in the presence of AT-III, a lower level of AT-III attenuates such action. Once the AT-III level in the blood falls to 60% of the usual levels, a dose of 35,000 U/day or greater UFH is required to prolong aPTT to attain the therapeutic range. The absence of AT-III is observed in congenital or acquired clinical events (sepsis, multiple trauma, burn injury, malignant tumor, and extracorporeal circulation). When UFH is administered to those patients, careful monitoring of the AT-III level is needed because AT-III is consumed during the use of UFH. If AT-III decreases to 60% or below, the risk of venous thrombosis increases. Heparin cofactor II (HC-II), unlike AT-III, is not a core factor. However, the thrombin neutralization rate is further accelerated by the mediation of dermatan and heparan sulfate. Normally, when vascular injury occurs in the subendothelium and dermatan sulfate increases, HC-II deserves the effects of thrombin neutralization. When coronary artery angioplasty was performed with UFH in a patient with congenital HC-II deficiency, recurrent restenosis occurred in a very short period; however, subsequent angioplasty with argatroban, a direct thrombin inhibitor, did not result in restenosis (6). With the reduced level of HC-II, even with a normal/adequate level of AT-III, UFH could not inhibit sufficiently fibrin-bound thrombin generated during a PCI procedure. It is possible that restenosis might be predicted in situations where there is a lower than normal level of AT III and/or HC-II. UFH does not demonstrate an adequate anticoagulant action without these cofactors.

Heparin-induced thrombocytopenia and platelet stimulation Heparin-induced thrombocytopenia (HIT) is a serious adverse drug reaction to heparin (Fig. 1). HIT is caused by the

platelet activation and aggregation/tissue factor expression PF4 release amplification of platelet activation activation of coagulation thrombin generation arterial/venous thrombosis (HIT)

Figure 1 Model of the pathogenesis of heparin-induced thrombocytopenia (HIT). Heparin forms heparin/platelet factor 4 (PF4) complex in vivo. Thereafter, autoantibodies (HIT antibodies) against this complex are generated and further form an immune complex. This immune complex binds to the Fc receptor on the surface of platelets, which are activated, leading to further secretion of PF4 and platelet aggregation. The activated platelets also produce microparticles which amplify thrombin generation. Moreover, released PF4 is also responsive to heparan sulfate on the endothelium to form a complex. HIT antibodies also bind to this complex and induce not only endothelial damage but also the expression of tissue factor on endothelial cells. Platelet activation and thrombin generation are mainly pathogenic in a hypercoagulable state at the onset of HIT. Abbreviation: HIT, heparin-induced thrombocytopenia.

transient production of autoantibodies (HIT antibodies) following heparin administration. HIT antibodies are generated against antigen of PF4-heparin complex approximately 5 to 10 days after the first exposure to heparin. HIT antibodies are composed of immunoglobulin G (IgG) primarily, and also IgA and IgM. After the generation of HIT antibodies, complications of thrombocytopenia and arterial/venous thrombi may be observed. The pathogenicity of thrombus formation is suspected as follows: first, HIT antibodies activate platelets through Fc␥IIIa receptor and release microparticles from it, second, the antibodies bind to the heparan sulfate–PF4 complex on endothelial cells, and finally, the endothelium is activated, expressing tissue factor and producing thrombogenic activation (7). As UFH is used routinely in PCI, attention

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Introduction

should be paid to the risk of HIT. HIT is unavoidable as long as UFH is employed in PCI procedures (3,8–10). Unfortunately, HIT-associated complications are not always properly recognized in cardiovascular events. Such failure of recognition happens in the following way: (i) the use of oral antiplatelet agents masks the signs and symptoms, (ii) heparin is administered for only a short period and most HIT is underestimated, and (iii) the level of HIT antibodies becomes undetectable during the long period of non-use of heparin between previous PCI and subsequent cardiac interventions. Some patients with acute myocardial infarction (AMI) are found to have HIT antibodies “career state of HIT antibodies” regardless of previous heparin usage. In those patients, earlyonset HIT has been observed, which occurs within a very short period after UFH administration during PCI even if it is the initial exposure to UFH (10). Once HIT antibodies are generated after the exposure to UFH, the antibodies do not disappear for approximately 100 days after the cessation of UFH. If UFH intervention is resumed while the antibodies remain, HIT may readily develop as “rapid-onset type of HIT” (11). Thrombotic complications are highly anticipated following the abrupt onset of HIT in patients who have been exposed recently to UFH. In some patients carrying HIT antibodies, “delayed-onset type of HIT” occurs a couple of days to several weeks after the cessation of heparin therapy (12,13). Recently, thanks to more sophisticated equipment, the post-PCI hospitalization period has become shorter. Nevertheless, it is alarming that patients treated with UFH for PCI have a potential risk of HIT onset after hospital discharge. All interactions between UFH and platelets are complex and only partially elucidated, but it is known that heparin itself stimulates platelets via a platelet-binding domain of heparin (14). In the therapeutic range, UFH induces the release of P-selectin and activates GPIIb/IIIa receptors when adenosine diphosphate (ADP) or thrombin receptor agonist peptide stimulates platelet responsibility, and then enhances platelet aggregation (15,16). Even in healthy individuals, agonist-induced platelet aggregation is often enhanced when heparin is added.

Polymorphonuclear leukocyte elastase Polymorphonuclear leukocyte elastase as a marker of leukocyte activation is a GP with a molecular weight of about 30,000, and there are three isozymes. It has a biological role in host defense mechanisms, but it sometimes induces abnormal blood coagulation and injury of the vascular intima. In particular, polymorphonuclear leukocyte elastase has a strong deteriorating effect on fibrinolytic enzymes and antithrombin and induces hypercoagulability in the presence of UFH. In high level of polymorphonuclear leukocyte elastase in ACS, an anticoagulant effect of heparin is presumably attenuated owing to degradation of heparin-induced AT-III activity.

95

Options of other anticoagulants for percutaneous coronary intervention UFH has long been used empirically as a conventional anticoagulant for PCI procedures; however, no placebo-controlled studies have been conducted to confirm the efficacy and safety of UFH in patients undergoing PCI (Fig. 2). Thus, in daily practice, at a catheter laboratory, UFH is used without evidence. The pathogenic mechanism of ACS is that coronary arteriosclerotic plaques rupture and erode leading to thrombosis. Once injury to the coronary endothelial cells occurs, collagen and von Willebrand factor exposed to subendothelial matrix adhere to platelets. Consequently, these platelets are

Tissue factor Fibrinogen DTI

DTI

collagen ADP TXA2

Thrombin DTI DTI

coagulation factors

platelet activation gylcoprotein IIb/IIIa inhibitor

Fibrin platelet aggregation

t-PA or SK

Thrombus formation DTI = direct thrombin inhibitor

Figure 2 Critical role of thrombin in thrombogenesis. Thrombin plays a critical and central role in thrombogenesis through platelet activation, fibrin generation, and clot stabilization at the site of arterial disruption, which are caused by percutaneous coronary intervention or plaque rupture in acute coronary syndromes. Tissue factor released at the site of vessel injury or plaque rupture activates coagulation, resulting in the generation of small amounts of thrombin. The small amount of thrombin activates platelets and other coagulation factors, which amplifies this process and causes an explosive burst of thrombin generation. Furthermore, thrombin is the most potent physiological activator of platelets. The morphology of platelets changes and then adheres to the site of the damaged vessel. Activated platelets recruit additional platelets by synthesizing thromboxan A2 and releasing adenosine diphosphate. Platelet activation induces conformational changes in glycoprotein IIb/IIIa receptor resulting in platelet aggregation. Clotting factors form a stable thrombus on the surface of aggregated platelets. Abbreviation: DTI, direct thrombin inhibitor.

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activated leading to platelet adhesion. Tissue factors exposed on the damaged endothelium and subendothelial matrix and released into blood circulation trigger an extrinsic pathway activation, which leads to thrombin generation and then fibrin clot formation (17,18). And also, as a key factor of thrombotic events, share stress to vascular wall by arterial flow results in tissue factor expression on endothelial cells, release of procoagulant factors from activated platelets and finally thrombin generation. Anticoagulation using DTIs may be a better option in patients with ACS undergoing PCI or not. In the meta-analysis with 11 randomized studies, anticoagulant effects in ACS and PCI were compared between a direct antithrombin agent and UFH. The direct thrombin inhibitor showed better outcome in death or myocardial infarction than UFH (19). DTIs are expected to be an alternative to UFH for PCI.

Direct thrombin inhibitors DTIs (Fig. 3, Table 1) have been developed to overcome the drawbacks of UFH therapy and aim to effectively inhibit thrombin without involving antithrombin. Thrombin plays a critical role in thrombogenesis through platelet activation, fibrin generation, and clot stabilization at the site of endothelial disruption. Thrombin generation also occurs following endothelial injury due to physical pressure during angioplasty. Furthermore, increased thrombin generation is found to be a trigger at the onset of ACS. Therefore, DTIs have been investigated to see if they can achieve greater clinical efficacy than that of conventional UFH therapy (20–22).

Bivalirudin Hirudin

Argatroban

Active site Fibrinogen binding site THROMBIN

Argatroban Argatroban (Table 2) is a selective direct thrombin inhibitor discovered by Okamoto et al. in 1978 in Japan. In the United States, argatroban is licensed as an anticoagulant for the prophylaxis and treatment of thrombosis in patients with HIT as well as for patients with or at risk for HIT undergoing PCI check. In some European countries, including Sweden and Germany, argatroban is also available for anticoagulation in adult patients with HIT. In Japan, the approved indications are for use in patients with chronic arterial occlusion, in hemodialysis patients with a deficiency or a decrease in AT-III levels, and in patients with acute cerebral thrombosis. With its arginine-based structure and molecular weight of 527 Da, argatroban binds directly to the active site of thrombin with an inhibitory constant (Ki) of 0.04 ␮M. It shows no inhibitory effects on serine protease inhibitors such as trypsin, plasmin, and factor Xa, but is highly selective for thrombin and exerts its anticoagulant action independent of AT-III and HC-II as cofactors. Pharmacodynamically, argatroban can bind to both free and fibrin- or clot-bound thrombin. Its inhibitory action on bound thrombin is much greater than those of UFH or hirudin (23). As argatroban reversibly binds to thrombin, the likelihood of significant hemorrhagic events is reduced. Argatroban strongly inhibits thrombin-induced platelet aggregation (24), but does not cause platelet stimulation, which is commonly observed in heparin. In patients with HIT undergoing PCI (25) or dialysis (26), argatroban has been used as an alternative to UFH. Owning to its low molecular weight and synthetic nature, argatroban does not cause biological antibodies (27). For anticoagulation therapy in patients with a high polymorphonuclear leukocyte elastase level, argatroban is more effective than heparin plus AT-III (28). The metabolism of argatroban is via hepatic hydroxylation and aromatization by cytochrome enzymes CYP3A4/5 and elimination via biliary excretion (29); however, argatroban is not altered by its concomitant use with erythromycin (a CYP3A4/5 inhibitor), which suggests no significant drug–drug interaction (30). In hepatically impaired patients, argatroban clearance is decreased four-fold and so dose reduction and careful monitoring are required (31). Argatroban can be used as a substitute for UFH in HIT patients with renal insufficiency requiring hemodialysis treatment (32).

Figure 3 Pharmacologic differences between hirudin, argatroban, and bivalirudin. Hirudin and bivalirudin are bivalent direct thrombin inhibitors. They bind to both the active site and the fibrinogen binding site. Argatroban is a univalent inhibitor and binds to the active site only (no fibrinogen binding site). Hirudin is an irreversible inhibitor, while argatroban and bivalirudin exhibit reversible binding. After binding to thrombin, bivalirudin is cleaved by thrombin at the active site, restoring thrombin activity (80).

Argatroban in percutaneous coronary intervention During a PCI procedure, thrombin generation in the vessels damaged by the manipulation cannot be suppressed by UFH but can be by argatroban (4,33). The feasibility and safety of argatroban in combination with GPIIb/IIIa inhibition were studied in 152 patients who

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Direct thrombin inhibitors

Table 1

97

Characteristics of unfractionated heparin and direct thrombin inhibitors UFH

Argatroban

Lepirudin

Bivalirudin

Nature

Mixture of mucopolysaccharide

Synthetic arginine analog

Recombinant protein

Synthetic peptide

Molecular weight

5000–30,000 Da

527 Da

6980 Da

2180 Da

Antithrombotic action

Thrombin ⬇ Xa

Thrombin

Thrombin

Thrombin

Fibrin-bound, free-thrombin



Thrombin inhibition

Irreversible

Reversible

Irreversible

Reversible

Necessary cofactor

AT III · HC II

No

No

No

Half-life

60 min

40–50 min

80 min

25 min

Target aPTT (x baseline)

x 1.5–2.5

x 1.5–3.0

x 1.5–2.5

x 1.5–3.0

Antidote

Protamin

No

No

No

Elimination

Liver (Kidney)

Liver

Kidney

Kidney

Platelet stimulation

⫹⫹

—

—

—

Interaction with PF-4

⫹⫹

—

—

—

Thrombocytopenia

⫹⫹

—

—

—

Trigger for HIT

⫹⫹

—

—

—

—

⫹a

⫹

US, EU

—

—

⫹

Antigenecity Approved indication Prophylaxis of HIT Treatment of HIT

US, EU

US, EU

—

PCI in HIT

US

—

US

PCI

—

—

US, EU

aReadministration

could lead to anaphylaxis.

Abbreviations: aPTT, activated partial thromboplastin time; AT, antithrombin; HC, heparin cofactor; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention; PF, platelet factor; UFH, unfractionated heparin.

underwent PCI. The integrin GPIIb/IIIa receptor on platelets is the final common pathway of platelet aggregation. PCI was performed in patients receiving argatroban to achieve an ACT of 275 to 325 seconds in combination with predominantly abciximab (a Fab fragment of the chimeric human-murine monoclonal antibody against the GPIIb/IIIa receptor) or eptifibatide (a synthetic cyclic heptapeptide with high specificity for the GPIIb/IIIa receptor). The primary endpoint, a composite of cardiovascular adverse events at 30 days, occurred in four patients. Two patients experienced major bleeding, one a retroperitoneal bleed and the other a groin hematoma. This trial shows that adequate anticoagulation can be achieved with a combination of a reduced dose of argatroban and a GPIIb/IIIa inhibitor, and moreover, this combination of treatment was well tolerated with an acceptable bleeding risk in patients undergoing PCI (34).

Argatroban as adjunctive therapy to thrombolytics in acute myocardial infarction In the Myocardial Infarction with Novastan and TissuePlasminogen Activator (MINT) trial, a comparative trial of effects of UFH and argatroban on reperfusion by tissueplasminogen activator (t-PA) was carried out in 125 patients with AMI (Table 3). Three treatment regimens were tested: UFH, low-dose argatroban and high-dose argatroban. A dose-dependent benefit over UFH in achieving Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow at 90 minutes after thrombolytic therapy was observed: P ⫽ 0.20: between low-dose argatroban versus UFH, P ⫽ 0.13: between highdose argatroban versus UFH. The incidence of the composite

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Table 2

Pharmacodynamics and pharmacokinetics of argatroban

Pharmacology

Competitively and reversibly inhibits thrombin

Pharmacokinetics Half-life

40–50 min

Elimination

CYP 3A4/5 Hepatica

Metabolism/hepatic impairment

1/4 reduction of starting dose

Renal dysfunction

No dose modification

Pharmacodynamic effects on aPTT and ACT HIT

Continuous infusion starting with 2 ␮g/kg/min. aPTT is monitored 2 hr after start of infusion and infusion rate is adjusted to aPTT 1.5–3.0 times baseline not to exceed aPTT 100 sec and 10 ␮g/kg/min

PCI in HIT

A bolus of 350 ␮g/kg given over 3–5 min following by continuous infusion with 25 ␮g/kg/min. ACT is monitored 5–10 min after bolus dose is completed. If ACT ⬍300 sec another bolus dose of 150 ␮g/kg is given and infusion is increased to 30 ␮g/kg/min. If ACT ⬎450 sec infusion rate is reduced to 15 ␮g/kg/minb

aCYP

3A4/5: liver microsomal cytochrome P450 enzymes 3A4/5.

bThe

dose was reduced to 250 or 300 ␮g/kg bolus followed by 15 mg/kg/min infusion to achieve ACT of 275 to 325 seconds when GPIIb/IIIa inhibitors was co-

administrated in non-HIT patients undergoing PCI.

Abbreviations: aPTT, activated partial thromboplastin time; ACT, activated clotting time; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention.

endpoint of cardiovascular adverse events at day 30 was numerically lower in both argatroban groups than in the heparin group (P ⫽ 0.23) (35). The Argatroban in Acute Myocardial Infarction (ARGAMI) trial was conducted to compare the effects of argatroban and UFH as adjunctive therapy to t-PA in patients with AMI. One hundred and twenty seven patients were randomized to either the UFH group or the argatroban group. Patency rate at 90 minutes was not significantly different between the two groups (36). ARGAMI-2 was conducted to compare the effects of UFH and low and high doses of argatroban as adjunctive therapy to t-PA or streptokinase (SK) in 1200 patients with AMI. At the interim analysis, the low-dose argatroban group was discontinued due to the lack of efficacy. No statistically significant difference was observed in mortality or any other primary efficacy endpoints between the UFH and high-dose argatroban groups (37).

Dose description of argatroban The dose regimens for HIT and PCI in HIT patients are presented in Table 2. In the patients with HIT, it is recommended that argatroban is administered as a continuous intravenous infusion starting at 2 ␮g/kg/min. The dose was adjusted to attain an aPTT of 1.5 to 3.0 times the baseline,

but not exceeding 100 seconds (38,39). aPTT should be checked two hours after the initiation of argatroban to confirm that the desired aPTT range is achieved. The initial dose of argatroban should be one-fourth for patients with moderate hepatic impairment. However, it has been reported that the initial dose of 2.0 ␮g/kg/min led to excessive anticoagulation even in patients with normal hepatic function (40,41). In some patients in cardiothoracic intensive care units or with metastatic cancer, a dose reduction could be proposed. In the ongoing investigator’s initiated trial for HIT in Japan, lower initial dose of 0.7 ␮g/kg/min is used (42). Empirically lower doses are used in Japan than in Europe or United States. As an anticoagulant for patients with or at risk for HIT undergoing PCI, the recommended dosage is a bolus of 350 ␮g/kg/min followed by a continuous infusion of 25 ␮g/kg/min. ACT should be checked 5 to 10 minutes after the bolus dose is completed. The PCI procedure may proceed when the ACT is greater than 300 seconds. When the ACT is less than 300 seconds, an additional bolus dose of 150 ␮g/kg should be administered, the infusion dose increased to 30 ␮g/kg/min, and the ACT checked 5 to 10 minutes later. When the ACT is greater than 450 seconds, the infusion rate should be decreased to 15 ␮g/kg/min, and the ACT again checked 5 to 10 minutes later. Once an adequate therapeutic ACT of between 300 and 450 seconds has been achieved, this infusion dose should be continued for the duration of the

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Table 3

99

Clinical trials of argatroban in acute myocardial infarction with thrombolytics

Trial (reference)

Target population

Number of patients

Dose regimen

Results

MINT (35)

AMI with tPA

125

Argatroban (100 ␮g/kg bolus ⫹ 1 or 3 ␮g/kg/min infusion) vs. UFH (70 U/kg bolus ⫹ 15 U/kg/hr infusion)

Efficacy: non-significant benefit in TIMI 3 flow in argatroban. Safety: no difference in rate of major bleeding

ARGAMI (36)

AMI with tPA

127

Argatroban (100 ␮g/kg bolus ⫹ 3 ␮g/kg/min infusion) vs. UFH (5000 U bolus ⫹ 1000 U/hr infusion)

Efficacy: no difference in angiographic patency. Safety: no difference in rate of bleeding

ARGAMI-2 (37)

AMI with tPA or SK

1200

Argatroban (60 ␮g/kg bolus ⫹ 2 ␮g/kg/min or 120 ␮g/kg bolus ⫹ 4 ␮g/kg/min infusion) vs. UFH (5000U bolus ⫹ 1000U/hr infusion)

Efficacy: no difference in mortality. Safety: no difference in rate of major bleeding

Abbreviations: AMI, acute myocardial infarction; ARGAMI, argatroban in acute myocardial infarction; MINT, myocardial infarction with novastan and tissue plasminogen activator; SK, streptokinase; TIMI, thrombolysis in myocardial infarction; tPA, tissue plasminogen activator; UFH, unfractionated heparin.

procedure. When a patient requires anticoagulation after the procedure, argatroban may be continued, but at a lower infusion dose, such as the dose for HIT. Thrombin-specific inhibitors also prolong the prothrombin time/ international normalized ratio (INR). Thus, careful monitoring should be employed during transition from argatroban to oral anticoagulant. The dose of argatroban should be reduced to 2 ␮g/kg/min to predict the INR on oral anticoagulant alone. When the INR reaches four on combination therapy, argatroban can be discontinued and an INR on oral anticoagulant alone should lie in the range 2.0 – 3.7. The INR should be measured four to six hours again after the stop of argatroban (43,44). In the investigator’s initiated trial in Japan, argatroban is to be stopped when the INR on combination therapy reaches 2.5 to 3.0 (42).

Monitoring of argatroban Anticoagulation with argatroban is easily controlled with minimal inter-patient differences, but monitoring is recommended for safety use. aPTT and ACT are correlated predictably with doses up to 40 ␮g/kg/min infusion. This therefore allows the flexible use of aPTT and/or ACT depending on the clinical setting (45). A dose-proportional curve was also noted in ecarin clotting time (ECT) (46). ECT is measured based on the conversion from prothrombin to meizothrombin mediated by ecarin, the venom of the snake. Thrombin inhibitors can inhibit

meizothrombin converting fibrinogen to fibrin. ECT may be used as an index of the plasma level of argatroban in patients undergoing PCI (46,47). However, aPTT is used to monitor argatroban for doses used in the management of HIT type II as this test is widely available and understood by both specialists and general physicians. In the case of PCI, ACT is used as it is familiar to interventionalists and allows real-time monitoring at the cath lab.

Hirudin Hirudin, a protease inhibitor originally existing in the salivary glands of the medicinal leech, Hirudo medicinalis, is a singlechain polypeptide consisting of 65 amino acid residues (molecular weight: approximately 7000). Hirudin inhibits selectively thrombin but not factor Xa and binds to thrombin (1:1) to form an irreversible complex. Hirudin exerts better anticoagulation than UFH because it inhibits both fibrinbound thrombin and free thrombin in circulation. Hirudin does not stimulate platelets unlike heparin so that it can be used in patients with HIT (48). There are two forms of recombinant hirudin, lepirudin, and desirudin. In Europe and the United States, one of the recombinant hirudins, lepirudin, was approved for anticoagulation in patients with HIT and associated thromboembolic disease. Lepirudin has been reported to generate antihirudin antibodies in 40% or more of treated patients after infusion for

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more than five days. These antibodies may affect the enhancement and/or reduction of coagulation cascade. Occasionally this leads to drug accumulation because a lepirudin–immunoglobulin complex is formed and renal clearance of the drug is delayed. Fatal anaphylaxis has been reported in patients who received a repeat intravenous bolus administration of lepirudin after an interval of a few months (49). Since hirudin is excreted by the kidneys, dose reduction and careful monitoring are needed for patients with renal insufficiency.

Hirudin in percutaneous coronary intervention In the Hirudin in European Trial Versus Heparin in the Prevention of after PTCA (HELVETICA) trial, 1141 patients with unstable angina undergoing PCI were randomized to one of the following three groups: UFH or two dose regimens of hirudin. The primary endpoint of event-free survival at seven months was not significantly different in the three groups, but hirudin groups showed a significant relative risk reduction (P ⫽ 0.023) in the endpoint of early events occurring within 96 hours after PCI. The incidences of hemorrhagic complications were not different among the three groups (50).

Hirudin as adjunctive therapy to thrombolytics in acute myocardial infarction Hirudin has been studied extensively in ACS (Table 4). The TIMI 5 trial was conducted in 246 patients with AMI to compare the efficacy of UFH and hirudin as adjunctive therapy to t-PA (51). In the hirudin group, the rate of recanalization to achieve TIMI 3 coronary flow without death or reinfarction was greater than that in the UFH group (P ⫽ 0.07). No inter-group difference in the incidence of major hemorrhage was observed. In TIMI 6, the effects of UFH and hirudin were compared in 193 patients with AMI in combination with SK. The results of both groups were similar for both safety and efficacy endpoints (52). In the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-IIb trial, the effects of UFH and hirudin in combination with either t-PA or SK were compared in 3289 patients with AMI (53). When dosed in combination with SK, the benefit of hirudin over UFH was observed in the clinical efficacy endpoint with the same levels of bleeding complications. In the TIMI 9b trial, 3002 patients with AMI were dosed with hirudin or UFH in combination with t-PA or SK, but no difference between the groups was observed in the clinical efficacy endpoint up to 30 days after administration (54). The administration of UFH or hirudin was not initiated

during thrombolytic therapy but within 60 minutes after the completion of thrombolytics, which might have masked the difference between the groups.

Dose description of hirudin Lepirudin is indicated for anticoagulation in patients with HIT and thrombosis. The registered dose is 0.4 mg/kg for bolus and the infusion rate is started from 0.15 mg/kg/h, which can be adjusted to obtain an aPTT of 1.5 to 2.5 times the baseline, and the aPTT should be checked every four hours until steady state is achieved. Lepirudin is also reported to be an effective anticoagulant for patients with isolated HIT when administered at lower doses of 0.10 mg/kg/hr adjusted by aPTT without the initial bolus (55). Upon transition to oral anticoagulants, the dose of lepirudin should be reduced to attain prolongation of the aPTT by 1.5. When coumarin derivatives are initiated, lepirudin should be continued for four to five days and discontinued when the INR stabilizes within the target range.

Monitoring of hirudin Hirudin treatment has been monitored by aPTT and frequent aPTT monitoring is required in patients with renal impairment, serious liver injury, or an increased risk of bleeding (56). Stricter dose adjustment is required in renal impairment patients. ECT may be a more appropriate marker, particularly for high-dose hirudin (57).

Bivalirudin (formerly hirulog) Through the investigation of several hirudin-based analogs, bivalirudin has been developed. Bivalirudin is approved as an anticoagulant for patients undergoing PCI in the United States and Europe. Recently, the FDA has approved an extension to the indication, namely for HIT patients undergoing PCI. Bivalirudin is a synthetic 20-amino acid compound. The molecular weight is 2180 Da and the plasma half-life is 25 minutes. Bivalirudin can bind to both fibrin-bound thrombin and free thrombin. Dose reduction in proportion to the creatinine level is necessary in patients with renal insufficiency. Bivalirudin, like hirudin, interacts with both the active site and fibrinogen-binding site. Once bivalirudin binds to thrombin, however, its amino-terminal domain binding to the active site is cleaved, leading to the recovery of catalytic activities of thrombin. Although the carboxy terminal domain remains bound to the fibrinogen binding site, this interaction is weak. Thus, bivalirudin shows a short duration of thrombin inhibition. Some researchers have suggested that higher doses of bivalirudin can be used with less bleeding owing to this

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Table 4

101

Clinical trials of hirudin in acute myocardial infarction with thrombolytics

Trial (reference)

Target population

Number of patients

Dose regimen

Results

TIMI 5 (51)

AMI with tPA

246

Hirudin (0.15 mg/kg bolus ⫹ 0.05 mg/kg/hr infusion, 0.1 mg/kg bolus ⫹ 0.1 mg/kg/hr infusion, 0.3 mg/kg bolus ⫹ 0.2 mg/kg/hr infusion, or 0.6 mg/kg bolus ⫹0.2 mg/kg/hr infusion) vs. UFH 5000 U bolus ⫹ 1000 U/hr infusion

Efficacy: non-significant benefit in TIMI 3 flow in hirudin. Safety: no difference in rate of major bleeding

TIMI 6 (52)

AMI with SK

193

Hirudin (0.15 mg/kg bolus ⫹ 0.05 mg/kg/hr infusion, 0.3 mg/kg bolus ⫹ 0.1 mg/kg/hr infusion, or 0.6 mg/kg bolus ⫹0.2 mg/kg/hr infusion) vs. UFH 5000 U bolus ⫹ 1000 U/hr infusion

Efficacy: no effect. Safety: no difference in rate of major bleeding

TIMI 9b (54)

AMI with tPA or SK

3002

Hirudin (0.1 mg/kg bolus ⫹ 0.1 mg/kg/hr infusion) vs. UFH 5000 U bolus ⫹ 1000 U/hr infusion

Efficacy: comparable. Safety: comparable

GUSTO Iib (53)

AMI with tPA or SK

3289

Hirudin (0.1 mg/kg bolus ⫹ 0.1 mg/kg/hr infusion) vs. UFH 5000 U bolus ⫹ 1000 U/hr infusion

Efficacy: benefit of hirudin with SK but no benefit with t-PA. Safety: no difference in rate of bleeding

Abbreviations: AMI, acute myocardial infarction; GUSTO, Global Use of Strategies to Open Occluded Coronary Arteries; SK, streptokinase; TIMI, thrombolysis in myocardial infarction; tPA, tissue plasminogen activator; UFH, unfractionated heparin.

temporary inhibition of the thrombin catalytic site (58). However, bivalirudin’s shorter duration of action could induce rebound hypercoagulability on the cessation of antithrombin therapy (59). The molecular weight of bivalirudin is smaller than that of hirudin. Therefore, it is unlikely to cause anaphylactic responses; however, bivalirudin has been reported to show cross-reactivity to anti-lepirudin antibodies. Caution is required when administering bivalirudin to patients previously treated with lepirudin (60).

Bivalirudin in percutaneous coronary intervention Bivalirudin was studied at five doses in 291 patients undergoing coronary angioplasty (61). The incidence of hemorrhagic complications was markedly low during this trial. It was demonstrated that bivalirudin could be an alternative anticoagulant to UFH in preventing transient complications during coronary angioplasty. Further to the above pilot trial, the Bivalirudin Angioplasty Trial (BAT) was designed. In this trial, 4098 patients undergoing

PCI for their unstable or postinfarction angina were randomly assigned to either a bivalirudin or a UFH treatment arm in a double-blind manner. Bivalirudin did not significantly decrease the incidence of the above primary endpoints in the entire trial population when compared with UFH (62). The data from BAT were subsequently reanalyzed (63). The endpoints, incidences of death, myocardial infarction or repeat revascularization with a contemporary definition, were compared between bivalirudin and UFH at 7, 90, and 180 days after PCI in the entire intention-to-treat cohort of 4312 patients, whereas the original report analyzed the per-protocol population. The incidence of the combined endpoints of death, myocardial infarction or repeat revascularization was significantly lower with bivalirudin than with heparin (P ⫽ 0.039). The significant difference between bivalirudin and UFH for the combined endpoints persisted at 90 days (P ⫽ 0.012), but not at 180 days (P ⫽ 0.153). The bleeding rate was significantly lower in the bivalirudin group than the UFH group as in the original analysis (P ⬍ 0.001). In the Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 (64), bivalirudin with the provisional use of GPIIb/IIIa inhibitors and UFH with the planned use of GPIIb/IIIa inhibitors were compared in 6010 patients undergoing urgent

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or elective PCI. In this trial, both in primary and secondary clinical efficacy endpoints, noninferiority was shown statistically. In the incidence of major bleeding events, a significant reduction was observed in the bivalirudin group compared with the UFH group (P ⬍ 0.001). The median ACT five minutes after the trial drug bolus was longer in the bivalirudin group (358 seconds) versus UFH (317 seconds). A follow-up trial to one year showed that the clinical outcome of bivalirudin with provisional GPIIb/IIIa inhibitors was comparable with that of heparin with planned GPIIb/IIIa inhibition (65,67). These data suggest that bivalirudin could be used routinely as a substitute for heparin during PCI. Bivalirudin achieves approximately the same clinical effect as heparin when used in PCI, and there may be an early advantage in the high-risk subgroup of patients with postinfarction angina.

Bivalirudin as adjunctive therapy to thrombolytics in acute myocardial infarction The Hirulog Early Reperfusion or Occlusion (HERO) trial was conducted in patients with AMI to investigate the effects of bivalirudin in combination with SK and aspirin (Table 5) (66). Four hundred and twelve patients who presented with onset of ST elevation within 12 hours were randomized in a double-blind manner to one of three adjunctive anticoagulation regimens, UFH, low-dose or high-dose bivalirudin. The

Table 5

primary endpoint of TIMI grade 3 flow occurred in 48% of patients in the high-dose bivalirudin group, 46% of those in the low-dose bivalirudin group, and 35% of those in the UFH group (UFH vs. bivalirudin groups; P ⫽ 0.023). There was no significant difference in the incidence of clinical efficacy events. In the HERO-2 trial, bivalirudin and UFH were compared as adjunctive therapy to SK in patients with AMI. In the primary endpoint of mortality, there was no difference (10.8% with bivalirudin vs. 10.9% with heparin, P ⫽ 0.85), although the incidence of reinfarction was significantly lower in the bivalirudin groups (P ⫽ 0.001) (67).

Dose description of bivalirudin The clinically recommended dose of bivalirudin was originally 1.0 mg/kg bolus followed by infusion at 2.5 mg/kg/hr for four hours. After the REPLACE-2 trial, the dose was reduced to 0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hr for the duration of the PCI procedure, which is the dosage approved in the United States and Europe. The postprocedural infusion can be continued for up to four hours. It is recommended that ACT should be measured five minutes after bolus dosing, where ACT is expected to be 320 to 400 seconds, and a second bolus of 0.3 mg/kg should be administered if needed [if ACT is less than 225 seconds according to the EMEA Sm PC (68)]. Bivalirudin shows a linear correlation between the dose or plasma concentration and

Clinical trials of bivalirudin in acute myocardial infarction with thrombolytics

Trial (reference)

Target population

Number of patients

Dose regimen

Results

HERO (66)

AMI with SK

412

Bivalirudin (0.125 mg/kg bolus ⫹ 0.25 mg/kg/hr infusion for 12 hr ⫹ 0.125 mg/kg/hr for 60 hr or 0.25 mg/kg bolus ⫹ 0.5 mg/kg/hr infusion for 12 hr ⫹ 0.25 mg/kg/hr for 60 hr) vs. UFH (5000 U bolus ⫹ 1000–1200 U/hr infusion for 60 hr)

Efficacy: significant benefit in TIMI3 flow in bivalirudin groups; safety: lower rate of major bleeding in bivalirudin groups

HERO-2 (67)

AMI with SK

17073

Bivalirudin (0.25 mg/kg bolus ⫹ 0.5 mg/kg/hr infusion for 12 hr and then, 0.25 mg/kg/hr for 36 hr) vs. UFH (5000 U bolus ⫹ 800–1000 U/hr infusion)

Efficacy: no difference; safety: no difference in rate of severe bleeding

Abbreviations: AMI, acute myocardial infarction; HERO, hirulog early reperfusion or occlusion; SK, streptokinase; TIMI, thrombolysis in myocardial infarction; UFH, unfractionated heparin.

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UFH better –10

0

10

20

103

DTI better 30 (%)

MINT (+tPA)

argatroban

anticoagulation (ACT) (69,70). From systematic review of the relationship between dose, ACT and the clinical effects of bivalirudin, an ACT of 300 seconds or more provides adequate anticoagulation; in other words, no increase in clinical benefit is obtained with higher ACT levels and the incidence of bleeding was independent of ACT levels (71). The infusion dose should be reduced and ACT should be carefully monitored in patients with renal impairment (68,72).

ARGAMI (+tPA)

Hemorrhagic risk of DTIs vs. unfractionated heparin The use of DTIs as adjunctive therapy to thrombolytics has been extensively studied in comparison with UFH. Therefore, the risk of bleeding of DTI versus UFH could be evaluated from the results of these trials conducted in a substantial number of patients. The first trials with hirudin were terminated prematurely due to the high incidence of bleeding events (73–75). In the subsequent trials using a reduced dose of hirudin, the bleeding rate decreased to the level observed with UFH (54,76). Bleeding rates were compared between DTIs and UFH in thrombolytic trials of AMI when DTIs exerted similar anticoagulant efficacy to UFH. Differences in bleed rates and 95% confidence intervals are shown in Figure 4. The difference in bleeding rate was significant in one of the bivalirudin trials (HERO). An absolute risk reduction of 13% was obtained in the HERO trial as the maximum and ⫺0.2% in the HERO-2 trial as the minimum. Since the significant reduction of bleeding rate was not observed in the other eight trials, the bleeding risks of DTIs are said to be similar to those of UFH. To avoid unexpected bleeding events, monitoring of the drugs is necessary in the same manner as for UFH. Overall, these data show that the risk for bleeding with DTIs is no greater than that with UFH.

Alternative anticoagulant for heparin-induced thrombocytopenia patients undergoing percutaneous coronary intervention PCI induces endothelial injury and plaque disruption, causing platelet activation, subsequent release of PF4 which is a heparininduced antigen, thrombin generation, and an inflammatory response (Table 6). The addition of aspirin to UFH is used routinely to overwhelm the activation of platelets and the subsequently stimulated coagulation system. In a comparative trial between argatroban and UFH, inflammatory, hemostatic, and

hirudin (reduced dose)

ARGAMI-2 (+tPA/SK) TIMI 5 (+tPA) TIMI 6 (+SK) TIMI 9b (+tPA/SK) GUSTO IIb (+tPA/SK)

bivalirudin

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HERO (+SK) HERO-2 (+SK)

Figure 4 Bleeding rate difference between DTIs and unfractionated heparin (UFH) in nine thrombolytic trials of acute myocardial infarction. The difference in rate of major bleeding is shown when the DTI as an adjunctive therapy to thrombolytics showed similar efficacy to UFH. Aspirin was used to suppress activated platelet function in all trials. Black squares and bars indicate the point estimates and the intervals of 95% confidence of the rate differences in each trial. A different definition for bleeding classification was applied to the following trials; hemorrhagic stroke and hematoma greater than 5 cm in the ARGAMI trial and severe bleeding in the GUSTO IIb and HERO-2 trials. Abbreviations: ARGAMI, argatroban in acute myocardial infarction; DTI, direct thrombin inhibitor; HERO, hirulog early reperfusion or occlusion; GUSTO, Global Use of Stratigies to Open Occluded Coronory Arteries; SK, streptokinase; UFH, unfractionated protein.

endothelium-derived markers changed in patients with stable angina undergoing PCI. Both drugs had no effects on the PCIinduced inflammatory response, but argatroban appeared more effective in inhibiting thrombin and preventing antithrombin consumption during and after a PCI procedure (33). In HIT patients undergoing PCI, combination of argatroban and aspirin was administered as an alternative to UFH and obtained reliable anticoagulation (77). Argatroban has been evaluated in three multicenter, open-label, prospective trials in 91 patients in a total of 112 procedures with or at risk for HIT undergoing PCI (25). In these studies, argatroban was administered as a bolus of 350 ␮g/ kg followed by an infusion

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Table 6 Alternative anticoagulants in percutaneous coronary intervention in heparin-induced thrombocytopenia Drug

Dose regimen

Monitoring

Characteristics

Approved countries

Trial (reference)

Argatroban

350 ␮g/kg bolus ⫹ 25 ␮g/kg/min during procedure

Target ACT 300–450 sec

Low bleeding risk No antigenicity

US

ARG 216/310/311, n ⫽ 91 (76)

Hirudin

0.4 mg/kg bolus ⫹ 0.10–0.24 mg/kg/hr for 24 hr or/ ⫹ 0.04 mg/kg/hr for 24 hr

Target aPTT 60–100 sec

High bleeding risk Antibody formation (⬇40%)

—

n ⫽ 25 (77)

Bivalirudin

0.75 mg/kg bolus ⫹ 1.75 mg/kg/hr for 4 hr during procedure

Target ACT 350 sec

Low bleeding risk Antibody formation (⬍1.0%)

US

ATBAT, n ⫽ 52 (78)

Abbreviations: ACT, activated clotting time; aPTT, activated partial thromboplastin time.

of 25 ␮g/kg/min, adjusted to achieve an ACT of 300 to 450 seconds. Argatroban was found to be a safe and effective anticoagulant in HIT patients undergoing PCI without a significant increase in bleeding. On this basis, argatroban was approved by the FDA as an anticoagulant for patients with or at risk for HIT undergoing PCI. When used in combination with GPIIb/IIIa inhibitors, the dose of argatroban was reduced to a bolus of 250 or 300 ␮g/kg followed by a 15 ␮g/kg/min infusion to target lower ACT of about 300 seconds in non-HIT patients (34). Strict monitoring by ACT is required to avoid unexpected overdose of argatroban in intensive-care patients with hepatorenal failure, especially after cardiac surgery. Hirudin has been used for anticoagulation in non-HIT patients undergoing PCI treatment (50). The molecular structure of drug is completely different from UFH, and the drug does not stimulate generation of HIT antibodies. Although theoretically hirudin might be employed as an alternative to UFH, it has not been studied in HIT patients undergoing PCI, because of its higher incidence of bleeding. In a trial with 25 HIT patients who underwent PCI and were enrolled after platelet recovery to greater than 50,000/␮L, the drug was clinically and angiographically efficacious (78). However, generation of antibodies against hirudin was detected in about half of the hirudin-treated patients after five days of treatment. The antibodies could interfere with anticoagulant activity of the drug. Again, strict monitoring is necessary to avoid unexpected bleeding complications. Bivalirudin is indicated as an anticoagulant for HIT patients undergoing PCI (79). In the Anticoagulant Therapy with Bivalirudin to Assist in the Performance of Percutaneous Coronary Intervention in Patients with Heparin-Induced Thrombocytopenia (ATBAT) trial, 52 patients undergoing PCI with current or previous HIT were enrolled. These included high-risk patients such as those with an increased risk of

ischemic and bleeding complications, a higher population of women, a majority of patients with prior MI, and 21% reported a history of HITTS. The bivalirudin treatment appeared safe, and 98% of patients undergoing PCI had a successful procedure. One patient had major bleeding. Two dose regimens, high and low dosages, were used. Despite the relatively small number of patients, this trial suggests that bivalirudin in high-risk patients with HIT undergoing PCI may be used safely and with a good effect. The lowdose, a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr during a procedure, is the one recommended for this indication.

Conclusion UFH has been a valuable therapeutic option for ACS. UFH remains unsurpassed by any drugs discovered within the last century, and the prevention and treatment of ACS are still achieved by routine use of heparin. For heparin anticoagulation, careful monitoring is required due to the individual variation in efficacy and the risk of bleeding. To achieve improved efficacy and safety of heparin, new drugs such as low-molecular weight heparins and DTIs have been introduced, and new drugs are continuously studied. It has been delineated that platelet activation and subsequent thrombin generation are pathogenic for thrombus formation in ACS, and the neutralization of thrombin is crucial not only for the treatment of ACS but also for a successful PCI procedure. Three DTIs, argatroban, hirudin, and bivalirudin, have been studied to explore if these are better treatments than UFH in ACS and PCI. In the trials of DTIs as adjunctive therapy to thrombolytics in AMI, it is suggested that hemorrhagic complications of DTIs would be less or at least have the same

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References

frequency as those of UFH. Now the DTIs are anticipated to be alternatives to UFH, but they are still unrecognized and not used as frequently as UFH in ACS. HIT is the most avoidable adverse reaction in heparin anticoagulation, but it is not uncommon in clinical settings and is often unrecognized. Platelet activation induced by heparin/PF4 complex antibodies and subsequent thrombin generation play a central role in the pathophysiology of HIT, which result in thrombocytopenia and the thrombotic complications of HIT. Patients with HIT should be treated with an alternative anticoagulant to avoid potentially fatal thrombotic complications. DTIs have been used for the treatment of HIT. In particular, argatroban has been also recommended to substitute for heparin in HIT patients undergoing PCI. One of the advantages of argatroban is that it does not generate anti-bodies. The other two DTIs generate more or less antibodies, leading to intricate anticoagulant action, especially antibodies for lepirudin are considered to be relevant to anaphylactic shock. As the number of aged patients with ACS and/or undergoing PCI is increased, heparin exposure is repeated and it promotes the generation of HIT antibodies and subsequently develops to HIT. Risk for HIT by re-exposure to heparin should be given careful attention to in the current clinical settings.

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Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85:435–440. Swan SK, St Peter JV, Lambrecht LJ, et al. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects. Pharmacotherapy 2000; 20:756–770. Callas D, Fareed J. Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Res 1996; 83:463–468. Ahmad S, Ahsan A, Iqbal O, et al. Pharmacokinetics and pharmacodynamics of argatroban as studied by HPLC and functional methods: implications in the monitoring and dosageoptimizations in cardiovascular patients. Clin Appl Thromb Hemost 1998; 4:243–249. Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (Lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia. A prospective study. Circulation 1999; 99:73–80. Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108:2062–2065. Serruys PW, Herrman J-P, Simon R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 333:757–763. Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) 5 trial. J Am Coll Cardiol 1994; 23:993–1003. TIMI 6 Investigators. Initial experience with hirudin and streptokinase in acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) 6 trial. Am J Cardiol 1995; 75:7–13. Metz BK, White HD, Granger CB, et al. Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb trial. J Am Coll Cardiol 1998; 31:1493–1498. Antman EM for the TIMI 9b Investigators. Hirudin in acute myocardial infarction: thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9b trial. Circulation 1996; 94:911–921. Lubenow N, Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of three prospective studies. Blood 2004; 104:3072–3077. Zeymer U, von Essen R, Tebbe U, et al. Frequency of “optimal anticoagulation” for acute myocardial infarction after thrombolysis with front-loaded recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW 023). ALKK Study Group. Am J Cardiol 1995; 76:997–1001. Potzsch B, Hund S, Madlener K, et al. Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay. Thromb Res 1997; 86:373–383. Bates SM, Weitz JI. Direct thrombin inhibitors for treatment of arterial thrombosis: potential difference between bivalirudin and hirudin. Am J Cardiol 1998; 82:P12–P18.

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Shah PB, Popma JJ, Piana RN. Bivalirudin in percutaneous coronay interventions and acute coronary syndromes: new concepts, new directions. Curr Interv Cardiol Rep 1999; 1:346–358. Eichler P, Lubenow N, Strobel U, et al. Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. Blood 2004; 103:613–616. Topol EJ, Bonan R, Jewitt D, et al. Use of a direct antithrombin, Hirulog, in place of heparin during coronary angioplasty. Circulation 1993; 87:1622–1629. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable angina or postinfarction angina. N Engl J Med 1995; 333:764–769. Bittl JA, Chaitman BR, Feit f, et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142:952–959. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289:853–863. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004; 292:696–703. White HD, Aylward PE, Frey MJ, et al. Randomized, doubleblind comparison of Hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96:2155–2161. The Hirulog and Early Reperfusion or Occlusion (HERO) -2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001; 358:1855–1863. Angiox: EMEA Summary of Product Characteristics. 2006 September.

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Sciulli TM, Mauro VF. Pharmacology and clinical use of bivalirudin. Ann Pharmacother 2002; 36:1028–1041. Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy 2002; 22(part2):105S–111S. Lui HK. Dosage, pharmacological effects and clinical outcomes for bivalirudin in percutaneous coronary intervention. J Invasive Cardiol 2000; 12(suppl F):41F–52F. The Medicines Company. Angiomax US label. 2005 December. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO IIa) Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90:1631–1637. Antman E for the TIMI 9A Investigators. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation 1994; 90:1624–1630. Neuhaus KL, von Essen R, Tebbe U, et al. Safety observations from the pilot phase of the randomized r-hirudin for improvement of thrombolysis (HIT-III) study. Circulation 1994; 90:1638–1642. GUSTO II b Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335:775–782. Suzuki S, Sakamoto S, Koide M, et al. Effective anticoagulation by argatroban during coronary stent implantation in a patient with heparin-induced thrombocytopenia. Thromb Res 1997; 88:499–502. Cochran K, DeMartini TJ, Lewis BE, et al. Use of lepirudin during percutaneous vascular interventions in patients with heparin-induced thrombocytopenia. J Invas Cardiol 2003; 15: 617–621. Mahaffey KW, Lewis BE, Wildermann NM, et al. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparininduced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol 2003; 15:611–616. Pifarre R, Scanlon PJ. Evidence-Based Management of the Acute Coronary Syndrome. Philadelphia: Hanley & Belfus, 2001:132.

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9 Oral antithrombin drugs Brigitte Kaiser

Introduction Improved understanding of the molecular mechanisms of blood coagulation has led to the development of new anticoagulants for the prevention and treatment of thromboembolic disorders in order to overcome the limitations of existing anticoagulants. These limitations include the need for coagulation monitoring and subsequent dose adjustment for vitamin K antagonists (Table 1), the difficulty of continuing prophylaxis out of hospital due to require parenteral administration for heparins, and the risk of heparin-induced thrombocytopenia (1). Various new anticoagulants target specific coagulation enzymes or different steps in the coagulation cascade, that is, the initiation of coagulation by factor VIIa/tissue factor (FVIIa/TF), its propagation by factors IXa, Xa and their cofactors, and the thrombin-mediated fibrin formation (2). The serine proteinase thrombin is the central enzyme in the coagulation pathway. It catalyzes the conversion of fibrinogen to fibrin by cleaving the peptide bond between arginine and glycine in the fibrinogen sequence GlyVal-Arg-Gly-Pro-Arg, activates the factors V, VIII, and XIII, and strongly stimulates platelet aggregation. Besides its procoagulant activities, thrombin also exhibits anticoagulant properties via the activation of the protein C pathway. Because of its pivotal role in the coagulation process, thrombin has been a target for the development of specific and selective inhibitors for many years (3). Intensive structure-based design over the last 20 years resulted in the development of numerous direct thrombin inhibitors (TIs), most of which have been peptidomimetic compounds that mimic the fibrinogen sequence interacting with the active site of thrombin (4). The new TIs bind directly to thrombin and block its interaction with different thrombin substrates. At present, the most important TIs that have been extensively evaluated for clinical use are the bivalent inhibitors, hirudin and bivalirudin, which interact with both the active site and the exosite-1 of thrombin in an irreversible and reversible manner,

respectively, as well as argatroban, which reversibly binds to the active site. Unfortunately because of their chemical structures, these new agents are not sufficiently absorbed after oral administration and have to be administered parenterally. Thus, they are less suitable for long-term anticoagulation. The development of orally effective, direct TIs seems to be a promising alternative to the existing direct or indirect anticoagulants for long-term use in patients with thromboembolic disorders. However, the design of those new drugs is difficult because different physicochemical properties are required for either the binding of a compound to the active site of thrombin or its absorption from the gastrointestinal tract (5). At present, various oral direct TIs are reported to be under development, of which ximelagatran and dabigatran etexilate are in a more advanced stage of clinical development (6,7).

Ximelagatran Chemistry Ximelagatran (Exanta®) was the first oral TI and the first new oral anticoagulant to become available since the development of warfarin more than 50 years ago. Ximelagatran is a prodrug of the small-molecule noncovalent tripeptidomimetic direct TI melagatran, which mimics the D-Phe-Pro-Arg sequence. Melagatran has a strong basic amidine structure, a free carboxylic acid, and, in addition, a less basic amine function, implying that it will be positively charged under physiological conditions, and thus it exhibits poor bioavailability and absorption upon oral dosing. Chemical modification of the melagatran molecule by N-hydroxylation at the amidine function and inclusion of an ethyl group at the carboxylic acid structure leads to the development of the double prodrug ximelagatran (Fig. 1). Ximelagatran is 170 times more

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Oral antithrombin drugs

Table 1 Comparison of vitamin K antagonists (warfarin sodium) with oral direct thrombin inhibitors (melagatran / ximelagatran) Warfarin sodium

Melagatran/Ximelagatran

Reduces synthesis of clotting factors (II, VII, IX, and X, protein C and S)

Targeted specificity for thrombin; direct competitive and reversible inhibition of both free and clot-bound thrombin

Slow onset and offset of action

Rapid onset of action, rapid reversal of thrombin inhibition after cessation of therapy (dependent on plasma concentration and elimination half-life)

Large interindividual dosing differences

Predictable and reproducible pharmacokinetic and pharmacodynamic profile

Multiple drug and food interactions

No interactions with food and alcohol, only low potential for drug interactions

Individual dose adjustment required

Use of fixed-dose regimens, no dose adjustment

Need for frequent and careful monitoring

No routine monitoring of the anticoagulant effect; control of liver enzymes at long-term therapy

Reversal of anticoagulation with vitamin K or with plasma or clotting factors replacement

No antidote available

Once daily oral administration

Twice daily oral administration

lipophilic than melagatran and uncharged at intestinal pH, resulting in a much better penetration of the gastrointestinal barrier, and thus an increased bioavailability (8–10). Melagatran binds rapidly, reversibly, and competitively to the active site of thrombin with a Ki value of 0.002 mol/L. It has a high selectivity for -thrombin; except for trypsin, the Ki value for thrombin is at least 300-fold lower than for other serine proteases involved in blood coagulation and fibrinolysis (11).

Pharmacodynamics Melagatran inhibits both thrombin activity and its generation and it effectively inactivates free and clot-bound thrombin with similar high potency (8,12–16). Using routine coagulation assays, clotting times in human plasma are prolonged to twice the control value at low concentrations of melagatran, that is, at 0.010, 0.59, and 2.2 mol/L for thrombin time, activated partial thromboplastin time, and prothrombin time, respectively. The IC50 value for thrombin-induced platelet aggregation is 0.002 mol/L. Inhibition of fibrinolysis is not observed at concentrations below the upper limit of the proposed therapeutic concentration interval (0.5 mol/L) (11). The antithrombotic effectiveness of ximelagatran was demonstrated in different species using experimental models of venous (9,17,18) and arterial (16,19–22) thromboembolism, as an adjunct in coronary artery thrombolysis (23), and in animal models of disseminated intravascular coagulation (24). In healthy volunteers, melagatran was effective in

inhibiting thrombus formation at low and high shear rates in an ex vivo model of human arterial thrombosis (25). In experimental models, ximelagatran was at least as effective as warfarin in the prevention of thrombus formation, but with a wider separation between antithrombotic effects and bleeding (7,21).

Pharmacokinetics Studies on the pharmacokinetic behavior of ximelagatran and melagatran have been carried out in animal species (26), as well as in healthy volunteers (26,27), orthopedic surgery patients (28,29), patients with deep venous thrombosis (DVT) (30), and volunteers with severe renal impairment (31) and mild-to-moderate hepatic impairment (32). After oral administration, ximelagatran is rapidly absorbed from the small intestine and undergoes rapid biotransformation to the active agent melagatran. The absorption of ximelagatran is at least 40% to 70% in rats, dogs, and humans, whereas the bioavailability of melagatran following oral administration of ximelagatran is 5% to 10% in rats, 10% to 50% in dogs, and about 20% in humans. The reason for the lower bioavailability of melagatran is a first-pass metabolism of ximelagatran with subsequent biliary excretion of the formed metabolites (26). After absorption, ximelagatran is rapidly bioconverted to its active form melagatran via two minor intermediates, that is, ethyl-melagatran, which is formed by reduction of the hydroxyamidine, and N-hydroxy-melagatran, which is formed by hydrolysis of the ethyl ester. Both intermediates

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Introduction

O

H N

O

H 3C

O

O

Figure 1

OH

N

HN 2

H N

111

Ximelagatran

N

Chemical structures of the thrombin inhibitors, melagatran and dabigatran, and their orally effective prodrugs, ximelagatran and dabigatran etexilate. Source: From Refs. 4, 26, 33, 68.

Reductioin (→ ethyl-melagatran) Hydrolysis (→ N-melagatran) NH

O

H N

HO

NH O

NH 2

N

N N

CH 3

Dabigatran etexilate

NH

O

O

O

N H

N

N

HO

N H

N

N

O

Melagatran

N

O

O H3C

NH2

H N

O

O

N

Dabigatran

N H

are subsequently metabolized to melagatran. Ethyl-melagatran is an active metabolite but due to its low plasma concentration, it unlikely contributes to the anticoagulant action of ximelagatran (9,26,27). Biotransformation of ximelagatran and its intermediates is catalyzed by several enzyme systems located in microsomes and mitochondria of liver, kidney, and other organs (33). Intravenously injected melagatran has a relatively low plasma clearance, a small volume of distribution, and a short elimination half-life. Its oral absorption is low and highly variable. In contrast, ximelagatran is rapidly absorbed after oral administration and then metabolized to melagatran. The plasma concentration of melagatran after oral dosing with ximelagatran declines in a mono-exponential manner with a plasma half-life of four to five hours. Melagatran is primarily excreted unchanged in urine; the renal clearance correlates well with the glomerular filtration rate (Table 2). Only trace amounts of ximelagatran are renally excreted; the major compound in urine and feces is melagatran. In feces of all species, appreciable quantities of ethyl-melagatran are recovered, suggesting a reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract (26). In contrast to vitamin K antagonists, the potential of melagatran for drug–drug interactions is very low (34–36). Pharmacokinetic interactions between melagatran and various other drugs mediated via the most common drug-metabolizing

enzymes of the CYP 450 system have not been observed (37). Concomitant intake of food or alcohol does not alter the bioavailability of melagatran which also shows only low inter- and intraindividual variability (38–40). The pharmacokinetic/pharmacodynamic profile of ximelagatran and its active form melagatran is consistent across a broad range of different patient populations and is unaffected by gender, age, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment (39,41–43). In patients with severe renal impairment, excretion of melagatran is delayed, resulting in longer half-life, increased plasma concentrations, and stronger and prolonged anticoagulation (31). Mild-to-moderate hepatic impairment has no influence on the pharmacokinetics and pharmacodynamics of melagatran, thus requiring no dose adjustment in those patients (32). After oral administration, neither ximelagatran nor its two intermediates and only trace amounts of melagatran were detected in milk of breastfeeding women (44).

Clinical studies Oral direct TIs have a promising role in the management of venous thromboembolism and other associated medical conditions (3,7,45–48). Ximelagatran has been successfully

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Table 2 Pharmacokinetic parameters of melagatran after oral administration of ximelagatran in various species

Oral dose of ximelagatrana

Human

Rat

Dog

50 mg (105 mol)

40 mol/kg

40 mol/kg

Oral absorption in all species Melagatran

Low and highly variable 40–70%

Ximelagatran Bioavailability (%)

19 6

13 3

50 13

Maximum melagatran plasma concentration (Cmax) (mol/L)

0.36 0.03

2.16 0.22

15.9 5.0

Time to reach Cmax (tmax) (hr)

1.85 0.78

0.80 0.27

1.13 0.6

Elimination half-life (t1/2)

(hr)b

3.6 0.7

1.4 0.4

11 3

Elimination half-life (t1/2)

(hr)c

1.6 0.2

0.4 0.03

1.2 0.2

Plasma clearancec

145 15 mL/min

15.8 2.1 mL/min/kg

7.0 1.0 mL/min/kg

Volume at distribution (Vss)c

17.3 1.7 L

0.37 0.02 L/kg

0.36 0.04 L/kg

Renal clearance

120 mL/min

23.1 mL/min/kg

4.37 mL/min/kg

Urine

82.6 3.9

65.9 3.5

42.5 7.8

Feces

5.7 2.2

24.3 4.3

38.9 15.5

Urine

25.2 4.3

21.3 1.9

22.6 2.4

Feces

71.1 4.5

71.3 1.1

66.9 3.1

Excretion of melagatran

(%)c

Excretion of ximelagatran (%)b

an

5 for humans and rats; n 4 for dogs.

bMeasured

after oral administration at the aforementioned doses.

cMeasured

after IV administration of melagatran at 2.3 mg (5.3 mol) in humans and 2 mol/kg in dogs and male rats.

Source: From Ref. 26.

studied in large phase III trials in various clinical settings (49–52). Based on its predictable pharmacokinetic and pharmacodynamic properties without significant time- and dose-dependencies, ximelagatran can usually be administered in fixed doses without the need for individualized dosing or coagulation monitoring. Ximelagatran is effective and welltolerated for the prevention of venous thromboembolism in high-risk orthopedic patients after hip and knee replacement surgery (EXPRESS EXpanded PRophylaxis Evaluation Surgery Study; EXULT EXanta Used to Lessen Thrombosis; METHRO MElagatran for THRombin inhibition in Orthopedic surgery) (29,53–56). Ximelagatran is also effective in the acute treatment of venous thromboembolism and long-term secondary prevention of recurrent venous thromboembolism (THRIVE THRombin Inhibitor in Venous thromboEmbolism) (57–59), for the prevention of stroke in patients with nonvalvular atrial fibrillation (SPORTIF Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation) (60–64), and in the prevention of

major cardiovascular events after myocardial infarction (ESTEEM Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage) (65). A survey of the phase III clinical trials with ximelagatran is given in Table 3. The different clinical trials demonstrated at least comparable efficacy of ximelagatran and warfarin; in terms of prevention of primary events, bleeding, and mortality, the oral TI may offer a promising alternative to the vitamin K antagonist. Together with the convenience of fixed oral dosing and the consistent and predictable anticoagulation, with no need for coagulation monitoring, ximelagatran has a great potential as a new option for long-term prophylaxis and therapy of thromboembolic disorders. Although clinical trials indicated that ximelagatran can potentially be used in clinical indications, the Food and Drug Administration recently refused to approve ximelagatran over concerns about liver toxicity. In clinical trials, in 6% to 10% of patients, raised aminotransferase levels were observed during

Stroke prevention in nonvalvular atrial fibrillation

Stroke prevention in nonvalvular atrial fibrillation

Acute therapy for proximal DVT

Extended secondary prevention of DVT

Hip and knee replacement

Hip and knee replacement

Knee replacement

Knee replacement

SPORTIF III

SPORTIF V

THRIVE II and IV

THRIVE III

METHRO III

EXPRESS

EXULT A

EXULT B

Randomized double-blind






Double-blind

Open-label

Study design Ximelagatran

Ximelagatran 24 mg or 36 mg twice daily for 7–12 days, initiated morning after surgery

Ximelagatran 24 mg or 36 mg twice daily for 7–12 days, initiated 12 hr after surgery

Melagatran 2 mg s.c. immediately before surgery, melagatran 3 mg s.c. 8 hrs after surgery, then ximelagatran 24 mg twice daily

Melagatran 3 mg s.c. 4–12 hrs after surgery; then ximelagatran 24 mg twice daily for 8–11 days

24 mg twice daily for 18 months

36 mg twice daily for 6 months

36 mg twice daily for at least 12 months

36 mg twice daily for at least 12 months

1410

1399

612

1240

1960

1704

Ximelagatran

1148

(85)

(56)

(53)

(54)

(58,59,84)

(57)

(61,83)

(60,83)

Reference

Introduction

Source: From Refs. 29, 55, 63, 65, 86.

surgery; SPORTIF, Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation; THRIVE, THRombin Inhibitor in Venous thromboEmbolism.

EXPRESS, EXpanded PRophylaxis Evaluation Surgery Study; EXULT, EXanta Used to Lessen Thrombosis; INR, international normalized ratio; s.c., subcutaneous; METHRO, MElagatran for THRombin inhibition in Orthopedic

Abbreviations: DVT, deep venous thrombosis; ESTEEM, Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage;

Warfarin initiated evening 1151 after surgery and adjusted to INR 2.5

608

1425

1389

611

1249

1962

1703

Control

Number of patients

Warfarin initiated evening 614 (24 mg), after surgery and adjusted 629 (36 mg) to INR 2.5

Enoxaparin 40 mg s.c. once daily for 8–11 days starting 12 hrs before surgery

Enoxaparin 40 mg s.c. once daily for 8–11 days starting 12 hrs before surgery

Placebo for 18 months

Enoxaparin (1 mg/kg s.c. twice daily) warfarin (INR, 2.0–3.0)

Warfarin, target INR, 2.0–3.0

Warfarin, target INR, 2.0–3.0

Control

Interventions

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Note: SPORTIF II and IV, THRIVE I, METHRO I, METHRO II, and ESTEEM were dose-guiding studies.

Indication

Clinical phase III trials with ximelagatran

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Table 3

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long-term use (35 days) of ximelagatran. The increase in levels of alanine aminotransferase (more than three-fold over the upper level of normal) occurred one to six months after initiation of therapy, but in 96% of patients, recovery was confirmed regardless of continuation of therapy or not (66). Although the true clinical significance of these findings remains unclear at this time, it likely requires regular liver function monitoring. Furthermore, because melagatran is renally eliminated, dose adjustment will be required in patients with renal impairment. Finally, there is no known antidote for the reversal of ximelagatran’s effect, though it is much shorter-acting than warfarin (67).

activity. Dabigatran is conjugated to activated glucuronic acid to form an acylglucuronide conjugate (69). Following oral administration of dabigatran etexilate in healthy volunteers, the median time to reach maximum concentration (tmax) was 2 hours and the mean terminal half-life (t1/2) was 8.7 hours. Coadministration of food delayed the absorption with increasing tmax to four hours. In the majority of patients undergoing total hip replacement, dabigatran etexilate was also welltolerated and adequately absorbed. However, there was a high interindividual variability in the AUC (area under the plasma concentration–time curve), Cmax (maximum plasma concentration), and tmax (median tmax six hours) (69).

Clinical studies

Dabigatran etexilate Dabigatran etexilate is another promising oral TI which is being evaluated in experimental and clinical studies, although the presently available data are still limited and not as comprehensive as for ximelagatran and its active form melagatran.

Chemistry, pharmacodynamics, and pharmacokinetics Dabigatran etexilate (BIBR 1048) is the orally active double prodrug of the small molecule, direct TI dabigatran (BIBR 953 ZW) (Fig. 1). Dabigatran belongs to a new structural class of nonpeptidic inhibitors employing a trisubstituted benzimidazole as the central scaffold and 4-amidinophenylalanine as a mimetic of arginine (68). Dabigatran is a specific, competitive, and reversible inhibitor of thrombin which exhibits a strong thrombin inhibitory activity (Ki 4.5 nM), as well as a high selectivity to thrombin; the Ki value for other serine proteases except trypsin (Ki 50 nM) is at least 400-fold higher (68). Dabigatran also shows a favorable activity profile in vivo, following intravenous administration into rats. Because of its highly polar, zwitterionic nature, its oral absorption is insufficient. From a number of synthesized prodrugs, dabigatran etexilate exhibited strong and long-lasting anticoagulant effects after oral administration into different animal species, and thus was chosen for clinical development (68). After oral administration, dabigatran etexilate is rapidly converted to dabigatran. In healthy volunteers, dabigatran was well-tolerated and primarily renally excreted. The absolute oral bioavailability of dabigatran etexilate is not reported, but urinary excretion of dabigatran amounted to 3.5% to 5%. This indicates a low oral bioavailability, as 80% of dabigatran is cleared renally (7). Cytochrome P450 isoenzymes are not involved in the metabolism of dabigatran and the compound neither induces nor inhibits cytochrome P450 isoenzyme

An open-label, dose-escalating safety study, BISTRO I, was conducted in 314 patients with total hip replacement surgery. Dabigatran etexilate was given orally at doses from 12.5 to 300 mg twice daily or 150 and 300 mg once daily administered 4 to 8 hours after surgery for 6 to 10 days. The TI demonstrated an acceptable safety profile with a therapeutic window above 12.5 mg and below 300 mg twice daily, as well as a satisfactory antithrombotic potential. Only two patients with reduced renal clearance suffered bleeding from multiple sites at the highest dose (70). The dose-dependent effectiveness and safety of dabigatran etexilate was also demonstrated in the BISTRO II study, a double-blind study in patients undergoing total hip or knee replacement. Dabigatran etexilate given at doses of 50, 150, and 225 mg twice daily or 300 mg once daily starting 1 to 4 hours after surgery and continuing for 6 to 10 days was compared to enoxaparin 40 mg subcutaneous (s.c.) once daily starting 12 hours prior to surgery (71). At present, various phase II and phase III clinical trials with oral dabigatran etexilate are mainly in the stage of recruiting patients (72). The different studies will investigate the (i) efficacy and safety of three doses of dabigatran etexilate in preventing venous thromboembolism in patients with total knee replacement surgery (placebo controlled), administered 11 to 14 days postoperatively; (ii) dabigatran etexilate as longterm anticoagulant therapy for stroke and systemic embolism prevention in patients with nonvalvular atrial fibrillation (RE-LY study, two blinded doses of dabigatran etexilate with openlabel warfarin); (iii) efficacy and safety of two different dabigatran etexilate dose regimens compared to enoxaparin (30 mg sc twice daily) in patients with primary elective total knee replacement surgery; (iv) efficacy and safety of two different dose regimens of dabigatran etexilate compared to enoxaparin (40 mg once daily) for 6 to 10 days in the prevention of venous thromboembolism in patients with total knee replacement surgery (RE-MODEL) and for 28 to 35 days in patients with total hip replacement surgery (RE-NOVATE). The PETRO Extension Trial (PETRO-Ex) is a follow-up treatment study of patients with atrial fibrillation who have been previously treated with BIBR 1048.

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References

Other direct oral thrombin inhibitors Current pharmaceutical research is focused on the design of novel anticoagulants with improved pharmacologic and clinical profiles that offer benefits over traditional therapies. Specific progress has been made in the development of small molecule factor Xa and TIs that are characterized by a predictable pharmacological profile, oral formulation, and decreased need for coagulation monitoring. Most of the newly developed oral TI are in a less advanced stage of development; they are mainly undergoing preclinical testing, and some compounds are in phase I clinical trials (73). The potential role of many of the new inhibitors as clinically useful antithrombotic agents still remains to be evaluated.

Clinical indications for oral thrombin inhibitors Clinical studies with oral direct TIs demonstrated that these drugs are effective and promising agents for the prevention and therapy of various thromboembolic disorders. The simplicity of drug administration and their benefits over established therapeutic strategies suggest that they will find increasing use in clinical practice for various indications (2,3,7,45,74). Patients undergoing major orthopedic surgery, such as total hip or knee replacement, are at high risk of venous thromboembolism. DVT may lead to life-threatening pulmonary embolism, disabling morbidity in the form of the postthrombotic syndrome, and risk of recurrent thrombotic events. Oral direct TIs are expected to represent an effective, safer, and/or more convenient alternative to vitamin K antagonists, low molecular weight heparins, or unfractionated heparin for the prevention of venous thrombosis after major orthopedic surgery, as well as for acute therapy and secondary prevention of DVT (47,75–77). Atrial fibrillation is increasing in incidence in developed countries and, because of the risk of embolic stroke, most patients require continuous anticoagulation. A large number of patients with atrial fibrillation are currently treated with vitamin K antagonists. Results of clinical trials in patients with atrial fibrillation indicate that oral direct TIs may become potential drugs for the prevention of embolic stroke and may replace warfarin (62,78,79–81). Patients with acute coronary syndromes such as acute myocardial infarction and unstable angina remain at risk for recurrent myocardial ischemia despite therapy with antiplatelet agents and heparin. Although first clinical trials indicate a possible use of oral direct TIs for the prevention of cardiovascular events in patients after acute myocardial infarction, the presently available data are still limited and it has not

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yet been demonstrated that oral TIs are more efficacious and safer for long-term use after acute coronary syndromes than the established drugs (48,82).

Conclusions The central position of thrombin in the coagulation cascade has made it a popular target for the discovery of novel antithrombotic agents, and several direct TIs are currently under development or even in clinical use for certain indications. The ultimate goal of most research program and drug optimization strategies is to develop an oral anticoagulant that overcomes the interactions, safety concerns, and the need for monitoring that limits the use of vitamin K antagonists. Structure-based design resulted in the development of orally bioavailable, small-molecule, direct TIs; among them, ximelagatran and dabigatran etexilate are the furthest along in clinical development. Although highly effective as an anticoagulant and safe with regard to bleeding, ximelagatran has been associated with liver function abnormalities the importance of which needs resolution. Dabigatran etexilate is much earlier in development and is currently of unproven value. A number of other oral direct serine proteinase inhibitors with distinct pharmacological profiles are presently undergoing preclinical and clinical testing and it is highly likely that alternatives to conventional anticoagulants and especially to warfarin will be available in the near future.

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10 Rationale for direct factor Xa inhibitors in acute coronary syndromes Volker Laux and Markus Hinder

Acute coronary syndromes (ACS) are a major cause of morbidity and mortality. They are characterized by intracoronary thrombus formation at the site of atherosclerotic plaques. Coronary thrombosis is the underlying mechanism in the transition from stable angina to the unstable angina (UA) syndrome, characterized by embolization of the developed thrombus and atherosclerotic plaque rupture.

Pathophysiology of acute coronary syndromes Generally, the pathophysiology of ACS can be divided into four phases: (i) the development of the atherosclerotic plaque, (ii) plaque rupture, (iii) acute ischemia, and (iv) longterm risk of recurrent ischemia (1). Thrombus formation on the atherosclerotic plaque leads to partial or total obstruction of the vessel, with subsequent thromboembolism representing the acute event. The presence of thrombi on atherosclerotic plaques has been demonstrated at autopsies and on angiographic and atherectomy specimens from patients with UA (2–5). Biomarkers of ongoing thrombosis (e.g., platelet activation, thrombin generation, and thrombin activity) indicate the central role of the coagulation and the platelet system. Atherosclerosis and thrombosis in arterial conditions are closely connected and form the clinical picture of atherothrombosis. Five pathophysiological processes contribute to the development of an acute atherothrombotic event (6): nonocclusive thrombus on the pre-existing plaque, dynamic obstruction of a coronary vessel (e.g., spasm), progressive mechanical obstruction, inflammatory and infection processes, and secondary UA.

Coronary vasoconstriction has been demonstrated for major epicardial coronary arteries (7) and for the small intramural coronary resistance vessels (8) and may occur because of local vasoconstrictors derived from platelets present in the thrombus, such as serotonin, thromboxane A2, and thrombin.

Current management of acute coronary syndromes ACS can be classified into UA, myocardial infarction (MI) without ST-segment elevation [non-ST-elevation MI (NSTEMI)], or STEMI. The presence of cardiac troponin in ACS indicates worse prognosis than the absence of troponin (9). Diagnosis and risk stratification in ACS is closely connected. Depending on the presence or absence of ST-elevation together with other risk factors, patients will undergo reperfusion therapy [thrombolysis, primary percutaneous coronary intervention (PCI)], coronary angiography, or pharmacological treatment. In NSTEMI, there exist two major strategies: an early invasive strategy in which all patients routinely undergo cardiac angiography for potential PCI or coronary artery bypass grafting (CABG) and an early conservative strategy consisting of medical treatment for lower risk patients. The pharmacological treatment options for ACS include agents that either reduce oxygen demand (beta blockers) or increase oxygen supply (nitrates, potassium channel activators, calcium channel blockers) to the heart and antiplatelet (aspirin, ADP-receptor antagonists, GPIIb/IIIa receptor blockers) and antithrombin therapy (unfractionated heparin, low molecular weight heparin, direct thrombin inhibitors) (10).

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The majority of patients with MI and UA have high plasma levels of FpA (15–17). FpA is also found in the urine of these patients (18). These data correlate with clinical findings in angiographic and pathologic studies demonstrating the importance of intracoronary thrombosis (19). In TIMI-5, the main levels for F1 ⫹ 2, FpA, TAT, and B␤1-42 were elevated in patients with ST-elevation (20), clearly reflecting an activation of the coagulation cascade in MI. Moreover, in this study it could be demonstrated that FpA and TAT levels were associated with increased mortality. In about 50% of ACS patients, abnormally high plasma levels of F1 ⫹ 2 and FpA were found during the acute phase of the disease (21). However, no difference was found between patients with UA and acute MI, indicating that F1 ⫹ 2 and FpA are not dependent on the nature of the thrombus (22). Procoagulant activity and thrombus-associated thrombin activity have also been demonstrated during coronary interventions measuring plasma levels of F1 ⫹ 2 (23) or FpA (24). Interestingly, FpA also increased despite maximal anticoagulation with heparin. The correlation between increased FpA plasma levels and increased incidence of complications and ischemic events indicated the involvement of heparinresistant thrombin activity into the failure of the intervention (25). Beneath the activation of the coagulation system, it has been demonstrated that platelet activation in the coronary sinus of patients undergoing coronary intervention is significant (26).

Role of biomarkers in acute coronary syndromes Several biomarkers describe the severity of ACS and can be used as a guidance for clinical risk stratification. The decrease of the cardiac enzymes CK and CK-MB have been regarded for a long time as the gold standard for diagnosis of MI (11). However, it has been observed in histological specimens that small damages of myocardial cells do not necessarily increase CK-MB (12). With the isolation of cardiac isoforms of the troponins, it has been demonstrated that troponin T (TnT) and troponin I (TnI) are well suited for diagnosis of ACS (13,14). In contrast to CK-MB, troponins are also sensitive to minimal myocardial cell necrosis. The magnitude of the increase of these myocardium-specific enzymes reflects the extent of the myocardial damage. Biomarkers that are involved in the early stages of the pathogenetic process can be used to identify patients at risk (Fig. 1). One of the key players in thrombogenesis is thrombin, which is involved not only in the coagulation part of the thrombus formation but also promotes platelet aggregation. The formation of thrombin from prothrombin after activation by prothrombinase can be measured by means of prothrombin fragment 1 ⫹ 2 (F1 ⫹ 2), a small activation peptide of 32 amino acids. F1 ⫹ 2 represents the “factor Xa activity” in vivo. The physiological reaction of inactivation of thrombin through irreversible binding to antithrombin III to its catalytic site is used for a second sensitive test of thrombin generation, the thrombin–antithrombin complex assay (T-AT). The proteolytic activity of thrombin on fibrinogen is described by the release of fibrinopeptide A (FpA), a 16-amino acid peptide from fibrinogen’s A␣-chain, and fibrinopeptide B (FpB) with 14 amino acids from fibrinogen B␤-chain. FpA is a useful biomarker for thrombin activity and often used for diagnosis of the ACS and its progression. The B␤ 15 to 42-related peptides are small peptide cleavage products released by the action of plasmin on fibrinogen and represent a sensitive indicator of fibrinolytic activity. Plasma D-dimers are generated when the endogenous fibrinolytic system degrades fibrin. They consist of two identical subunits that are derived from two fibrin molecules. D-dimers are indicative of crosslinked fibrin in contrast to fibrinogen cleavage products.

The involvement of platelets and the coagulation system in the development of ACS indicate that both antiplatelets and anticoagulants are possible approaches for pharmacological treatment (Fig. 2). The benefit of acetylsalicylic acid (ASA), an inhibitor of cyclooxygenase-1, in decreasing death or MI in patients has been clearly demonstrated, and its use is recommended in all patients with UA (27–29).

Figure 1

Prothrombinase activity

Coagulation derived biomarker in acute coronary syndromes.

TAT ATIII

Prothrombin

Standard therapy for acute coronary syndromes

Plasmin Fibrinogen

Thrombin

Bβ1-42 F1+2

FpA Plasmin

Fibrin D-Dimer

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Figure 2 Antithrombotic Therapy in Acute Coronary Syndromes

Anticoagulants

Indirect

Standard Low Molecular Heparins Weight Heparins • Nadroparin • Dalteparin • Enoxaparin

Currently existing antithrombotic therapy in acute coronary syndromes. Abbreviations: ADP, adenosine diphosphate; COX, cyclooxygenase; GP2b/3a, glycoprotein 2b/3a.

Antiplatelets

Direct

Thrombin Inhibitors

COXinhibitors

ADPantagonists

GP2b/3ainhibitors

• Hirudin • Argatrobana • Bivalirudin

• Aspirin

• Ticopidine • Eptifibatide • Clopidogrel • Tirofiban • Abciximab

a

only indicated in HIT patients undergoing percutaneous coronary intervention

Antagonists of the ADP P2Y12 receptor, ticlopidine and its safer successor clopidogrel, are also potent inhibitors of platelet aggregation and have demonstrated their efficacy alone and on top of ASA in numerous in clinical studies. The results of the CAPRIE study, a large study involving 19,185 patients with recent MI, stroke, or established peripheral arterial disease (PAD) demonstrated an 8.7% overall risk reduction versus ASA in the combined endpoints of the first occurrence of MI, stroke, or other vascular death (30). The CURE trial investigated the efficacy and safety of clopidogrel in 12,562 patients when administered together with aspirin in patients with ACS (UA or non–Q-wave MI). The combination demonstrated a 20% relative risk reduction in the combined endpoints of MI, stroke, or cardiovascular death compared with placebo (31). The inhibition of platelet–platelet interaction can be achieved with antagonists of the integrin glycoprotein (GP) IIb/IIIa receptor, which is the platelet receptor for fibrinogen (32). Three types of GPIIb/IIIa antagonists have been developed, which compete with fibrinogen to occupy the receptors: a monoclonal antibody (abciximab), a cyclic heptapeptide (eptifibatide), and nonpeptide mimetics (tirofiban, lamifiban). A large number of multi-center trials have been performed with GPIIb/IIIa antagonists in ACS including PCI (EPIC, CAPTURE, EPILOG, EPISTENT, IMPACT-II, PURSUIT, RESTORE, PRISM, PRISMPLUS) (33) and indicate that inhibition of GPIIb/IIIa is effective in decreasing the risk of acute clinical events in patients where there is a higher risk of an occluding clot forming, for example, in patients undergoing PCI. Although the GPIIb/IIIa antagonists have been shown to effectively reduce the major outcome, they have a high liability for increased risk of bleeding. Therefore, different alternatives are currently being tested, including the front-loaded regimen of clopidogrel and also new anticoagulants with an indirect platelet inhibition potential beneath the anticoagulant function. The presence of markers of thrombin generation, thrombin activity, and fibrin (fibrinogen) degradation indicates that

coagulation is involved in the pathophysiology of ACS. To prevent the development of fibrin during the coagulation process, antithrombin therapy is recommended. Heparinoids bind to antithrombin III, thereby accelerating inhibition of clotting factors IIa and Xa by antithrombin III. Unfractionated heparins (UFH) inhibit FXa and FIIa at a ratio of 1:1, whereas low-molecular-weight heparins (LMWH) preferentially inhibit FXa at a ratio of 2:1 to 4:1 (34). The recommendation for UFH is based on documented efficacy in many older mid-sized trials. Meta-analyses showed a clear reduction in MI and death, but at the cost of an increase in major bleeding rates (35,36). The advantages of LMWH over unfractionated heparin include a better bioavailability, a stronger and longer anti-Xa activity, less platelet activation, and no need for monitoring. A major drawback of standard heparin therapy is the potential risk of heparin-induced thrombocytopenia, which is considerably reduced with LMWH (37). In the ESSENCE trial, the LMWH enoxaparin led to a relative risk reduction of 15% to 16% in the rate of death, MI, or refractory ischemia as compared to unfractionated heparin at 30 days in UA/NSTEMI patients (38). Nadroparin [FRAXIS study (39)] and dalteparin [FRIC study (40)] did not demonstrate superiority against unfractionated heparin. Human pharmacokinetic data indicate that these differences in clinical efficacy might be explained by different elimination half-lives of antifactor Xa activity (dalteparin: 2.8 hours, nadroparin: 3.7 hours, enoxaparin 4.1 hours) (41). Several direct thrombin inhibitors have been studied in NSTEMI and STEMI patients and were compared to unfractionated heparin. In the GUSTO IIb- and OASIS-2 trial (42,43), hirudin was studied versus heparin in patients with ACS. Despite early benefits, no statistical significance could be demonstrated at 30 days. Together with the OASIS-1 data, a combined analysis indicated a 22% relative risk reduction in cardiovascular death or MI at 72 hours, 17% at 7 days, and 10% at 35 days (42). A comprehensive meta-analysis comprising different thrombin inhibitors (hirudin, bivalirudin, efegatran, argatroban) indicates a

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superiority of direct thrombin inhibition over unfractionated heparin for the prevention of death or MI in patients with ACS including STEMI (44). Hirudin has been approved for patients with heparin-induced thrombocytopenia; however, it is not approved specifically for ACS (45). The direct thrombin inhibitor bivalirudin is a synthetic, 20 amino acid peptide that binds reversibly to the active site and to the substrate recognition site of thrombin. Cleavage of the inhibitor by thrombin results in the recovery of the active site (46). In the REPLACE-2 trial, bivalirudin, with GP IIb/IIIa inhibition on a provisional basis for complications during PCI, was compared with unfractionated heparin plus planned Gp IIb/IIIa blockade in patients undergoing urgent or elective PCI. The primary composite endpoint was 30-day incidence of death, MI, urgent repeat revascularization, or in-hospital major bleeding. Bivalirudin with provisional Gp IIb/IIIa blockade demonstrated noninferiority to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI. Moreover, bivalirudin was associated with less bleeding (47).

Role of coagulation factor Xa in acute coronary syndromes Coagulation factor X is a vitamin K-dependent GP and the zymogen of factor Xa. Factor Xa plays a central role in coagulation because it is located at the convergence point of the intrinsic and extrinsic pathway. Factor X is activated by excision of a small peptide from its heavy chain by either the extrinsic tenase complex (tissue factor–factor VIIa) or by the intrinsic tenase complex (factor VIIIa–factor IXa). Together with its cofactor, coagulation factor Va, factor Xa forms the prothrombinase complex, which converts prothrombin into thrombin in a process requiring several binding steps (Fig. 3). The prothrombinase complex is generated on a phospholipid surface, which is provided by platelets during activation. In the unactivated state, platelets do not express significant amounts of phosphatidylserine. During activation, phosphatidylserine is

translocated from the inner to the outer leaflet of the platelet membrane (48). This outward phosphatidylserine shuttle is accompanied by an increased ability of the platelets to enhance the prothrombin–thrombin conversion by factor Xa, in the presence of factor Va and calcium (49). Factor V is stored in platelet ␣-granules (50) and activated after secretion during platelet activation by factor Xa (51,52). After the Xa/Va complex is formed, thrombin formation occurs, which results in a rapid acceleration of procoagulant activity (53). The procoagulant activity within a clot primarily depends on the formation of thrombin induced by the prothrombinase complex on the platelet surface (54,55). This prothrombinase activity can also be demonstrated on pathological thrombi from patients with arterial thrombosis. In a balloon-induced arterial injury study in rabbits, bound prothrombinase activity to injured segments was detected within 15 minutes and it induced activation of prothrombin for 96 hours (56). These data indicate that inhibition of factor Xa within the prothrombinase complex is a valid concept to treat or prevent arterial thrombosis and might be superior to the current established therapy.

Preclinical data for factor Xa inhibitors In contrast to unfractionated heparin, the factor Xa inhibitor tick anticoagulant peptide (TAP) effectively inhibited coronary arterial thrombosis in a canine electrolytic injury model (57). TAP was also effective in inhibition of the procoagulant properties of whole blood clots in vitro; however, it was stated that TAP might be not optimal due to its slow binding kinetics (54). Meanwhile, several low molecular weight direct factor Xa inhibitors are in clinical development (Table 1), some of them specifically for the treatment and secondary prevention of ACS. DX-9065a, ZK-807834 and otamixaban have been intensively characterized in vitro and in vivo and are in clinical investigations for the treatment of acute arterial thrombosis.

Figure 3

Platelets

Thrombin

Thrombin Activity Thrombin Generation

Platelet Adhesion

Shear Forces

Factor Xa/Va

subendothelial matrix

Schematic view of the role of coagulation factor Xa in arterial thrombosis. After endothelial injury, platelets adhere to the subendothelial matrix. The procoagulant activity of the arterial clot can be attributed to the formation of the prothrombinase complex on the platelet surface which cleaves prothrombin and produces thrombin. Thrombin subsequently acts as a strong agonist of further platelet aggregation.

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Table 1 Direct factor Xa inhibitors in clinical development Name

Company

Clinical phase

BAY 59-7939

BayerHealthcare

III

Otamixaban

Sanofi-Aventis

II

BMS-562247

Bristol-Myers Squibb

II

LY-517717

Eli Lilly

II

ZK-807834

Berlex/Schering

II

DU-176b

Daiichi Sankyo

II

YM-150

Astellas

II

DX-9065a

Daiichi

II

KFA-1982

Kissei

I

TC-10

Teijin

I

The compounds potently inhibit factor Xa in vitro with reversible binding kinetics and are able to inhibit not only free but also prothrombinase-bound factor Xa (Ki 41 nM, 0.11 nM, and 0.5 nM, respectively) (58–60). In contrast, no direct effect on platelet aggregation has been described (60–62). Antithrombotic activity in arterial and venous thrombosis models has been demonstrated and it has a reduced effect on hemorrhage in comparison to standard therapy (58,60,63). Factor Xa inhibitors are able to reduce the endogenous thrombin potential in platelet-poor as well as in platelet-rich plasma (64,65). Thus, thrombin generation seems to be a suitable biomarker for clinical evaluation and has been evaluated in phase I studies (66,67). In preclinical models of ACS, factor Xa inhibitors have been investigated and compared to standard treatments. Otamixaban was compared to bivalirudin in a Folts model in pigs (68). Both treatments were effective in inhibiting cyclic flow variations as indicators of unstable coronary artery thrombosis. In contrast to bivalirudin, otamixaban did not prolong bleeding times, indicating a larger therapeutic window for factor Xa inhibition. Moreover, ZK-807834 (69) and otamixaban (70) were able to reduce reocclusion rates on top of thrombolytic therapy in dogs as compared to unfractionated heparin and achieved better reocclusion rates than the former.

Clinical data on direct factor Xa inhibitors in acute coronary syndromes The first evidence for the ex vivo antithrombotic effects of a direct factor Xa inhibitor in humans was provided in the Badimon chamber (71). Healthy volunteers received escalating

123

intravenous doses of DX-9065a with and without concomitant aspirin. Porcine tunica media served as thrombogenic surface in the flow chamber. DX-9065a alone and in combination with aspirin significantly inhibited thrombus formation in this ex vivo assay at low and high shear rates. These data suggest that inhibitors of factor Xa can be considered efficacious antithrombotic agents to prevent the acute complications of thrombosis. Other phase I studies investigated the effects of the coadministration of the direct factor Xa inhibitor otamixaban with aspirin and tirofiban on both anticoagulation and platelet inhibition (72,73). It was demonstrated that the factor Xa inhibitor alone had no effect on ex vivo platelet aggregation and both platelet inhibitors alone did not change anticoagulation global and factor Xa-specific coagulation parameters. Equally important, the studies showed that both therapeutically relevant principles in the treatment of ACS, that is, anticoagulation and platelet-inhibition, are maintained following the co-administration of otamixaban with the platelet inhibitors. The XANADU-1B trial investigated for the first time the pharmacokinetics, pharmacodynamics, and the safety profile of the direct factor Xa inhibitor DX-9065a after 72 hours intravenous infusion in patients with stable coronary disease (74). A dose- and concentration-dependent increase of antiFXa activity, international normalized ratio (INR), and activated partial thromboplastin time (aPTT) was observed. However, the classical measurements of anticoagulant activity, PT, INR, and aPTT, correlated less well with plasma concentrations during the early infusion time compared with the later time points. Anti-Fxa activity revealed a strong correlation with plasma concentrations, indicating a close relationship between these two parameters. The compound was well tolerated: no major or minor bleeding (according to the TIMI criteria) and no serious adverse effect occurred during the infusion period of 72 hours. In the highest dose group, a small, nonsignificant increase in GUSTO-minor bleeding was observed. Significant correlations between plasma concentrations, prothrombin fragment F1 ⫹ 2 and D-dimer could be observed within this study, indicating a reduction of thrombin generation and the formation of fibrin by means of factor Xa inhibition (75). The XANADU-PCI trial (76) was performed to investigate the pharmacokinetics, the effect on coagulation markers, and the preliminary efficacy and safety of four different doses of DX-9065a during PCI. Patients undergoing elective, nativevessel PCI were randomized to four escalating DX-9065a doses/concentrations. Infusion was stopped at completion of the PCI. All patients were treated concomitantly with aspirin and clopidogrel; in most cases GPIIb/IIIa receptor antagonists were also administered. Dose levels I–III were designed to achieve drug concentrations of DX-9065a of ⬎75 ng/mL, ⬎100 ng/mL, and ⬎150 ng/mL, respectively. Dose level IV was comparable to stage III regimen but included patients recently given heparin. Arterial sheaths were removed one to two hours after the procedure or at the time of measurement

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of activated clotting time (ACT) ⬍170 seconds. INRs were 1.9, 2.6, 3.2, and 3.8 in the four levels, and anti-FXa levels were 0.33, 0.36, 0.45, and 0.62 U/mL, respectively. Dose level II was stopped after occurrence of one serious thrombotic event suspicious of insufficient anticoagulation. A close correlation between plasma concentration and INR or antiFXa activity could be demonstrated. In general, ischemic and bleeding events were rare. However, probably due to the small population size (n ⫽ 175), no clear relation to the DX9065a dose could be observed. The authors of the study concluded that elective PCI is feasible using direct FXa inhibition for anticoagulation. In the XANADU-ACS trial (77), 402 patients with ACS were randomized to unfractionated heparin, low-dose DX-9065a, or high-dose DX-9065a. The primary end-point was the composite of death, MI, urgent revascularization, or ischemia on continuous ST-segment monitoring. These patients were representative for a high-risk ACS population. More than 80% of them had MI. Nearly all patients received aspirin, more than 75% received clopidogrel or ticlopidine, and over 60% received GP IIb/IIIa inhibitors. Ninety-eight percent underwent catheterization, 55% PCI, and 17% CABG. According to Rajagopal and Bhatt (78), the trial population represented a realistic ACS population with state-of-the-art care. The antiFXa activity increased during infusion in the low/high dose DX9065a groups from 0.09/0.10 to 0.23/0.41 U/mL (in the heparin group from 0.14 to 0.44 U/mL). Whole-blood INRs increased to approximately 2.0 with low-dose DX-9065a and to 2.5 with high-dose DX-9065a (1.5 with heparin). The primary efficacy endpoint occurred with similar frequency in all treatment groups. In the patients treated with high-dose DX-9065a, a tendency for lower rates of clinically important endpoints was observed. Major or minor bleeding rates were similar among patients in the heparin and highdose DX-9065a group, but lower in patients in the low-dose DX-9065a group. It can be concluded that direct inhibition of factor Xa is an attractive alternative to currently available anticoagulants in ACS. A further direct factor Xa inhibitor, otamixaban, is currently being investigated in the SEPIA-PCI trial in patients undergoing nonurgent PCI in comparison to heparin (78).

New small molecule FXa inhibitors currently in development are able to enter the clot/prothrombinase complex and inhibit free and bound factor Xa regarded as the key enzyme in ACS. Although direct FXa inhibitors do not inhibit platelet aggregation, they abolish platelet-dependent thrombus formation in canine coronary thrombosis. Thus, direct inhibition of FXa may have higher efficacy and better risk/benefit profile than existing antithrombotic therapies in the treatment and prevention of ACS.

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Conclusions ACSs are a major cause of morbidity and mortality. They are characterized by intracoronary thrombus formation at the site of atherosclerotic plaques resulting in UA and MI. Although effective treatments and procedures are available, patients remain at high risk of reinfarction and death. In addition to the presently available treatments, a new concept is evolving that targets and inhibits the prothrombinase multienzyme complex on the platelet surface thus inhibiting further thrombin generation in arterial thrombosis.

11

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Bertrand ME, Simoons ML, Fox KAA, et al. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2002; 23:1809–1840. Bates SM, Weitz JI. The mechanism of action of thrombin inhibitors. J Invasive Cardiol 2000; 12(suppl):F27–F32. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention. JAMA 2003; 289:853–863. Hoffman M, Monroe DM III. A cell-based model of hemostasis. Thromb Haemost 2001; 85:958–965. Bevers EM, Comfurius P, Zwaal RF. Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 1983; 736:57–66. Tracy PB, Eide LL, Bowie EJ, et al. Radioimmunoassay of factor V in human plasma and platelets. Blood 1982; 60:59–63. Foster WB, Nesheim ME, Mann KG. The factor Xa-catalyzed activation of factor V. J Biol Chem 1983; 258:13970–13977. Monkovic DD, Tracy PB. Functional characterization of human platelet released factor V and its activation by factor Xa and thrombin. J Biol Chem 1990; 265:17132–17140. Mann KG. The coagulation explosion. Ann N Y Acad Sci 1994; 714:265–269. Eisenberg PR, Siegel JE, Abendschein DR, et al. Importance of factor Xa in determining the procoagulant activity of wholeblood clots. J Clin Invest 1993; 91:1877–1883. McKenzie CR, Abendschein DR, Eisenberg PR. Sustained inhibition of whole-blood clot procoagulant activity by inhibition of thrombus-associated factor Xa. Arterioscler Thromb Vasc Biol 1996; 16:1285–1291. Ghigliotti G,Waissbluth AR, Speidel C, et al. Prolonged activation of prothrombin on the vascular wall after arterial injury. Arterioscler Thromb Vasc Biol 1998; 18:250–257. Lynch JJ Jr, Sitko GR, Lehman ED, et al. Primary prevention of coronary arterial thrombosis with the factor Xa inhibitor rTAP in a canine electrolytic injury model. Thromb Haemost 1995; 74:640–645. Becker RC, Alexander J, Dyke CK, et al. Development of DX9065a, a novel direct factor Xa antagonist, in cardiovascular disease. Thromb Haemost 2004; 92:1182–1193. Post JM, Sullivan ME, Abendschein D, et al. Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807834 (CI-1031). Thromb Res 2002; 105:347–352. Chu V, Brown K, Colussi D, et al. Pharmacological characterization of a novel factor Xa inhibitor, FXV673. Thromb Res 2001; 103:309–324. Posta JM, Sullivana ME, Abendschein D, et al. Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807834 (CI-1031). Thromb Res 2002; 105:347–352. Morishima Y, Tanabe K, Terada Y, et al. Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor: comparison with a direct thrombin inhibitor and antithrombin III-dependent anticoagulants. Thromb Haemost 1997; 78:1366–1371. Abendschein DR, Baum PK, Martin DJ, et al. Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and

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venous thrombosis in rabbits. J Cardiovasc Pharmacol 2000; 35:796–805. Gerotziafas GT, Elalamy I, Chakroun T, et al. The oral, direct factor Xa inhibitor—BAY 59-7939—inhibits thrombin generation in vitro after tissue factor pathway activation. J Thromb Haemost 2005; 3(suppl 1):P2295. Lorenz M, Stamm S, Hinder M, et al. Inhibition of thrombin generation by Otamixaban (XRP0673), a direct and selective factor Xa inhibitor. J Thromb Haemost 2005; 3(suppl 1):P0716. Harder S, Graff J, von Hentig N, et al. Effects of BAY 59-7939, an innovative, oral, direct Factor Xa inhibitor, on thrombin generation in healthy volunteers. Pathophysiol Haemost Thromb 2003; 33(suppl 2):PO078. Paccaly A, Ozoux ML, Chu V, et al. Pharmacodynamic markers in the early clinical assessment of otamixaban, a direct factor Xa inhibitor. Thromb Haemost 2005; 94:1156–1163. Just M, Lorenz M, Skrzipczyk HJ, et al. Otamixaban, a direct factor Xa inhibitor, more potently inhibits experimental coronary thrombosis than bivalirudin, a direct thrombin inhibitor. J Thromb Haemost 2005; 3(suppl 1):P0115. Abendschein DR, Baum PK, Verhallen P, et al. A novel synthetic inhibitor of factor Xa decreases early reocclusion and improves 24-h patency after coronary fibrinolysis in dogs. J Pharmacol Exp Ther 2001; 296:567–572. Rebello SS, Bentley RG, Morgan SR, et al. Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis. Br J Pharmacol 2001; 133:1190–1198. Shimbo D, Osende J, Chen J, et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor: a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002; 88:733–738. Hinder M, Paccaly A, Frick A, et al. Anticoagulant and antiplatelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, with tirofiban in healthy volunteers. Thromb Haemost 2005; 93:794–795. Hinder M, Frick A, Rosenburg R, et al. Anticoagulant and antiplatelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid. Thromb Haemost 2006; 95:224–228. Dyke CK, Becker RC, Kleiman NS, et al. First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation. Circulation 2002; 105:2385–2391 Becker RC, Alexander JH, Dyke C, et al. Effect of the novel direct factor Xa inhibitor DX-9065a on thrombin generation and inhibition among patients with stable atherosclerotic coronary artery disease. Thromb Res 2006; 117:439–446. Alexander JH, Dyke CK, Yang H, et al. Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI Pilot. J Thromb Haemost 2004; 2(2):234–241. Alexander JH, Yang H, Becker RC, et al. First experience with direct, selective factor Xa inhibition in patients with non-STelevation acute coronary syndromes: results of the XaNADU-ACS Trial. J Thromb Haemost 2005; 3:439–447. Rajagopal V, Bhatt DL. Factor Xa inhibitors in acute coronary syndromes: moving from mythology to reality. J Thromb Haemost 2005; 3:436–438.

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11 Combined anticoagulant and antiplatelet therapy Harry L. Messmore, Erwin Coyne, Meghan Businaro, Omer Iqbal, William Wehrmacher, and Walter Jeske

Introduction To understand the evolution of therapy of the acute coronary syndrome (ACS), which includes unstable angina, acute myocardial infarction, and interventional therapy— percutaneous coronary intervention (PCI), it is most useful to trace the historical events that provided a rationale for the use of anticoagulant and antiplatelet drugs. The focus of this chapter is upon the explosion in knowledge of the physiology of the hemostatic mechanism and will trace the rational development of therapy based upon the pathophysiology of the ACS over the past 40 years.

History The 1912 paper by James Herrick set the stage for the subsequent use of antithrombotic drugs to treat ACS. In his landmark paper, he reviewed the clinical and pathological findings of this disorder that had been published over the preceding 70 years (1). He correlated clinical history and physical findings with anatomic pathology. He included studies of experimental coronary occlusion in animals. These published animal studies reproduced the human clinical and pathologic features of the disorder, but the means used to reproduce the human syndrome consisted of ligations of main coronary arteries or their branches. This did not take into account the fact that human cases usually had lesions in several coronary artery sites, which restricted collateral flow in some cases. The anatomic description of the lesions in the

human at autopsy included partial occlusion of coronary arteries by atherosclerosis including thrombi. Some cases had total occlusion by plaque alone. (Herrick’s personal observation included one classic clinical case of death due to coronary occlusion that had a fresh red thrombus in the proximal left coronary artery at a site of severe narrowing on autopsy.) The entire clinical course was 52 hours. In all his report, he offered convincing evidence that thrombosis was a major mechanism of coronary occlusion in such cases. No experiments were carried out on animals until 26 years later. The discovery of heparin by McClean four years after Herrick’s report made it possible to consider antithrombotic therapy for ACS (2). Solandt and Best were the first to carry out such experiments using animal models, primarily dogs. Theirs was one of the few laboratories to have heparin available, an early product developed by Best and coworkers at the Connaught Laboratories associated with the University of Toronto in Canada. In their experiments, they produced coronary thrombosis using chemical injury to the endothelium thereby inducing coronary thrombosis in approximately 20 hours. Pretreatment with parenteral heparin in doses to prolong the whole blood clotting time to approximately three times normal for the dog prevented early death due to myocardial infarction as compared with untreated controls. Electrocardiographic monitoring showed a diminution of the R-wave, which was similar to that seen in controls in which the coronary arteries were ligated. This report was published in 1938 (3). It was a remarkable coincidence that Irving S. Wright, a prominent internist and vascular specialist, experienced deep vein thrombosis following an appendectomy in 1938, and

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Combined anticoagulant and antiplatelet therapy

Figure 1 Platelet

GP IIb/IIIa Tirofiban Eptifibatide Abciximab

Saratin

Aspirin, NSAIDs

Fibrinogen Collagen PGG2,Cyclooxygenase-1 AA PGH2 ZD-9583 GP Ia/IIa

Heparin-AT Argatroban Hirudin Bivalirudin

PAR-1, PAR-4

TxA2 Synthase

TxA2

PGI2 Receptor

ADP IVIg

BM-531 BM-573

Fc γRIIa

GPIb Thrombin

cAMP

AMP

Phosphodiesterase

5HT2 R-96544 Sarpogrelate AT-1015

Thromboxane receptor Epoprostanol PGI2 (endothelium)

Clopidogrel Ticlopidine Prasugrel AR-C69331MX

Sites of action of currently approved and experimental antiplatelet drugs. Antiplatelet drugs are capable of inhibiting platelet activation by blocking cell surface receptors and inhibiting the generation of bioactive substances. Platelet aggregation is potently inhibited by blocking fibrinogen binding to GP IIb/IIIa. The sites of action of currently used and experimental (bold) antiplatelet agents are depicted. Abbreviations: AA, arachidonic acid; AT, antithrombin; GP, glycoprotein; 5HT, serotonin; IVIg, intravenous immunoglobulin; NSAID, nonsteroidal anti-inflammatory drug; PAR, protease activated receptor; PG, prostaglandin; Tx, thromboxane.

Serotonin Dipyridamole, cilostazol BM-573, BM-531, Bay U3405, ZD-9583

shortly thereafter in the same year was consulted by a 31-year-old man with extensive bilateral migratory thrombophlebitis involving both legs, veins of the abdominal wall, and mesentery. Dr. Wright was able to obtain heparin from the Toronto group to administer to this patient. A remarkable recovery occurred. The heparin had to be stopped eventually because the available supply was exhausted. A few months later there was a recurrence of the venous thrombosis in the patient in association with adult mumps. Heparin was resumed and continued until the newly discovered dicumarol became available for clinical use on a compassionate basis in 1941 (4,5). Dr. Karl Link and coworkers of the University of Wisconsin and their clinical collaborators at the Mayo Clinic had recently published this discovery (5). Dr. Wright and his associates along with Link and his group in Wisconsin and physicians at the Mayo Clinic in Rochester, Minnesota developed guidelines for the clinical use of dicumarol (6). A laboratory monitoring system called the prothrombin time, discovered by Armand Quick (7) in 1935 was introduced for clinical use. Investigators in Canada, the United States, and Sweden showed that both heparin and warfarin were reasonably safe and effective anticoagulants for human use (8). James et al. (9) showed that its effect could be neutralized by the injection of vitamin K. There were never any randomized clinical trials of heparin for thrombotic disorders until 1960 when it was shown that it was clearly superior to placebo for the treatment of pulmonary embolism (10). At this point, the empiric approach to therapy with heparin began to become more rational based upon in-depth basic science studies of the physiology of the hemostatic system and of the pathology of the vascular lesions of atherosclerosis.

Physiology of platelets and endothelium Basic studies beginning in the 1960s and continuing to the present have shown that the endothelial cell is metabolically active, providing components of the coagulation systems such as tissue plasminogen activator, tissue factor pathway inhibitor (TFPI), von Willebrand Factor (vWF), and vasodilator substances such as nitric oxide (NO) and prostacyclin (PGI2). These substances are elaborated under the influence of stimuli from the coagulation enzymes such as thrombin and from platelet factors such as PGG2 (Fig. 1). Tissue factor may be generated on the surface of the endothelial cells by specific stimuli as are surface receptors for cytokines and adhesion molecules for leukocytes, platelets and activated coagulation factors. vWF produced in the endothelial cells and in megakaryocytes attaches to the subendothelium at sites of injury or plaque rupture. High-molecular-weight multimers of vWF induce thrombosis in arterioles when the enzyme ADAMTS 13 is decreased on a hereditary or an acquired basis [thrombotic thrombocytopenic purpura (TTP)] (11,12).

Pathophysiology of plaque rupture The rupture of a subendothelial plaque into the vascular lumen is a major factor in the initiation of thrombosis by causing a platelet-rich thrombus to develop at that site. The persistence of this thrombus at the site is promoted by

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129

Figure 2 Endothelium Adhesion Recruitment Release Reaction Aggregation TFPI Shear vWf

Thrombin

Heparin

ADP TxA2 TFPI TFPI TFPI

vWf

Formation of thrombus at the site of endothelial damage. Von Willebrand factor exposed at sites of endothelial damage acts to bind platelets to the vessel wall. Tissue factor, expressed on subendothelial tissue and cytokine-primed macrophages, acts to generate thrombin, which activates platelets and produces fibrin. TFPI, normally present on the endothelial surface, can be released by heparins and can inhibit tissue factor-induced thrombin generation. Abbreviations: ADP; adenosine disphosphate; TFP1, tissue factor pathway inhibitor.

vWf

Tissue factor Collagen Macrophage

vascular narrowing due to the atherosclerotic process. High shear rates at that point promote the binding of vWF to the platelet surface and to the subendothelial connective tissue. Thrombin is simultaneously generated at the site, converting fibrinogen to fibrin that binds the platelets into a mass that further occludes the vessel. The release of thromboxane A2 (TXA2) from the platelets causes aggregation of adjacent platelets and it causes adenosine diphosphate (ADP) to be released from platelet-dense granules. TXA2 is a potent vasoconstrictor further narrowing the coronary vessels. In Figure 2, the interaction of platelets with damaged endothelium is depicted, showing key endothelial and platelet release factors. Lipid-laden macrophages are the major components of the plaque and when the endothelial cells and the fibrous cap covering the plaque are disrupted, tissue factor is generated at the site as well as platelet-derived growth factor, promoting further fibrin deposition, platelet aggregation, and proliferation of smooth muscle cells. Leukocytes attracted to the vicinity may also release TXA 2, enhancing vasospasm that is partially reversed by the synthesis of NO by the endothelial cells. (As thrombin is generated it also “feeds back” to factor V and FVIII, activating them and accelerating the process of coagulation.) Thrombin also cleaves FXIII that cross-links the fibrin strands rendering them somewhat resistant to lysis by plasmin. Thrombin also binds to thrombomodulin on the endothelium that activates protein C, an inhibitor of the coagulation process. Another action of thrombin is to activate thrombin activatable fibrinolysis inhibitor also known as procarboxypeptidase. The process we have just described occurs at the site of plaque rupture, an autochthonous (local) process that is not easily modulated by antithrombotic drugs, and which may in fact be caused by heparin or low molecular weight heparin (LMWH) in the heparininduced thrombocytopenia (HIT) syndrome (11–15). In Figure 1, the platelet is shown to have multiple surface receptors, multiple organelles, and biochemical pathways that facilitate its communication and interaction with the

environment. These receptors and biochemical pathways are each potential targets for anticoagulant and antiplatelet drugs. (Blocking single enzymes and single platelet receptors by various drugs only partially blocks platelet function.) When glycoprotein (GP) IIb/IIIa is blocked, platelet–platelet interaction is blocked, which has a more profound inhibitory effect on thrombus formation than the blocking of other sites. Thus, inhibition of GPIIb/IIIa may be highly effective but is also a great risk for bleeding (14–16).

Pharmacology of the anticoagulant and antiplatelet drugs Anticoagulants Anticoagulants are essential to the management of the ACS. The anticoagulants in current clinical use include heparin, LMWH, fondaparinux, bivalirudin, lepirudin, and argatroban. Recent studies of fondaparinux (OASIS 5–Michelangelo Trial) show it to be undergoing trials effective in non-ST-elevation myocardial infarction and therefore it is included in this anticoagulant group (17). Heparin is a glycosaminoglycan extracted from animal tissues (porcine mucosa, beef lung, etc.). It is a mixture of molecules having a mean molecular weight of 15,000 Da. A pentasaccharide sequence found in approximately one third of the molecules binds to antithrombin in mammalian blood, enhancing its inhibitory effects on the enzymes thrombin, factor Xa, factor VIIa, and factor IXa. The reaction is reversible, heparin being released after the antithrombin molecule binds to the procoagulant enzymes. Heparin binds to platelets, platelet factor-4 (which neutralizes it), histidinerich GP, vWF, and a number of other proteins. Its half-life is about one hour in the circulation (18). Antibodies to heparin

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bound to PF4 and other positively charged proteins cause severe thrombotic problems in less than 1% to 3% of patients treated for five days or more (19). Hemorrhage related to circulating blood levels is the major side effect of heparin, occurring in about 6% of patients given therapeutic doses, but major bleeding occurs in less than 1% (18). It is poorly absorbed by the oral route. Its bioavailability is relatively low by the subcutaneous route that must therefore be dose adjusted according to laboratory test results, which is the case with intravenous heparin as well (18). LMWHs are derivatives of standard heparin in which reduction of the mean molecular weight of the original heparin has been chemically reduced from a mean of 15,000 Da to a mean of approximately 5000 Da. To accomplish this, heparin molecules are treated with nitrous acid, heparinases, or benzylation and alkaline hydrolysis. The resultant product has the intact pentasaccharide sequence in at least one-third of the molecules and interaction with antithrombin is preserved in those molecules. Interactions and binding to platelets, proteins in the blood and endothelium is less than that of heparin. This property is advantageous because it permits prediction of circulating blood levels for a given subcutaneous dose. Monitoring of blood levels is unnecessary except in patients with significant renal impairment. A major difference is in the binding of the LMWH to factors Xa and thrombin when it is complexed to antithrombin. (Many of the molecules lack enough sugar moieties (⬍18) to bind to thrombin and AT, simultaneously precluding the inhibition of thrombin.) Factor Xa inhibition is not a problem. The resultant anti-Xa/IIa ratio is variable depending upon the method of degradation, but is 4:1, 3:1, or 2:1, for example, depending upon the manufacturing process. Each of these are unique drugs and mimic the properties of heparin to varying degrees. Their properties are

Table 1

the same as heparin but they manifest these properties to varying degrees as compared with heparin and with each other. They, like heparin, do not inhibit factor Xa or thrombin bound to fibrin in thrombi (18). Comparison of these properties is shown in Table 1. Fondaparinux is a chemically synthesized pentasaccharide that mimics the antithrombin-binding site of heparin and LMWH. Its molecular size (1728 Da) is too small to bind to thrombin molecules while it is bound to antithrombin. Therefore, it is a pure anti-Xa inhibitor. It binds very little to platelets, proteins, or endothelium and is excreted in the urine. It does not form a complex with PF4 or other positively charged molecules. It is not neutralizable by protamine sulfate. Recent clinical trials have resulted in FDA approval for prophylaxis of deep vein thrombosis in orthopedic surgery. It has been shown to be effective and safe for the treatment of pulmonary embolism (20,21) and ACS (non-ST-elevation MI) (OASIS 5—Michelangelo Trial) (17). Bivalirudin is a direct thrombin inhibitor that has found utility for reducing the rate of acute reocclusion in patients treated with PCI. It is preferential to heparin in PCI when HIT is present. This drug is a derivative of hirudin, which is a dedicated thrombin inhibitor with no other in vivo activities of significance. The molecule is semisynthetic; the C-terminal of hirudin is linked by a polyglycine spacer to the tetrapeptide region of the N-terminal that reacts with the thrombin active site (22). It is monitored by the activated clotting time test. Its pharmacologic properties are shown in Table 1. Hirudin is a direct thrombin inhibitor marketed in a recombinant form (lepirudin). It is a protein derived from a salivary gland of the medicinal leech. It binds tightly to exosite 1 and the apolar site near the catalytic site. It is used as a substitute for

Pharmacologic properties of anticoagulant and antiplatelet drugs used to treat ACS

Drug

Target

Route

Lab monitoring

Reference

Aspirin

Cox-1

Oral

No

16

Clopidogrel

ADP-R

Oral

No

16

Tirofiban

GPIIb/IIIa

IV

No

16

Eptifibatide

GPIIb/IIIa

IV

No

16

Abciximab

GPIIb/IIIa

IV

No

16

LMWH

Xa, IIa

SC

No

18

Fondaparinux

Xa

SC

No

18

Heparin

Xa, IIa

IV

Yes

18

Bivalirudin

IIa

IV

Yes

25

Argatroban

IIa

IV

Yes

24

Lepirudin

IIa

IV

Yes

25

Abbreviations: ADP, adenosine diphosphate; Cox-1, cyclooxygenase; GPIIb/IIIa, glycoprotein; IV, intravenous; IIa, factor IIa-thrombin; SC, subcutaneous; Xa, factor Xa.

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heparin or LMWH in patients who have HIT where the risk of thrombosis is high. Laboratory monitoring of the anticoagulant effects of the parenterally administered drug is necessary. The activated partial thromboplastin time (APTT) or the ecarin clotting time tests may be used for this purpose but only the APTT has been clinically evaluated for HIT (Table 1) (23). Argatroban is a synthetic arginine derivative that is a competitive inhibitor of the action of thrombin on fibrinogen. It is given parenterally and monitored by the APTT test. It has a short half-life. It is nonantigenic. It is approved for use in HIT and has undergone trials for PCI in some patients (Table 1) (24).

131

because of its propensity to cause TTP. Clopidogrel is a prodrug that must be converted to an active drug in the liver. It binds to and blocks the ADP receptor on platelets, a measurable effect lasting at least five days. An initial loading dose is necessary if prompt action is desired, otherwise a maintenance dose of three to seven days will be necessary before the platelet function is optimally impaired. Resistance to clopidogrel has been reported. This can be detected by platelet aggregometry utilizing ADP as the agonist (16,25).


Antiplatelet drugs Aspirin is a direct-acting antiplatelet drug. (Its prolonged duration of action after therapy is discontinued will be discussed below under clinical use of the combination of anticoagulant and antiplatelet drugs.) A summary of its pharmacology is in Table 1.

GP IIb/IIIa Inhibitors These direct-acting inhibitors bind to the IIb/IIIa GPs that are expressed on the platelet surface when platelets are activated. Three such drugs are in routine clinical use (16). 1. 7E3 monoclonal antibody to GPIIb/IIIa (abciximab) is very useful as an antiplatelet drug in high-risk ACSs and PCI. It can be used in conjunction with reduced levels of heparin and with aspirin (Table 1). Patients may uncommonly experience sudden severe thrombocytopenia within the early hours of treatment as a side effect. 2. Eptifibatide (Integrelin), a cyclic heptapeptide based on a peptide sequence in snake venom, is a GPIIb/IIIa inhibitor used in conjunction with heparin and aspirin for the treatment of ACS or in PCI, with or without stenting and clopidogrel (Table 1). 3. Tirofiban (Aggrastat) is a nonpeptide antagonist of the GPIIb/IIIa receptor. It is administered intravenously. Its properties are shown in Table 1. It is used in ACS for unstable angina and in PCI along with aspirin and heparin.

Thienopyridines The thienopyridines include clopidogrel, ticlopidine, and prosugel. Clopidogrel is the only member of this class in clinical use at this time. A second generation of this drug, Prosugel, is undergoing trials (27). Ticlopidine is not used

In Figure 3, an abbreviated coagulation cascade beginning with tissue factor is flanked by drugs that inhibit the coagulation enzymes and platelet function. The action of these drugs on platelets may be direct, as in the case of aspirin where the action is directed to a platelet enzyme or to a receptor as in the case of clopidogrel. Heparin, LMWH, and thrombin inhibitors act indirectly by blocking the agonist thrombin. The effect of aspirin and clopidogrel lasts for several days after the drug has been withdrawn but the effect of heparin, LMWH, and thrombin inhibitors disappear in minutes to hours after the drug is withdrawn. Patients on aspirin and/or clopidogrel may bleed if taken to surgery on an emergency basis. The GPIIb/IIIa inhibitor abciximab may also have a prolonged effect (16). Resistance to aspirin and synthetic IIb/IIIa inhibitors have been described (16). Patients with unstable angina are at varying risk for thrombosis and it has been determined that the higher risk patient requires a combination of anticoagulants and antiplatelet agents. LMWH has largely replaced standard heparin in most treatment regimens with the exception of PCI. Direct thrombin inhibitors have been given in clinical trials (25). A newer drug, fondaparinux, a synthetic LMWH, which is a factor Xa inhibitor undergoing clinical trial (17). Idraparinux, a longer acting version of fondaparinux, is being developed (26).

Clinical use of the combination of anticoagulant and antiplatelet drugs The combination of heparin and aspirin for the treatment of ACS began in the 1980s. Aspirin had been synthesized by the Bayer Pharmaceutical Company in 1895 and marketed as an analgesic and antipyretic drug. Approximately 60 years later, it was found to enhance the bleeding tendency observed in known hemorrhagic disorders (1956) and to prolong the bleeding time of normals in 1964 (27,28). During this period,

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the morphology of platelets and their ultrastructure was being intensively studied, and the biochemistry of platelet aggregation induced by ADP was described (29). By 1970, the effect of aspirin on platelets was shown to be via the acetylation of cyclooxygenase, an enzyme that converts arachidonic acid to prostaglandin (16). This was an irreversible effect that lasted for the life of the platelets. Generation of TXA2 and the prostaglandins, PGG2 and PGH2, was blocked. Thus the production of PGI2 by the endothelium was temporarily blocked. Vane (30) discovered the effect on prostaglandin synthesis in 1971. He was awarded the Nobel prize for that work in 1982. Some of the more relevant biochemical pathways within the platelets are shown in Figure 1. (It is to be noted that the agonists thrombin, collagen, and ADP acting on their respective receptors are clinically the most relevant.) It is important to note the feedback pathway of platelet polyphosphate and platelet microparticles (Fig. 3) on the coagulation cascade and the specific enhancement of FV activity and the suppression of TFPI by the polyphosphates, as well as the contributions of platelet microparticles to enhance the coagulation pathway activity. Polyphosphate release from activated platelets is not blocked by aspirin (31).

Most of the clinical studies devoted to the treatment of unstable angina during the 1970s were devoted to comparing the medical therapy of this disorder with coronary artery bypass graft surgery. The medical arm of these studies did not include heparin (32). It was controversial as to whether heparin improved the major outcome criteria of myocardial infarction, revascularization, and death. Beta-blockers, nitroglycerin, oxygen, and bed rest were standard therapy. (Beginning in 1980s, the aspirin trials began, followed in the late 1980s by the combination of aspirin and heparin.) In 1981, a study showed the incidence of myocardial infarction to be only 3% in aspirin-treated patients as compared with 15% in the control group (33). These findings were confirmed in studies by Lewis et al. and Cairns et al. (32,33), showing a very clear benefit of aspirin without heparin. In these studies, the dose of aspirin varied from 325 mg twice daily to four times daily. Other investigators showed that doses as low as 80 mg/day were as effective in blocking cyclooxygenase, as were doses of 160 and 325 mg or more (16). However, the lower doses did not reach peak effect as early as did the higher doses, prompting the initial use of the higher doses.

Figure 3

Pharmacologic Inhibitors of Thrombin

Factor Xa Inhibitors Bay 59-7939 DX-9065a Heparin-AT LMWH-AT Fondaparinux-AT

XI TF-VIIa IXa

Microparticles Phospholipid

Xa

Thrombin Inhibitors* Argatroban Hirudin Bivalirudin Heparin-AT

Va VIIIa

Thrombin

Polyphosphate

*Also indirect platelet inhibitors Fibrinogen

XIII

XIIIa

Platelets

Platelet-Fibrin Thrombus

Damaged Endothelium

Direct Platelet Inhibitors IIb-IIIa Clopidogrel Aspirin Phosphodiesterase? TXa2 synthase?

Pharmacologic inhibitors of thrombin. Thrombin is a key enzyme in the hemostatic system in that it leads to the formation of fibrin strands and is a potent stimulus for platelet activation. Thrombin inhibitors, factor Xa inhibitors, and antiplatelet drugs act at different points in the hemostatic system to regulate the amount of thrombin that is generated.

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References

(A very important study by Theroux et al. (34) in 1988 was the first to demonstrate the use of aspirin in combination with in ACS.) It was shown in the study that the incidence of all major endpoints was significantly reduced to 3.3% with aspirin, 0.8% with heparin, and 1.6% with a combination. The incidence of serious bleeding was not prohibitive. The fact that the combination of aspirin and heparin was better than aspirin alone but worse than heparin alone could be taken as evidence for using heparin alone, but subsequent studies showed that a rebound in the acute ischemic events occurred when heparin was stopped unless the aspirin was continued (34). Subsequent studies combining two or more antiplatelet drugs with heparin or LMWH gave better results than heparin and aspirin in the moderate- and high-probability patients and in PCI (27). The modern era (1990 and beyond) has seen many new antiplatelet drugs become available for clinical use along with newer anticoagulants. The motivation for developing these drugs has been the perceived need for a broader inhibition of platelet function and of the coagulation system in patients with ST-elevation with or without Q-waves and the perception that PCI, particularly with stent placement, required the more potent IIb/IIIa inhibitors along with aspirin and clopidogrel in order to more completely suppress procoagulant tendencies in these patients. The currently available anticoagulant drugs for use in ACS and PCI are shown in Table 1. Note that the thienopyridines and the several IIb/IIIa inhibitors have become available and are being selectively used in higher risk patients. Bleeding risks are greater with the IIb/IIIa inhibitors when used in combination with heparin, but are reasonably safe when the heparin dose is reduced. When the acute reocclusion rate is high, they are required (27). Among the anticoagulant drugs, the LMWHs developed during the 1980s have replaced heparin for use in unstable angina based upon greater bioavailability with dosing that is more predictable than with heparin and with less tendency to cause HIT. One disadvantage of the LMWHs is their tendency to reach unpredictably high blood levels in patients with renal insufficiency. Furthermore, a reliable antidote is not available for patients who bleed (18). Protamine sulfate neutralizes the antithrombin effects of LMWHs but is unable to block the anti-Xa activity (18). The numerous clinical trials that have been widely published and that are summarized in other chapters of this textbook attest to the need for combination drug therapy in the ACS. It is to be expected that results obtained in clinical practice will vary somewhat from those found in clinical trials but on balance it is important to treat patients in accordance with guidelines derived from clinical trials unless there are contraindications or relative risks. It is not possible to state that a given drug is more effective or safer than another drug without a head-to-head clinical trial of the drug in question. Factors that the practicing clinicians can control better than in some clinical trials include ascertaining the fact that the patient is in fact taking or being given the drug in the appropriate doses and that appropriate monitoring is carried

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out and acted upon in a timely manner. This is not always the case as shown in a recent study (35). We have attempted to find evidence for gender differences that could alter the information we have provided in this chapter but we could not find reliable human studies in this regard. This does not include differences that may exist in the endothelium or in the coronary artery anatomy or in the pathophysiology of atherosclerosis, but refers to effectiveness of antiplatelet and anticoagulation drugs as compared to the opposite sex.

Future antithrombotic agents There are a number of additional targets that may lead to effective antithrombotic therapy in ACS. In terms of anticoagulants, the concepts of agents that have dual inhibitor sites such as the one we find in heparin but that lack in some of its undesirable qualities could be very useful. The same concept may apply to drugs that have both anticoagulant and antiplatelet properties. It is quite probable that inhibitors of tissue factor as well as of the platelet ADP receptor when combined with aspirin might be very effective. An ability to block the feedback action of the polyphosphates released from platelets upon activation is also an attractive aim (Fig. 3). Several in-depth reviews of this subject have been recently-published (36,37).

References 1 2 3 4 5 6 7 8

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Herrick J. Certain clinical features of sudden obstruction of the coronary arteries. Trans Am Assoc Phys 1912; 27:100–116. McClean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41:250–257. Solandt DY and Best CH. Heparin and coronary thrombosis in experimental animals. Lancet 1938; ii:130–132. Best CH. Preparation of heparin and its use in the first clinical cases. Circulation 1959; 19:79–86. Wright IS. Experience with anticoagulants. Circulation 1959; 29:110–115. Link KP. The discovery of dicumarol and its sequels. Circulation 1959; 19:97–107. Quick AJ. The thromboplastin reagent for the determination of prothrombin. Science 1940; 92:113–114. Butt HR, Allen EV, Bollman JL. A preparation from spoiled sweet clover (3,3⬘)-methylene-bis-(4 hydroxycoumarin) which prolongs coagulation and prothrombin time of the blood: preliminary report of experimenta and clinical studies. Proc Staff Meet Mayo Clin 1941; 16:388–395. James DF, Bennett IL Jr, Scheinberg P, et al. Clinical studies on dicumarol hypoprothrombinemia and vitamin K preparations. Int Med 1949; 83:632–652.

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Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960; I: 1309– 1312. Kroll MH, Rezendiz JC. Mechanism of platelet activation. In: Loscalzo J, Schafer A, eds. Thrombosis and Hemorrhage. 3rd ed. Philadelphia: Lippincott Williams, 2003:187–205. Rosenberg RD, Aird WC. Vascular bed specific hemostasis and hypercoagulable states. N Engl J Med 1999; 340:1555–1564. Kraegel AH, Reddy SC, Willes H, et al. Morphometric analysis of the composition of coronary arterial plaques in isolated unstable angina pectoris with pain at rest. Am J Cardiol 1990; 66:562–567. Fuster V, Lewis A. Connor memorial lecture. Mechanisms leading to myocardial infarction. Insight from studies of vascular biology. Circulation 1994; 90:2126–2146. Sakharov DV, Plow EF, Rifken DC. On the mechanism of the antithrombin activity of plasma carboxypeptidase B. J Biol Chem 1997; 272:14477–14482. Patrono C, Coller B, FitzGerald GA, et al. Platelet active drugs. The relationship among dose, effectiveness and side effects. Chest 2004; 126(suppl):234S–264S. Michelangelo OASIS 5 Steering Committee. Design and rationale of the MICHELANGELO Organization to Assess Strategies in acute Ischemic Syndrome (OASIS)-5 trial. Am Heart J 2005; 150:1107. Hirsh J, Raschke R. Heparin and low molecular weight heparin. Chest 2004; 126(suppl):188S–203S. Warkentin T, Greinacher A. Heparin-induced thrombocytopenia. Chest 2004; 126(suppl):311S–337S. Buller HR, Davidson BL, Decausus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep vein thrombosis: a randomized trial. Ann Int Med 2004; 140:867–873. The Matisse Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003; 349: 1695–1702. Weitz JI, Hirsh J, Samama M. New anticoagulant drugs. Chest 2004; 126:265S–286S. Lubenow N, Greinacher A. Management of patients with heparin-induced thrombocytopenia: focus on recombinant hirudin. J Thromb Thrombolysis 2000; 10:S47–S57. Iqbal O, Ahmad S, Lewis BE, et al. Monitoring of argatroban in ARG310 study: potential recommendations for its use in

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interventional cardiology. Clin Appl Thrombosis/Hemostasis 2002; 8(3):217–224. Becker RC. Hirudin-based anticoagulant strategies for patients with suspected heparin-induced thrombocytopenia undergoing percutaneous coronary interventions and bypass grafting. J Thromb Thrombolysis 2000; 10:S59–S68. Herbert JM, Herault JP, Bernat A, et al. Biochemical and pharmacological properties of SANORG 34000, a potent long-acting pentasaccharide. Blood 1998; 91:4197–4205. Harrington RA, Becker RC, Ezekowitz M, et al. Antithrombotic therapy for coronary artery disease. Chest 2004; 126(suppl): 513S–548S. Stuart MJ. The post aspirin bleeding time. A screening test evaluating hemostatic disorders. Br J Haematol 1979; 43: 649–656. Born GVR. Aggregation of blood platelets by adenosine diphosphate. Nature 1962; 94:927–929. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971; 231: 232–235. Smith SA, Mutch NJ, Baskar D, et al. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 2006; 103:903–908. Lewis HD Jr, Davis JW, Archebald DG, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a veterans administration cooperative study. N Engl J Med 1983; 309: 396–403. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med 1985; 313:1369–1375. Theroux P, Ouimet H, Mc Cans J, et al. Aspirin, heparin or both to treat unstable angina. N Engl J Med 1988; 319: 1105–1111. Raschke R, Hirsh J, Guildry JR. Suboptimal monitoring and dosing of unfractionated heparin in comparative studies with lowmolecular weight heparin. Ann Int Med 2003; 138:720–723. Messmore HL, Jeske W, Wehrmacher W. Antiplatelet agents: current drugs and future trends. Hematol Oncol Clin N Am 2005; 19:89–117. Pipe SW. The promise and challenges of bioengineered recombinant clotting factors. J Thromb Haemost 2005; 3(8): 1692–1701.

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12 Fibrinolytic therapy Freek W. A. Verheugt

Acute myocardial infarction has become the largest mortality and morbidity problem of health care in the West. Epidemiology, pathophysiology, diagnosis, and treatment of acute myocardial infarctions were studied and developed gradually after Einthoven invented electrocardiography in 1901. Since acute myocardial infarction in patients presenting with STelevation is caused by a thrombotic occlusion of a major epicardial coronary artery, the largest step taken forward in the causal treatment of acute myocardial infarction has been in the introduction of reperfusion therapy. The key element of benefit with reperfusion therapy is the time taken to complete it [thrombolysis in myocardial infarction (TIMI) flow grade 3]. The benefit of this strategy rises exponentially, the earlier the therapy is initiated (Fig.1). The highest number of lives are saved by reperfusion therapy when it is used within the first hour after symptom onset thus creating a window of opportunity (golden hour) (1). Clearly and logically, the mechanism of this benefit relates in maximizing myocardial salvage by early restoration of adequate coronary blood flow, resulting in the preservation of left ventricular function, and thereby enhancing both early and long-term survival. According to the principle of the infarct wavefront, a brief interruption of blood flow is associated with a small infarct size. The temporal dependence of the beneficial effect of coronary reperfusion has also been characterized by multiple metrics, including positron emission tomography (2). Irrespective of the methodology, however, the relationship between the duration of symptoms and the infarct size remains consistent. The exponential curve illustrating the benefit of reperfusion therapy upon mortality and myocardial salvage has major implications on the timing of undertaking the treatment. Fibrinolytic therapy is less beneficial and contraindications are more stringent the later a patient is presented and the smaller the size of the area at risk. Consequently, reducing the delays will have a much more positive return in patients presenting early compared to those presenting late (3). These considerations have provided a

strong incentive for the initiation of very early reperfusion therapy, including the use of prehospital fibrinolysis (4), which shortens the treatment time by about an hour and improves clinical outcome compared to inhospital therapy. Unfortunately, patient delay is still the main factor and does not seem to be influenced by public campaigns (5). On the other hand, fibrinolytic therapy can be initiated in the prehospital setting. Two major forms of reperfusion therapy are available: fibrinolytic therapy and primary coronary intervention. This review mainly addresses the former.

Mechanism of fibrinolysis Fibrinolytic agents ( Table 1) aim at plasminogen activation at the site of the thrombotic occlusion (Fig. 2) during the early hours of acute transmural myocardial infarction. Besides lysis of fibrinogen, plasmin also splits several important clotting factors, such as prothrombin. When prothrombin is split, thrombin generation occurs and this has strong procoagulant effects. Although the procoagulant effect of fibrinolysis can be diminished by the concomitant heparin therapy, the nature of this therapy with its unpredictable efficacy and bleeding risk makes unsure the complete abolishment of the procoagulant effect of fibrinolytic therapy. Guidelines advice an intravenous bolus of 60U/kg to a maximum of 4000 U unfractionated heparin followed by a continuous infusion for at least 48 hours, with a target activated partial thromboplastin time (aPTT) of 50 to 70 seconds, measured 3, 6, 12, and 24 hours after the first dose. Finally, aspirin must be given immediately with a loading dose of 200 to 300 mg, followed by a maintenance dose of 75 to 160 mg daily.

Indications for fibrinolysis Since most patients with ST-elevation acute coronary syndrome have acutely occluded vessels (6), fibrinolytic

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Figure 1 Relationship of time to treatment with early mortality in fibrinolytic therapy for acute myocardial infarction. Source: From Ref. 1.

therapy is indicated in most cases if primary balloon angioplasty cannot be done within 90 minutes of the first medical contact (7). Only a few patients with acute coronary syndrome without ST-elevation have a total thrombotic coronary occlusion. Therefore, in such patients reperfusion therapy is not indicated and may be even harmful through its procoagulant effect. In several trials on fibrinolytic therapy in acute coronary syndrome, bleeding and thrombotic complications have made this therapy unpopular (8). The indication for fibrinolytic therapy has to be weighed against the absolute or relative contraindications. The earlier the patient is presented and the larger the area at risk recorded in the presenting electrocardiogram, the more beneficial fibrinolytic therapy is, and more contraindications are relative. The later the patient is presented and the smaller the area at risk, the less fibrinolytic therapy is beneficial and the more contraindications are stringent.

The major risk of fibrinolytic therapy is in its inherent bleeding complications. The most severe bleeding complication is the occurrence of intracerebral hemorrhage. This is seen in about 0.5% of patients treated with fibrinolysis. Risk factors for the development of cerebral bleeding following fibrinolytic therapy are low body weight (⬍65 kg), female sex, hypertension, and the use of oral anticoagulants prior to fibrinolysis. Other bleeding complications are gastrointestinal bleeding and hemorrhage following arterial punctures. In most cases, these bleeding complications can be managed conservatively and have a rather good prognosis. A second problem after fibrinolytic therapy is the occurrence of reocclusion (9). Reocclusion is seen after fibrinolysis in about 10% of cases in hospital and about 30% in the following year. So far, only parenteral and oral anticoagulation have proven to be effective against reocclusion (10,11). Finally, fibrinolytic agents may be immunogenic. This is especially seen with streptokinase and streptokinase-derived agents like anistreplase. The recombinant endogenous plasminogen activator, the tissue plasminogen activator (rt-PA), or alteplase, has a low incidence of immunologic reactions and can be given to patients with streptokinase allergy or in patients who have had streptokinase before. Currently, there are mutants of rt-PA that can be given as single bolus (TNK-tPA, or tenecteplase). This has the major advantage of ease of administration: for example, in an ambulance. The cost of fibrinolytic agents is considerable: streptokinase costs about US $100, and rt-PA and its mutants about US $2000. However, these agents have different early (90 minutes) recanalization rates: over 50% for front-loaded tissue rt-PA versus only 30% to 35% for streptokinase. Since early patency is correlated with early survival (12), the initial cost of the thrombolytic drug alone is not important. Patients who present early with a large myocardial infarction benefit more from a drug with a high early patency rate than patients presenting late with a small myocardial infarction. Patients without ST-segment elevation usually do not have an acute coronary occlusion. Therefore, they will not benefit by thrombolytic therapy, but do have the risk of its complications.

Table 1 Available fibrinolytic agents Nonfibrin specific Streptokinase Anisoylated plasminogen streptokinase complex (anistreplase) Urokinase Fibrin specific Recombinant tissue plasminogen activator (or alteplase) TNK t-PA (tenecteplase) Reteplase

Alternatives to fibrinolytic therapy The clear alternative to fibrinolytic therapy in the reperfusion strategy of ST-segment elevation acute myocardial infarction is primary coronary angioplasty. This therapy has a clinical benefit over the optimal thrombolytic strategy: front-loaded rt-PA or tenecteplase (13). The major drawback of primary angioplasty is its limited availability and treatment delay. The

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fibrin degradation products

fibrin

plasmin streptokinase, anistreplase, urokinase (aspecific activators) tissue plasminogen activator (tPA) and its mutants (fibrin-specific activators) plasminogen

Figure 2 Mechanism of fibrinolytic drugs.

delay is caused by preparation of the catheterization laboratory and mobilization of personnel to perform the procedure. Moreover, when patients have to be transferred for primary angioplasty, the delay can be considerable. The initial cost of primary angioplasty is higher than that of thrombolytic therapy, but the patency achieved is superior to thrombolytic therapy: up to 90% (14). The risk of thrombolytic therapy is higher than that of primary angioplasty, since cerebral bleeding is absent with primary angioplasty. During the treatment delay, patients may be treated with a thrombolytic to speed up reperfusion prior to angioplasty (facilitated angioplasty). However, the trials evaluating this therapy show better preangioplasty patency but no benefit over plain primary angioplasty, and bleeding is significantly increased (15). Also lower doses of fibrinolytic agents alone or in combination with platelet glycoprotein receptor antagonists failed to improve outcome.

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2

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Boersma E, Maas AC, Deckers JW, Simoons ML. Early thrombolytic therapy in acute myocardial infarction: reappraisal of the golden hour. Lancet 1996; 348:771–775. Bergmann SR, Lerch RA, Fox KAA, et al. Temporal dependence of beneficial effects of coronary thrombolysis characterized by positron emission tomography. Am J Med 1982; 73:573–580. Gersh BJ, Stone GW, White HD, Holmes DR. Pharmacological facilitation of primary percutaneous coronary intervention for acute myocardial infarction: is the slope of the curve the shape of the future? JAMA 2005; 293:979–986. Morrison LJ, Verbeek PR, McDonald AC, Sawadsky BV, Cook DJ. Mortality and prehospital thrombolysis for acute myocardial infarction. JAMA 2000; 283:2686–2692. Lupker RV, Raczynski JM, Osganian S, et al. Effect of a community intervention in patient delay and emergency medical service use in acute coronary heart disease: the Rapid Early

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Action for Coronary Treatment (REACT). JAMA 2000; 284:60–67. DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303:897–902. Van de Werf F, Ardissino D, Betriu A, et al. Management of acute myocardial infarction in patients presenting with STelevation. Eur Heart J 2003; 24:28–66. TIMI-IIIB Investigators. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI-IIIB trial. Circulation 1994; 89:1545–1556. Verheugt FWA, Meijer A, Lagrand WK, Van Eenige MJ. Reocclusion: the flip side of coronary thrombolysis. J Am Coll Cardiol 1996; 27:766–773. Ross AM, Molhoek P, Lundergan C, et al. Randomized comparison of enoxaparin, a low molecular weight heparin, with unfractionated heparin adjunctive to tissue plasminogen activator thrombolysis and aspirin: second trial of Heparin and Aspirin Reperfusion Therapy (HART II). Circulation 2001; 104:648–652. Brouwer MA, Van den Bergh PJPC, Vromans RPJW, et al. Aspirin plus medium intensity coumadin versus aspirin alone in the prevention of reocclusion after successful thrombolysis for suspected acute myocardial infarction: results of the APRICOT-2 study. Circulation 2002; 106:659–665. Stone GW, Cox D, Gracia E, et al. Normal flow (TIMI-3) before mechanical reperfusion therapy is an independent determinant of survival in acute myocardial infarction: results from the primary angioplasty in myocardial infarction trials. Circulation 2002; 104:636–641. Keeley EC, Boura JA, Grines CL. Primary coronary angioplasty versus intravenous fibrinolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003; 361:13–20. Grines CL, Serruys PW, O’Neil WW. Fibrinolytic therapy: is it a treatment of the past? Circulation 2003; 107:2538–2542. Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary intervention for ST-elevation myocardial infarct: quantitative review of randomized trials. Lancet 2006; 367:579–588.1

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13 Resistance to antiplatelet drugs Paul A. Gurbel and Udaya S. Tantry

Introduction Acute coronary syndromes (ACSs) are major causes of morbidity and mortality around the world. The common underlying pathological events during ACS are endothelial denudation and formation of occlusive thrombus. Platelets are not only central to thrombotic processes (the platelet hypothesis), but also play an important role in atherosclerosis, coagulation, and inflammation (1,2). Platelets are small anucleate subcellular fragments that circulate freely in the blood in the normal physiological state. However, disruption of the normal protective nature of the endothelium occurs during ACSs and percutaneous coronary intervention (PCI), exposing the subendothelial matrix. Transient binding of platelet surface receptors, glycoprotein (GP) Ib-IX-V and GPVI to von Willebrand’s factor and collagen, respectively, present in the subendothelial matrix facilitates initial platelet adhesion to the vessel wall. Subsequent intracellular signaling events trigger platelet activation, granule secretion, and finally the activation of GPIIb/IIIa receptors (final common pathway). Binding of fibrinogen and vWF to the activated GPIIb/IIIa receptor facilitates irreversible platelet aggregation and further recruitment of platelets (3–5). Thrombin is initially generated through tissue factor released from the vessel wall and is another primary agonist responsible for platelet activation. Platelet activation leads to the activation of phospholipase A2 (PLA2), which cleaves membrane phospholipids to release arachidonic acid. Arachidonic acid is converted to thromboxane A2 (TxA2) by sequential actions of cycloxygenase-1 and thromboxane synthase present in platelets. Secreted TxA2 binds to a specific Gq-coupled thromboxane receptor (TP) and activates and recruits surrounding platelets as a positive feedback mechanism (6). Adenosine diphosphate (ADP) released from dense granules activates surrounding platelets via autocrine and paracrine mechanisms by binding to specific G-protein-coupled purinergic receptors, P2Y12 and P2Y1 (1,3). Concomitant activation of both purinergic receptors is needed for complete

aggregation by ADP. However, the binding of ADP to the P2Y12 receptor and subsequent intracellular signaling pathways are predominantly responsible for the activation of the GPIIb/IIIa receptor (4,7). Thus, ADP and TxA2 amplify platelet activation processes and recruitment of platelets during stable thrombus generation. In addition, platelet activation also results in the expression of adhesion molecules, especially P-selectin and CD40 ligand (CD40L) on the platelet surface. These molecules play an important role in the heterotypic aggregation of platelets with leukocytes, inflammation and amplification of thrombin generation (Fig. 1) (8–10).

Rationale for antiplatelet therapy Experiments in animal models and autopsy studies have demonstrated the primary involvement of platelets during thrombus formation and plugging of microvasculature (11,12). Increased expression of platelet surface molecules and heightened platelet reactivity have been demonstrated in patients with ACS and during PCI (2,13,14). High platelet reactivity has been associated with stent thrombosis, restenosis, inflammation, myocardial infarction (MI), and other ischemic events (15–22). Platelet activation and high platelet reactivity have also been associated with diabetes, hypertension, and hyperlipidemia (23–25). Therefore, the rationale for antiplatelet therapy is to prevent the development of occlusive thrombus formation, to arrest the procoagulant activity and inflammatory processes, to promote disaggregation of platelets, and finally to facilitate the reperfusion of occluded blood vessels. The determination of optimal platelet inhibition is dependent on the degree of ischemic risk and is counterbalanced by the risk of bleeding.

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Heterotypic Aggregation With Leukocytes

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Inflammation and Increased Thrombin Generation

Figure 1 (See color plate.) Role of platelet activation and aggregation in cardiovascular diseases. Binding of primary (collagen, Thrombin, and vWF) and secondary (ADP, TxA2, etc.) agonists to specific receptors leads to final activation of GPIIb/IIIa receptors and irreversible platelet aggregation. Abbreviations: ADP, adenosine diphosphate; CD40L, CD40 ligand; ExctoADPase, ectoadenosine diphosphatase; GP, glyocoprotein; NO, nitric oxide; PAR1 and PAR4, proteaseactivated thrombin receptors; PGI2, prostaglandin I2; TF, tissue factor; TxA2, thromboxane A2; P2Y1, P2Y12, ADP receptors; vWF, von Willebrand factor.

3. Aggregation

Thrombotic Events Myocardial Infarction

Resistance to antiplatelet drugs Large-scale clinical trials have demonstrated the central role of platelet inhibition by antiplatelet agents in the primary treatment of ACS, in the prevention of complications during and after PCI, and in the long-term treatment of cardiovascular disease. Effective platelet inhibition immediately before and during PCI attenuates the development of in-hospital and postdischarge thrombotic complications (26–30). Extensive laboratory evaluations of the platelet response to aspirin or clopidogrel have not studied in these large-scale clinical trials. Despite the well-documented overall clinical efficacy of antiplatelet therapy, response variability and nonresponsiveness have been demonstrated for aspirin and clopidogrel treatment based on the ex vivo laboratory evaluation of the platelet response (31–33). This phenomenon has also been described as “resistance,” “hyporesponsiveness,” or “treatment failure” (Box 1). Thrombosis is a multifactorial process that involves multiple pathways of platelet activation and factors other than platelets. Therefore, we believe that treatment failure is a poor definition since certain vascular complications are unrelated to plateletspecific mechanisms and hence antiplatelet drugs may not have any effect in these clinical conditions (34). Moreover, the underlying pathobiology may differ between clinical disease entities in atherothrombotic disease. Aspirin may be effective in certain disease states through shear-dependent mechanisms, whereas clopidogrel or GPIIb/IIIa blockers may be effective in preventing other atherothrombotic complications through shear-independent mechanisms (35,36). Finally, since multiple agonists activate platelets, clinical ischemic events can occur despite complete drug-induced inhibition of a particular pathway of activation. It is

Box 1 Definition of antiplatelet resistance Antiplatelet Drug Nonresponsiveness/ target Resistance

⫽ Failure to Inhibit

Antiplatelet Drug Nonresponsiveness/ Resistance

⫽ Clinical Failure

No single pathway mediates all thrombotic events–multiple pathways of platelet activation

our opinion that resistance to a specific antiplatelet agent as measured by ex vivo testing is best indicated by persistent activity of the target despite treatment with the specific antiplatelet agent that inhibits the target. This definition also implies that patients are receiving sufficient dosing to produce optimal drug levels for inhibition of the target. Therefore, the occurrence of clinical events during treatment (treatment failures) with a specific antiplatelet agent should not be regarded as “resistance” to the therapeutic agent (37).

Aspirin Mechanism of action Aspirin is the most economical and effective antiplatelet drug prescribed for the treatment of cardiovascular and cerebrovascular (CV) diseases. Initially, Vane et al. (38)

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demonstrated that aspirin inhibits prostaglandin generation (TxA2) in platelets and has a potent antiplatelet effect. This antiplatelet effect is due to irreversible acetylation of a serine residue (Ser529) on COX-1 in platelets that prevents the binding of arachidonic acid to the catalytic site of cyclooxygenase (39,40). In addition, aspirin elicits anti-inflammatory effects by inhibiting the COX-2-dependent synthesis of other prostaglandins in endothelial and inflammatory cells (26). Because the inhibitory effects of aspirin on the COX-1 enzyme is 50- to 100-fold more potent than those on the COX-2 enzyme, COX-2-related effects are comparatively low using the doses recommended for patients with cardiovascular diseases (26). However, aspirin has been demonstrated to inhibit collagen- induced inhibition in a modest dose-dependent manner (41). Additional antithrombotic effects of aspirin include antioxidant, anti-inflammatory, and antiatherosclerotic effects on endothelial cells and leukocytes (42). These additional effects of aspirin may contribute to antithrombotic properties in preventing cardiovascular events (Fig. 2). Aspirin is rapidly absorbed; peak plasma concentrations are achieved within 40 minutes; and significant platelet inhibition is observed within an hour. Although the plasma half-life is 20 minutes, irreversible binding and the lack of de-novo protein synthesis in platelets results in COX-1 inhibition for the life span of platelets (~10 days). The stable metabolite of TxA2, can be measured in plasma or urine and is a specific indicator of platelet response to aspirin therapy (43,44). The extensive analyses of primary and secondary clinical trials have indicated that aspirin treatment is associated with a 20% to 44% reduction in cardiovascular adverse events (26,27). Based on the results of these trials, the US Preventive Services Task Force (USPSTF) recommends that low-dose aspirin (81 mg/day) should be administered in patients whose 5-year risk of a first CV event is ⱖ3% and whose 10-year risk is ⱖ6%. Whenever rapid and

complete inhibition of platelet aggregation is desired, such as in the setting of acute MI, unstable angina, or PCI, a 160 to 325 mg aspirin-loading dose is favored (45). The Antithrombotic Trialists’ Collaboration (ATC), the European Society of Cardiology (ESC) Committee for practice guidelines, the American College of Chest physicians, and the American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommended aspirin therapy to prevent atherothrombotic complications (26, 27,46,47).

Aspirin resistance Despite the well-recognized effect of aspirin in inhibiting arachidonic acid-induced platelet aggregation, other major activation pathways through ADP and thrombin are unaffected, except at low agonist concentrations (Fig. 2). Elevated levels of collagen, ADP, and thrombin can stimulate platelet aggregation independent of the thromboxane pathway. Thromboxane, unlike collagen and thrombin, is not involved in the primary activation of platelets. These properties may limit the efficacy of aspirin in preventing thrombosis in patients with ACS (5). Earlier, Mehta et al. (48) in 1978 reported that about 30% of patients with coronary artery disease (CAD) had minimal inhibition (unchanged bleeding time) of platelet function by aspirin therapy. Since then, numerous studies evaluated the efficacy of aspirin therapy using various laboratory methodologies to demonstrate the phenomenon of aspirin “resistance.” Since the target of aspirin is COX-1, resistance to aspirin is indicated by persistent activity of COX-1 in the presence of aspirin therapy. In cases where excessive bone marrow stimulation is present creating young platelets with high COX-2 activity, arachidonic acid stimulation may produce aggregation despite adequate COX-1 inhibition.

COX-1 Specific Methods

CO XP Ac 1 In IIb tiv d /II at ep Ia ion en Re o de ce f nt pt or

1. AA-Induced Platelet Aggregation - LTA(PRP) - TEG (Whole Blood) 2. TxB2 Metabolite - Plasma - PRP (AA-Induced) TxA2 - Urine Receptor 3. Verify Now (AA-induced) 4. Flow Cytometry AA-induced G P-selectin, PAC-1 P PI

ADP, Collagen, Thrombin

Receptor Platelet Activation

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COX-1 Non-Specific Non-Specific Methods 1. LTA- ADP and Collagen- Induced 2. PFA-100

AA

X COX-1

TxA2 lat Ib ele /III tAaA gg cti re vat ga io tio n, n

141

ASA

The Relevant Pathway to Measure Platelet Aspirin Responsiveness

Figure 2 (See color plate.) Mechanism of action of aspirin and laboratory evaluation of aspirin responsiveness. Abbreviations: AA, arachidonic acid; ADP, adenosine diphosphate; ASA, aspirin; COX-1 and COX-2, cyclooxygenase isoenzymes; GP, glycoprotein; LTA, light transmission aggregometry; platelet function analyzer-100; TxA2, thromboxane A2; TxB2, metabolite of TxA2; PRP, platelet-rich plasma; TEG, thrombelastography; Tx, thromboxane; PFA-100.

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Laboratory evaluation of aspirin resistance The laboratory evaluation of platelet response to aspirin therapy has demonstrated response variability and nonresponsiveness. Based on different ex vivo methods, studies have shown wide variability in the prevalence of aspirin resistance (⬍1–54.7%) (45,49–58) (Table 1). Potential reasons for these discrepancies include (i) wide variability in the criteria to define aspirin resistance, (ii) variability in the methods to measure responsiveness, (iii) the timing of the laboratory test after aspirin treatment, (iv) the duration of aspirin treatment, and (v) the dose of aspirin administered. Platelet response to aspirin may vary over the course of time. Decreased inhibition of platelet COX-1 was observed in some patients chronically treated with aspirin (59). Use of agonists such as ADP, epinephrine, or collagen that can aggregate platelets in the presence of complete COX-1 inhibition and therefore do not isolate COX-1 activity may overestimate the prevalence of aspirin nonresponsiveness. Moreover, point-of-care assays similarly employ methods based on platelet responses induced by epinephrine, ADP, or collagen. Finally, the relevance of these methods to the in vivo response to aspirin is unknown. More specific methods that indicate the degree of COX-1 activity include arachidonic acid-induced platelet aggregation and the measurement of the stable metabolite of TxA2 following aspirin therapy in urine and plasma (43,44,60–62). Thus, there are important limitations in the specificity of the widely used laboratory methods. A validated criterion to prove the concept of aspirin resistance has not yet been established. Nevertheless, recent studies have correlated laboratory measurements of aspirin resistance in patients taking aspirin to the occurrence of thrombotic events, indicating a potential link between the measurement of ex vivo platelet function and in vivo events.

Mechanism of aspirin resistance There are many potential mechanisms responsible for the occurrence of aspirin resistance or nonresponsiveness. Many of these studies reporting aspirin resistance have employed methods that did not isolate COX-1 inhibition and/or used treatment failure as their definition for aspirin resistance. Cigarette smoking, noncompliance, transient expression of COX-2 in newly formed platelets, and extra-platelet sources of PGG2/PGH2 (endothelial cells, monocytes/macrophages) may contribute to an attenuated clinical response to aspirin (63–66). Erythrocytes may attenuate the effect of aspirin by

enhancing the prothrombotic effects of platelets and this property may contribute to aspirin resistance (67). Concomitant use of ibuprofen inhibits the irreversible binding of aspirin to COX-1 (68). Increased platelet turnover soon after surgical operations may influence the response of aspirin, and studies have found that aspirin resistance is increased transiently soon after cardiac surgery (69,70). Finally, genetic polymorphisms of the COX-1 gene or GPIIb/IIIa may contribute to variability in the platelet response to aspirin therapy and the occurrence of aspirin resistance (71,72).

Clinical relevance of aspirin resistance In an earlier study, Grotemeyer et al. measured platelet aggregates in stroke patients after a 500 mg aspirin dose and found that 30% of patients had a platelet reactivity index greater than 1.25. These patients were defined as aspirin resistant. At a follow-up of two years with 500 mg aspirin treatment three times daily, aspirin-resistant patients had a 10-fold increase in the risk of recurrent vascular events as compared to aspirin-sensitive patients (44% vs. 4.4%, P ⬍ 0.001) (51). Using a whole blood aggregometry method to evaluate aspirin resistance, Mueller et al. (62) found an 87% increase in the incidence of reocclusion in “aspirin-resistant” patients who underwent peripheral balloon angioplasty and were treated with 100 mg aspirin daily for 18 months. Using a more COX-1-specific method by measuring urinary thromboxane metabolite levels, among patients enrolled in Heart Outcomes Prevention Evaluation (HOPE) trial for aspirin responsiveness, Eikelboom et al. (44) found that the risk of MI, stroke, or cardiovascular death was greatest in patients with the highest quartile of urinary thromboxane levels. Gum et al. found a 5% incidence of aspirin resistance in patients with stable cardiovascular disease taking 325 mg aspirin daily for up to 2.5 years. These investigators included the classic method of arachidonic acid-induced platelet aggregation in their definition of resistance. Aspirin resistance was associated with a significant increase in the composite endpoint of death, MI, or stroke (53,54). Recently, Chen et al. used a point-of-service assay employing cationic propyl gallate as the agonist to determine the incidence of aspirin resistance in patients with CAD scheduled for nonurgent PCI. Among 151 patients, 19.2% of patients met the criteria of aspirin resistance. Despite treatment with clopidogrel and heparin, aspirin resistance was associated with ~2.9-fold increase in the occurrence of myonecrosis (elevated serum CKMB levels) (56) (Table 2).

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Aspirin

Table 1

143

Aspirin resistance studies

Investigators

n

ASA dose (mg/day)

Time

Method

Criteria for aspirin resistance

%AR

Comments

Hurlen et al. (49)

143

AMI

75–160

2–24 hr

PAR

PAR ⬍ 0.82 PAR ⬍ 0.82 after additional ASA

9.8 1.4

No clinical relevance

Buchanan et al. (50)

40

CABG

325

Bleeding time No prolongation Platelet TxA2, of bleeding time 12-HETE and above baseline platelet adhesion

43

Increased 12HETE and platelet adhesion associated with AR

Buchanan et al. (51)

287

CABG

325

24 hr 2 yr follow-up

Bleeding time

54.7

AR associated with no change in thrombotic event rate

Grotemeyer et al. (52)

180

Stroke 1500

1 yr follow-up

Platelet reactivity Normal PR index (PR) (⬎1.25) at 2 or 12 hr

33.3

40% of AR patients had major endpoints (MI, stroke, and death)

Gum et al. (53,54)

325

Stable CAD

325

ⱖ 7 days 2 yr follow-up

LTA- AA and ADP PFA-100 collagen/ ADP or collagen/EPI

⬎ 70% ADP-induced aggregation ⫹ AA (0.5 mg/ml) induced ⬎20% after ASA. Normal (⬍193 sec) collagen/EPI closure time after ASA

5.5 9.5

AR associated with 3 ⫻ higher risk (death, MI, CVA)

75–325 follow-up

5 yr follow-up

Urinary 11dehydro TxA2

Elevated urinary 11-dehydro TxA2 Upper quartile

25

Upper quartile had 1.8 ⫻ higher risk (MI, stroke, CVA)

Eikelboom 488 et al. (44) (HOPE Study)

No prolongation of bleeding time above baseline

Wang et al. (55)

422

Stable CAD

81–325

ⱖ 7 days

RPFA

ARU ⬎ 550

23

Patients with a history of CAD had twice the odds of being AR

Chen et al. (56)

151

Non- 81–325 urgent PCI

ⱖ 7 days

RPFA Myonecrosis (CK-MB ⫹TnI)

ARU ⬎ 550

19.2

AR associated with 2.9-fold increase in myonecrosis

GonzalezConejero et al. (57)

24

HS

100 and 500

2 wk

PA – 1 mM AA or 10 ug/ml Collagen, 11-dehydro TxA2. PFA100, genotyping

⬍ 300 sec closer time

33.3 (100 mg) 0 (500 mg)

AR can be overcome by increased dose of aspirin

Tantry et al. (58 )

223

PCI

325

Long-term

LTA -1 mM AA

⬎ 50% aggregation

⬍ 1.0

Abbreviations: AA, arachidonic acid; AMI, acute myocardial infarction; AR, aspirin resistance; ASA, aspirin; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CK-MB, creatinine kinase-MB; CVA, cerebrovascular accident; EPI, epinephrine; HS, healthy subjects; LTA, light transmittance aggregometry; mm, millimolar; PAR, platelet activity ratio; PCI, percutaneous coronary intervention; PR, platelet reactivity; RPFA, rapid platelet function analyzer; TXA2, thromboxane A2.


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Table 2

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Clinical relevance of aspirin resistance

Investigators

n

Patients

Method

Results

Grotmeyer et al. (52)

180

CVA

Platelet aggregates

10 ⫻ increase in vascular events

Mueller et al. (62)

100

PVD

Platelet aggregation (whole blood)

87% increase in incidence of reocclusion

Eikelboom et al. (44)

976

HOPE trial

Urinary TxB2

Increase in MI/stroke/death with increase in TxB2

Gum et al. (53,54)

325

Stable CAD

Platelet aggregation (LTA)

3.12 ⫻ increase in MI/stroke/death

Chen et al. (56)

151

PCI

RPFA

2.9 ⫻ increase in myocardial necrosis

Abbreviations: CAD, coronary artery diseases; CVA, cerebrovascular accident; HOPE, heart outcomes prevention evaluation; LTA, light transmittance aggregometry; MI, myocardial infarction; PCI, percutaneous coronary intervention; PVD, peripheral vascular diseases; RPFA, rapid platelet function analyzer; TxB2, thromboxane B2.


Therapeutic intervention for aspirin resistance Initial studies have suggested that the inhibition of COX-1 by aspirin can reach saturable levels (⬎95% inhibition) with a 100 mg daily dose (26,73,74). A higher dose (⬎75– 325 mg/day) is not clearly associated with an increased clinical benefit but may be accompanied by an elevated risk of bleeding (26,27). In a recent study, normal volunteers were found to be resistant to aspirin treatment (100 mg/day) as determined by the platelet function analyzer (PFA-100), a device that measures shear-induced platelet aggregation. However, an increased dose of aspirin (325 mg/day) was effective in overcoming aspirin resistance as measured by PFA-100 (57). Similarly, it has been reported by measuring serum thromboxane B2 (TxB2) levels and arachidonic acid-induced platelet aggregation that low-dose (75 mg/day) aspirin treatment is not sufficient to completely inhibit the platelet COX-1 activity in some stable cardiovascular patients. Complete inhibition of arachidonic acid-induced aggregation by the addition of exogenous aspirin to platelets indicated that a higher dose might be needed in select patients (75). In a recent study, aspirin response was measured by arachidonic acid-induced aggregation in platelet-rich plasma using standard light transmittance aggregometry (LTA) and in whole blood using thrombelastography (TEG) in patients undergoing elective coronary stenting treated with 325 mg daily aspirin. About 3.5% patients were found to be noncompliant with aspirin therapy and all responded well to in-hospital treatment. Only one patient met the aspirinresistance criteria (⬎20% arachidonic acid-induced aggregation). Thus, a higher dose and strict compliance to the therapy can effectively overcome the occurrence of “aspirin resistance” in selected patients (58). Dual antiplatelet therapy with aspirin and P2Y12 blockers may improve clinical

outcomes in those infrequent patients who are truly resistant to aspirin (58).

Clopidogrel The thienopyridines, ticlopidine and clopidogrel, are effective inhibitors of platelet aggregation. Clopidogrel was compared to aspirin therapy in patients with atherosclerotic vascular disease in the CAPRIE trial and was associated with superior protection against thrombotic events (28). Earlier, ticlopidine had been extensively used in the treatment of patients with cardiovascular disease. However, the more favorable side effect profile of clopidogrel has led to its establishment as the thienopyridine of choice. Since clopidogrel and aspirin inhibit platelet aggregation through different pathways, dual antiplatelet therapy provides complementary and additive benefits compared to either agent alone (2,5).

Mechanism of action Clopidogrel is absorbed from the intestine and extensively converted by the hepatic cytochrome P450 (CYP) 3A4 to an active thiol metabolite (76,77). This short-lived active metabolite irreversibly binds to the P2Y12 receptor through a disulfide bridge linking the reactive thiol group and two cysteine residues (cys17 and cys270) present in the extracellular domains of the P2Y12 receptor. This permanent binding of the metabolite to the P2Y12 receptor results in effective blockade of ADP-induced platelet activation and aggregation (78). The importance of P2Y1 in pathological conditions, as

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Clopidogrel

well as efficiency of P2Y1 receptor antagonist as an antiplatelet agent remain unclear (Fig. 3) (79). Ex vivo measurements of platelet aggregation induced by ADP, and low concentrations of collagen and thrombin are decreased after clopidogrel treatment. Little information is available on the effect of clopidogrel treatment on arachidonic acid metabolism or arachidonic acid-induced platelet aggregation (5). By attenuating ADP-induced platelet activation, clopidogrel also inhibits the expression of P-selectin and CD-40L and the formation of heterotypic aggregates. The latter effect results in the attenuation of inflammatory processes, as indicated by reduced release of C-reactive protein and tumor necrosis factor (80,81). In addition, attenuation of thrombin generation by clopidogrel has also been reported (82–84). Based on large clinical trials, a 300 mg clopidogrel-loading dose with a 75 mg clopidogrel daily dose, in addition to an 81 to 325 mg aspirin daily dose, had been considered the gold standard to prevent adverse cardiovascular events following PCI. However, recent studies employing a 600 mg loading dose have been conducted and use of this loading dose has increased (47).

Laboratory evaluation of platelet response to clopidogrel treatment Since clopidogrel specifically inhibits one of two ADP receptors, ex vivo measurement of ADP-induced platelet aggregation by LTA is the most commonly used laboratory method to evaluate clopidogrel responsiveness. LTA is a cumbersome, time-consuming method that requires trained technicians. In this method, maximum platelet aggregation in response to 5 and 20 µM ADP is determined in platelet-rich plasma before and after treatment with clopidogrel. Patients with an absolute difference in aggregation of ⱕ10% have been considered nonresponders or “resistant”; those with 10% to 20% considered semi-responders; and those with ⱕ30% are considered responders (85,86). Recently, ex vivo “final” platelet aggregation measured at six minutes following stimulation by ADP was proposed as a better measure of clopidogrel response than maximum aggregation (87).

Carboxyl Inactive Metabolite

Hydrolysis 85% Clopidogrel Bisulfate/ Prasugrel

15%

Intestinal Absorption

ADP TxA2 Collagen Thrombin

P2Y1 Gg

CYP3A4 Conversion

X

G12

P2Y12

Gi

Gg

Rho Kinase Shape Change

Granule Secretion

– Pl3K

Adenylyl Cyclase cAMP

? RAP-1b Akt

VASP-P

3. ADP-Induced Platelet Aggregation - LTA (PRP) - TEG (Whole Blood) 4. P2Y12 Reactivity Ratio - Flow cytometry VASP-P levels 5. P-selectin, activated PAC-1 expression and PLAs folllowing ex-vivo ADP stimulation- Flow Cytometry 6. Point-of-Care Methods - Thrombelastography, PFA-100 and VerifyNow P2Y12 with ADP as agonist

ADP

P-selectin and CD40L Expression, Platelet-Leukocyte Aggregation

Laboratory Evaluation of Clopidogrel Responsiveness

1. Plasma unchanged dopidogrel. active and inactive metabolites of dopidogrel Active Thiol - LC-MS/MS assay Metabolite AZD-6140, 2. Hepatic CYP3A4 activity Cangrelor - Erythromycin breath test-

12 G

Ca++ Mobilization

145

GPllb/llla Activation, Platelet Aggregation

Figure 3 (See color plate.) Mechanism of action of clopidogrel and laboratory evaluation of clopidogrel nonresponsiveness. Abbreviations: ADP, adenosine diphosphate; CYP3A4, hepatic cytochrome 3A4; Gai2, G12, and Gq, G family protein-associated platelet receptors; GP, glycoprotein; IP3, P2Y1, and P2Y12, ADP receptors; LS-MS/MS, liquid chromatography-mass spectrometry; LTA, light transmittance aggregometry; TxA2, thromboxane A2; PFA-100, platelet function analyzer-100; PLA, platelet-leukocyte aggregation; PI3K, phosphoionisitol-3-kinase; PRP, platelet-rich plasma; TEG, thromelastography; VASP-P, vasodilator stimulated phosphoproteinphospohrylated. Source: From Ref. 115.

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Flow cytometric determinations of P-selectin and activated GPIIb/IIIa receptor expression following ADP stimulation have been used to assess platelet inhibition by clopidogrel. Flow cytometry is also a cumbersome method and requires sophisticated instrumentation and well-trained technicians. The phosphorylation state of vasodilator-stimulated phosphoprotein (VASP) is a specific intracellular marker of clopidogrel-induced P2Y12 receptor inhibition and can also be measured by flow cytometry. Permeation of the membrane and the use of monoclonal antibodies specific for phosphorylated VASP are required in this method (15,88). The TEG using the platelet mapping assay with ADP as the agonist, and the recently developed VerifyNowTM P2Y12 assay have been proposed as reproducible point-of-care methods to assess platelet inhibition by clopidogrel (21,89,90). These methods are undergoing investigation in clinical studies.

Clinical studies of clopidogrel response variability Similar to other drugs, response variability and nonresponsiveness have been demonstrated for clopidogrel. In an earlier study, marked response variability to clopidogrel treatment (300 mg loading dose followed by 75 mg per day maintenance dose) following stent implantation was demonstrated by LTA and changes in the expression of activation-dependent markers following stimulation with ADP. A certain percentage of patients were found to have no demonstrable antiplatelet effect (85). In this study, 63% of patients were resistant to clopidogrel treatment at two hours, 30% were resistant at day 1 and day 5 post-stenting, and 15% were resistant at day 30 post-stenting (Fig. 4). Therefore, clopidogrel “resistance” in this study appeared to be time dependent. In addition, post-stenting platelet reactivity to ADP was greater than pre-stenting in a certain proportion of these patients. These patients were regarded as having “heightened” platelet reactivity to ADP. The phenomenon of clopidogrel “resistance” has been confirmed by multiple investigators and is now variously described as “nonresponsiveness,” “hyporesponsiveness,” or “clopidogrel resistance.” (Table 3) (85,86,91–95). Clopidogrel nonresponsiveness is also dependent on dose. In the largest pharmacodynamic study comparing 300 and 600 mg clopidogrel-loading doses, treatment with a 600 mg loading dose during PCI reduced clopidogrel nonresponsiveness to 8% compared to 28% to 32% with a 300 mg loading dose (Fig. 5). Moreover, the latter study demonstrated a narrower response profile, following treatment with 600 mg clopidogrel (86). Despite the well-documented clinical efficacy of dual antiplatelet therapy of clopidogrel and aspirin, it has been

repeatedly demonstrated that a certain percentage of patients may not be protected by this regimen and may suffer recurrent ischemic events, including stent thrombosis.

Mechanism of clopidogrel nonresponsiveness The mechanisms responsible for clopidogrel response variability are incompletely defined. Pharmacokinetic and pharmacodynamic differences in clopidogrel metabolism have been proposed to explain variable platelet inhibition.

Pharmacokinetic mechanisms Inadequate production of the active metabolite to sufficiently block the P2Y12 receptor may be responsible for clopidogrel nonresponsiveness. Poor bioavailability may be due to reduced intestinal absorption of clopidogrel, decreased conversion to the active metabolite, or drug–drug interactions at the CYP3A4 level. In recent studies, measurement of active and inactive metabolites of clopidogrel suggested that intestinal absorption was the primary factor affecting the production of active metabolite (96,97). A ceiling effect in unchanged clopidogrel and clopidogrel metabolite levels and platelet inhibition with a 600 mg loading dose in patients undergoing stenting was observed and no additional effect was seen with a 900 mg loading dose (97). The same authors suggested that in only selected patients hepatic conversion was a determinant factor in nonresponsiveness, following treatment with a 600 mg loading dose (98). However, convincing evidence supporting the pivotal role of hepatic CYP3A4 activity in mediating the antiplatelet effect of clopidogrel comes from the work of Lau et al. Their studies have demonstrated that the activity of CYP3A4 by using the radioactive erythromycin breath test is directly related to the extent of platelet inhibition induced by clopidogrel (76,99). Pharmacologic manipulation of CYP3A4 activity with stimulators such as rifampin and St. Johns wort enhanced the inhibitory effect of clopidogrel, whereas agents that inhibited CYP3A4 activity such as erythromycin attenuated the effect of clopidogrel (99). Atorvastatin, unlike statins that are not metabolized by CYP3A4, compete with clopidogrel for the active site of CYP3A4 and may affect clopidogrel active metabolite levels. Lau et al. (99) have demonstrated that atorvastatin attenuates platelet inhibition by clopidogrel. However, retrospective analyses of clinical trials have found no evidence of an atorvastatin drug–drug interaction (100,101). It has been suggested that a 600 mg clopidogrel-loading dose may be

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Pharmacodynamic mechanisms

2 Hours

12

Resistance

20

Resistance = 63%

% of Patients

% of Patients

24 Hours

Resistance

24

(A)

Resistance = 31%

10

(B) 60

(50,60)

∆ Aggregation (%)

∆ Aggregation (%) 5 Days

30 Days 28

22

Resistance = 31%

Resistance = 15%

Resistance

% of Patients

% of Patients

147

11

60

∆ Aggregation (%)

Resistance

14

(D)

60 (–30,–20) (–10,0) (10,20) (30,40) (50,60)

∆ Aggregation (%)

Figure 4 Relationship between frequency of patients and absolute change in aggregation [D aggregation (%)] in response to 5mM ADP at A), 24 hours (B B), 5 days (C C), and 30 days (D D) after stenting. D Aggregation (%) is defined baseline aggregation (%) minus two hours (A post-treatment aggregation (%). Resistance, as defined herein, is D aggregation # 10%. Resistance is present in those patients subtended by double-headed arrow. Curves represent normal distribution of data. Source: From Ref. 85.

effective in overcoming the drug–drug interaction between clopidogrel and statins (102).

Pharmacodynamic mechanisms Suboptimal platelet response to clopidogrel may be due to an increased number of platelet P2Y12 receptors or polymorphism of platelet receptors. Genetic polymorphisms of platelet GPIIb/IIIa, GPIa/IIa, or P2Y12 receptors have been reported to affect platelet function and may influence clopidogrel response variability (103–105). Recently, it was reported that an increased percentage of patients with peripheral arterial disease have the P2Y12 receptor H2 haplotype (104). However, in another study, the relation of this haplotype to clopidogrel responsiveness could not be demonstrated (105). Since the relation

of genetic polymorphisms to clopidogrel responsiveness is inconclusive, further studies are required to establish a correlation between receptor polymorphisms and clopidogrel nonresponsiveness. It has been shown that patients with diabetes exhibit platelet activation and increased reactivity to agonists. The heightened platelet reactivity may be related to the increased prevalence of nonresponders and occurrence of ischemic events reported in patients with diabetes (106,107). It has also been reported that patients with a high body mass index (BMI) exhibited a suboptimal platelet response with the standard 300 mg loading dose (108). All of the data mentioned earlier strongly support insufficient metabolite generation as the primary explanation for nonresponsiveness rather than genetic polymorphisms of platelet receptors or intracellular signaling mechanisms. The latter mechanisms may be relevant in those patients who may remain resistant and with high platelet reactivity to ADP even after treatment with high doses of clopidogrel.

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Table 3

Clopidogrel resistance studies

Investigators

n

Patients

Clopidogrel dose (mg, load/qd)

Definition of clopidogrel resistance

Time

Incidences (%)

Gurbel et al. (85)

92

PCI

300/75

5 and 50 µM ADP-induced aggregation ⬍10% absolute change

24 hr

31–35

Jaremo et al. (91)

18

PCI

300/75

ADP-induced fibrinogen binding ⬍40% of baseline

24 hr

28

Muller et al. (92)

119

PCI

600/75

5 and 50 µM ADP-induced aggregation ⬍10% relative change

4 hr

5–11

Mobley et al. (93)

50

PCI

300/75

1 µM ADP-induced aggregation, TEG and Ichor PW; ⬍10% absolute inhibition

Pre and post

30

Lepantalo et al. (89)

50

PCI

300/75

2 or 5 µM AD-induced aggregation and PFA-100 10% inhibition and 170s

2.5 hr

40

Serebruany et al. (94)

544

Heterogeneous population

300 loading dose

5 µM ADI-induced aggregation, 2 standard deviation below mean

Up to 30 days

4.2

Angiolillo et al. (95)

48

PCI

300/75

6 µM ADP-induced aggregation ⬍40% inhibition

10, 4 and 224 hr

44

Matetzky et al. (16)

60

STEMI

300/75

5 µM ADP-induced aggregation and CPA ⬍10% inhibition

Daily for 5 days

25

Gurbel et al. (86)

190

PCI

300 or 600/75

5 and 20 µM ADIinduced aggregation ⬍10% absolute inhibition

24 hr

28–32 with 300 mg 8 with 600 mg

Abbreviations: AD, adenosine diphosphate; CPA, cone and platelet analyzer; PCI, percutaneous coronary interventions; PFA, platelet function analyzer; TEG, thrombelastography.


Clinical relevance of clopidogrel nonresponsiveness and high post-treatment platelet reactivity Limited data are available to link clopidogrel nonresponsiveness to the occurrence of thrombotic events. Matetzky et al. studied clopidogrel responsiveness in patients undergoing stenting for acute ST-elevation MI. They found that patients who exhibited the highest quartile of ADP-induced aggregation had a 40% probability for a recurrent cardiovascular

event within six months (16). Moreover, it has been reported that some clopidogrel nonresponders have low pretreatment reactivity to ADP, whereas some responders have high posttreatment reactivity to ADP. Given these observations, the evaluation of thrombotic risk based on platelet inhibition may be flawed and either overestimate or underestimate the risk in selected patients. Therefore, the most reliable predictor of thrombotic risk may be the measurement of post-treatment platelet reactivity (109,110). In the PREPARE POSTSTENTING study (Platelet reactivity in patients and recurrent events post-stenting), patients suffering a recurrent ischemic event within six months of the procedure had high post-stent platelet reactivity to ADP compared to patients without ischemic events (21). In the CLEAR PLATELETS and CLEAR

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Patients (%)

Conclusions

33 30 27 24 21 18 15 12 9 6 3 0

300 mg Clopidogrel 600 mg Clopidogrel Resistance = 28% (300 mg) Resistance = 8% (600 mg)

70

∆ A (5 µM ADP-Induced Aggregation) at 24 Hours

Figure 5

Distribution of the absolute change in 5 µM ADP-induced aggregation (⌬ aggregation) and incidence of clopidogrel resistance in patients treated with 300 and 600 mg clopidogrelloading dose. All of the patients under double-headed arrow meet the definition of clopidogrel resistance. The distribution is shifted rightward and narrower in the 600 mg group indicating greater inhibition (responsiveness to clopidogrel) and lower incidence of resistance. Source: From Ref. 86.

PLATELETS-Ib studies, a 600 mg loading dose was associated with increased platelet inhibition compared to a 300 mg loading dose. In turn, increased platelet inhibition was accompanied by a decrease in the release of myocardial necrosis and inflammation (19,20). In a very recent study of 106 patients undergoing stenting, high post-treatment platelet reactivity was asso-ciated with an increased risk of recurrent cardiovascular events (22). Three small studies suggest that despite standard clopidogrel treatment, high platelet reactivity may be a risk factor for stent thrombosis. Barragan et al. (88) demonstrated high P2Y12 receptor reactivity as measured by VASP phosphorylation levels in patients with stent thrombosis. In the recent CREST (Clopidogrel effect on platelet reactivity in patients with stent thrombosis) study, platelet function was evaluated in patients with and without stent thrombosis by using platelet aggregation, stimulated expression of active GPIIb/IIIa expression, and the P2Y12 reactivity ratio measured by VASP phosphorylation (15). Elevated levels of all of these measurements were observed in patients with stent thrombosis, indicating that the P2Y12 receptor was inadequately inhibited (15). Finally, Ajzenberg et al. (17) observed increased shear-induced platelet aggregation in patients with stent thrombosis compared to patients without stent thrombosis who were on dual antiplatelet therapy and to normal controls who were not on dual antiplatelet therapy. Prasugrel is a new thienopyridine derivative that produces more potent platelet inhibition, and a rapid onset of action. The latter properties may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of nonresponsiveness (111). All of these small

149

studies support that insufficient inhibition of P2Y12 receptors by clopidogrel therapy and high post-treatment platelet reactivity are pivotally related to the occurrence of stent thrombosis and recurrent ischemic events following PCI.

Therapeutic interventions for clopidogrel nonresponsiveness In recent clinical studies, a 600 mg clopidogrel-loading dose was associated with a higher level of platelet inhibition and lower incidence of nonresponsiveness when compared to a 300 mg dose (19,20,86). Moreover, a 600 mg clopidogrelloading dose was associated with a narrower response profile (86). Kastrati et al. (112) found that patients achieved additional platelet inhibition when a 75 mg/day clopidogrel maintenance dose was followed by an additional 600 mg loading dose. In the CLEAR PLATELETS and CLEAR PLATELETS-Ib studies, a 600 mg loading dose was associated with increased platelet inhibition compared to a 300 mg clopidogrel-loading dose (19,20). Standardized methods to quantify ex vivo clopidogrel responsiveness and criteria to define nonresponsiveness and high post-treatment platelet reactivity are still lacking. In order to firmly link high platelet reactivity and poor clopidogrel responsiveness to the occurrence of adverse ischemic events, a standard methodology is mandatory. These advances will facilitate the conduction of large-scale clinical trials. High loading doses may be considered for selected patients, but its superiority and associated risk profile compared to standard dose has to be established in largescale clinical trials. Despite these limitations, the current ACC/AHA guidelines for PCI provide a Class IIa recommendation that “a regimen of greater than 300 mg is reasonable to achieve higher levels of antiplatelet activity more rapidly.” Finally, the ACC/AHA guidelines provide a Class IIb recommendation that “in patients in whom subacute thrombosis may be catastrophic or lethal … platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated” (47). New P2Y12 receptor antogonists are undergoing investigation. AZD 6140 (Astra-Zeneca; Södertälje, Sweden) and cangrelor (Medicines Company; Parsippany, NJ, U.S.A.) are reversible, direct, and potent inhibitors. AZD 6140 is an oral P2Y12 inhibitor, whereas cangrelor is administered parentally. Both of these agents exhibit more consistent and greater platelet inhibition compared to clopidogrel (113–115). The short onset and offset of action makes cangrelor an appealing adjunctive antiplatelet agent during PCI when maximum and rapid platelet inhibition of ADP-induced aggregation is required (115). Prasugrel (Eli Lily and Company Indianapolis, IL, and

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Sankyo Co. Ltd. Tokyo, Japan) is a new thienopyridine derivative that produces more potent platelet inhibition, and a rapid onset of action. The latter properties may provide a superior alternative to clopidogrel, with less response variability and a decreased prevalence of nonresponsiveness (111).

References 1

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Conclusions Reports of high incidences of aspirin resistance may be due to laboratory measurements based on nonspecific methods that do not isolate the response of platelet COX-1 to aspirin or due to an inadequate dose required to fully inhibit the COX-1 in selected patients. Clopidogrel nonresponsiveness is a consistent phenomenon observed in research studies conducted at multiple medical centers around the world. Data from small studies support that patients with high ex vivo platelet reactivity to ADP during and after percutaneous intervention may be at greatest risk for subsequent ischemic events. However, at this time, there are no uniformly established methods to quantify ex vivo platelet reactivity after clopidogrel and aspirin treatment or the extent of platelet inhibition by clopidogrel and aspirin. Therefore, specific treatment recommendations for patients exhibiting high platelet reactivity during clopidogrel or aspirin therapy or who have poor platelet inhibition by clopidogrel or aspirin are not established. A higher aspirin dose (ⱖ325 mg/day) and strict compliance to therapy may effectively overcome the occurrence of “aspirin resistance” in selected patients. A clopidogrel maintenance dose of 150 mg may be considered in patients exhibiting clopidogrel nonresponsiveness. In the near future, new P2Y12 receptor blockers will likely overcome the limitations of clopidogrel. Demonstration of nonresponsiveness to antiplatelet agents in certain patients by laboratory methods indicate that treating all patients with the same dose may not be advisable, and that a patient-specific antiplatelet treatment strategy is needed to achieve maximum benefit of antiplatelet treatment (5,111). Finally, the so-called “resistance” to antiplatelet drugs will be more meaningful only when a standardized user-friendly laboratory method to isolate the effect of the drug is available, and only after a strong relation of laboratory “resistance” to the occurrence of adverse clinical outcomes is established in large-scale clinical trials. Routine measurement of platelet function in patients with cardiovascular disease should become the standard of care leading toward the future of personalized antithrombotic treatment strategies determined by the critical pathways influencing thrombotic risk in the individual patient. Finally, measurement of platelet function in isolation ignores the critical influences of coagulation and platelet–fibrin interactions in determining individual thrombotic risk (21). Future risk assessment strategies will likely employ methods that measure platelet–coagulation pathway crosstalk.

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113 Peters G, Robbie G, Single dose pharmacokinetics and pharmacodynamics of AZD6140—an oral reversible ADP receptor antagonist (abstr). Haematologica 2004; 89:14–15. 114 Greenbaum AB, Grines CL, Bittl JA, Becker RC. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized,

placebo- and active-controlled trial. Am Heart J 2006; 151:689, e1–e689, e10. 115 Wiviott SD, Antman EM, Winters KJ, et al. JUMBO-TIMI 26 Investigators. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 2005; 28:111:3366–3373.

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14 Lipid-lowering agents Andrew M. Tonkin and Omar Farouque

Atherosclerosis depends on the interplay between genetic, behavioral, and environmental factors. However, the landmark INTERHEART study (1) and other large-scale population studies have established that over a life course this is a largely preventable process. The INTERHEART study showed that approximately 85% of the variation in rates of myocardial infarction (MI) was associated with nine risk factors. Of these, population-attributable risk both for older and younger subjects was highest for the ratio of apolipoprotein B/apolipoprotein A1. This ratio is a measure of atherogenic particle number [apolipoprotein B, superior to low-density lipoprotein (LDL) cholesterol concentration alone] and antiatherogenic particles [apolipoprotein A1, reflecting high-density lipoprotein (HDL) cholesterol]. Elevated blood cholesterol, considered to be greater than 147 mg/dL (3.8 mmol/L), was also found to be the leading risk factor for coronary heart disease (CHD), and estimated to account for more than half of cases worldwide in the recent World Health Report (2).

Epidemiology There is clear epidemiologic evidence of a continuous (log linear) relation between cholesterol levels and the risk of CHD events and mortality, both within communities and when comparing different populations (3). Although it has been estimated that each 1% decrement in total cholesterol is associated with a 2% to 3% decrease in CHD risk, regression dilution bias underestimates the strength of the association. From the meta-analysis of international studies, it has been suggested that each 10% decrement in total cholesterol is associated with 38% reduction in CHD events (4).

Overview of clinical trials Older primary prevention trials had often been undertaken in cohorts at low absolute risk of CHD events. The initial secondary prevention studies had typically involved patients with elevated cholesterol levels. In addition, these older trials had tested diet and previous lipid-lowering agents, which only lowered cholesterol by an average of approximately 10% (5). As a consequence, these trials were typically underpowered and had not shown a clear reduction in all-cause mortality. There had been good evidence that lipid-modifying therapy could prevent fatal and nonfatal CHD events (5). However, there were some concerns that noncardiovascular events particularly related to cancers and violence or trauma could be increased. In summary, there was considerable uncertainty about the overall effects of treatment. Attitudes to lipid-modifying therapy have been changed particularly by the large-scale clinical trials of statins, which have been published over the last decade. The statins competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme that catalyses the rate-limiting step in cholesterol biosynthesis in the liver (6). The reduction in cholesterol synthesis by HMG CoA reductase inhibition triggers increased expression of LDL cholesterol receptors on hepatic cells that clear circulating LDL cholesterol and its precursor. Statins have other effects. They are associated with a relatively smaller increase in HDL cholesterol concentrations and modest reductions in triglyceride concentrations (7). The beneficial effects of statins may also involve nonlipidmodifying mechanisms by an effect on inflammatory responses, atherosclerotic plaque stability, endothelial function, and thrombosis (8). These pleiotropic effects of statins may have particular importance following acute coronary syndromes and will be discussed further. These large-scale

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Lipid-lowering agents

ONGOING TRIALS

General population

Diabetes, CKD

Stroke

At-risk individuals and groups

CHD patients (“equivs.”)

CHF

Heart failure

ACS WOSCOPS AF/TexCAPS Mega

HPS, PROSPER ALLHAT-LLT ASCOT, CARDS

4s, HPS CARE, LIPID TNT, IDEAL

MIRACL PROVE-IT A to Z

Figure 1 Major large-scale trials of statins. Abbreviations: ACS, acute coronary syndrome; CHD, coronary heart disease; CHF, congestive heart failure; CKD, chronic kidney disease.

trials have also established the overall safety of the agents in clinical use at this time. Figure 1 indicates the major large-scale trials of statins and their key features are summarized in Table 1. The trials can be categorized according to population subgroups in which they have been undertaken:

1. In the general population for primary prevention of CHD: The West of Scotland Coronary Prevention Study (WOSCOPS) (9), Air Force/Texas coronary atherosclerosis Prevention study (AFCAPS/TexCAPS) (10), and the completed but unpublished MEGA study in Japan (A. Nakamura, presented to AHA Scientific Sessions, November 2005). 2. In high-risk individuals and groups: people with clinical evidence of macrovascular disease other than CHD, the Heart Protection Study (HPS) (11); with diabetes, the HPS and Collaborative Atorvastatin Diabetes Study (CARDS) (12); the elderly, Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) (13) or with hypertension, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (14) and AngloScandinavian Cardiac Outcomes Trial (ASCOT) (15). 3. In patients with known CHD: the 4S (16), Cholesterol and Recurrent Events (CARE) (17) and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) (18) studies, HPS (11), Treating to New Targets (TNT) (19), and the incremental decrease in endpoints through aggressive lipid lowering (IDEAL) (20) study. 4. Patients enrolled early after acute coronary syndromes: Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) (21), Fluvastatin On Risk

Table 1 Design features (A) and major cardiovascular endpoints (B) in controlled trials of statin therapy (A) Trial

Prevention strategy

Drug

Number of patients and sex

Age (years)

Baseline cholesterol level (mmol/L)

Follow-up (years)

Primary endpoint

WOSCOPS

Primary

Pravastatin

6595, M

45–64

ⱖ6.5

4.9

CHD events

AFCAPS/ TexCAPS

Primary

Lovastatin

5608, M 997, F

45–73 55–73

4.6–6.8

5.2

CHD events

ASCOT-LLA

Primary

Atorvastatin

8363, M 1942, F

40–79

ⱕ6.5

3.3

CHD death and nfMI

ALLHAT

Primary

Pravastatin

5304, M 5051, F

LDL 2.6–4.9

4.8

All-cause mortality

4S

Secondary

Simvastatin

3617, M 827, F

35–70

5.5–8.0

5.4

Total mortality

CARE

Secondary

Pravastatin

3583, M 576, F

21–75

⬍6.2

5.0

CHD events

LIPID

Secondary

Pravastatin

7498, M 1516, F

31–75

4.0–7.0

6.0

CHD mortality

HPS

Primary and secondary

Simvastatin

15,454, M 5082, F

40–80

⬎3.5

5.0

Vascular events

PROSPER

Primary and secondary

Pravastatin

2804, M 3000, F

70–82

4.0–9.0

3.2

CHD death, nfMI, stroke (Continued)

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Overview of clinical trials

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Table 1 Design features (A) and major cardiovascular endpoints (B) in controlled trials of statin therapy (Continued) (B)a Trial and treatment

CHD mortality %

Total mortality %

MI (fatal and nonfatal) %

UAP %

CABG %

PCI %

Coronary revascularization

Stroke %

—

2.5

—

1.4

—

1.7d

—

1.4

WOSCOPS Placebo

1.9

4.1

6.5

Pravastatin

1.3b

3.2

4.6c

0.9

2.3

5.6

5.1

9.3

—

—

0.6

2.4

3.3d

3.5b

6.2c

—

—

Placebo

3.0e

4.1

0.5

2.4

Atorvastatin

1.9c

3.6

0.4

1.7b

Usual care

3.9

14.9

0.4

Pravastatin

3.7

15.3

0.4

Placebo

8.5

11.5

Simvastatin

5.0c

AFCAPS/TexCAPS Placebo Pravastatin ASCOT-LLA

ALLHAT

4S 8.2c

15.2 9.0d

14.9

17.2

—

4.3

13.3

11.3c

—

2.7

17.3

10.0

10.5

3.8

15.2

7.5

8.3

2.6

CARE Placebo Pravastatin

5.7

9.4

4.6

8.7

Placebo

8.3

14.1

Pravastatin

6.4d

Placebo Simvastatin

10.0 7.5d

LIPID 10.3

24.6

11.6

15.7

4.5

11.0

7.4c

22.3d

9.2c

13.0

3.7

6.9

14.7

5.6

10.0

5.7c

12.9c

3.5c

Placebo

4.2

10.5

Pravastatin

3.3b

10.3

HPS 7.1

5.7

5.0c

4.3c

8.7

1.6

7.3

7.7

1.3

7.1

8.6c

PROSPER

aThe

primary endpoint differed between studies. Also, because of different definitions of CHD events, it is inappropriate to present the numbers needed to treat to prevent

an event to allow comparisons between the trials. bP

⬍ 0.05.

cP

⬍ 0.001.

dP

⬍ 0.01.

eIncludes

nonfatal MI.

Abbreviations: ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm; CABG, coronary artery bypass grafting; CARE, Cholesterol and Recurrent Events; CHD, coronary heart disease; F, female; HPS, Heart Protection Study; LIPID, Long-Term Intervention with Pravastatin in Ischemic Disease; M, male; MI, myocardial infarction; nfMI, nonfatal myocardial infarction; PCI, percutaneous coronary intervention; PROSPER, Pravastatin in Elderly Individuals at Risk of Vascular Disease; UAP, unstable angina pectoris; WOSCOPS, West of Scotland Coronary Prevention Study.

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Diminishment after Acute Myocardial Infarction (FLORIDA) (22), Pravastatin in Acute Coronary Treatment (PACT) (23), Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) (24), and A to Z (25) studies. The major features of treatment guidelines concern indications for treatment, the particular treatments to be used, and in the case of biomedical risk factors, target levels following intervention. Figure 2 shows how these aspects are informed by clinical trials. In particular, net benefit depends on the absolute risk reduction (related to both baseline risk and relative risk reduction) and safety of the treatment. The greater the risk of the patient group or individual for future events, the greater is the absolute risk reduction with therapy (Fig. 3). Health policy decisions are informed not only by outcome data but also by cost-effectiveness analyses. Cost-effectiveness in turn relates to the absolute benefits that are observed.

Treatment in patients with known coronary artery disease Patients with clinical evidence of coronary heart disease or other vascular diseases

with previous acute MI whose cholesterol levels were lower (⬍242 mg/dL, 6.2 mmol/L) than in subjects enrolled in 4S. The LIPID study (18) took these observations further by demonstrating a reduction in all-cause mortality and all major cardiovascular events in patients who were stable after either acute MI or unstable angina and whose cholesterol levels at baseline were in an “average” range for patients (155–271 mg/dL, 4.0–7.0 mmol/L). The HPS (11) provided further important answers. Among 20,536 patients aged 40 to 80 years with CHD, cerebrovascular or peripheral arterial disease or diabetes, simvastatin reduced all-cause mortality from 14.7% to 12.9% (P ⫽ 0.0003). The reduction in vascular events was similar and significant in important prespecified subgroups. These included those in whom there had been residual uncertainty, including patients with manifestations of vascular disease other than CHD, women, those aged over 70 years at baseline, and those with LDL or total cholesterol levels less than 3.0 or 5.0 mmol/L (116 or 193 mg/dL), respectively.

Patients with stroke and peripheral arterial disease

The 4S (16) was a landmark study which demonstrated that among patients with previous acute MI, simvastatin decreased not only CHD events but also CHD and all-cause mortality. The CARE study (17) extended these findings by demonstrating that pravastatin reduced subsequent CHD events in patients

The 4S (16), CARE (17), and LIPID (18) studies demonstrated a reduction in stroke in patients with known CHD. However, manifest CHD was necessary for inclusion in these trials. The HPS (11) showed a reduction in subsequent vascular events (but not recurrent stroke) in patients who had previous stroke but no previous clinical manifestations of CHD—from 23.6% to 18.7% (P ⫽ 0.001). At this time, guidelines usually support statin therapy in patients with previous stroke, although it is noted that stroke patients included in HPS were younger, less likely to be hypertensive, and differed in other features from usual stroke patients.

Figure 2

CLINICAL TRIALS

GUIDELINES

Absolute risk reduction

Treatment indications

(Relative risk reduction; baseline risk)

Safety

Treatment(s)

Target levels

LDL (HDL) (CRP, apolipos)

Cost

C-E

Net benefit ARR

ARR & Harm

Harm Risk

Major features of treatment guidelines and clinical trials. Abbreviations: CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

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Target low-density lipoprotein cholesterol level

Abs. Redn. CHD death & nfMI (Intervention) (Events per 1000 persons years)

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20

Absolute reduction in risk of coronary heart disease death and nonfatal myocardial infarction in landmark large-scale statin trials depends on rates of events in control limbs of the trials. Abbreviations: CHD, coronary heart disease; nfMI, nonfatal myocardial infarction.

x4S* 15

10

5

159

CARE HPS x WOSCOPS x x LIPID x x AFCAPS PROSPER x x x ALLHAT-LLT ASCOT-LLA 10

20

30

* Possibly multiple events 40

50

Control: CHD deaths and nfMI (Events per 1000 person years)

Similarly in HPS, simvastatin reduced vascular events over five years from 30.5% to 24.7% (P ⬍ 0.0001) in patients with manifest peripheral arterial disease but no CHD. Patients with peripheral arterial disease are at very high risk of future CHD events and stroke and an aggressive approach to therapy is indicated, irrespective of cholesterol level.

primary endpoint of major CHD events, revascularization, or stroke from 9.0% to 5.8% over 4.5 years (P ⫽ 0.001) (12). Should all people with diabetes receive a statin? The answer is an emphatic yes in those who already have CHD, stroke, or peripheral arterial disease. Guidelines differ on whether all those with diabetes but no clinical vascular disease should also be treated. This is recommended in many countries, whereas others suggest an individual approach based on the estimated risk of future events.

People with diabetes There are now substantial data on the benefits of statins in people with diabetes. In the HPS, among 5963 individuals with diabetes, major vascular events were reduced by simvastatin from 25.1% to 20.2% (P ⬍ 0.0001) (26). Among the subgroup of 2912 people with diabetes without prior vascular disease, the rate of major cardiovascular events was reduced from 13.5% to 9.3% (P ⫽ 0.0003). The CARDS randomized 2838 people with Type 2 diabetes plus retinopathy, microalbuminuria, hypertension, or smoking and no history of macrovascular disease to receive either atorvastatin or placebo. Atorvastatin reduced the combined

Target low-density lipoprotein cholesterol level In an analysis of the landmark randomized controlled trials, the Cholesterol Treatment Triallists Collaboration has shown a linear relationship between the reduction in cardiovascular events and amount of LDL cholesterol lowering (27). This is shown in Figure 4. For example, each 1.0 mmol/L reduction in LDL cholesterol was associated with a 13% reduction in all-cause mortality. More recent trials have specifically tested whether or

Figure 4

50%

Proportional effects on major vascular events by mean difference in low-density lipoprotein cholesterol. Abbreviation: LDL, low-density lipoprotein. Source: From Ref. 27.

40% 30%

20% 10%

0.5

1.0 1.5 Reduction in LDL cholesterol

2.0

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not achieving lower levels of LDL cholesterol translates to increased benefit. Some of these studies (19,20) have been performed in stable CHD patients, whereas others have been undertaken in patients randomized early after onset of an acute coronary syndrome as discussed later in the chapter (24,25). The TNT study compared atorvastatin 10 or 80 mg daily in 10,001 subjects with stable CHD who had achieved an LDL cholesterol less than 130 mg/dL (3.4 mmol/L) during openlabel run-in with atorvastatin 10 mg daily (19). Those assigned 10 mg atorvastatin in the double-blind phase achieved a mean LDL cholesterol of 101 mg/dL (2.6 mmol/L) compared to a mean LDL cholesterol of 77 mg/dL (2.0 mmol/L) on 80 mg atorvastatin. Over a median follow-up of 4.9 years, the primary endpoint, a composite of CHD death, nonfatal nonprocedure-related MI, resuscitation after cardiac arrest or fatal or nonfatal stroke was reduced from 10.9% to 8.7% with more aggressive LDL cholesterol lowering (P ⬍ 0.001). The IDEAL study included 8888 subjects with stable CHD (20). The trial had an open-label design with blinded endpoint evaluation. During treatment, those randomized to receive 20 or 40 mg simvastatin daily had a mean LDL cholesterol of 104 mg/dL (2.7 mmol/L) compared to an LDL cholesterol of 81 mg/dL (2.1 mmol/L) in those assigned 80 mg atorvastatin daily. There was an insignificant risk reduction in the primary endpoint, a composite of coronary death, hospitalization for nonfatal MI, or cardiac arrest with resuscitation from 10.4% in the simvastatin group to 9.3% in the atorvastatin group (P ⫽ 0.07), after a median follow-up of 4.8 years. However, a significant reduction in some secondary endpoints was noted in the high dose atorvastatin arm, including nonfatal MI, major cardiovascular events (any primary event or stroke), and any coronary event (any primary event, coronary revascularization, or hospitalization for unstable angina). Use of any treatment in usual practice should consider the balance between benefit and harm with an intervention. In each of these trials, some side effects were more common in those on the more intensive LDL-lowering regimen. However, the risk of rhabdomyolysis is very low, although increased with higher statin doses. Overall, the body of data is consistent and supports a target LDL cholesterol of less than 2.0 mmol/L in known CHD patients. A similar conclusion has been reached by the National Cholesterol Education Program—Adult Treatment Panel who suggested that a target LDL cholesterol of 70 mg/dL (1.8 mmol/L) is a very reasonable therapeutic option in very high-risk patients (28).

High-density lipoprotein cholesterol Robust epidemiologic evidence has identified an inverse relationship between HDL-cholesterol levels and CHD risk. Indeed, HDL-cholesterol is included in the Framingham CHD risk prediction scores (29). HDL-cholesterol protects against

atherosclerosis by enhancing reverse cholesterol transport, inhibition of LDL cholesterol oxidation in the atherosclerotic plaque, and anti-inflammatory effects by inhibiting monocyte adhesion to the vascular endothelium (30). The Veterans Affairs HDL-cholesterol Intervention Trial (VA-HIT) included 2531 men with documented CHD and low-serum HDL-cholesterol concentrations (mean 40 mg/dL), but without elevated LDL cholesterol (mean 111 mg/dL) (31). Treatment with gemfibrozil, 1200 mg/day, for five years resulted in a significant reduction in the risk for death from CHD or nonfatal MI, from 21.7% in the placebo group to 17.3% in the gemfibrozil group (P ⫽ 0.006). This was associated with a 4% reduction in total cholesterol, a 6% increase in HDL-cholesterol, and a 31% reduction in serum triglycerides, compared with placebo. Gemfibrozil did not decrease LDL cholesterol. Although triglyceride reduction was the largest lipid change, triglyceride levels at baseline or on treatment did not predict CHD levels. Multivariate analysis showed that the incidence of CHD events decreased by 11% for each 5 mg/dL (0.13 mmol/L) increase in HDL-cholesterol concentrations. In gemfibrozil-treated patients, HDL-cholesterol was the only significant predictor of CHD events, but the decrease in CHD events was greater than could be explained by changes in HDL-cholesterol alone. At this time in clinical practice, the role of fibrates is particularly in combination therapy with a statin. Monitoring of creatine phosphokinase levels is appropriate because of the very small, although increased risk of rhabdomyolysis. In addition, a recent study in which reconstituted HDL was infused into human subjects after acute coronary syndromes showed a significant reduction in plaque volume in the coronary arteries as assessed by intravascular ultrasound (32).

Triglycerides It is now recognized that elevated plasma triglyceride levels also predict future events, independent of the levels of other lipid subfractions (33). It is also known that when triglyceride levels are raised to levels above 130 mg/dL (1.5 mmol/L), the predominant LDL phenotype is more atherogenic small dense LDL particles rather than large buoyant LDL particles (34). This is particularly relevant in the context of diabetes and the metabolic syndrome. Apolipoprotein B measures the total number of atherogenic lipid particles, including very LDL cholesterol and chylomicrons, as well as LDL (34). In this context, it is important that a number of studies have demonstrated that apolipoprotein B is superior to LDL cholesterol and also nonHDL cholesterol in predicting future risk of atherosclerotic events (35,36). It might be anticipated that future guidelines will ascribe greater importance to apolipoprotein B that also does not require fasting samples, and particularly in those individuals who have elevated triglyceride levels.

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Lipid-lowering following acute coronary syndromes

Other targets Atherosclerosis including acute coronary syndromes is an inflammatory process (37). Among biomarkers of inflammation, most attention and data has focused on C-reactive protein (CRP), which have been reported to be independently related to risk of future CHD events (38). Moreover, in the PROVE-IT TIMI 22 study, CRP levels at 30 days after treatment were not only independent of LDL cholesterol levels at that time but outcomes were improved in those who achieved not only an LDL cholesterol level of ⬍ 70 mg/dL (1.8 mmol/L) but also CRP levels less than 2 mg/L (39). However, uncertainties still remain and at this time it is considered premature to include CRP levels as a specific target.

Lipid-lowering following acute coronary syndromes Several randomized clinical trials of lipid lowering therapy with statins have been conducted in patients with acute

161

coronary syndromes ( Table 2). The first of these trials was the MIRACL study, which enrolled 3086 subjects (baseline total cholesterol ⬍7–8 mmol/L) with unstable angina or nonQ-wave MI and randomized them to atorvastatin 80 mg daily or placebo within 96 hours of hospital admission (21). Mean LDL cholesterol levels at the end of the study were 135 mg/dL (3.5 mmol/L) in the placebo group and 72 mg/dL (1.9 mmol/L) in the atorvastatin group. The primary endpoint of death, nonfatal MI, cardiac arrest with resuscitation, or recurrent ischemia requiring hospitalization occurred in 17.4% of the placebo group compared to 14.8% of the atorvastatin group (P ⫽ 0.048) at four months. The difference in the primary endpoint was driven by a reduction in recurrent ischemia in the atorvastatin group (6.2% vs. 8.4%; P ⫽ 0.02) without any significant change in the other elements of the composite endpoint. The FLORIDA study recruited 540 patients with MI and a total cholesterol level of ⬍6.5 mmol/L and randomized them to either fluvastatin 80 mg daily or placebo at a median time of eight days after symptom onset (22). The primary composite endpoint of the study was ischemia on ambulatory electrocardiogram monitoring or a major clinical event defined as death,

Table 2

Summary of published randomized statin trials in acute coronary syndromes

Trial

Therapy

Comparator

Number of patients

Follow-up

Primary endpoint (composite)

LDL-C on treatment

Outcome for primary endpoint

MIRACL

Atorvastatin 80 mg (ACS ⬍ 24 hr)

Placebo

3086

4 mo

Death, nfMI, cardiac arrest, hospitalization for recurrent ischemia

1.9 mmol/L vs. 3.5 mmol/L

14.8% atorvastatin vs. 17.4% placebo (P ⫽ 0.048)

FLORIDA

Fluvastatin 80 mg (ACS ⬍ 24 hr)

Placebo

540

1 yr

Ischemia on AECG, 2.7 mmol/L death, recurrent vs 3.9 mmol/L MI or ischaemia, revascularization

33% fluvastatin vs. 36% placebo (P ⫽ 0.24)

PACT

Pravastatin Placebo 20/40 mg (ACS ⬍ 24 hr)

3408

1 mo

Death, MI, hospitalization for UAP

11.6% pravastatin vs. 12.4% placebo (P ⫽ 0.48)

PROVE-IT TIMI 22

Atorvastatin 80 mg (ACS ⬍ 10 days)

Pravastatin 40 mg

4162

2 yr

Death, MI, 1.60 mmol/L vs. hospitalization for 2.46 mmol/L UAP, revascularization or stroke

A to Z (Z phase)

Simvastatin 40 mg for 4 mo then 80 mg (ACS ⬍ 5 days)

Placebo for 4 mo then simvastatin 40 mg

4497

2 yr

Cardiovascular death, nfMI, readmission for ACS, stroke

Not reported

22.4% atorvastatin vs. 26.3% pravastatin (P ⫽ 0.005)

1.71 mmol/L vs. 14.4% simvastatin 2.10 mmol/L vs. 16.7% at 2 yr placebo/ simvastatin (P ⫽ 0.14) at 2 yr

Abbreviations: ACS, acute coronary syndrome; AECG, ambulatory electrocardiogram; FLORIDA, fluvastatin on risk diminishment after acute myocardial infarction; MI, myocardial infarction; MIRACL, myocardial ischemia reduction with aggressive cholesterol lowering; nfMI, nonfatal myocardial infarction; PACT, pravastatin in acute coronary treatment; PROVE-IT TIMI 22, pravastatin or atorvastatin evaluation and infection therapy—thrombolysis in myocardial infarction 22; UAP, unstable anginapectoris.

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recurrent MI, or recurrent ischemia requiring hospitalization or revascularization. In this negative trial, which was underpowered for clinical events, there was no difference in the composite endpoint at 12 months (36% placebo arm vs. 33% fluvastatin arm; P ⫽ 0.24). Mean LDL cholesterol in the fluvastatin group was 103 mg/dL (2.7 mmol/L) compared to 149 mg/dL (3.9 mmol/L). The PACT study was designed to examine the efficacy of pravastatin given within 24 hours of the onset of unstable angina or MI. The aim was to recruit 10,000 patients, but the study was stopped early by the sponsor after 3408 patients had been enrolled, thus it was underpowered. In the early phase of the study, pravastatin 20 mg daily was compared with placebo, although the dose of pravastatin was later increased to 40 mg daily. There was no statistical difference in the primary endpoint of death, recurrent MI, or rehospitalization for unstable angina at one month (11.6% pravastatin arm vs. 12.4% placebo arm; P ⫽ 0.48). The PROVE-IT TIMI-22 trial compared 40 mg pravastatin and 80 mg atorvastatin daily in 4162 patients randomized within 10 days of an acute coronary syndrome (24). Unlike MIRACL, FLORIDA, and PACT where planned coronary revascularization was an exclusion criterion, 69% of trial participants had already had percutaneous coronary intervention (PCI) prior to randomization. This reflects contemporary clinical practice. Treatment in other regards would also be seen as standard accepted therapy. Median LDL cholesterol during treatment was 95 mg/dL (2.46 mmol/L) and 62 mg/dL (1.60 mmol/L) for those on 40 mg pravastatin and 80 mg atorvastatin, respectively (P ⬍ 0.001). Over a mean of 24 months follow-up, there was a significant reduction in the primary endpoint (a composite of all-cause death, MI, unstable angina requiring rehospitalization, revascularization more than 30 days after randomization, and stroke) from 26.3% in the less intensively treated group to 22.4% in those randomized to 80 mg atorvastatin (P ⫽ 0.005). As in the MIRACL study, the benefit of intensive lipid lowering with high dose atorvastatin was evident early (P ⫽ 0.07 at 30 days). The A to Z trial compared early initiation of an intensive statin regimen (40 mg daily of simvastatin for one month, then 80 mg simvastatin daily) with delayed initiation of a less intensive regimen (placebo for four months, then 20 mg simvastatin daily) in 4497 patients following acute coronary syndromes (25). In this study, 44% of patients underwent PCI prior to randomization, and mean LDL cholesterol at eight months was 63 mg/dL (1.63 mmol/L) compared to 77 mg/dL (1.99 mmol/L) in those assigned to the more and less intensive treatment, respectively. There was a nonsignificant reduction in the primary endpoint, a composite of cardiovascular death, nonfatal MI, readmission for acute coronary syndrome and stroke over a 24-month follow-up, from 16.7% to 14.4% with intensive treatment (P ⫽ 0.14). However, there was a significant reduction in this primary endpoint in the period of 4 to 24 months during follow-up.

A number of observational studies also support the early administration of statins in the high-risk subset of patients with acute coronary syndromes (40–42). These data are consistent with the findings of randomized trials, which indicate that early administration of intensive lipid-lowering therapy with statins leads to improved clinical outcomes within months. Currently, the data favors the use of high dose atorvastatin based on the findings of MIRACL and PROVE-IT TIMI-22 studies. Moreover, the results of PACT and A to Z studies do not support an early clinical advantage for moderate intensity statin therapy. Whether there is any difference in clinical endpoints between statins prescribed at high dose is unknown, as there have not been any prospective head-tohead comparisons in this setting. Despite the large body of evidence supporting the use of lipid-lowering therapy in patients with CHD, these drugs remain underutilized. Data from the U.S. National Registry of Myocardial Infarction 3 (NRMI-3) reveal that lipid-lowering therapy was part of the discharge prescription in only 32% of patients presenting with acute MI (43). There are advantages to initiating therapy early, as the likelihood that an acute coronary syndrome patient will use lipid-lowering therapy in the medium- to long-term is enhanced when these agents are begun in-hospital (44). Encouragingly, there has been an increase in the usage of lipid-lowering therapy over recent years, although there is still room for considerable improvement (45,46).

Lipid-dependent and pleiotropic effects of statins Several mechanisms have been put forth to explain the remarkable clinical benefits observed with statin therapy. These include lipid-dependent and lipid-independent (or pleiotropic) effects. In view of the strong association between atherogenic lipoproteins and CHD, the traditional thinking has been that the potent LDL cholesterol lowering effect of statins was the explanation for the reduction in clinical events in the large trials. Indeed, LDL cholesterol lowering may result in a reduction of proatherogenic oxidized LDL particles, and have salutary effects on endothelial function (47,48), platelet function (49,50), vascular inflammation (48), and the slowing of atherosclerotic lesion progression (51,52). In recent years, there has been great interest in the pleiotropic effects of statins (Table 3). Many of these effects have been attributed to HMG-CoA reductase inhibition and the subsequent impairment in the synthesis of isoprenoid intermediates, which are downstream products of the cholesterol biosynthetic pathway. As a consequence, isoprenylation of proteins involved in intracellular signaling may be prevented, resulting in a variety of effects, such as an increase in bioavailability of endothelium-derived nitric oxide (53).

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Lipid-dependent and pleiotropic effects of statins

Table 3

163

Pleiotropic effects of statins

Beneficial effects

Proposed mechanisms

Improved endothelial vasodilator function

Increased nitric oxide production Prevents downregulation of endothelial nitric oxide synthase Decreased synthesis of endothelin-1

Anti-inflammatory effects

Reduced endothelial and soluble adhesion molecules Reduced CD40 expression and CD40-related activation of vascular cells Reduced leukocyte–endothelial cell interactions Reduced C-reactive protein levels and proinflammatory cytokines Inhibition of LDL oxidation Reduced cytotoxicity of T-lymphocytes Inhibition of proinflammatory T helper 1 cell development and augmentation of anti-inflammatory T helper 2 cell development

Plaque stabilization

Reduced oxidized LDL uptake Decreased matrix metalloproteinases Increased tissue inhibitor of metalloproteinase 1 Increased collagen and fewer inflammatory cells in atherosclerotic plaque

Antithrombotic effects

Reduced tissue factor expression and thrombin generation Reduced platelet reactivity Increased t-PA and decreased plasminogen activator inhibitor-1

Other effects

Increased circulating endothelial progenitor cells

Abbreviation: LDL, low-density lipoprotein. Source: From Refs. 8, 54–56, 79, 95–113.

There is debate in the literature about the relative importance of lipid-dependent mechanisms versus pleiotropic effects of statins. Several lines of evidence suggest that the pleiotropic effects of statins are clinically relevant: 1. The earlier appearance of clinical benefit in statin lipidlowering trials compared to nonstatin lipid-lowering trials despite significant reductions in LDL cholesterol. 2. The early clinical benefits observed in statin trials of acute coronary syndrome patients (MIRACL and PROVE-IT TIMI-22) where coronary vascular inflammation, thrombosis, and unstable plaque are critical pathophysiologic elements that may be positively modified by statins compared to the more delayed benefits observed in statin trials of patients with stable coronary artery disease. 3. The rapid improvement of peripheral endothelial vasodilator function in studies of subjects given statin

drugs before changes in serum cholesterol are observed (54,55). In an elegant randomized study in patients with chronic heart failure, simvastatin improved endothelial function but ezetimibe did not despite a similar change in LDL cholesterol (56). 4. The reduction in stroke observed in long-term statin trials despite the lack of association between cholesterol levels and stroke in most epidemiological and observational studies. Adding to the controversy, however, a recent metaregression analysis demonstrated that the reduction in CHD risk can be explained by the degree of LDL cholesterol lowering alone without having to invoke alternative lipidindependent mechanisms (57). One of the difficulties in resolving this issue is that some of the biologic effects ascribed to statin pleiotropy may be accounted for by LDL cholesterol lowering. Moreover, experimental studies indicate differences

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between statins in their lipid-independent effects. Our current state of knowledge precludes a firm conclusion to be made on the potential clinical significance of the welldocumented pleiotropic effects of statins. From a practical perspective, the goal of lipid-lowering therapy should be in attaining recommended lipid targets as discussed earlier.

Specific issues relating to percutaneous coronary intervention Randomized clinical trials The Atorvastatin Versus Revascularization (AVERT) study compared aggressive lipid-lowering therapy with PCI in 341 low-risk patients with single or double vessel coronary disease who had mild angina or were asymptomatic (58). Subjects with LDL cholesterol levels of 115 mg/dL (ⱖ3.0 mmol/L) were randomized to atorvastatin 80 mg daily or PCI followed by usual lipid-lowering care. On-treatment LDL cholesterol was 77 mg/dL (1.99 mmol/L) in the atorvastatin group and 119 mg/dL (3.08 mmol/L) in the angioplasty group. There was a strong trend to reduction in the primary endpoint, which was a composite of coronary and cerebrovascular ischemic events in the atorvastatin arm at 18 months (13% vs. 21%), and this was driven mainly by fewer hospitalizations for unstable angina. The atorvastatin arm had a longer time to a first ischemic event (P ⫽ 0.03); however, those in the angioplasty arm had better relief of anginal symptoms (improvement in 54% vs. 41%; P ⫽ 0.009). Bare-metal stents were used in only 30% of lesions treated with PCI, which is not reflective of present day practice. The Lescol Intervention Prevention Study (LIPS) randomized 1677 patients with coronary disease and total cholesterol levels between 135 and 270 mg/dL (3.5–7.0 mmol/L) to fluvastatin 40 mg twice daily or placebo at hospital discharge after successful completion of their first PCI (59). The study was designed to examine the clinical efficacy of statin therapy in the post-PCI setting and the primary endpoint was a composite of cardiac death, nonfatal MI, and coronary revascularization. The mean baseline LDL cholesterol in the study population was 132 mg/dL (3.4 mmol/L). Bare-metal stents were used in just over 60% of patients. The primary endpoint occurred in 21% of the fluvastatin group and 27% in the placebo group over a median follow-up of 3.9 years (P ⫽ 0.01). The event-free survival curves began to diverge at 1.5 years. The benefits of statin therapy were observed in patients with acute coronary syndromes and also those with diabetes (60,61). The median reduction in LDL cholesterol levels was 27% with fluvastatin at six weeks compared to a 11% increase in the placebo group. In a further analysis where

clinical restenosis events (target vessel reinterventions) in the first six months were excluded, the event-free survival curves began to diverge at about six months (59). It is possible that similar early advantages may be observed with the combination of statin therapy and drug-eluting stents, which have minimized the problem of restenosis. As in the case with acute coronary syndromes, long-term compliance with therapy is also enhanced if lipid-lowering therapy is initiated in-hospital after PCI (62). Prescription of aggressive lipid-lowering therapy and PCI should not be seen as competing strategies but rather complementary treatment modalities with different aims in patients with coronary artery disease. The large-scale Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial will examine this issue further by randomizing patients with coronary artery disease to aggressive medical therapy alone (including lipid-lowering) or PCI with aggressive medical therapy.

Use of intravascular ultrasound A recent trend in lipid-lowering clinical trials is the use of serial intravascular ultrasound (IVUS) studies with automated pullback to quantitate coronary atheroma burden. Plaque burden can be measured at different time points using volumetric analysis of a specific coronary segment, as determined by predetermined landmarks such as side branches, and is highly reproducible (63). This methodology has superseded the use of angiography in evaluating the impact of pharmacologic interventions on plaque progression or regression, as in the following clinical trials. In the apoliprotein A-1 Milano trial, weekly infusions of a recombinant HDL particle over a fiveweek period resulted in a reduction in mean atheroma volume (32). In the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) randomized trial, intensive lipid-lowering with atorvastatin 80 daily was compared to moderate intensity lipid-lowering with pravastatin 40 mg daily (52). On-treatment LDL cholesterol was 79 mg/dL (2.05 mmoL) versus 110 mg/dL (2.85 mmol/L), respectively. Median atheroma volume decreased by 0.4% in the atorvastatin arm, but increased by 2.7% in the pravastatin arm over an 18-month period.

Peri-procedural myocardial infarction Cardiac enzyme elevation (creatine kinase-MB, cardiac troponin) may occur on average in 20% to 30% of patients after PCI and is associated with adverse clinical outcomes in the short- and long-term (64). Magnetic resonance imaging

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studies have demonstrated that these elevations are due to myocardial microinfarcts (65,66). The pathophysiology of this complication may include distal embolization of plaque and thrombotic debris, vasoconstriction, and inflammation (64). Retrospective studies indicate that statin pretreatment is an independent predictor for survival at six months after PCI, and that this benefit begins to emerge as early as one month after PCI (67). Recent randomized trials indicate that these agents reduce the incidence of postprocedural MI. Pasceri et al. (68) randomized 153 patients to atorvastatin 40 mg daily or placebo seven days before elective PCI. Elevations of markers of myocardial injury above the upper limit of normal were significantly lower in the statin arm compared to placebo (CK-MB 12% vs. 35%, P ⫽ 0.001; troponin I 20% vs. 48%, P ⫽ 0.0004; myoglobin 22% vs. 51%, P ⫽ 0.0005). Briguori et al. (69) randomized 451 patients to statin treatment (atorvastastin, pravastatin, simvastatin or fluvastatin) or no statin treatment at least three days before PCI. The occurrence of large non-Qwave MI was reduced in the statin arm from 15.6% to 8% (P ⫽ 0.012). Potential mechanisms of benefit may relate to the pleiotropic effects of statins on thrombosis, plaque stability, endothelial function, and inflammation.

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Coronary blood flow after primary percutaneous coronary intervention There is evidence that coronary blood flow is improved in patients pretreated with statins after acute infarct PCI (73,74). Celik et al. (74) found that Thrombolysis In Myocardial Infarction (TIMI) frame counts were lower, implying better coronary blood flow, in patients who underwent successful acute infarct PCI and were taking atorvastatin for ⱖ6 months compared to patients not taking statins. Iwakura et al. found a lower incidence of coronary no-reflow in patients on chronic statin therapy compared to those not taking statin after successful MI (9.1% vs. 34%; P ⫽ 0.003). Multivariate analysis indicated that statin pretreatment was a protective factor against no-reflow. In this study, the statin-treated patients also had better wall motion, smaller left ventricular dimensions and ejection fraction (73). These studies suggest that statin therapy may help to preserve coronary microvascular function in the setting of acute infarct PCI.

Contrast-induced nephropathy Potential interaction of HMGCoA reductase inhibitors and clopidogrel Clopidogrel is a thienopyridine antiplatelet agent that irreversibly inhibits the platelet P2Y12 adenosine diphosphate receptor. It is a critical part of the regimen used to prevent stent thrombosis, and like statin drugs is often prescribed to patients with coronary artery disease. In vitro studies show that clopidogrel is metabolized to its active form in the liver through the cytochrome P450 3A4 enzyme (70), as are some statins such as atorvastatin, simvastatin, and lovastatin, raising the theoretic possibility of drug interactions. In an ex vivo platelet function study, Lau et al. (70) showed that clopidogrel was a less effective inhibitor of platelet aggregation when administered with atorvastatin, but not pravastatin, which is not significantly metabolized by the cytochrome P450 system. A subsequent post hoc analysis of the Clopidogrel for the Reduction of Events During Observation (CREDO) trial showed that the clinical benefits of clopidogrel were similar regardless of whether the statin used was metabolised by cytochrome P450 3A4 or not (71). Further reassurance was provided by a prospective study examining 19 different platelet characteristics in patients undergoing coronary stenting, which found that statins did not attenuate the antiplatelet effects of clopidogrel (72).

Contrast-induced nephropathy has been defined as an increase in serum creatinine of at least 25% or an absolute increase in serum creatinine of at least 0.5 mg/dL within 48 to 72 hours of iodinated contrast administration and is associated with significant morbidity and mortality (75). Important risk factors include diabetes mellitus, chronic renal insufficiency, administration of large volumes of high osmolar contrast agents, and intravascular volume depletion. Numerous pharmacologic preventive measures have been studied, but consistent benefits have not been demonstrated. In a recent large retrospective study, preprocedural statin therapy was independently associated with a lower risk of contrast nephropathy and nephropathy requiring dialysis (76).

Coronary endothelial dysfunction after drug-eluting stenting Recent studies have demonstrated evidence for coronary endothelial dysfunction after drug-eluting stenting. Togni et al. (77) studied coronary endothelial function in 25 patients six months after stent deployment and found paradoxic exerciseinduced vasoconstriction in coronary segments adjacent to sirolimus-eluting stents, but vasodilation in patients with baremetal stents. Similarly, Hofma et al. (78) noted a pronounced

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vasoconstrictor response to intracoronary acetylcholine in the coronary segment immediately distal to sirolimus-eluting stents at six months, but not in patients receiving bare-metal stents. The mechanisms, clinical relevance, and therapeutic implications of these finding are uncertain. Given the salutary effects of statins in improving coronary and peripheral endothelial vasomotor function (54–56,79), it is conceivable that they may have a beneficial role in this setting.

Restenosis after percutaneous coronary intervention Restenosis in the era of balloon angioplasty and bare-metal stenting was regarded as the primary limitation of PCI, often necessitating repeat revascularization procedures. Mechanisms included varying degrees of elastic recoil, neointimal hyperplasia, and negative arterial remodeling stimulated by direct injury to vascular cellular elements, inflammation, and thrombosis (80). The dramatic effect of drug-eluting stents in reducing restenosis has sidelined efforts to lower restenosis using systemic pharmacologic therapies. The majority of studies examining the impact of lipidlowering therapies on restenosis were performed in the pre-stent era. Most studies demonstrate a lack of association among serum lipids, lipoprotein subfractions, plasma levels of oxidized LDL, and restenosis (81,82). Similarly, the larger prospective trials indicate the statin therapy does not prevent restenosis after balloon angioplasty (83–85). There are conflicting data on the role of statins in preventing bare-metal instent restenosis with some (86), but not all studies indicating an antirestenotic effect (87). Other drugs that have an impact on serum lipids have also been examined. Probucol pretreatment has been shown to lower the rate of restenosis after balloon angioplasty in clinical trials (88,89). Although its lipid-lowering effect is due to an increase in the fractional catabolic rate of LDL cholesterol (90), its antirestenotic effect is believed to be related to other properties, including inhibition of LDL oxidation, promotion of endothelial regeneration, and anti-inflammatory effects (91). However, probucol is not widely available due to its ability to lower HDL-cholesterol and concerns relating to proarrhythmia. Fibrates also have properties that may be beneficial in preventing restenosis beyond lipid lowering. Activation of peroxisome proliferative activated receptor (PPAR)-alpha may result in suppression of inflammation and reduction in restenosis after coronary balloon angioplasty in animal models (92); however, clinical data are lacking. Omega-3 fatty acids have modest effects on lowering triglycerides and raising HDLcholesterol. A meta-analysis of 12 randomized trials in the balloon angioplasty era showed that pretreatment with omega-3 fatty acids did not have a significant impact on reducing restenosis (93).

Bioengineered stents and endothelial progenitor cells In a preliminary study, Aoki et al. (94) reported the feasibility of deploying a bioengineered stent coated with murine monoclonal anti-human CD34 antibodies to capture CD34 1 endothelial progenitor cells in humans. The aim of this stent is to enhance re-endothelialization after stent implantation. Atorvastatin 40 mg daily and simvastatin 10 mg daily have been shown to increase the number of circulating endothelial progenitor cells in humans within four weeks (56,95). This property of statins may have a potential therapeutic use if used in conjunction with bioengineered stents.

Conclusion An extremely robust evidence base supports the essential role of statins among cardiovascular therapies in CHD patients. Benefits relate to the magnitude of LDL cholesterol lowering and an overview of trials are consistent with a target LDL cholesterol of 2 mmol/L (77 mg/dL). Pleiotropic effects independent of LDL cholesterol lowering may be particularly relevant in the context of acute coronary syndromes. In addition, there is increasing evidence for other beneficial effects of statins in patients undergoing PCI.

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Serruys PW, Foley DP, Jackson G, et al. A randomized placebo-controlled trial of fluvastatin for prevention of restenosis after successful coronary balloon angioplasty; Final results of the fluvastatin angiographic restenosis (FLARE) trial. Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor after Transluminal Coronary Angioplasty. Eur Heart J 1999; 20:58–69. Weintraub WS, Boccuzzi SJ, Klein JL, et al. Lack of effect of lovastatin on restenosis after coronary angioplasty. Lovastatin Restenosis Trial Study Group. N Engl J Med 1994; 331:1331–1337. Walter DH, Schachinger V, Elsner M, Mach S, Auch-Schwelk W, Zeiher AM. Effect of statin therapy on restenosis after coronary stent implantation. Am J Cardiol 2000; 85:962–968. Petronio AS, Amoroso G, Limbruno U, et al. Simvastatin does not inhibit intimal hyperplasia and restenosis but promotes plaque regression in normocholesterolemic patients undergoing coronary stenting: a randomized study with intravascular ultrasound. Am Heart J 2005; 149:520–526. Tardif JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med 1997; 337:365–372. Yokoi H, Daida H, Kuwabara Y, et al. Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: the Probucol Angioplasty Restenosis Trial. J Am Coll Cardiol 1997; 30:855–862. Steinberg D. Studies on the mechanism of action of probucol. Am J Cardiol 1986; 57:16H–21H. Lau AK, Leichtweis SB, Hume P, et al. Probucol promotes functional reendothelialization in balloon-injured rabbit aortas. Circulation 2003; 107:2031–2036. Kasai T, Miyauchi K, Yokoyama T, Aihara K, Daida H. Efficacy of peroxisome proliferative activated receptor (PPAR)-alpha ligands, fenofibrate, on intimal hyperplasia and constrictive remodeling after coronary angioplasty in porcine models. Atherosclerosis 2005; 188:274–280. Balk EM, Lichtenstein AH, Chung M, Kupelnick B, Chew P, Lau J. Effects of omega-3 fatty acids on coronary restenosis, intimamedia thickness, and exercise tolerance: a systematic review. Atherosclerosis 2006; 184:237–246. Aoki J, Serruys PW, van Beusekom H, et al. Endothelial progenitor cell capture by stents coated with antibody against CD34: the HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) registry. J Am Coll Cardiol 2005; 45:1574–1579. Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103:2885–2890. Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000; 6:1004–1010. Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest 1998; 101:2711–2719.

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Ridker PM, Rifai N, Pfeffer MA, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of Creactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999; 100:230–235. Pruefer D, Scalia R, Lefer AM. Simvastatin inhibits leukocyteendothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterioscler Thromb Vasc Biol 1999; 19:2894–2900. Seljeflot I, Tonstad S, Hjermann I, Arnesen H. Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease. Atherosclerosis 2002; 162:179–185. Mulhaupt F, Matter CM, Kwak BR, et al. Statins (HMG-CoA reductase inhibitors) reduce CD40 expression in human vascular cells. Cardiovasc Res 2003; 59:755–766. Koh KK, Son JW, Ahn JY, et al. Comparative effects of diet and statin on NO bioactivity and matrix metalloproteinases in hypercholesterolemic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2002; 22:e19–e23. Rezaie-Majd A, Maca T, Bucek RA, et al. Simvastatin reduces expression of cytokines interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 in circulating monocytes from hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2002; 22:1194–1199. Suzumura K, Yasuhara M, Tanaka K, Suzuki T. Protective effect of fluvastatin sodium (XU-62-320), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro. Biochem Pharmacol 1999; 57:697–703. Blanco-Colio LM, Munoz-Garcia B, Martin-Ventura JL, et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors decrease Fas ligand expression and cytotoxicity in

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activated human T lymphocytes. Circulation 2003; 108: 1506–1513. Hakamada-Taguchi R, Uehara Y, Kuribayashi K, et al. Inhibition of hydroxymethylglutaryl-coenzyme a reductase reduces Th1 development and promotes Th2 development. Circ Res 2003; 93:948–956. Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation 2001; 103:926–933. Li DY, Chen HJ, Mehta JL. Statins inhibit oxidized-LDLmediated LOX-1 expression, uptake of oxidized-LDL and reduction in PKB phosphorylation. Cardiovasc Res 2001; 52:130–135. Fuhrman B, Koren L, Volkova N, Keidar S, Hayek T, Aviram M. Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes. Atherosclerosis 2002; 164:179–185. Solem J, Levin M, Karlsson T, Grip L, Albertsson P, Wiklund O. Composition of coronary plaques obtained by directional atherectomy in stable angina: its relation to serum lipids and statin treatment. J Intern Med 2006; 259:267–275. Undas A, Brummel-Ziedins KE, Mann KG. Statins and blood coagulation. Arterioscler Thromb Vasc Biol 2005; 25:287–294. Casani L, Sanchez-Gomez S, Vilahur G, Badimon L. Pravastatin reduces thrombogenicity by mechanisms beyond plasma cholesterol lowering. Thromb Haemost 2005; 94:1035–1041. Wiesbauer F, Kaun C, Zorn G, Maurer G, Huber K, Wojta J. HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins. Br J Pharmacol 2002; 135:284–292.

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15 Improving the diagnosis and management of high blood pressure in the cardiac patient Clarence E. Grim

There is nothing that cardiologists (and all other practitioners) do that is more cost effective than accurately diagnosing and managing high blood pressure (BP). Lowering BP reduces risk from all causes of death by at least 20%, as well as deaths due to all forms of cardiovascular (by 25–50%) and renal diseases (by 50%). And the older the patient, the greater the benefit. Therefore, cardiologists must be skilled in diagnosing and controlling the BP to defined goals in all patients before and after the onset of coronary artery disease and its treatments. This chapter highlights a common BP measurement error made by cardiologists, demonstrates how to validate automated device accuracy in the individual patient, and discusses a systematic approach to bringing the difficult patient’s BP to goal. The key concept that is developed here is that the control of BP is always an individual experiment in the individual patient, as we currently have no good way to predict which drug or drugs will work best in each patient. The stepwise “combination of combinations” program that I set out has evolved over 40 years of practice in patients with difficultto-manage high BP. The cardiologist is frequently the referral resource for other practitioners who are having problems managing a patient’s high BP but, in general, cardiologists have received little direct training or update in the evaluation and management of the difficult, hypertensive patient. Deficiencies in basic skills needed for the evaluation and treatment of these patients include a lack of attention to BP measurement during office visits by failing to use the recommended mercury manometer and the auscultatory technique, cessation of which diagnose and manage high BP to the highest level of accuracy. In many offices, the BP is measured while the patient is seated on the examining table (1), which falsely increases diastolic BP by about 7 mmHg and results in overdiagnosis and over-treatment of many patients. Over-treatment increases side effects, such as fatigue and dizziness, and the patient’s dissatisfaction with the regimen and the practitioner, which can lead to stopping therapy.

Another common failure is neglecting to instruct the patient to measure BP at home in order to use this to guide therapy. Measuring BP at home allows the practitioner to make decisions based on many more samples of BP rather than relying on readings taken every few months in the office. This also leads to overdiagnosis and overtreatment in those who have office hypertension but normal BP at home. However, many office and home devices now utilize the oscillometric technique, which leads to serious inaccuracies in at least 50% of patients. When BP is measured with an automated device, office staff should document the accuracy of each device on each patient, as all automated devices make serious systematic errors in at least 50% of patients, ⱖ5 mmHg (2).

How to test the accuracy of an electronic blood pressure device The American Heart Association (AHA) Guidelines 2005 state that “Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure related-risk and to guide management. The auscultatory technique with a trained observer and mercury manometer continues to be the method of choice in the office.” The oscillometric method can be used for office measurement, but only devices independently validated according to standard protocols should be used, and individual calibration is recommended (3). The beauty of the mercury manometer is that you can assess its accuracy by simply looking at it. If the mercury meniscus is at zero when there is no pressure in the cuff and the column moves smoothly with inflation and deflation it is accurate and can be used as the gold standard for pressure measurement. All other devices must be calibrated against a

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mercury manometer at regular intervals. Commercial electronic calibration manometers (such as the NETECH DigiMano) must be sent back to the manufacturer yearly for calibration against a mercury standard. Devices that pass the validation protocols of the American Association of Medical Instrumentation (AAMI) will have systematic errors of more than 5 mmHg in a substantial number of individual patients. The calibration check of a nonmercury device requires two steps: (i) validation of the manometer in the device and (ii) validation of the ability of the device to estimate the pressure in an individual patient. For an up-to-date list of validate devices go to http://www.bhsoc.org/bp_monitors/automatic.stm

Does this automated device estimate the pressure accurately enough in my patient? The second step is to assess the error (if any) of the BP estimated by the automated device. This is done by simultaneous or by sequential readings.

Simultaneous readings This is the preferred option. If the device can deflate at a constant rate of 2 to 3 mm/sec, one can do simultaneous readings. Record the BP by the auscultatory method as the automated device takes the BP. To be certain the automatic device inflates high enough to get an accurate pressure, you must obtain the palpated systolic pressure and then ensure that the automatic device inflates at least 30 mm above that. Then listen as the automatic device deflates and record the systolic and diastolic pressure you hear. After you have recorded your reading, record the reading from the automated device. This should be done at least three times and then analyzed as in Table 1.

Does the manometer in my nonmercury device record pressure accurately? First, you must document whether the manometer of the device (electronic or aneroid) registers pressure accurately. Connect the device to be tested to the reference device (mercury, aneroid, or electronic) with a Y tube, as shown in Figure 1. The Y tube transmits pressure equally to the reference device and the device to be tested. Using the bulb connected to the Y, pressure is increased to 300 mmHg and then lowered by 10 mmHg. Recording the pressure on each device validates the accuracy of the aneroid or electronic device. Any device that differs by more than 3 mmHg from the mercury or reference standard is considered to be out of calibration and should be removed from service.

Sequential readings Many devices deflate too fast or in steps, and so you must use sequential readings. We recommend that this be done enough times to ensure that you have a good estimate of the BP recorded by the machine and the human observer. AAMI recommends that this be done at least five times. The averages are then calculated and compared. Your local guidelines should be used to assess whether the device is accurate enough to be used in your patient. An error of more than 5 mmHg and a

170 (10 mm too low) 300 290 280 270 260 250 240 230 220 210 200

180

190 180 170 160 150 140 130 120 110

Pump air into the system until the mercury manometer reads standard say 180. Then record the pressure that the aneroid reads. Do this throughout the range to be tested. Aneroid should be ±3 mm Hg.

100 90 80 70 60 50 40 30 20 10 0

Inflation bulb Electronic readout (6 mm too high)

To test the electronic device connect the pressure sensing input to the Y tube to the Mercury primary standard. Raise and lower pressure in system with the bulb.

186

Electronic device

Figure 1 If using an electronic calibration standard, it is connected in place of the mercury manometer. You should test only one device at a time.

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References

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Table 1 How to test an automated blood pressure device against a trained and certified human observer using a mercury manometer and stethescopea Reading

Human systolic

Human diastolic

Device systolic

Device diastolic

Systolic error

Diastolic error

1

156

90

150

95

⫺6

5

2

150

86

145

90

⫺5

4

3

146

82

140

87

⫺6

5

Average

151

86

145

91

⫺6

⫹5 Mean error

SD aSee

4

3

4

3

⫺5.7

4.7

0.5

0.5

text on how to set up in an Excel file.

standard deviation (SD) of more than 8 is generally considered unacceptable. Inform the patient and note this error in the patient’s chart so others will be aware of it. To use this table in an Excel spreadsheet, you enter three readings made by your trained observer and three made by the device. The mean error and its SD is calculated by using Excel functions. If the error is more than 5 mmHg, this device should not be used in this patient. Failure to document these directional errors will also lead to decisions being made on the basis of only a single BP reading. Another important approach is to take a home reading and to use a systematic approach to the clinical and laboratory evaluation of the new patient to exclude secondary causes of high BP and to guide treatment. Finally, recent advances in the genetics of high BP need to be kept in mind while evaluating new patients and their families.

agents that, except for diuretics, will lead to a rapid increase in BP if they are not given every 24 hours (Appendix 2). Therefore the agents should not be stopped on the night before or the day of interventional studies, as the BP may rapidly increase during or after the study and lead to complications, including hemorrhage around puncture sites or acute pulmonary edema. When BP control is needed during interventional procedures, one can use intravenous nitrates or combined alpha-beta blockers such as labetalol. When these agents fail, I use Nipride, which I have never had fail to control the BP in patients with Cushing’s, primary aldosteronism, renal artery stenosis, pheochromocytoma, and scleroderma with malignant hypertension. In the postoperative state, BP control can be continued even if the patients are nil per os (NPO) as the medications can be crushed and given via a nasogastric tube.

How to quickly bring blood pressure under control in the most difficult patient

Summary

In my experience, many cardiologists fail to recognize that secondary causes of high BP tend to be much higher in their referral practice and they miss important clues to secondary causes. Appendix 1 outlines a systematic approach to be certain that one is not missing secondary causes of high BP.

Blood pressure control before and after surgery or angiography In contrast to older agents, which had much longer half lives, that are used to control BP this combination of combinations uses

This chapter discusses some key features for BP measurement and management in the office and the home and stresses the continued use of the mercury manometer as recommended by the newest AHA guidelines. A method to validate home and office device accuracy is detailed. Finally a stepwise “combination of combinations” approach to BP control in the difficult patient is reviewed, which can be used in the in- and outpatient setting.

References 1

Cushman WC, Cooper KM, Horne RA, Meydrech EF. Effect of back support and stethoscope head on seated blood pressure determinations. Am J Hypertens 1990; 3: 240–241.

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3

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Gerin W, Schwartz AR, Schwartz JE, et al. Limitations of current validation protocols for home blood pressure monitors for individual patients. Blood Press Monit 2002; 7(6):313–318. Pickering TG, Hall JE, Appel LJ, et al. Part 1: blood pressure measurement in humans: a statement for professionals from the Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure Research. Hypertension 2005; 45:142–161.

4

5 6

Grim CE. Evolution of diagnostic criteria for primary aldosteronism: why is it more common in “drug-resistant” hypertension today? Curr Hypertens Rep 2004; 6(6):485–492. Grim CE. Management of malignant hypertension. Comprehensive Therapy 1980; 6:44–48. Appel, LJ, Moore, TJ, Obarzanek, E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med 1997; 336:1117–1124; May 13–16, 1998.

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Appendix

Appendix 1 Secondary causes of high blood pressure (office clues) 1. Observe in the patient: cushing’s, acromegaly, hyper–hypothyroid, neurofibromas, web neck, short 4th metacarpal, café-au-lait spots, swollen feet? 2. Listen to the patient: 2.1. Family history—low K, hypertension (HTN) pregnancy, early stroke in men (suggests some of the new single gene causing high BP), etc. 2.2. Medical history—low K; BP with pregnancy; birth control pills (BCP); licorice; over the counter (OTC) phrine; renal trauma; episodes of HTN inferring pheochromocytoma, that is, headache; hyperhidrosis; high heart rate; hypermetabolism, etc. 3. Smell the patient: alcohol (EtOH), tobacco, uremia? 4. Examine the patient: fundi, bruits, left ventricular hypertrophy (LVH), large kidneys, radial-femoral (R-F) pulse lag, edema? 5. Labs: lytes, blood urea nitrogen (BUN)/creatinine, urine albumin, plasma aldosterone/plasma renin ratio to screen for excess aldosterone or mineralocorticoid production, or renin for renal artery stenosis (RAS) or renin-secreting tumor. 6. Patient’s education: 6.1. Teach self-BP. If they do not have one, have them get an Omron or AND device with right-sized cuff (arm circum ⬎33, use large cuff). 6.2. Instruct on self-BP measurement: Shared Care video (sharedcareinc.com)—sit 5 minutes, take three readings, write them all down, and average the last two. Take BP in AM before taking treatment (RX) and any other time they feel like BP is high or they are dizzy. 6.3. Record in the book and bring in. 7. Dietary approaches to stopping hypertension (DASH) eating plan: Have the patient got the DASH Diet for Hypertension Book by Thomas Moore, read it, and use it for the 14-day test. They may wish to visit bloodpressureline@yahoogroups. com for support. 8. Review medications 8.1. If not on a diuretic, always use hydrochlorothiazide (HCTZ) half of 25 mg (costs $8–15/100). Have them buy this. 9. Change to a combination of combinations: Consider stopping all other RX and begin 9.1. Lotrel 2.5/10 bid, if on Norvasc, switch to Lotrel, and 9.2. Bisoprolol (BIS) 2.5/HCTZ 6.25 each AMor bid. 10. Titrate to get BP control: Have patient call with BPs in two to three days.

175

10.1. If not at goal, increase Lotrel two AM (and two PM and BIS to two AM, two PM—do this till at Lotrel 10/20 bid and BIS 10/6.25 bid. 10.2. If BP not at goal in four weeks, then add Minoxidil 5 mg every morning. Increase every few days by using 5 mg AM, 5 PM, 10 mg AM, 10 PM, etc. Patient needs to be weighed daily. If weight goes up, then add furosemide 40 bid and increase. If still edema, add metolazone 10 mg every morning. 10.3. Check for out eating your BP RX: 24-hour urine for Na/K/creatinine if the 24-hour sodium excretion is ⬎1500 mg a day then tell patient they are not adhering to the DASH diet. 11. Diagnose drug resistant HTN, likely primary aldosteronism (4): If aldo/renin ratio is high, then add Spironolactone 50 mg/day and may increase to 400 mg/day. If gynecomastia, use Inspra 25 to 50/d. Consider adrenal computed tomography and adrenal vein aldo/cortisol with ACTH stim. If the family history (Hx) is positive for low K then do overnight dex test for aldo/cortisol and/or genotype for glucocorticoid remedial aldosteronism (GRA). 12. Look for other causes of HTN: 12.1. If you would do an angioplasty or an operation, do classical renal arteriogram—not MRA or nuclear scan; the only way to exclude renal artery stenosis as a cause of HTN is by selective transfemoral angiography to get details of main and branch renal arteries. 12.2. Pheochromocytoma: 24-hour urine for catecholamines, Na, K, and creatinine.

Appendix 2 How to get rapid blood pressure control in the hospital or in the clinic—the combination of combinations approach The following protocol has been developed and modified over the last 30 years and has been very successful in bringing BP quickly under control in the hospital and in the outpatients’ clinic. The physiological rational is based on the complex and redundant BP control systems that must be overcome to bring BP to goal. The basic concept is that the BP-regulatory control systems are designed to keep the pressure constant. Any attempt to block one system to lower the pressure activates the other systems that try to keep the pressure at its current set point. Thus, the regimen includes diuretics to get at the volume factor that is the key to all forms of high BP, beta blocker (BB) or other agents to block the SNS response to volume depletion and BP lowering, angiotension converting enzyme/angiotensin receptor blocker (ACE/ARB)

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1inhibition to counteract activation of this system with BP lowering, and finally agents that act directly on the vascular smooth muscle such as CCBs or minoxidil. 1. Immediate reduction needed: very rare. Nipride never fails (5). Take BP every two minutes. Infuse with pump Nipride (mix as per instructions). Double dose every two minutes till BP falls, then back down to 1/2 of last step up and adjust till at goal—usually takes about 30 minutes to stabilize. Add oral agents as given in the table. 2. If reduction not needed immediately: Take BP every hour and use a stepwise increase by using a combination of combinations. In the outpatient clinic, one can use this

approach by stepping up the intensity of control every day or two, or even every week, if the patient or family member is measuring BP regularly. 3. Volume contol: Give HCTZ 25 po q 12 hours. If edema or Cr ⬎2, use furosemide 40 q 12 hours. Leave orders that stress that you want the BP to be measured every hour and you want to increase meds as given in the table, every four to six hours. Always implement the DASH 1500-mg sodium diet as well (6). 4. Renin-angiotensin-aldosterone system (RAAS), calcium channel blocker (CCB), and BB: The combination of the drug Lotrel contains ACE and CCB, and the other combination is BIS and HCTZ.

Diuretic

Lotrel

BIS/HCTZ

Step 1: 1st dose at 8 AM

25 HCTZ or 40 furosemide if (EGFR ⬍ 50)

2.5/10

2.5/6.25

Step 2: 2

PM

BP not at goal, give At goal repeat

5/10 2.5/10

5/6.25 2.5/6.25

Step 3: 8

PM

At goal Not at goal, repeat diuretic + increase other agents.

2.5/10 q 12 hr 5/20

2.5/6.25 q 12 hr 5/6.25

Step 4: 2

AM

Not at goal At goal

10/20 None

10/6.25 None

Step 5: 8

AM

At goal, –HCTZ 12.5 or 25 q Not at goal

Give last dose q AM Add Minoxidil 5

Give last dose q AM Lotrel 10/20 q AM BIS 10/6.25 q

AM

Step 6: 2

PM

Not at goal At goal

Minoxidil 10 Minoxidil 5 mg q day

Step 7: 8

PM

Not at goal At goal

Minoxidil 15 Minoxidil 10 q day

Step 8: 2

AM

Not at goal At goal

Minoxidil 20 mg Minoxidil 20 mg q day

Step 9: 8

AM

At goal, watch the weight for increase on Minoxidil. May need to add furosemide and metolazone

Repeat last dose of Minoxidil q day

Lotrel 10/20 q AM, BIS 10/6.25 q AM, Consider Lotrel 5/10 bid BIS 5/6.25 bid

Note: Others to add as outpatient: Spironolactone up to 300/day. Cough → ARB, Catapres if intolerant of BB. Abbreviations: BB, beta blocker; BIS, bisoprolol; BP, blood pressure; EGFR, estimated glomerular filtration rate; HCTZ, hydrochlorothiazide.

AM

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16 Homocysteine regulators Torfi F. Jonasson and Hans Ohlin

Introduction Homocysteine is a nonprotein-building amino acid formed as a metabolite in the methionine cycle. It was first associated with disease in 1962 (1,2). Individuals with a mutation in cystathionine-␤-synthase (CBS) develop classical homocystinuria with extremely elevated plasma tHcy (⬎100 ␮mol/L) (3). Homocystinuria is characterized by early atherosclerosis and thromboembolism as well as mental retardation and osteoporosis and is ameliorated by vitamin supplementation aimed at reducing the blood concentration of homocysteine (4). Moderately elevated plasma homocysteine, defined as levels between 15 and 30 ␮mol/L (5), has emerged as a new risk factor for ischemic heart disease and stroke (6).

In the folate cycle, which is linked to the methionine cycle, homocysteine is remethylated to methionine by the vitamin B12-dependent enzyme methionine synthase (MS), thereby completing the cycle. 5-Methyltetrahydrofolate (CH3-THF) acts as a methyl donor in this reaction, which produces methionine and tetrahydrofolate (THF). Continuing the folate cycle, THF reacts with serine to produce 5,10-methylenetetrahydrofolate, a reaction catalyzed by the vitamin B6-dependent enzyme serine/glycine hydroxymethyltransferase. 5,10-Methylenetetrahydrofolate is then reduced to CH3THF by the vitamin B2 (riboflavin)-dependent enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), using NADPH as cosubstrate. MTHFR is the key enzyme for diverting 5,10-methylentetrahydrofolate to methylation of homocysteine or to DNA synthesis though the conversion of uracil to thymidine.

The metabolism of homocysteine Homocysteine is formed as an intermediary amino acid in the methionine cycle (Fig. 1). Methionine is metabolized to s-adenosylmethionine (SAM), the methyl donor in most methylation reactions and essential for the synthesis of creatinine, DNA, RNA, proteins, and phospholipids. SAM is converted by methyl donation to s-adenosylhomocysteine (SAH), which is then hydrolyzed to homocysteine. SAH is an inhibitor of methyl group donation from SAM. Homocysteine is eliminated via the trans-sulfuration pathway by conversion to cysteine in two steps. The vitamin B6-dependent enzyme CBS catalyzes the first step, in which homocysteine reacts with serine to form L-cystathionine. In the second step, L-cystathionine is converted to L-cysteine, a-ketobutyrate, and ammonia by the vitamin B6-dependent enzyme cystathionase (7). The trans-sulfuration pathway is present in the liver, kidneys, small intestine, and pancreas, where it is linked to the production of glutathione.

Causes of elevated plasma concentrations of homocysteine There are a number of enzyme disorders that cause plasma tHcy elevation (8–12); the two most important are discussed later. CBS deficiency is inherited as an autosomal recessive trait. Homozygous individuals (1 in 200,000 births) have classical homocystinuria with extremely high plasma tHcy. The 677 C ⬎ T polymorphism in MTHFR is believed to be one of the most common causes of mildly elevated plasma tHcy. The frequency of the homozygous genotype is 11% to 15% in North Americans, 5% to 23% in Europeans, 11% in healthy Japanese populations, and only 2.5% in the Indian population in New Delhi (12–14). The polymorphism induces thermolability in the enzyme, resulting in defect remethylation of

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Figure 1 Metabolism of homocysteine. Abbreviations: BHMT, betaine homocysteine methyltransferase; CBS, cystathionine ␤-synthase; MAT, methionine adenosine transferase; MS, methionine synthase; MTHFR, 5,10-methylenetetrahydrofolate reductase; SAH, s-adenosylhomocysteine; SAM, s-adenosylmethionine; THF, tetrahydrofolate.

homocysteine and increased plasma levels. The high plasma levels of tHcy caused by the 677 C ⬎ T polymorphism respond to folate supplementation (15). As shown in the review of the homocysteine metabolism, vitamin B12, vitamin B6, and folate are important cofactors in the metabolic pathways for homocysteine elimination, and consequently, deficiencies of these vitamins are characterized by elevated plasma concentrations of tHcy. Hyperhomocysteinemia is also frequently found in diseases such as renal failure, rheumatic and auto-immune diseases, hypothyroidism, and malignancies. Several drugs are also known to increase plasma tHcy concentrations (16–24).

Homocysteine: a risk factor for cardiovascular disease Many studies published during the last few decades have suggested that hyperhomocysteinemia is a risk factor for coronary artery disease (CAD), stroke, and thromboembolic disease. The Homocysteine Studies Collaboration metaanalysis of 30 studies concluded that elevated tHcy is a moderate risk factor for ischemic heart disease; a level 3 ␮mol/L lower reduces the risk with an odds ratio of 0.89 (95% CI ⫽ 0.83–0.96). The same was true for homocysteine as a risk factor for stroke (odds ratio ⫽ 0.81; 95%5CI ⫽ 0.69–0.95) (6). A meta-analysis of 40 studies of the MTHFR 677 C ⬎ T polymorphism demonstrated a mildly increased risk of coronary heart disease with an odds ratio of 1.16 (95% CI ⫽ 1.05–1.28) (25).

Homocysteine and extent of coronary artery disease Several studies have demonstrated an association between plasma tHcy levels and extent of CAD in populations not exposed to fortification of flour products with folic acid, even after controlling for conventional risk factors (26,27). In contrast, Brilakis et al. (28) found no association between plasma tHcy and angiographic CAD in a North American population consuming cereal grain flour fortified with folic acid. Silberberg et al. (29) found an association between plasma folate and CAD independent of tHcy.

Possible mechanisms of action Oxidative stress In vitro studies have shown that homocysteine can undergo autoxidation, leading to the formation of oxygen free radicals (30–32). Homocysteine is involved in oxidative modification of low-density lipoprotein in vitro (33). Increased lipid peroxidation in humans with hyperhomocysteinemia has been reported (34,35). However, vitamin supplementation that resulted in substantial reduction of tHcy concentrations did not normalize either the homocysteine redox status or the increased lipid peroxidation in CAD patients (35,36).

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Effects on nitrous oxide Homocysteine decreases the bioavailability of nitrous oxide (NO) via a mechanism involving glutathione peroxidase (37). Tawakol et al. (38) reported that hyperhomocysteinemia is associated with impaired endothelium-dependent vasodilation in humans. Homocysteine impairs the NO synthase pathway both in cell culture (39) and in monkeys with hyperhomocysteinemia, by increasing the levels of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor (40). Elevation of ADMA may mediate endothelial dysfunction during experimental hyperhomocysteinemia in humans (41). However, Jonasson et al. (42) did not find increased ADMA levels in patients with coronary heart disease and hyperhomocysteinemia, nor did vitamin supplementation have any effect on ADMA levels in spite of substantial plasma tHcy reduction.

Effects on coagulation Subjects with homocystinuria suffer from thromboembolic events. Epidemiological studies indicate that elevated plasma tHcy increases the risk of venous thromboembolism (43,44). In homocystinuria, the presence of the factor V Leiden mutation further increases the risk of thromboembolism (45). It has been proposed that hyperhomocysteinemia might interfere with the inhibition of activated factor V by activated protein C, possibly via similar effects as those caused by the factor V Leiden mutation (46,47). However, one in vitro study (48) and one large clinical study failed to demonstrate an association between hyperhomocysteinemia and activated protein C resistance (49). Hcy has been shown to reduce binding of tPA to its endothelial cell receptor, annexin II, in cell cultures (50). Animal studies have indicated that elevated plasma tHcy could cause acquired dysfibrinogenemia, leading to the formation of clots that are abnormally resistant to fibrinolysis (51). Elevated plasminogen activator inhibitor and tHcy in patients with acute coronary syndrome have been shown to be associated with increased risk for major adverse cardiac events (MACE) after successful percutaneous coronary intervention (PCI) and stenting (52), whereas factor V Leiden mutation and lipoprotein (a) were not.

Inflammation Several prospective studies have shown that markers of inflammation, such as sensitive C-reactive protein and serum amyloid A (S-AA), are predictors of increased risk for myocardial infarction, stroke, or peripheral vascular disease (53–56).

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Increases in plasma S-AA levels have previously been reported in patients with coronary disease (57). S-AA and plasma intracellular adhesion molecule-1 were elevated in patients with CAD and hyperhomocysteinemia, but only S-AA decreased after vitamin supplementation (35). Homocysteine activates nuclear factor-kB in endothelial cells, possibly via oxidative stress (58), and increases monocyte chemoattractant protein-1 expression in vascular smooth muscle cells (59). Additionally, it stimulates interleukin-8 expression in human endothelial cultures (60). These inflammatory factors are known to participate in the development of atherosclerosis. Taken together, these reports suggest an association of elevated tHcy and low-grade inflammation in CAD.

Homocysteine and smooth muscle proliferation Proliferative effects of homocysteine have been demonstrated in several in vitro studies. Brown et al. (61) found that homocysteine activates the MAP kinase signal transduction pathway in vascular smooth muscle cells. Buemi et al. reported that the addition of Hcy to the medium of smooth muscle cells in tissue culture caused a significant increase in cell proliferation and death through apoptosis and necrosis. When folic acid was added to the culture medium, homocysteine concentrations in media were reduced and the effects of Hcy on the proliferation/apoptosis/necrosis balance of cells in culture were inhibited (62). Ozer et al. (63) showed that the MAPK kinase pathway is involved in DNA synthesis and proliferation of vascular smooth muscle induced by homocysteine. Carmody et al. found that the addition of homocysteine to a culture of vascular smooth muscle cells resulted in a dosedependent increase in DNA synthesis and cell proliferation, but vitamins B6 and B12 alone did not substantially inhibit the effect of homocysteine. However, the addition of folic acid resulted in significant inhibition of DNA synthesis (64). Rosiglitazone has been shown to reduce serum tHcy levels, smooth muscle proliferation, and intimal hyperplasia in Sprague–Dawley rats fed a diet high in methionine (65). The results of the in vitro studies are promising with respect to possible positive in vivo effects of vitamin supplementation. However, the recent results of large prospective clinical trials of vitamin supplementation have been disappointing; these results are further discussed later. To conclude, hyperhomocysteinemia is associated with oxidative stress, inflammation, endothelial dysfunction, and dysfunction of coagulation in animals and in humans, but vitamin supplementation does not consistently normalize these changes in spite of large reductions in homocysteine. It still remains be seen whether homocysteine per se causes the pathological processes or whether it is simply an innocent bystander.

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Vitamin therapy for prevention of cardiovascular disease Three large-scale clinical trials of vitamin supplementation have been published. In the Vitamin Intervention for Stroke Prevention Study (VISP), 3680 adults with nondisabling cerebral infarction were randomized to either a high-dose vitamin formulation containing 25 mg pyridoxine, 0.4 mg cobalamin, and 2.5 mg folic acid or a low-dose formulation containing 200 ␮g pyridoxine, 6 ␮g cobalamin, and 20 ␮g folic acid. The mean reduction of tHcy was 2 ␮mol/L greater in the highdose group than in the low-dose group. The primary outcome, the risk of ischemic stroke within two years, was 9.2% in the high-dose group and 8.8% in the low-dose group (risk ratio ⫽ 1.0; 95% CI ⫽ 0.8–1.3) (66). The Norwegian Vitamin (NORVIT) trial included 3749 patients who had had an acute myocardial infarction within seven days before the start of the trial. The patients were randomly assigned in a two-by-two factorial design to receive one of the following four daily treatments: 0.8 mg folic acid, 0.4 mg vitamin B12, and 40 mg vitamin B6; 0.8 mg folic acid and 0.4 mg B12; 40 mg vitamin B6; or placebo. The mean total homocysteine level was reduced by 27% in patients given folic acid and B12, but the treatment had no significant effect on the primary outcome, a composite of recurrent myocardial infarction, stroke, and sudden death due to coronary heart disease (risk ratio ⫽ 1.08; 95% CI ⫽ 0.93–1.25). Treatment with vitamin B6 was not associated with any significant benefit. In the group given folic acid, vitamin B12, and vitamin B6, there was a trend toward an increased risk (relative risk ⫽ 1.22; 95% CI ⫽ 1.00–1.50; P ⫽ 0.05) (67). In the Heart Outcomes Prevention Evaluation 2 (HOPE-2) study, 5522 patients aged 55 or older with vascular disease or diabetes were randomized to treatment with either placebo or a combination 2, 5 mg of folic acid, 50 mg vitamin B6, and 1 mg vitamin B12, for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. Mean plasma homocysteine levels decreased by 2.4 ␮mol/L in the treatment group and increased by 0.8 ␮mol/L in the placebo group. The primary outcome occurred in 18.8% of patients assigned to active therapy and in 19.8% of those assigned to placebo (relative risk ⫽ 0.95; 95% CI ⫽ 0.84–1.07; P ⫽ 0.41) (68). The results of these three large trials are consistent and lead to the conclusion that there is no clinical benefit from vitamin supplementation in patients with cardiovascular disease (CVD). As suggested by Loscalzo (69), the results indicate that either homocysteine is not a important atherogenic determinant or the vitamin therapy might have other adverse effects that offset its homocysteine-lowering effects, such as cell proliferation through synthesis of thymidine, hypermethylation of DNA, or increased methylation potential leading to elevated levels of ADMA.

Homocysteine and restenosis after percutaneous coronary intervention Is homocysteine involved in the pathogenesis of restenosis? An association between homocysteine and restenosis is not unlikely, given the fact that homocysteine appears to induce inflammation, impair endothelial function, and stimulate smooth muscle proliferation; all these mechanisms are potentially implicated in the development of restenosis. However, the data regarding tHcy levels and the risk of restenosis after coronary angioplasty are conflicting. Some investigators found an increased risk of restenosis after PCI in patients with high plasma levels of homocysteine, especially in patients not treated with stents (70–72), whereas others did not find any increased risk either in patients with (73–75) or without stents (76).

Homocysteine-lowering therapy and restenosis after coronary angioplasty In the Swiss Heart Study (77), 205 patients were randomly assigned after successful angioplasty to receive either placebo or a combination therapy of folic acid (1 mg), vitamin B12 (400 ␮g), vitamin B6 (10 ␮g) or placebo. The primary endpoint was restenosis within six months, as assessed by quantitative coronary angiography. Angiographic follow-up was achieved in 177 patients. Vitamin treatment significantly decreased plasma tHcy levels from 11.1 to 7.2 ␮mol/L (P ⬍ 0.001). At follow-up, the minimal luminal diameter was significantly larger in the treatment group, 1.7 mm versus 1.45 mm (P ⫽ 0.02), and the degree of stenosis was less severe (39.9% vs. 48.2%, P ⫽ 0.01). The treatment group had a lower rate of restenosis (19.6% vs. 37.6%, P ⫽ 0.01) and less need for revascularization of the target lesion (10.8% vs. 22.3%, P ⫽ 0.047). A difference in treatment effect between stented and nonstented lesions was evident. In 101 lesions treated with balloon angioplasty only, vitamin treatment reduced the rate of restenosis from 41.9% to 10.3% (P ⬍ 0.001). In 130 stented lesions, only a nonsignificant trend to treatment effect was found; restenosis rate in the treatment group was 20.6% versus 29.9% with placebo (P ⫽ 0.32). However, the subgroups cannot readily be compared, since it was left to the discretion of the operator whether to use stents or not. Similar results were obtained in the subgroup of patients with small coronary arteries (⬍3 mm) (78). The authors suggest that vitamin therapy might be an attractive therapeutic alternative, especially in small coronary arteries that are considered less suited for stent therapy.

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In an extension of the original study, including 553 patients after successful angioplasty, the clinical outcome of the combined vitamin therapy for six months was compared to placebo. After one year, the composite endpoint (death, nonfatal myocardial infarction, and need for revascularization) was significantly lower in patients treated with vitamin therapy (15.4% vs. 22.8%, P ⫽ 0.03), primarily due to a reduced rate of target lesion revascularization. The benefit was evident at the end of the six months and was maintained at 12 months after the angioplasty procedure. The findings remained unchanged after adjustment for potential confounders (78). In contrast, the Folate After Coronary Intervention Trial (FACIT) demonstrated adverse effects of vitamin treatment in patients treated with coronary stenting (75). In this study, 636 patients who had undergone successful coronary stenting with bare metal stents were randomized to either vitamin therapy or placebo. In the vitamin group, 1 mg of folic acid, 5 mg of vitamin B6 and 1 mg of B12 were given intravenously, followed by oral therapy. The 1, 2 mg dose of folate given orally was slightly higher than that previously used in the Swiss Heart Study (1 mg). The dose of B6, 48 mg, was higher than in the previous study (10 mg), while the B12 dose, 60 ␮g, was lower (400 ␮g). At the end of the six-month treatment, the study endpoints (minimal luminal diameter, late loss, and restenosis rate) were evaluated by means of quantitative coronary angiography. tHcy levels decreased significantly from a mean of 12.2 ␮mol/L at baseline to 9.0 ␮mol/L at six months in the folate group (P 48 hours, unknown duration or high risk of embolism

Immediate cardioversion (DC or pharmacological)

Delayed cardioversion (adequate anticoagulation for 3 weeks)

TEE possible or necessary

No thrombi: immediate cardioversion (DC or pharmacological)

Thrombi: delayed cardioversion (adequate anticoagulation for 3 weeks)

Figure 2 Flow chart for recent onset atrial fibrillation.

5. Intravenous flecainide (150 mg) converts recent onset AF in 55% to 65% of patients (41). 6. Cardiac proarrhythmic effects of flecainide include aggravation of ventricular arrhythmias and threat of sudden death

as in the CAST study (42). The proarrhythmic effect is due to nonuniform slowing of conduction. Monitoring the QRS interval seems logical but no safety margins have been established. Furthermore, late proarrhythmic effects can

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occur. In patients with pre-existing sinus node or AV conduction problems, there may be worsening of arrhythmia. In AF or AFL, the drug can cause the atrial rate to fall, with a subsequent rise of the ventricular rate: it should therefore always be prescribed with an AV-nodal depressing drug such as digitalis, betablockers, or verapamil to avoid fast AV conduction. Also, ventricular arrhythmias may be precipitated. 7. More effective than procainamide, sotalol, propafenone, and amiodarone (43–47).

7.

Propafenone 1. Class Ic antiarrhythmic drug similar to flecainide, blocking sodium channels in both activated and inactivated states, additional weak betablocking effect. 2. T 1/2 2 to 12 hours, poor metabolizers 10 to 12 hours, steady state after 72 hours (T 1/2 of active metabolite). 3. Dosage: Oral 450 to 600 mg, iv: 1.5 to 2.0 mg/kg over 10 to 20 minutes. 4. Oral propafenone is an effective drug for conversion of AF to sinus rhythm (48,49). A review of the literature found that a single oral loading dose converted AF in 58% to 83% of patients, depending upon the duration of AF (50). 5. Increased mortality and cardiac arrest recurrence when structural heart disease (51). 6. Useful in reducing the ventricular response (52).

8.

9.

10.

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termination of AF and AFL with both single and repeated intravenous infusions (54). In patients with persistent AF or AFL, ibutilide has a conversion efficacy of 44% for a single dose and 49% for a second dose (56). Efficacy is higher in AFL than in AF and is related to an effect on the variability of the cycle length of the tachycardia (57) due to the phenomenon of reverse use dependence: prolongation of refractoriness becomes less pronounced at higher tachycardia rates. Has the potential to provoke torsade de pointes. The rate of torsade de pointes ranged between 3.6% and 8.3% (55,56,58,59) and may be more common in women (59). Sustained episodes requiring cardioversion were seen in 1.7% to 2.4%. In addition to polymorphic VT, nonsustained monomorphic VT occurred in 3.2% to 3.6% (55,56). Therefore, continuous ECG monitoring for at least four hours after the infusion or until the QTc interval has returned to baseline. In comparative studies, ibutilide has been more effective for AF reversion than procainamide (51% vs. 21% and 32% vs. 5%) (60,61) or intravenous sotalol (44% vs. 11%) (show Fig. 7) (53). It is as effective as amiodarone in cardioversion of AFL (1,62). After cardiac surgery: dose-dependent effect in conversion of atrial arrhythmias with 57% conversion at a dose of 10 mg (63). The drug is more effective when given as pretreatment prior to cardioversion (64).

Dofetilide Ibutilide 1. Class III antiarrhythmic drug, which prolongs repolarization by inhibition of the delayed rectifier potassium current (Ikr) and by selective enhancement of the slow inward sodium current. Ibutilide has no known negative inotropic effects (53). 2. Only available as intravenous preparation 3. T 1/2 2 to 12 hours (54). 4. Dose- and concentration-related increase in the uncorrected and rate-corrected QT interval 5. Dosage: less than 60 kg—0.01 mg/kg infused over 10 minutes. If the arrhythmia does not terminate 10 minutes after the end of the infusion, a second bolus (same dose over 10 minutes) can be given. More than 60 kg—1 mg over 10 minutes. If arrhythmia does not terminate 10 minutes after the end of the infusion, a second bolus of 1 mg over 10 minutes can be given. 6. The acute AF conversion rate is higher with ibutilide than with placebo and can be expected to occur about 30 minutes after infusion (55,56). It is efficacious in the

1. Useful, but not commercially available.

Amiodarone 1. Class III antiarrhythmic agent with additional classes I, II, III, and IV actions. Prolongs action potential duration and effective refractory period in all cardiac tissues. 2. Dosage: Oral: 1.2 to 1.8 g in divided doses until 10 g, then 200 to 400 mg/day or 30 mg/kg as a single daily dose. Intravenous: 5 to 7 mg/kg over 30 minutes, then 1.2 to 1.8 g in continuous infusion over 24 hour, then 200 to 400 mg daily (1). 3. Intravenous amiodarone has been reported to be effective, converting 60% to 70% of patients to sinus rhythm in some trials (65–67). The efficacy has been evaluated in studies with different durations of AF. 4. Oral amiodarone: A number of mostly small trials have evaluated the efficacy of oral amiodarone which, as with other drugs, appears to vary with the duration of AF (66,68). The SAFE-T trial of patients with persistent AF

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who were on anticoagulation therapy showed that patients randomly assigned to amiodarone or sotalol had a higher frequency of cardioversion to sinus rhythm after one month compared to placebo. Patients who were still in AF underwent DC cardioversion of which efficacy was similar in all groups (69). 5. Cardiac side effects: Torsade de pointes (⬍0.5%), severe bradycardia (one-year risk of bradycardia 2.4% on amiodarone vs. 0.8% on placebo). Non-cardiac side effects: Pulmonary toxicity 1% per year with fatal cases: discontinue and treat symptomatically, hepatotoxicity 0.6%, periferal neuropathy 0.3%, hypothyroidism 6%, hyperthyroidism 0.9%. Routine toxicity screening is required. This includes periodic (usually every six months) measurement of thyroid (sensitive serum T4), hepatic (AST), and pulmonary function (chest X-ray), as well as clinical evaluation (70).

Rate control: slowing conduction in the AV-node Rate control can be effectively achieved using a betablocker, calciumantagonist, and/or digoxin either in monotherapy or combined as necessary. Caution must be taken that combining intravenous betablocker and calciumantagonist may cause severe depression of the left ventricular function and AVnode. In the setting of heart failure digoxin may be prefereble since it has a positive inotropic effect, with diltiazem as a second choice agent.

Betablockers Propranolol

Procainamide 1. Intravenous procainamide converts 20% to 60% of cases to sinus rhythm, particularly if the AF is of recent onset. It can be used with caution (hypotension, QRS widening), when the more effective, previously described drugs are not available.

1. Noncardioselective betablocker with a plasma half-life of one to six hours and a hepatic metabolisation. 2. Intravenous dose is 1 to 6 mg as needed. 3. Contraindications include hypotension, second and third degree heart block, cardiogenic shock and overt cardiac failure, peripheral ischemia, and bronchospasm. 4. Multiple drug interactions have been described with numerous compounds due to interference with hepatic clearance.

Quinidine 1. Should not be used in emergency settings (71).

Sotalol 1. Intravenous sotalol appears to be less effective than intravenous flecainide or ibutilide (47). 2. Oral sotalol is less effective than quinidine for conversion of recent onset (⬍48 hours) AF and is comparable to amiodarone for conversion of AF of ⬎48 hours in duration (69,72).

Metoprolol 1. ␤1-selective betablocker with a plasma half-life of three to seven hours and mainly hepatic elimination. 2. Bolus 2.5 to 5 mg over two minutes, repeated at five minutes interval up to 15 mg. 3. Contraindications: Hypotension, second and third degree heart block, cardiogenic shock and overt cardiac failure, and bronchospasm. 4. Drug interactions: Catecholamine-depleting drugs such as reserpine may have an additive effect in combination with betablockers. Drugs that inhibit CYP2D6 (quinidine, fluoxetine, paroxetine, and propafenone) increase metoprolol concentration.

Digoxin 1. The rate of conversion with digoxin is no better than placebo. Digoxin may restore sinus rhythm when AF is due to heart failure (73,74). In this setting, reversion is the result of improved hemodynamics and a reduction in left atrial pressure.

Esmolol 1. Rapidly and very short acting betablocker (half life of nine minutes).

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2. Bolus of 0.5 mg/kg over one minute followed by 50 ␮g/kg per minute. After four minutes another bolus can be given and infusion increased to 100 ␮g/kg per minute. Infusion rate can be increase to a maximum of 200 ␮g/kg per minute, guided by clinical response. 3. Contraindications include hypotension, peripheral ischemia, confusion, thrombophlebitis, skin necrosis from extravasation, bradycardia, second and third degree heart block, cardiogenic shock, overt heart failure, and bronchospasm. 4. Interactions with cathecholamine depleting drugs and increases digoxin blood levels.

Calciumantagonists Verapamil 1. Non-dihydropyridine calciumantagonist (Class IV AAD) that inhibits the calcium mediated depolarization of the AV-node, increasing the nodal effective refractory period and reducing ventricular rate in AF. 2. Can be given as a slow intravenous bolus of 5 to 10 mg over two to three minutes, repeated after 10 to 15 minutes. Acts within five minutes of intravenous administration. Plasma half-life is two to eight hours. Is metabolized in the liver by the P-450 system, with ultimately 75% renal and 25% gastrointestinal excretion. 3. Contraindications are hypotension, cardiogenic shock, marked bradycardia, second or third degree AVblock, Wolff-Parkinson-White (WPW) syndrome, wide complex tachycardia, VT and uncompensated heart failure. 4. Multiple drug interactions have been discribed (decreased serum concentrations of phenobarbital, phenytoin, sulfinpyrazone and rifampin, increased serum concentrations of quinidine, carbamazepine, cyclosporin). Important in this setting is that a marked interaction exists between digoxin and verapamil, increasing the serum concentrations of the former due to decreased renal excretion.

Diltiazem 1. Non-dihydropyridine calciumantagonist (Class IV AAD) with similar action as verapamil. 2. Initial intravenous dose is 0.25 mg/kg over two minutes followed by 0.35 mg/kg after 15 minutes as required. Continuous infusion rate after initial bolus of 5 to 10 mg/hr may be further increased to 15 mg/hr. Plasma

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half-life is three to five hours, but may be longer in an elderly population. 3. Contraindications are similar to verapamil. 4. Drug interactions include rise in plasma concentration when concomittant administration with cimetidine and lowering of the concentration with barbiturates, phenytoin, rifampin. Digoxin levels may be variably affected, can rise.

Digoxin 1. Digoxin is a cardiac glycoside acting through inhibition of the sodium pump (Na/ K-ATPase) causing a transient increase in intracellular sodium, which in turn promotes calcium influx by a sodium⫺calcium exchange mechanism resulting in an enhanced myocardial contractility. It also causes sinus slowing and atrioventricular nodal inhibition by parasympathetic activation, combined with a modest direct nodal inhibition. Digoxin inhibits sympathetic nerve discharge and inhibits renin release from the kidney with a natriuretic effect. 2. Intravenous loading with 500 ␮g produces a detectable effect in 5 to 30 minutes and becomes maximal in one to four hours. Additional doses of 250 ␮g can be given with six to eight hour intervals. Serum digoxin concentrations should be ranging from 0.8 to 2.0 ng/ml; however there can be a clinical benefit below this range. Sampling should be performed at least six to eight hours after the last dose. 3. Serum half-life is 36 hours, 70% by renal secretion, 30% hepatic/gastrointestinal. 4. Contraindications are hypertrophic obstructive cardiomyopathy (increase in inotropism can increase outflow tract obstruction), AF in WPW syndrome (can cause precipitation of the arrhythmia to ventricular fibrillation (VF) by preferential conduction over the accessory pathway), significant AV-block or sick sinus syndrome, hypokalemia (causes increased digoxin sensitivity and supraventricular/ventricular arrhythmia), thyreotoxicosis, postinfarction status (increased mortality). Caution should be exerted in renal failure, and coadministration of other drugs depressing sinus node or AV-nodal function. 5. Caution should be taken when administered in pulmonary disease because of the sensitivity to intoxication due to hypoxia, electrolyte disturbances and sympathetic discharge. Digoxin also experimentaly increases infarct size. 6. Drug interactions are multiple but of special interest is the interaction with other AADs such as quinidine and verapamil, both increasing the serum concentration. 7. Diuretics may induce hypokalemia, which sensitizes the heart to digoxin toxicity and stops the tubular excretion of the drug. Toxicity has gastrointestinal (nausea,

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vomiting, anorexia, diarrhea), neurologic (malaise, fatigue, confusion, insomnia, facial pain, depression, vertigo, colored vision), and cardiac (palpitations, arrhythmias, syncope) effects, hypokalemia is also common in the typical patient. Digoxin arrhythmias range from AV-block and bradycardia, due to increased vagal tone, to accelerated atrial, junctional or ventricular arrhythmias, due to increased automaticity of junctional tissue in His-Purkinje tissue. Bidirectional tachycardia is rare but very suggestive. Blood level and electrolytes should be checked to confirm. Lidocaine can be given to reduce ventricular ectopy without increasing the AV-block, phenytoin reverses the latter (dose of 100 mg intravenously every five minutes to a total of 1000 mg or side effects). When faced with severe ventricular arrhythmias and thus life threatening intoxication, Digoxin-specific antibodies can be administered.

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McNamara RL, et al. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003; 139(12):1018–1033. Majeed A, Moser K, Carroll K. Trends in the prevalence and management of atrial fibrillation in general practice in England and Wales, 1994–1998: analysis of data from the general practice research database. Heart 2001; 86(3):284–288. Sakurai K, et al. Left atrial appendage function and abnormal hypercoagulability in patients with atrial flutter. Chest 2003; 124(5):1670–1674. Odell JA, et al. Thoracoscopic obliteration of the left atrial appendage: potential for stroke reduction? Ann Thorac Surg 1996; 61(2):565–569. Kamath S, et al. A study of platelet activation in atrial fibrillation and the effects of antithrombotic therapy. Eur Heart J 2002; 23(22):1788–1795. Investigators AF. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994; 154(13):1449–57. Fuster V, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation 2001; 104(17):2118–2150. Group TEAFTS. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993; 342(8882):1255–1262. Pearson AC, et al. Superiority of transesophageal echocardiography in detecting cardiac source of embolism in patients with

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cerebral ischemia of uncertain etiology. J Am Coll Cardiol 1991; 17(1): 66–72. Zabalgoitia M, et al. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll Cardiol 1998; 31(7):1622–1626. Tunick PA, et al. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002; 90(12):1320–1325. Feinberg WM, et al. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995; 155(5):469–473. Stafford RS, Singer DE. Recent national patterns of warfarin use in atrial fibrillation. Circulation 1998; 97(13):1231–1233. Bungard TJ, et al. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 2000; 160(1):41–46. Stein PD. Antithrombotic therapy in valvular heart disease. Clin Geriatr Med 2001; 17(1):163–172, viii. ACC/AHA guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association. Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). J Am Coll Cardiol 1998; 32(5):1486–1588. Bjerkelund CJ, Orning OM. The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 1969; 23(2):208–216. Arnold AZ, et al. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 1992; 19(4):851–855. Haissaguerre M, et al. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998; 339(10):659–666. Haissaguerre M, et al. Mapping-guided ablation of pulmonary veins to cure atrial fibrillation. Am J Cardiol 2000; 86(9 Suppl 1):K9–K19. Pappone C, et al. Atrial electroanatomic remodeling after circumferential radiofrequency pulmonary vein ablation: efficacy of an anatomic approach in a large cohort of patients with atrial fibrillation. Circulation 2001; 104(21):2539–2544. Passman R.S, et al. Radiofrequency ablation of atrial flutter: a randomized controlled study of two anatomic approaches. Pacing Clin Electrophysiol 2004; 27(1):83–88. Zhou L, et al. Thromboembolic complications of cardiac radiofrequency catheter ablation: a review of the reported incidence, pathogenesis and current research directions. J Cardiovasc Electrophysiol 1999; 10(4):611–620. Kok LC, et al. Cerebrovascular complication associated with pulmonary vein ablation. J Cardiovasc Electrophysiol 2002; 13(8):764–767. Manolis AS, et al. Thrombogenicity of radiofrequency lesions: results with serial D-dimer determinations. J Am Coll Cardiol 1996; 28(5):1257–1261. Dorbala S, et al. Does radiofrequency ablation induce a prethrombotic state? Analysis of coagulation system activation and comparison to electrophysiologic study. J Cardiovasc Electrophysiol 1998; 9(11):1152–1160. Anfinsen OG, et al. The activation of platelet function, coagulation, and fibrinolysis during radiofrequency catheter ablation

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42 Contrast-induced nephropathy after percutaneous coronary interventions Ioannis Iakovou

Contrast media (CM) are used to enhance visualization during diagnostic angiograms and to guide percutaneous coronary interventions (PCI). The increased use of PCI led to the increased number of patients receiving CM (1,2). However, use of CM is not without risks. Although some complications associated with CM are mild and transient, such as discomfort and itching, others are more serious such as anaphylaxis, hypotension, cardiovascular events, and renal dysfunction (1–3). Contrast-induced nephropathy (CIN) is the most serious complication associated with the use of CM and can negatively affect long-term patient morbidity and mortality (4–10). CIN is usually defined as an acute decline in renal function characterized by an absolute rise of 0.5 mg/dl (44 µmol/l) in serum creatinine (SCr) or a 25% increase from baseline, occurring after the systemic administration of CM in the absence of other risk factors such as atheroembolic disease, hypotension and low blood volume, surgery, or nephrotoxins (1,2,6,7,10–13). Typically, patients with CIN will experience changes in SCr 1–5 days following contrast exposure. The decline in renal function often occurs within 24–48 hours of CM, with peak elevations in SCr occurring after 3–5 days, and a return to baseline or near baseline in 7–10 days (1,2). While reduction in renal function is generally small and transient, some patients experience a more prolonged decrease and, in rare cases, require dialysis (5,14). The incidence of CIN varies among studies and is dependent on the definition, background risk, type, and dosage of CM, and imaging procedure. Whereas it is estimated to be 0.6–2.3% in the general population, it is higher in hospitalized patients (1–20%) and in patients with cardiovascular disease undergoing angiography procedures, ranging between 3.3% and 14.5% (1,2,5,14,15). These rates can be as high as 50% among patients with baseline renal dysfunction and diabetes (1,2,5,6,14–17). While most cases of CIN are characterized by seemingly small and transient changes in renal function, up to 30% of patients experiencing CIN might have some permanent decline in

renal function (4,5,7,9). More importantly, patients who develop CIN are at significantly higher risk of in-hospital and one-year mortality (2,7–9,13,18). The risk is even greater in patients with preexisting renal compromise (1,2,5,14,15). The aim of the present article is to review the pathogenesis, the risk factors, and the outcomes of CIN and reviews current opinion on how best to prevent CIN.

Pathogenesis The precise mechanisms behind the pathogenesis of CIN are as yet unclear. In vitro as well as animal studies suggest a combination of toxic injury to the renal tubules and ischemic injury (prerenal mechanism) partly mediated by reactive oxygen species (19,20). In addition, factors other than osmolality (such as viscosity, hydrophilicity) contribute substantially to the toxic effects of CM (20,21). Increased perivascular hydrostatic pressure, high viscosity, or changes in vasoactive substances (i.e., endothelin, nitric oxide, and adenosine) might result in low blood flow in the medulla, which has a high demand for oxygen and thus produce ischemic injury (22–24). Similarly, factors impairing medullary vasodilation, such as nonsteroidal anti-inflammatory drugs, may worsen CIN (1,4,5,14,25,26). In addition, all water-soluble, nephrotropic, iodinated CM exert direct toxic effects on renal epithelial cells and might produce contrastinduced renal medullary ischemia (20,21). CM can also produce direct cytotoxic effects such as cytoplasmic vacuolization and lysosomal alteration in the proximal convoluted tubular cells and in the inner cortex of the kidneys (27). Animal studies have suggested that oxidant-mediated injury might arise due to an enhanced production of oxygen-free radicals concomitant with a reduction in the activity of the antioxidant enzymes, such as catalase and superoxide dismutase, in the

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renal cortex (28). Lipid peroxidation of biologic membranes might also be implicated and significant morphologic alterations in proximal tubules, along with elevated renal levels of malondialdehyde, a marker of lipid peroxidation, have been found in rats after exposure to iodinated CM (29). Regarding ischemic injury, the deeper portion of the outer medulla of the kidney is particularly vulnerable, since this area is maintained at the verge of hypoxia, with pO2 levels often as low as 20 mmHg (30). Possible mechanisms for medullary hypoxia and ischemia in response to CM exposure include: (1) CM might cause direct renal vasoconstriction and (2) CM might impair oxygen delivery indirectly by causing red blood cell aggregation (20,31,32).

Osmolality of contrast media and contrast-induced nephropathy CM can be classified according to osmolality, which reflects the total particle concentration of the solution (the number of molecules dissolved in a specific volume) (1,2). CM with osmolality greater than that of blood may be more difficult for the kidney to excrete. Over the past 40 years, the osmolalities of available CM have been gradually decreased to physiologic levels. In the 1950s, only high-osmolar CM (e.g., diatrizoate)

Table 1

with osmolality five to eight times that of plasma were available (1). In the 1980s, CM such as iohexol, iopamidol, and ioxaglate were introduced. While these are classified as the so-called low-osmolar CM, their osmolalities are two to three times greater than that of plasma (33). In the 1990s, isosmolar CM with the same physiologic osmolality as blood were developed (e.g., iodixanol) (33). Physiologic and chemical characteristics of water-soluble, iodinated CM are shown in Table 1. Whether different types of CM have different mechanisms of nephrotoxicity or produce different degrees of renal effects have been the matter of intense scurtiny (5,25,33,34). Lowosmolar nonionic CM have long been known to have fewer direct cytotoxic effects compared to high-osmolar agents (35,36). However, controversial data have been reported by other investigators (35–38). Recently, Heinrich and Uder (39) have shown that nonionic dimeric CM have stronger direct cytotoxic effects on renal proximal tubular cells in vitro than nonionic monomeric CM. Experimental studies have suggested that iso-osmolar dimeric CM may worsen medullary hypoxemia more than low-osmolar CM, and even more than high-osmolar CM (40,41). A diminished transit time of the more highly viscous dimeric CM in the tubule might lead to a decrease of both glomerular filtration rate and renal blood flow by the compression of peritubular vessels (32). Moreover, the diminished tubular transit time of the nonionic dimers might result in an increased time for solute transport and increased oxygen utilization (42).

Physiologic and chemical characteristics of water-soluble, iodinated contrast media

Ionicity

Osmotic class

Agent contrast

Iodine/particle (ratio)

Iodine concentration (mgI/kg)

Osmolality (mOsm/kg)

Viscosity (cPs at 37⬚C)

Ionic

High-osmolar monomers

Diatrizoate (renografin)

3/2 (1.5)

370; 300

1870; 1500

2.34; 5.2

Low-osmolar dimers

Ioxaglate (hexabrix)

6/2 (3.0)

320

600

7.5

Low-osmolar monomers

Iohexol (omnipaque)

3/1 (3.0)

140–350

322–844

1.5–10.4

Iomeprol (iomeron)

150–400

301–726

1.4–12.6

Iopamidol (isovue)

250–370

524–796

3.0–9.4

Iopentol (imagopaque)

150–350

310–810

1.7–12.0

Iopromide (ultravist)

150–370

330–770

1.5–10.0

Ioversol (optiray)

240–350

502–792

3.0–9.0

Nonionic

Ioxilan (oxilan) Iso-osmolar dimers

Source: Modified from Ref. 20.

300–350

585–695

5.1–8.1

Iodixanol (visipaque)

6/1

270–320

290

6.3–11.8

Iotrolan (isovist)

(6.0)

240–300

270–290

3.9–8.5

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In summary, further studies are needed before isoosmolar CM can be recommended in place of low-osmolar CM. Exceeding a volume of CM of 5 ml/kg of body weight divided by the SCr level in milligrams per deciliter strongly predicts nephropathy requiring dialysis (5,13).

Risk factors for contrast-induced nephropathy Various conditions have been proposed as risk factors for CIN. However, it is uncertain to what extent these factors independently worsen renal function, as opposed to serving as markers for coexisting conditions. Chronic kidney disease (CKD) is a major determinant of CIN (5,7,19,43). McCullough et al. (44) reported that SCr levels rose by more than 25% in 14.5% of patients who underwent coronary angiography. On the contrary, in the absence of preexisting renal disease, the incidence is much lower. In a series of 1196 patients, Rudnick et al. (45) reported that only 8% of patients whose baseline SCr level was below 1.5 mg/dl (135 µmol/L) had an increase in the SCr level of more than 0.5 mg/dl, and none had an increase of more than 1 mg/dl (89 µmol/L). In another study by Freeman et al. (46), 0.8% of 1826 patients required dialysis after exposure to the CM; the baseline estimated creatinine clearance rate was below 47 mL/min/1.73 m2 of body-surface area in all patients requiring dialysis. Serum creatinine levels rose by less than 1 mg/dl (89 µmol/L) in 29% of those requiring dialysis, indicating advanced preexisting kidney disease (46). Patients with preexisting renal dysfunction undergoing PCI are at increased risk for adverse outcomes compared with those with normal renal function (47). Similarly, an analysis of more than 130,000 elderly postmyocardial infarction patients found that one-year survival was progressively reduced as creatinine clearance declined (48). Acute renal failure occurring after cardiovascular procedures has been estimated to occur in 5–15% of patients. Nevertheless, patients who manifest mild CKD after exposure to CM who also have coronary artery disease may have a worse prognosis than patients without renal impairment. Their incidences of recurrent hospitalization, subsequent bypass surgery, and mortality are increased. Over a period of years, patients with mild CKD who had PCI were hospitalized more frequently than patients without (3.6% vs. 2.4%, p⫽0.003). After initial revascularization, more patients with chronic renal failure than without needed subsequent bypass surgery two years later (20% vs. 12%, respectively) (47). Best et al. (6) showed a renal function-dependent rise in the mortality rate in a study of more than 5000 patients. In patients with acute myocardial infarction undergoing PCI, moderate CKD compared with normal renal function at baseline was associated with a marked increase in mortality at 30 days (7.5% vs. 0.8%, p ⬍ 0.0001) and at one year (12.7% vs. 2.4%, p ⬍ 0.0001) (49). Among 7230 consecutive patients, CIN (ⱖ25% or ⱖ0.5 mg/dl increase in preprocedure SCr 48 hours after the procedure) developed in 381 of 1980 patients

Cumulative percentage of death

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25 p < .0001 20 15

CKD/CIN

10

No CKD/CIN

5

CKD/No CIN No CKD/No CIN

0 0

3

6

9

12

Time in months Number at risk CKD/CIN CKD/No CIN No CKD/CIN No CKD/No CIN

364 1641 637 4906

313 1599 608 4858

305 1580 595 4806

289 1539 591 4788

251 1378 542 4375

Figure 1 The prognostic significance of the proposed risk score for CIN extended to prediction of one-year mortality, as indicated by the results obtained from both the development and validation datasets. (Solid bars) development dataset; (open bars) validation dataset Abbreviations: CIN, contrast-induced nephropathy; CKD, chronic kidney disease. Source : From Refs. 7, 13.

(19.2%) with baseline CKD (estimated glomerular filtration rate ⬍60 mL/min/1.73 m2) and in 688 of 5250 patients (13.1%) without CKD. CIN was one of the most powerful predictors of one-year mortality in patients with preexisting CKD (odds ratio 2.37, 95% confidence interval 1.63 to 3.44) or preserved eGFR (odds ratio 1.78; 95% confidence interval 1.22 to 2.60) (Fig. 1) (7). Thus, regardless of the presence of CKD, baseline characteristics and periprocedural hemodynamic parameters predict CIN, and this complication is associated with worse in-hospital and one-year outcomes. Nevertheless, the additional burden of CIN in PCI patients with already compromised renal function markedly increases the risk of adverse outcomes. Diabetes is a major risk factor for deterioration in renal function after angiography (2,7,13). Other factors variably associated with increased rates of CIN include age over 75 years, anemia, female gender, periprocedural volume depletion, heart failure, cirrhosis, hypertension, proteinuria, concomitant use of nonsteroidal anti-inflammatory drugs, and intra-arterial injection (2,4,5,7,10,13,14,19,43,44). In the setting of acute myocardial infarction or PCI, hypotension or use of an intra-aortic balloon pump has been associated with a higher rate of acute renal failure after exposure to a contrast medium (13,50). Finally, high doses of CM also increase the likelihood of renal dysfunction (51).

Clinical outcomes of contrastinduced nephropathy If CIN occurs in PCI patients, its clinical course is usually benign, and spontaneous recovery of renal function ensues within one to two weeks (4–6,19,52). However, serious

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clinical consequences, including death, occur in certain patient subpopulations. Despite the widespread use of less toxic low osmolality CM for more than a decade, mortality rates associated with CIN have not decreased (4–6,19,52). Patients with CIN developing post-PCI were observed to have a multitude of noncardiac in-hospital complications, including hematoma formation, pseudoaneurysms, stroke, coma, adult respiratory distress syndrome, pulmonary embolus, and gastrointestinal hemorrhage (5,53). Other frequent complications include serum electrolyte abnormalities and extrarenal comorbidities such as sepsis, respiratory failure, and bleeding. Episodes of bleeding as a result of acute renal deterioration affected about two-thirds (61%) of patients with CIN who later died during hospitalization (54). In another study, bleeding complications were shown to be significantly more frequent in PCI patients with CIN compared with those without CIN, with a respective 11.3% versus 4.8% of patients having gastrointestinal bleeding events (p ⫽0.02) and 42.8% versus 15.9% requiring blood transfusions (p ⫽0.001) (55). An analysis of almost 20,500 patients who underwent PCI showed that the 2% of patients who developed CIN had a 15-fold higher rate of major adverse cardiac events during hospitalization than patients without CIN. They also had a sixfold increase in myocardial infarction and a 11fold increase in vessel reocclusion (p ⬍ 0.0001) (56). CIN requiring dialysis after PCI is rare; ⬍1% of patients will require transient dialysis (acute hemodialysis, ultrafiltration, or peritoneal dialysis within five days of intervention) (44). These patients have a more complicated clinical outcome than patients who do not require dialysis, with a significantly higher rate of non-Q-wave myocardial infarction, creatinine kinasemyocardial band elevation, pulmonary edema, vascular complications such as gastrointestinal bleeding and they have significantly increased lengths of stay (1). Probably as a result of the morbidities described, inhospital mortality in PCI patients is significantly increased by CIN. Mortality was 5.5-fold higher in patients who developed CIN compared with control index patients in a study of more than 16,000 patients who underwent procedures using CM including CT of the head and body, and cardiac or peripheral angiography (54). These results have been verified by similar findings from other researchers (7,55). Patients who survive to discharge after an episode of CIN continue to be at high risk of adverse events during long-term follow-up, especially if dialysis is required. A study by Rihal et al. (53) showed that only 88% of patients who experienced CIN survived for one year, and only 55% survived for five years, compared with 96% and 85%, respectively, of patients without CIN (p ⬍ 0.0001). An even worse long-term outcome was found in patients requiring dialysis. The majority of patients (80%) in the study who developed CIN requiring permanent dialysis after coronary intervention did not survive for one year (44). This survival rate was confirmed in a later study that found a one-year mortality rate of 55% in patients undergoing PCI who required dialysis, compared with a 6% rate in the

control group (p ⬍ 0.0001) (9). The patients receiving dialysis also had a higher rate of myocardial infarction (4.5% vs. 1.6%, p ⫽0.006).

Prevention of contrast-induced nephropathy Evaluation of risk The first steps in reducing the risk of kidney injury are to look for risk factors and review the indications for the administration of CM. Most risk factors for CIN can be detected by history taking and physical examination. Conditions such as dehydration can be at least partially corrected before exposure to the CM. The risk of a decline in kidney function after the administration of CM rises with the number of risk factors present (5,10,16,17,57). A useful tool in the form of validated risk-prediction model to be used in the routine clinical practice has been suggested by Mehran et al. and is summarized in Table 2 (13). The prognostic significance of the proposed risk score for CIN extended to prediction of one-year mortality, as indicated by the results obtained from both the development and validation datasets shown in Fig. 2. It is not necessary to measure the SCr levels of every patient before exposure to CM, but measurements should be made before intra-arterial use of the CM in patients with a history of kidney disease, proteinuria, kidney surgery, diabetes, hypertension, or gout (5,58). The creatinine clearance rate or the glomerular filtration rate should be estimated from the SCr level, according to either the Cockcroft–Gault or the Modification of Diet in Renal Disease formula to identify more accurately patients with values below 50 ml/min/1.73 m2, who are at increased risk for nephropathy (50,59,60). Alternative imaging methods not requiring CM should be considered for use in patients with any risk factors. If CM has to be given, SCr levels should be measured 24 to 48 hours after administration of the CM. Because of the risk of lactic acidosis when CIN occurs in a patient with diabetes who is receiving metformin, it is prudent to withhold this agent until the glomerular filtration rate is greater than 40 mL//min/1.73 m2 and for the 48 hours before exposure of the patient to the CM.

Volume expansion/administration of fluids The administration of fluids is recommended to reduce the risk of CIN. However, data are lacking that specify the optimal fluid regimen. In a small trial reported by Trivedi et al. (61), SCr levels increased by more than 0.5 mg/dl in nine patients (34.6%) given water orally as compared with one (3.7%) given intravenous saline for 24 hours beginning

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Table 2 Validation model to define contrast-induced nephropathy (CIN) risk score Risk factor

Score

Hypotension

5

Intra-aortic balloon pump

5

Congestive heart failure

5

Age ⬎75 years

4

Anemia

3

Diabetes

3

Volume of contrast medium

1 for each 100 mL

Serum creatinine ⬎1.5 mg/dL

4

Or 2 for 40 to ⬍60 mL/min/1.73 m2 4 for 20 to 39 mL/min/1.73 m2 6 for ⬍20 mL/min/1.73 m2

eGFR ⬍60 mL/min/1.73 m2

Anemia: baseline hematocrit value ⬍39% for men and ⬎36% for women; congestive heart failure: class III/IV by New York Heart Association classification and/or history of pulmonary edema; Hypotension: systolic blood pressure ⬍80 mmHg for at least 1 hr requiring inotropic support with medications or intra-aortic balloon pump (IABP) within 24 hours periprocedurally.

Abbreviation: eGFR, estimated glomerular filtration rate. Source: From Ref. 13.

12 hours before administration of the CM, but the trial was stopped early after an unplanned interim examination of the data. Prolonged intravenous fluid therapy is difficult to administer for ambulatory procedures. Another small trial comparing the use of intravenous fluids for 12 hours (before and after administration of the contrast medium) with oral fluids plus a single intravenous bolus of fluid showed better results in the former group (62). However, the results of another trial were contradictory (63). In a study of 1620 patients comparing isotonic saline with 0.45% saline, each

12-month mortality 40%

31%

20%

15% 1,9%

2%

0%

33%

14%

given at 1 mL/kg of body weight per hour for 24 hours starting the morning of the procedure involving the CM, a rise in the SCr level of more than 0.5 mg/dL within 48 hours after administration of the CM was less likely in patients who were given isotonic saline (0.7% vs. 2.0%, p ⫽0.04) (64). It has been hypothesized that alkalinization of tubular fluid might be beneficial by reducing the levels of pH-dependent free radicals. In a recently published study by Merten et al. (65), the creatinine level was less likely to rise more than 25% within two days after the administration of CM in patients who were given an infusion of isotonic sodium bicarbonate than in those given a saline infusion. However, there are methodologic concerns about these results. It is worth noting that the trial was terminated early because of a lower-than-expected rate of “events” in the bicarbonate group, but the timing of the interim analysis and the stopping rules were not prespecified, and the p value for the difference in event rates (p ⫽ 0.02) was higher than is standard for stopping a trial early.

6%

0% Low (16)

Development dataset

Figure 2 One-year survival after percutaneous coronary intervention in patients with or without chronic kidney disease and with or without contrast-induced nephropathy. Source: From Ref. 7.

Administration of agents N-acetylcysteine N-acetylcysteine has the potential to reduce the nephrotoxicity of CM through antioxidant and vasodilatory effects (66).

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In a small trial by Tepel et al., SCr levels rose by more than 0.5 mg/dL in 2% of patients who received N-acetylcysteine as compared with 21% of patients in the control group (p ⬍ 0.01) (67,68). This event rate in the control group is unexpectedly high for patients who received low-dose intravenous low-osmolar CM. Subsequent trials have involved patients with reduced kidney function who underwent coronary angiography. Their results are inconclusive since the majority of these trials are burdened by methodologic problems; they are limited by low power and/or a lack of randomization (66,69–71). Recent meta-analyses suggest some benefit to N-acetylcysteine (66,69–73). However, this finding must be interpreted with caution, given the heterogeneous results of the individual trials, and the underrepresentation of small negative studies (74). In addition, the effect of N-acetylcysteine on outcomes other than minor changes in SCr levels is unknown. More data are needed before N-acetylcysteine can be strongly recommended for the prevention of CIN.

five days of administration of the CM in patients who received ascorbic acid as an antioxidant than in those who received placebo (85). Theophylline and aminophylline have also been proposed as agents that may reduce the risk of CIN (4,5,86). A recent meta-analysis found that the mean rise in SCr levels was significantly lower [by 0.17 mg/dL (15 µmol/L)] at 48 hours after administration of the CM among patients receiving either of these medications than among those receiving placebo (86) However, the clinical importance of this finding is again questionable since there was heterogeneity among the studies included in this meta-analysis. Overall, no prophylactic administration of an agent has been shown conclusively to prevent clinically important CIN and confirmatory trials are required.

Clinical recommendations 1

Hemodialysis or hemofiltration Among patients with advanced kidney disease (mean creatinine clearance, 26 mL/min), an increase in SCr levels of at least 25% was significantly less common in patients randomly assigned to prophylactic hemofiltration before and after the administration of CM than in those assigned to receive fluid alone (5% vs. 50%, p ⬍ 0.001) (75). In-hospital death was also significantly less frequent in the hemofiltration group. However, the SCr level is directly altered by the intervention, and the relationship between the intervention and the reduced mortality rate is unclear. Thus, the role of hemodialysis in patients at high risk for CIN remains uncertain.

2

3

Other agents Several other interventions have been proposed to reduce the risk of CIN, but data to support them are limited. Forced diuresis with furosemide, mannitol, dopamine, or a combination of these given at the time of exposure to the CM has been associated with similar or higher rates of CIN when compared to prophylactic fluids alone (4,5,76–79). Deleterious effects may be explained by negative fluid balance in some instances. In generally small randomized trials, the use of various vasodilators, including dopamine, fenoldopam, atrial natriuretic peptides, calcium blockers, prostaglandin E1, or a nonselective endothelin-receptor antagonist, has not been shown to reduce the risk of CIN in comparison with fluid therapy (5,80–83). On the contrary, a small randomized trial showed a lower frequency of creatinine increase in serum levels in patients given captopril for three days as compared with those given placebo (84). In another small trial, SCr levels were significantly less likely to increase within two to

4

5

Identify the patient at risk for CIN—For patients likely to have reduced kidney function a measurement of the SCr level and estimation of the glomerular filtration rate can be recommended. If the glomerular filtration rate is less than 50 mL/min/1.73 m2, particularly in combination with other risk factors, consideration should be given to alternative imaging approaches. Hydrate adequately—Additional fluids should be given; although the optimal regimen is uncertain, available data support a regimen of 0.9% saline at 1 mL/kg/hr intravenously from up to 12 hours before administration of contrast medium and for up to 12 hours after, with careful observation of fluid balance. Discontinue nephrotoxic drugs—Nonsteroidal antiinflammatory drugs and diuretics should be withheld for at least 24 hours before and after exposure to contrast medium, if possible. Metformin should be withheld for 48 hours before the administration of CM and until it is certain that CIN has not occurred. Choose the CM with the lowest nephrotoxic effects—Low-osmolar CM have less effect on renal function than high-osmolar CM, and isosmolar CM have less effect on renal function than low-osmolar CM (LOCM) in high-risk patients with diabetes and renal insufficiency. Check SCr levels 24 to 48 hours postprocedure.

Conclusions CIN in at-risk patients is a clinical problem. The pathogenesis of CIN remains uncertain. The value of possible preventive strategies in reducing the risk of CIN and associated morbidity

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still is a matter of intense scrutiny and debate. Hydration has been shown consistently to prevent CIN, in contradiction to increased diuresis, hemodialysis, or pharmacologic prophylaxis.

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43 Erectile dysfunction Graham Jackson

Introduction Erectile dysfunction (ED) is common and increases in incidence with age (Fig. 1). It is estimated that 140 million men worldwide currently experience ED to a variable degree and by 2025 the prevalence is predicted to rise to over 300 million men (1). The Massachusetts Male Aging Study (MMAS) identified a prevalence of ED in 52% of men aged 40 to 70 years. As ED increases with age men over 70 years of age have three times the incidence of men in their forties. ED is an important cause of relationships breaking down with the man losing self-esteem, feeling inadequate, and a failure. The frustration affects the partner, who must not be forgotten as part of the evaluation—it may be a man’s problem but it is usually a couple’s concern. While the commonest cause is organic, it is important not to compartmentalize ED—the organic cause may have psychologic consequences, especially depression, so that the management needs to embrace more than just trying to restore erectile function as a lot of psychosocial support is often needed.

Increases with Age Complete

Moderate

Minimal

75 Prevalence %

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Figure 1 ED increases with age. Source: From Ref. 12.

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When advising cardiac patients about sexual activity it is important to individualize the advice. We have a statistical framework to support our recommendations but each person being advised will have, as well as a general cardiac condition (e.g., be post myocardial infarction), varying degrees of effort restriction, determined by, for example, the size of the infarction. In addition, each person will have personal issues regarding safety of sex, treatment of ED, and their confidence in returning to normal activities including sex. As we advise on sex we need to remember that the problems may have preceded the cardiac event with important relationship issues as a consequence.

Cardiovascular response to sexual activity Several studies have been performed using ambulatory ECG and blood pressure (BP) monitoring comparing the heart rate, ECG, and BP response to sexual activity with other normal daily activities (2). The energy requirement during sexual intercourse is not excessive for couples in a longstanding relationship. The average peak heart rate is 110–130 beats/min and the peak systolic BP 150–180 mmHg, resulting in a rate pressure product of 16,000–22,000. Expressed as a multiple of the metabolic equivalent (MET) of energy expenditure expanded in the resting state (MET ⫽ 1), sexual intercourse is associated with a work load of 2-3 METs before orgasm and 3–4 METs during orgasm. Younger couples, who are not usually the individuals we advise, may be more vigorous in their activity, expending 5–6 METs. The average duration of sexual intercourse is 5–15 minutes. Therefore, sexual intercourse is not an extreme or sustained cardiovascular stress for patients in a longstanding relationship who are comfortable with each other. Casual sexual intercourse, which must be separated from extramarital sexual intercourse with a longstanding “other partner”, may involve a greater

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Table 1 MET equivalents as a guide to relating daily activity to sexual activity Daily activity Sexual intercourse with established partner Lower range (normal) Lower range orgasm Upper range (vigorous activity) Lifting and carrying objects (9–20 kg) Walking one mile (1.6 km) in 20 min on the level Golf Gardening (digging) Do-it-yourself, wallpapering, etc. Light housework, e.g., ironing, polishing Heavy housework, e.g., making beds, scrubbing floors, cleaning windows

METs 2–3 3–4 5–6 4–5 3–4 4–5 3–5 4–5 2–4 3–6

Abbreviation: MET, metabolic equivalent.

cardiac workload because of lack of familiarity and age mismatch (usually older men with a younger woman) leading to different levels of activity and expectations (3). By using our knowledge of MET equivalents in the clinical setting we can advise on sexual safety by comparing sexual intercourse to other activities. Some of the daily activities and MET equivalents are shown in Table 1.

Exercise testing Using METs, sexual intercourse is equivalent to 3–4 minutes of the standard Bruce treadmill protocol. Where doubts exist about the safety of sexual intercourse, an exercise test can help guide decision–making. If a person can manage at least four minutes on the treadmill without significant symptoms, ECG evidence of ischemia, a fall in systolic BP or dangerous arrhythmias, it will be safe to advise on sexual activity (3,4). Drory et al. (5,6) studied 88 men with CAD (off therapy) using ambulatory ECGs and bicycle exercise tests. On ambulatory ECGs one-third of the men had ischemia during sexual intercourse and all of them had ischemia on the bicycle exercise ECG. All patients without ischemia on the exercise test (n ⫽ 34) also had no ECG changes during sexual intercourse. All ischemic episodes during sexual intercourse were associated with an increasing heart rate identifying a potentially important therapeutic role for heart rate lowering drugs (β-adrenoreceptor antagonists, verapamil, diltiazem). If a patient is unable to perform an exercise test because of mobility problems, a pharmacologic stress test should be utilized (e.g., Dobutamine stress echocardiography).A man who cannot achieve 3–4 METs should be further evaluated by angiography if appropriate (3). Advice on METs in the clinical setting and relating this advice to sexual intercourse should also include advice on

avoiding stress, a heavy meal or excess alcohol consumption prior to sexual intercourse. I personally find the ability to walk a mile on the flat in 20 minutes without undue chest pain or breathlessness a useful clinical marker of physical ability equivalent to sex. Adding climbing up and down two flights of household stairs without symptoms is also helpful (one flight ⫽ about 13 steps). Many couples continue to be sexually active short of penetrative sexual intercourse, so if they are able to do so advice on treating ED is much easier. The importance of asking cannot be over emphasized (3).

Positions As long as the couple are not stressed by the sexual position they use, there is no evidence of increased cardiac stress to a man or woman. Man on top, woman on top, side to side, oral sex, and masturbation are cardiologically equivalent. In homosexual relationships, other than casual, anal intercourse is not associated with increased cardiac stress provided proper lubrication is used and amyl nitrate (“poppers”) are not used in the presence of a phosphodiesterase type-5 (PDE-5) inhibitor by the patient or partner.

Cardiac risk There is only a small myocardial infarction risk associated with sex. The relative risk of a myocardial infarction (MI) during the two hours following sex is shown in Table 2 (7). The baseline absolute risk of an MI during normal daily life is low—one chance in a million per hour for a healthy adult, and 10 chances in a million per hour for a patient with documented cardiac disease. Therefore, during the two hours post-sex, the risk increases to 2.5 in a million for a healthy adult and 25 in a million for a patient with documented cardiac disease, but, importantly, there is no risk

Table 2 Relative risk of MI during the two hours after sexual activity: physically fit equals sexually fit Patient type

Relative risk (95% CI)

All patients Men Women Previous MI Sedentary life Physically active

2.5 2.7 1.3 2.9 3.0 1.2

(1.7–3.7) (1.8–4.0) (0.3–5.2) (1.3–6.5) (2.0–4.5) (0.4–3.7)

Abbreviations: CI, confidence interval; MI, myocardial infarction.

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increase in those who are physically active (physically fit ⫽ sexually fit). A similar study from Sweden reported identical findings (8). If we take a baseline annual rate of 1% for a 50-year old man, as a result of weekly sexual activity, the risk of an MI increases to 1.01% in those without a history of a previous MI and to 1.1% in those with a previous history. Coital sudden death is very rare. In three large studies, sex activity-related death was 0.6% in Japan, 0.18% in Frankfurt, and 1.7% in Berlin. Extramarital (casual) sex was responsible for 75%, 75%, and 77%, respectively, and the victims were men in 82%, 94%, and 93% of cases, respectively (2). An older man with a younger woman was the commonest scenario.

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Table 3 Shared risk factors for coronary artery disease and ED Coronary artery disease

ED

Age Dyslipidemia Hypertension Diabetes Smoking Sedentary lifestyle Obesity Depression Male sex

Age Dyslipidemia Hypertension Diabetes Smoking Sedentary lifestyle Obesity Depression Coronary artery disease Peripheral vascular disease

Abbreviation: ED, erectile dysfunction,

Vasculogenic ED Vascular diseases are the most common cause of ED with endothelial dysfunction now recognized as the common denominator (Fig. 2) (9). ED and coronary artery disease (CAD) share the same risk factors, which explains the endothelial link (Table 3) (10). However, before attributing ED to a purely vascular cause it is important to evaluate the patient thoroughly as other factors may be contributing to the problem or occasionally be the cause. As men age, there may be comorbid conditions which need to be addressed (endocrine, cellular, neural, or iatrogenic, e.g., drug therapy) and organic ED will have psychologic consequences needing counselling and support. A large number of drugs, whether prescribed or recreational, can affect sexual function (3). These drugs include: •

Cardiovascular drugs: Thiazide diuretics, β-adrenoceptor antagonists, calcium channel antagonists, centrally acting agents (e.g., methyl-dopa, clonidine, reserpine, ganglion

Risk Factors Coronary Heart Disease Smoking Blood Pressure Cholesterol Diabetes

Erectile Dysfunction

E.D.

Smoking Blood Pressure Cholesterol Diabetes

Endothelial Dysfunctionthe common denominator

Figure 2 Risk factors for erectile dysfunction (ED) and coronary heart disease; Endothelial dysfunction (ED) ⫽ Erectile dysfunction (ED). Source: From Ref. 9.

•

•

•

blockers), digoxin, lipid-lowering agents, ACE inhibitors, recreational drugs, such as alcohol (ethanol), marijuana, amphetamines, cocaine, anabolic steroids, heroin (diamorphine); Psychotropic drugs: Major tranquillisers, anxiolytics and hypnotics, tricyclic antidepressants, selective serotonin reuptake inhibitors; Endocrine drugs: Antiandrogens, oestrogens, gonadotropinreleasing hormone analogues; Others: Cimetidine, ranitidine, metoclopramide, carbamazepine

The negative impact may be on erections, ejaculation, or sex drive. There is little evidence that changing cardiovascular drug therapy will restore erectile function, suggesting it is the underlying disease process that is more important. However, if there is a strong temporal relationship between the commencement of treatment and the onset of ED (2 ⫺ 4 weeks) it is logical to change therapy if it is safe to do so. Antihypertensive agents, especially thiazide diuretics, are the most frequently incriminated and a switch to angiotensin II receptor antiantagonists or ␣-adrenoceptor antagonists should be considered (11). Where drugs are prognostically important, such as ß-adrenoceptor antagonists post myocardial infarction, the decision to discontinue therapy should be approached with caution and only undertaken after considering overall risks (4).

ED and cardiovascular disease MMAS (12) was a random sample, cross-sectional, observational study of 1709 healthy men aged 40–70 years to assess the impact of aging on a wide range of health-related issues. Fiftytwo percent of respondents reported some degree of ED (17% mild, 25% moderate, 10% complete) with the prevalence

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increasing with age (Fig. 1). Cardiovascular disease was significantly associated with ED. The incidence was doubled in patients with hypertension, tripled in diabetic patients, and in those with established coronary disease it was quadrupled. Cigarette smoking increased the prevalence twofold for all of these conditions and a positive relationship was found for reduced high-density lipoprotein-cholesterol and ED. The association between hyperlipidaemia and ED has been studied in apparently healthy men who complained of ED (13). Over 60% had hyperlipidaemia and 90% of these had evidence of penile arterial disease using Doppler ultrasound studies. Diabetes is commonly associated with ED with a prevalence of 50% (range 27–70% depending on age and disease severity). The onset of ED usually occurs within the first 10 years of the diagnosis of diabetes (14). Men aged over 50 years with established CAD have an ED incidence of 40% and in those post myocardial infarction or post vascular surgery the incidence ranges from 39% to 64%, depending on diagnostic criteria (15).

ED as a marker of vascular disease As ED and vascular disease share the same risk factors, the possibility arises that ED in otherwise asymptomatic men may be a marker of silent vascular disease, especially CAD (16). This has now been established to be the case and represents an important new means of identifying those at risk of vascular disease. Pritzker (17) studies 50 asymptomatic men (other than ED) aged 40–60 years who had cardiovascular risk factors (multiple in 80%). An exercise ECG was abnormal in 28 men and subsequent coronary angiography in 20 men identified severe CAD in six, moderate two vessel disease in seven, and significant single vessel CAD in a further seven men. In a study of 132 men attending day case angiography, 65% had experienced ED before their CAD diagnosis had been made (18). ED also correlates with the severity of CAD with single vessel disease patients having less difficulty in obtaining an erection (19). The smaller penile arteries (diameter 1⫺2 mm) suffer significant obstruction or endothelial disruption earlier from plaque burden than the larger coronary ( 3⫺4 mm), carotid (5⫺7 mm), or iliofemoral (6⫺8 mm) arteries; hence ED may be symptomatic before a coronary event (20). Addressing cardiovascular risk early after the presentation of ED and aggressive intervention to reduce risk may have long-term symptomatic and prognostic cardiac benefits (21). Most acute coronary syndromes follow from asymptomatic lipid-rich plaques rupturing and ED may therefore be a marker for reducing the risk of this happening (22). In Montorsi et al’s study of 300 men presenting with an acute coronary syndrome (mean age 62.5 years) the ED

prevalence was 49% (147/300) and in 99 (67%) the ED preceded the onset of cardiac symptoms by an average of three years (22). This time interval provides an important opportunity for risk reduction given the established benefits in both primary and secondary prevention of coronary disease and peripheral vascular disease. Several studies have now reinforced the concept that endothelial dysfunction is the common denominator for ED and CAD (9). In one study 30 men with Doppler proven ED and no clinical evidence of cardiovascular disease (mean age, 46 years) were compared with 27 healthy age matched controls using flow-mediated brachial artery vasodilatation studies (23). The men with ED exhibited significantly lower brachial artery flow-mediated endothelium dependent vasodilatation (p ⬍ 0.05, Fig. 3) and endothelium-independent vasodilatation judged by a blunted response to 0.4 mg glyceryl trinitrate sublingually (p ⫽ 0.02). Looking at biochemical markers P-selection, ICAM-1, VCAM-1, and endothelin-1 concentrations were significantly greater in men with ED and no cardiovascular disease symptoms compared to men without ED (24). Asymmetric demethyl arginine (ADMA) is an endogenous competitive nitric oxide (NO) synthase inhibitor and is an independent risk marker for cardiovascular disease impairing the L-arginine-NO pathway. Recent studies have found elevated levels of ADMA in men with ED and CAD (25⫺27). As the evidence accumulates that ED is a marker for asymptomatic CAD its importance as a barometer of the vasculature generally is being appreciated. Vlachopoulos et al. studied 50 asymptomatic men for CAD with ED and performed angiography in 47 (28). Nine (19%) had angiographic silent CAD. In a health screening program in Vienna 2869 men aged 20 to 80 years completed the International Index to Erectile Function (IIEF) questionnaire (29). Men with moderate to severe ED but not mild ED had a 10-year relative risk increase

Endothelium-Dependent Vasodilation* 5 Control

4

ED Flow3 Mediated Vasodilation 2 (%) 1 0 0

20

40

60

80

Time (sec) *Brachial artery response to 5-minute wrist cuff occlusion and release; % dilation from baseline to 60 seconds after cuff release (P=.05); significant increase in flow-mediated vasodilation of normal control subjects compared with ED over entire curve (P=.014).

Figure 3 Men with ED and no cardiac symptoms demonstrate impaired endothelial function compared to controls. Source: From Ref. 13.

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over 10 years of 65% for CAD and 43% for stroke. In the Prostate Cancer Prevention Trial 9457 men aged 55 or above were randomized to placebo and 8063 (85%) had no cardiovascular disease at entry (30). ED was present in 3816 (47%) at entry with a further 2420 developing ED after five years. Men with ED had a 25–45% increased risk of cardiovascular events during the nine-year study follow-up period. The Second Princeton Consensus on Sexual Function concluded that the recognition of ED as a warning sign of silent vascular disease has led to the concept that a man with ED and no cardiac symptoms is a cardiac (or vascular) patient until proved otherwise. Therefore any asymptomatic man who presents with ED that does not have an obvious cause (e.g., trauma) should be screened for vascular disease and have blood glucose, lipids, and BP measured. Ideally, all patients at risk should undergo an elective exercise ECG to facilitate risk stratification (31,32).

Treating ED in patients with cardiovascular disease Recognizing the need for advice on management of ED two consensus panels (UK and American) have produced similar guidelines dividing cardiovascular risk into three practical categories with management recommendations (3,4). The Princeton consensus guidelines have recently been updated (Table 4) (4). It is recommended that all men with ED should undergo a full medical assessment (Fig. 4). Baseline physical activity needs to be established and cardiovascular risk graded

Table 4

507

low, intermediate, or high. Most patients with low or intermediate cardiac risk can have their ED managed in the outpatient or primary care setting. There is no evidence that treating ED in patients with cardiovascular disease increases cardiac risk; however, this is with the proviso that the patient is properly assessed and the couple or individual (self-stimulation may be the only form of sexual activity) are appropriately counselled. Oral drug therapy is the most widely used because of its acceptability and effectiveness, but all therapies have a place in management. The philosophy is to always be positive during what, for many men and their partners, is an uncertain time.

Phosphodiesterase (PDE5) inhibitors To say that sildenafil has transformed the management of ED would be a substantial understatement. Its mechanism of action by blocking the degradation of cGMP by PDE5 promotes blood flow into the penis and the restoration of erectile function (Fig. 5). Vardenafil and tadalafil have been added to this family of drugs (33,34). Because their mechanism of action is the same, there is no reason to assume that there will be any significant differences in ED effectiveness, but their half-life may be of cardiac clinical importance. Hemodynamically, PDE5 inhibitors have mild nitrate-like actions (sildenafil was originally intended to be a drug for stable angina) (35). As PDE5 is present in smooth muscle cells throughout the vasculature and the NO/cGMP pathway is

Risk from sexual activity in cardiovascular diseases: Second Princeton Consensus Conference

Low risk: typically implied by the ability to perform exercise of modest intensity without symptoms Asymptomatic and ⬍3 major risk factors (excluding gender) Major CVD risk factors include age, male gender, hypertension, diabetes mellitus, cigarette smoking, dyslipidemia, sedentary lifestyle, and family history of premature CAD Controlled hypertension Betablockers and thiazide diuretics may predispose to ED Mild, stable angina pectoris Noninvasive evaluation recommended Antianginal drug regimen may require modification Postrevascularization and without significant residual ischemia ETT may be beneficial to assess risk Post-MI (⬎6–8 wk), but asymptomatic and without ETT-induced ischemia, or postrevascularization If postrevascularization or no ETT-induced ischemia, intercourse may be resumed 3–4 weeks post MI (Continued)

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Table 4

Risk from sexual activity in cardiovascular diseases: Second Princeton Consensus Conference (Continued)

Mild valvular disease May include select patients with mild aortic stenosis LVD (NYHA class I) Most patients are low risk

Intermediate or indeterminate risk: evaluate to reclassify as high or low risk Asymptomatic and ⱖ3 CAD risk factors (excluding gender) Increased risk for acute MI and death ETT may be appropriate, particularly in sedentary patients Moderate, stable angina pectoris ETT may clarify risk MI ⬎2 wk but ⬍6 wk Increased risk of ischemia, reinfarction, and malignant arrhythmias ETT may clarify risk LVD/CHF (NYHA class II) Moderate risk of increased symptoms Cardiovascular evaluation and rehabilitation may permit reclassification as low risk Noncardiac atherosclerotic sequelae (peripheral arterial disease, history of stroke, or transient ischemic attacks) Increased risk of MI Cardiologic evaluation should be considered

High risk: defer resumption of sexual activity until cardiological assessment and treatment Unstable or refractory angina Increased risk of MI Uncontrolled hypertension Increased risk of acute cardiac and vascular events (i.e., stroke) CHF (NYHA class III, IV) Increased risk of cardiac decompensation Recent MI (⬍2 wk) Increased risk of reinfarction, cardiac rupture, or arrhythmias, but impact of complete revascularization on risk is unknown High-risk arrhythmias Rarely, malignant arrhythmias during sexual activity may cause sudden death Risk is decreased by an implanted defibrillator or pacemaker Obstructive hypertrophic cardiomyopathies Cardiovascular risks of sexual activity are poorly defined Cardiologic evaluation (i.e., exercise stress testing and echocardiography) may guide patient management Moderate to severe valve disease Use vasoactive drugs with caution Abbrevations: CAD, coronary artery disease; CHF, congestive heard failure; CV, cardiovascular; CVA, cerebrovascular accident; ED, erectile dysfunction; ETT, exercise tolerance test; LVD, left ventricular dysfunction; MI, myocardial infarction; NYHA, New York Heart Association.

Source: Adapted from Ref. 4.

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Figure 4

Princeton II Algorithm

Princeton guidelines assessment algorithm. Source: From Ref. 4.

Sexual Inquiry

Clinical Evaluation Low Risk

• Initiate or resume sexual activity or • Treatment for sexual dysfunction

Indeterminate Risk

High Risk

Cardiovascular Assessment and Restratification

• Sexual activity deferred until stabilization of cardiac condition

Risk factor and coronary heart disease evaluation, treatment and follow up for all patients with ED

involved in the regulation of BP, PDE5 inhibitors have a modest hypotensive action. In healthy men, a single dose of sildenafil 100 mg transiently lowered BP by an average of 10/7 mmHg with a return to baseline at six hours post dose. There was no effect on heart rate (35). As NO is an important neurotransmitter throughout the vasculature and is involved in the regulation of vascular smooth muscle relaxation, a synergistic and clinically important interaction with oral or sublingual nitrates can occur. A profound fall in BP can result. The mechanism involves the combination of nitrates increasing cGMP formation by activating guanylate cyclase and PDE5 inhibition decreasing cGMP breakdown by inhibiting PDE5. The concomitant administration of PDE5 inhibitors and nitrates is a contraindication to their use and this recommendation also extends to other NO donors such as nicorandil. Clinical guidelines regarding timing of sublingual

Figure 5 Mechanism of action of PDE5 inhibitors. Abbreviations: NO, nitric oxide; PDE5, phosphodieterase type 5.

nitrate use post-PDE5 inhibitor are 12 hours for sildenafil and vardenafil (4). Tadalafil, with its long half-life, did not react with nitrates at 48 hours post use. Oral nitrates are not prognostically important drugs and they can therefore be discontinued and, if needed, alternative agents substituted (36). After oral nitrate cessation, and provided there has been no clinical deterioration, PDE5 inhibitors can be used safely. It is recommended that the cessation time interval prior to PDE5 inhibitor use is five halflives which equals five days for the most popular once-daily oral nitrate agents.

Sildenafil Sildenafil was the first oral treatment for ED and is the most extensively evaluated (35). Overall success rates in patients with cardiovascular disease of 80% or greater have been recorded with no evidence of tolerance. Patients with diabetes with or without additional risk factors, with their more complex, and extensive pathophysiology, have an average success rate of 60%. In randomized trials to date, open-label or outpatient monitoring studies the use of sildenafil is not associated with any excess risk of myocardial infarction, stroke, or mortality (38⫺40). In patients with stable angina pectoris there is no evidence of an ischemic effect due to coronary steal, and in one large, double-blind, placebo-controlled, exercise study sildenafil 100 mg increased exercise time and diminished ischemia (41). A study of the hemodynamic effects in men with severe CAD identified no adverse cardiovascular effects and a potentially beneficial effect on coronary blood flow reserve (42). Studies in patients with and without diabetes have demonstrated improved endothelial function acutely and after long-term oral dose administration, which may have implications beyond

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the treatment of ED (35). Sildenafil has also been shown to attenuate the activation of platelet IIb/IIIa receptor activity (43). Hypertensive patients on mono- or multiple therapy have experienced no increase in adverse events with the exception of doxazosin, a nonselective ␣-adrenoceptor antagonist. Occasional postural effects have occurred with sildenafil when taken within four hours of Doxazosin 4 mg; an advisory to avoid this time interval is now in place. Sildenafil has also been proven effective in heart failure patients who were deemed suitable for ED therapy (44). The incidence of ED in heart failure patients is 80%, making this finding of major clinical importance. On average, the sildenafil dose is 50 mg with 25 mg advised initially in those over 80 years of age because of delayed excretion. Sildenafil 100 mg is invariably needed in patients with diabetes. An empty stomach and avoiding alcohol or cigarette smoking facilitates the effect. Sildenafil 100 mg has no additional adverse cardiac effects above the 50 mg dose and should be routinely prescribed if the 50 mg dose after four attempts is not effective. Sildenafil’s short half-life makes it the drug of choice in patients with the more severe cardiovascular disease, allowing early use of support therapy if an adverse clinical event occurs.

Vardenafil

Tadalafil

Lifestyle factors

Tadalafil has also been extensively evaluated in patients with cardiovascular disease and has a similar safety and efficacy profile to sildenafil (45). Studies have shown no adverse effects on cardiac contraction, ventricular repolarization, or ischemic threshold. A similar hypotensive effect has been recorded with a dose of doxazosin 8 mg so caution is needed. As hypotension does not occur in the supine position and as tadalafil has a long half-life it is suggested that tadalafil is taken in the morning and doxazosin in the evening. There is no interaction of tadalafil with the selective ␣adrenoceptor antagonist tamsulosin, which can, therefore, be prescribed as an alternative to doxazosin for symptomatic benign prostate hypertrophy (46). Because of its long half-life, tadalafil may not be the first choice for the patients with more complex cardiovascular disease. However, as 80% of patients with cardiovascular disease stratify into low risk it is an alternative for the majority. Tadalafil 10 mg is equivalent to sildenafil 50 mg and 20 mg to 100 mg. Of particular interest is the daily use of tadalafil 10 mg which, after one week because of its half-life, is equivalent to 16–18 mg at steady state. In on-demand failures a regular dosing regime has been successful in 60% without increased adverse effects (47). This increases the chance of success with important implications for the more difficult cases and its use post radical prostatectomy as a daily regime is encouraging. There is no evidence of increased cardiovascular risk with on-demand, three times weekly, or daily dosing (48).

Lifestyle factors have been associated with ED in both crosssectional and longitudinal studies. In particular, obesity and sedentary lifestyle are clear-cut risk factors for ED, both in men with comorbid illnesses such as hypertension and diabetes, and especially in men without overt cardiovascular disease (50). Other lifestyle factors, such as smoking and alcohol consumption, have been implicated in some, but not all, studies to date. Intervening on cardiovascular and lifestyle factors may have broader benefits beyond restoration of erectile function. This important concept needs careful consideration, as recent studies have implicated the role of the metabolic syndrome, obesity, insulin resistance, and lack of exercise as independent risk factors for both ED and cardiovascular disease (51,52). The role of obesity in ED has been confirmed in largescale, cross-sectional, and longitudinal studies (53,54). In a study in The Netherlands, 1700 Dutch men between the age of 50 and 75 were evaluated for the presence of ED and other health conditions (55). Body mass index (BMI) was found to be a significant predictor of ED, both as a single factor and in combination with other risk factors (e.g., lower urinary tract symptoms (LUTS), hypertension, diabetes). Lack of physical activity is another lifestyle factor that has been strongly linked to the occurrence of ED in aging men. In the health professionals follow-up study (53), ED was associated with both increased BMI and decreased level of physical activity. Participants were categorized according to their level of exercise or physical activity. Higher levels of sedentary

Since vardenafil has a very similar chemical structure to sildenafil, it is not surprising that it has a similar clinical profile. One study has reported no impairment of exercise ability in stable CAD patients receiving vardenafil 20 mg (49). Similar clinical efficiency for all three agents has been observed in patients with diabetes.

Other therapies When oral agents are not effective, intracavernous injection therapy, transurethral alprostadil, or a vacuum pump are alternatives requiring specialized referral and advice (3,4). Warfarin is not a contraindication to vacuum pumps or injections but specialized training is needed. There is no evidence of increased cardiovascular risk from using any of these therapeutic options. If surgical intervention with general anesthetic is being anticipated, a full cardiologic risk evaluation is recommended.

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References

behavior (less physical activity) were found to be a strong, independent predictor of ED in this study. Frequent vigorous exercise was associated with an approximately 30% reduction in the risk for ED. The effects of weight loss and exercise were examined further in a randomized intervention trial of lifestyle modification in men with obesity-related ED (56). This study compared two years of exercise and weight loss with an educational control in 110 obese men (mean BMI ⫽ 36.4 kg/m2) with moderate to severe ED. Approximately one-third of men in the intervention group achieved normal levels of erectile function following treatment, compared with ⬍5% of men in the control group. Changes in weight loss and exercise were shown to affect endothelial function, as measured by forearm brachial Doppler assessment, and were highly correlated with improvements in erection. Taken together, these studies strongly support the role of adverse lifestyle factors in the development and maintenance of ED. Obesity and lack of exercise, in particular, have been strongly implicated in a number of cross-sectional and longitudinal studies. At least one long-term prospective study has shown that lifestyle intervention can effectively restore erectile function in a substantial number of men with obesity-related ED, at least among those without significant medical comorbidities. For clinicians, the implications are clear that men with ED and other cardiovascular risk factors (e.g., obesity, sedentary lifestyle) should be counselled on lifestyle modification.

511

coincidental given the widespread use of PDE-5 inhibitors in men who are at risk being older and with vascular disease. The only identifiable risk factor is a small cup-disc ratio. It seems sensible to avoid PDE-5 inhibitors in those previous suffering NAION in one eye.

Summary ED and vascular disease commonly coexist. They share the same risk factors and endothelial dysfunction is the common denominator. ED may develop in an otherwise asymptomatic male and be an important predictor of subsequent acute or chronic cardiac events. ED may therefore offer an opportunity for risk assessment and therapeutic intervention to reduce the chance of a subsequent cardiac presentation. Cardiac patients with ED need a careful assessment to judge the safety of sexual activity and suitability for ED treatment. Properly assessed and counselled patients can safely enjoy sexual activity. ED therapy with phosphodiesterase type five inhibitors is safe and effective providing the patient and partner are advised on their use and the importance of avoiding drug interactions, especially with nitrates.

Conclusion

Androgens The use of testosterone replacement therapy for the treatment of hypogonadism and ED may assist PDE5 inhibitors if they have failed to be effective (57). Testosterone levels within the normal range have neutral or potentially beneficial effects on the cardiovascular system (58). Androgen replacement therapy should be offered to men with CAD and hypogonadism if symptomatically appropriate. The absence of long-term studies needs to be addressed in terms of possible preventive properties on the vascular wall, reduction in low-density lipoprotein levels, and the reduction of insulin resistance in contrast to the increase in hematocrit and risk of exacerbating prostate cancer.

ED is common in patients with cardiovascular disease and should be routinely enquired about. The cardiac risk of sexual activity in patients with cardiovascular disease is minimal in properly assessed patients. The restoration of a sexual relationship is a possibility for the majority of patients with cardiovascular disease and ED using oral PDE5 inhibitors, which have an excellent safety profile (avoiding nitrate use). ED is a marker for cardiovascular disease as well as its consequence; therefore, its identification (in the asymptomatic male) provides the opportunity to address other cardiovascular risk factors and detect silent but significant vascular pathology.

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Nonarteritic anterior ischemic optic neuropathy (NAION) The reports of the risk of “blindness” following PDE-5 inhibitor use has caused concern (59). Several case reports have linked PDE-5 inhibitors to NAION. No explanation as to the mechanism currently exists and it is most likely to be

2 3

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Herrman HC, Chang G, Klugherz BD, et al. Haemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 2000; 342:1662–1666. Halcox JPJ, Nour KRA, Zalos G, et al. The effect of sildenafil on human vascular function, platelet activation and myocardial ischaemia. J Am Coll Cardiol 2002; 40:1232–1240. Katz SD. Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure. Congest Heart Fail 2003; 9:9–15. Jackson G, Kloner RA, Costigan TM, et al. Update on clinical trials of tadalafil demonstrates no increased risk of cardiovascular adverse events. J Sex Med 2004; 1:161–167. Kloner RA, Jackson G, Emmick JT, et al. Interaction between phosphodiesterase 5 inhibitor, tadalafil, and two alpha blockers, doxazosin and tamsulosin in healthy normotensive men. J Urol 2004; 172:1935–1940. McMahon C. Comparison of efficacy, safety, and tolerability of on demand tadalafil and daily dosed tadalafil for the treatment of erectile dysfunction. J Sex Med 2006;2:415–424. Kloner RA, Jackson G, Hutter AM, et al. Cardiovascular safety update of tadalafil: retrospective analysis of data from placebocontrolled and open-label clinical trials of tadalafil with as needed, three times-per-week or once-a-day dosing. Am J Cardiol 2006; 97:1778–1784. Thadani U, Smith W, Nash S, et al. The effect of vardenafil, a potent and highly selective phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction, on the cardiovascular response to exercise in patients with coronary artery disease. J Am Coll Cardiol 2002; 40:2006–2012. Nicolosi A, Glasser DB, Moreira ED, et al. Prevalence of erectile dysfunction and associated factors among men without

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concomitant diseases: a population study. Int J Impot Res 2003; 15:253–257. Esposito K, Giugliano D. Obesity, the metabolic syndrome and sexual dysfunction. Int J Impot Res 2005; 17:391–398. Rosen RC, Fisher W, Eardley I, et al. The multinational men’s attitudes of life events and sexuality (MALES) study; prevalence of erectile dysfunction and related health concerns in the general population. Curr Med Res Opin 2004; 20: 607–617. Bacon CG, Mittleman MA, Kawachi I, et al. Sexual function in men older than 50 years of age; results from the health professionals follow-up study. Ann Intern Med 2003; 139: 161–168. Blanker MH, Bosch JL, Groeneveld FP, et al. Erectile and ejaculatory dysfunction in a community-based sample of men 50–78 years old: prevalence, concerns and relation to sexual activity. Urology 2001; 57:763–768. Blanker MH, Bohnen AM, Groeneveld FP, et al. Correlates for erectile and ejaculatory dysfunction in older Dutch men: a community-based study. J Am Geriatr Soc 2001; 49:436–442. Esposito K, Giugliano F, Di Palo C, et al. Effect of lifestyle changes on erectile dysfunction in obese men: a randomized controlled trial. JAMA 2004; 291:1978–1984. Shabsigh R, Kaufman JM, Steidle C, et al. Randomised study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not response to sildenafil alone. J Urol 2004; 172:658–663. Muller M, Van Der Schouw YT, Thijssen JHH, et al. Endogenous sex hormones and cardiovascular disease in men. J Clin Endocrinol Metab 2003; 88:5076–5086. Fraunfelder FW, Pomeranz HD, Egan RA. Non-arteritic anterior ischaemic optic neuropathy and sildenafil. Arch Ophthamol 2006; 124:733–734.

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44 Peripheral arterial disease Zoran Lasic and Michael R. Jaff

Introduction The term “peripheral arterial disease” (PAD) covers a multitude of disorders involving arterial beds exclusive of the coronary arteries. There are numerous pathophysiologic processes that could contribute to the creation of stenoses or aneurysms of the noncoronary arterial circulation. Atherosclerosis represents the leading disease process affecting the aorta and its branch arteries. Patients undergoing percutaneous coronary intervention (PCI) who have PAD have been shown to have worse short- and long-term outcomes compared to patients without PAD (1–3). This chapter will cover pharmacotherapy and nonpharmacologic therapies for PAD involving lower extremities.

Cardiovascular risk reduction The clinical manifestations of PAD are associated with reduction in functional capacity and quality of life, but because of the systemic nature of the atherosclerotic process there is a strong association with coronary and carotid artery disease. Consequently, patients with PAD have an increased risk of cardiovascular and cerebrovascular ischemic events [myocardial infarction (MI), ischemic stroke, and death] compared to the general population (4,5). In addition, these cardiovascular ischemic events are more frequent than ischemic limb events in any lower extremity PAD cohort, whether individuals present without symptoms or with atypical leg pain, classic claudication, or critical limb ischemia (6). Therefore, aggressive treatment of known risk factors for progression of atherosclerosis is warranted. In addition to tobacco cessation, encouragement of daily exercise and use of a low cholesterol, low salt diet, PAD patients should be offered therapies to reduce lipid levels, control blood pressure, control blood glucose in patients with diabetes mellitus, and offer other effective antiatherosclerotic strategies. A recent position paper

describing antiatherosclerosis strategies includes patients with PAD, viewed as a coronary artery equivalent (7).

Treatment of hyperlipidemia A meta-analysis was performed on randomized trials assessing lipid-lowering therapy in 698 patients with PAD who were treated with a variety of therapies, including diet, cholestyramine, probucol, and nicotinic acid, for four months to three years (8). There was a significant difference in total mortality [0.7% in the treated patients, as compared with 2.9% in the patients given placebo (p ⫽ NS)], with an additional reduction in disease progression, as measured by angiography and the severity of claudication. Two studies evaluated the effects of lipid-lowering therapy on clinical endpoints in the leg. The Program on the Surgical Control of the Hyperlipidemias was a randomized trial of partial ileal-bypass surgery for the treatment of hyperlipidemia in 838 patients (9). After five years, the relative risk (RR) of an abnormal ankle-brachial index value (ABI) was 0.6 (95% CI, 0.4 to 0.9, absolute risk reduction, 15% points, p ⬍ 0.01), and the RR of claudication or limb-threatening ischemia was 0.7 (95% CI, 0.2 to 0.9, absolute risk reduction, 7% points, p ⬍ 0.01), as compared with the control group. In patients with PAD, therapy with a statin not only lowers serum cholesterol levels, but also improves endothelial function, as well as other markers of atherosclerotic risk, such as serum P-selectin concentrations (10,11). In a subgroup of patients treated with simvastatin in the Scandinavian Simvastatin Survival Study, the RR of new claudication or worsening of preexisting claudication was 0.6 (95% CI, 0.4 to 0.9, absolute risk reduction, 1.3% points), as compared with patients randomly assigned to placebo (12). Several studies have revealed that statins have a beneficial effect on exercise performance in patients with claudication (13). Statins also improve endothelial function and have other

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favorable metabolic effects, but the functional benefit of statins is not due to regression of atherosclerosis or gross change in limb hemodynamics. The National Cholesterol Education Program classifies patients with PAD in the group of coronary heart disease (CHD) risk equivalents. Other coronary heart equivalents include abdominal aortic aneurysm, carotid artery disease (transient ischemic attacks or stroke of carotid origin or ⬎50% obstruction of a carotid artery), diabetes mellitus, and patients with two or more risk factors for atherosclerosis which produces the 10-year risk for CHD ⬎20% (14). Patients with PAD and low-density lipoprotein (LDL) cholesterol (LDL-C) of 100 mg/dL or greater should be treated with a statin, but when risk is very high, an LDL cholesterol goal of less than 70 mg/dl is an appropriate therapeutic option. Factors that place patients in the category of very high risk are the presence of established cardiovascular disease (CVD) plus (i) multiple major risk factors (especially diabetes), (ii) severe and poorly controlled risk factors (especially continued cigarette smoking), (iii) multiple risk factors of the metabolic syndrome [especially high triglycerides, that is greater than or equal to 200 mg/dL plus non-HDL cholesterol greater than or equal to 130 mg/dL with low-HDL cholesterol (less than or equal to 40 mg/dL)], and (iv) on the basis of the PROVE IT trial (15), patients with acute coronary syndromes (16,17).

Treatment of hypertension Treatment of high blood pressure is indicated to reduce the risk of cardiovascular events (18). Betablockers, which have been shown to reduce the risk of MI and death in patients with coronary atherosclerosis (19), do not adversely affect walking capacity (20,21). These agents must be offered to patients with PAD who have already suffered a MI or have established coronary artery disease. Angiotensin-converting enzyme inhibitors reduce the risk of death and nonfatal cardiovascular events in patients with coronary artery disease and left ventricular dysfunction (22,23). The Heart Outcomes Prevention Evaluation trial found that in patients with symptomatic PAD, ramipril, a tissue-specific ACE-inhibitor reduced the risk of MI, stroke, or vascular death by approximately 25%, a level of efficacy comparable to that achieved in the entire study population (24). There is currently no evidence base for the efficacy of ACE inhibitors in patients with asymptomatic PAD, and thus, the use of ACE-inhibitor medications to lower cardiovascular ischemic event rates in this population must be extrapolated from the data on symptomatic patients. However, a recent small randomized prospective placebocontrolled trial of ramipril in patients with symptomatic PAD demonstrated a statistically significant improvement in painfree walking distance when compared with placebo (25). ACC/AHA 2005 guidelines for the management of patients with PAD recommend that antihypertensive therapy should

be administered to hypertensive patients with lower extremity PAD to achieve a goal of less than 140 mmHg systolic over 90 mmHg diastolic (nondiabetics) or less than 130 mmHg systolic over 80 mmHg diastolic (diabetics and individuals with chronic renal disease) to reduce the risk of MI, stroke, congestive heart failure, and cardiovascular death (26,27).

Treatment of diabetes mellitus Intensive pharmacologic treatment of diabetes is known to decrease the risk for microvascular events such as nephropathy and retinopathy, but there is less evidence that it decreases macrovascular disease (28,29). DCCT/EDIC trial, however, demonstrated reduction in CVD (nonfatal MI, stroke, death from CVD, confirmed angina, or the need for coronary-artery revascularization) in patients with type I diabetes assigned to intensive diabetes treatment compared with conventional treatment by 42% (p ⫽ 0.02) (30). Patients with lower extremity PAD and both type 1 and type 2 diabetes should be treated to reduce their glycosylated hemoglobin (Hb A1C) to less than 7%, per the American Diabetes Association recommendation (31). Subanalysis of the UKPDS showed no evidence of a threshold effect of Hb A1C; a 1% reduction in Hb A1C was associated with a 35% reduction in microvascular endpoints, an 18% reduction in MI, and a 17% reduction in all-cause mortality. Frequent foot inspection by patients and physicians will enable early identification of foot lesions and ulcerations and facilitate prompt referral for treatment (32).

Homocysteine-lowering drugs Patients with PAD have increased mortality risk from cardiovascular causes (4,5), which is significantly increased in the subgroup of patients with high serum homocysteine concentration (33,34). Association of a low ABI and high homocysteine level could be useful for identifying patients at excess risk for cardiovascular death (34). In spite of the efficacy in lowering homocysteine level with a folic acid supplement there is no evidence that reducing homocysteine concentration is beneficial in patients with CHD and PAD (26,35).

Antiplatelet and antithrombotic drugs The Antithrombotic Trialists’ Collaboration (ATC) investigated the effects of antiplatelet therapy in 287 studies involving

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135,000 patients in comparison with antiplatelet therapy versus control and 77,000 in comparison with different antiplatelet regimens in patients at high risk of occlusive vascular events (36). “Serious vascular event” (nonfatal MI, nonfatal stroke, or vascular death) was less common in patients allocated to antiplatelet therapy by about one quarter; nonfatal MI was reduced by one-third, nonfatal stroke by one quarter, and vascular mortality by one-sixth (with no apparent adverse effect on other deaths). Aspirin was the most commonly studied antiplatelet drug, with doses of 75 to 150 mg daily at least as effective as higher daily doses. Clopidogrel-reduced serious vascular events by 10% (4%) compared with aspirin, which was similar to the 12% (7%) reduction observed with its analog ticlopidine.

Aspirin Aspirin (acetylsalicylic acid—ASA) exerts its effect primarily by irreversibly inhibiting enzyme cyclo-oxygenase that blocks platelet synthesis of thromboxane A2—a promoter of platelet aggregation (37). The benefits of ASA in reducing cardiovascular death, MI, and stroke in patients with CHD (36) have led to the near universal use of this medication for patients undergoing PCI. Antithrombotic effects have been shown to be present at dosages between 50 and 100 mg/day, but the optimal dose for PCI has not been firmly established. Different aspirin doses compared in the ATC meta-analysis suggest that a daily dose of 75 to 150 mg is at least as effective as higher doses (⬎150 mg/day) and is less likely to cause gastrointestinal and bleeding complications (36). When given in combination with warfarin or thienopyridine class of antiplatelet agents the ASA dose is usually lowered to 80 to 100 mg based on a post hoc analysis of data from the clopidogrel in unstable angina to prevent recurrent events (CURE), which showed similar efficacy but less major bleeding with the low dose (⬍100 mg) of ASA (38). ASA nonresponsiveness or resistance is reported in 5% to 60% of patients (39,40). There is emerging clinical evidence that ASA resistance is associated with an increased risk of major adverse cardiovascular events. Five studies in patients with coronary peripheral, and/or cerebrovascular disease have reported a 1.8- to 10-fold increased risk of thrombotic events (41,42). In the Physicians’ Health Study aspirin treatment for primary prevention of PAD reduced the subsequent need for peripheral arterial surgery (43). Aspirin therapy significantly improved vascular-graft patency in 3226 patients with PAD who were treated surgically or with peripheral angioplasty during average follow-up to 19 months (43% reduction in the rate of vascular-graft occlusion: 25% in the control group as compared with 16% in the aspirin group) (44). Aspirin given as a monotherapy was as effective as the combination of aspirin and dipyridamole, sulfinpyrazone, or ticlopidine in preventing graft occlusion, without any difference between

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low-dose (75 to 325 mg/day) and high-dose aspirin (600 to 1500 mg/day). The ACC/AHA guidelines state that ASA in daily doses of 75 to 325 mg is recommended as a safe and effective antiplatelet therapy to reduce the risk of MI, stroke, or vascular death in individuals with atherosclerotic lower extremity PAD (26).

Thienopyridines Clopidogrel and ticlopidine are thienopyridine derivatives. They selectively and irreversibly inhibit the P2Y12 ADP receptor, which plays a critical role in platelet activation and aggregation (45). They work synergistically with ASA in providing greater inhibition of platelet aggregation than either agent alone (46). The inhibition of platelet aggregation by ticlopidine and clopidogrel is present after two to three days of therapy with ticlopidine 500 mg/day or clopidogrel 75 mg/day, and platelet function recovers in five to seven days after discontinuation owing to the synthesis of new platelets (47).

Clopidogrel In the CAPRIE trial (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events), clopidogrel reduced the risk of MI, stroke, or vascular death by 23.8% compared with aspirin in patients with PAD (48). Although this is an impressive reduction in major events, the benefits of clopidogrel over aspirin were identified as a subgroup analysis rather than a primary endpoint. The Charisma trial evaluated antiplatelet treatment with aspirin alone compared with aspirin plus clopidogrel among high-risk patients with stable CVD (49). High-risk patients with established vascular disease included 37.4% with coronary disease, 27.7% with cerebrovascular disease, and 18.2% with symptomatic PAD. There was no difference in the primary endpoint of CV death, MI, or stroke between the clopidogrel plus aspirin group (6.8%) and the placebo plus aspirin group (7.3%, RR 0.93, p ⫽ 0.22). The secondary endpoint of death, MI, stroke or hospitalization for ischemic event was lower in the clopidogrel plus aspirin group (16.7% vs. 17.9%, RR 0.92, p ⫽ 0.04). The benefit of clopidogrel was evident in the symptomatic cohort (with documented CVD at enrollment) for the primary endpoint (6.9% for clopidogrel vs. 7.9% for placebo, RR 0.88, p ⫽ 0.046) but not in the asymptomatic cohort (6.6% for clopidogrel vs. 5.5% for placebo, RR 1.20, p ⫽ 0.20, interaction p ⫽ 0.045). Severe bleeding trended higher in the clopidogrel group (1.7% vs. 1.3%, RR 1.25, p ⫽ 0.09), while moderate bleeding was significantly higher in the clopidogrel group (2.1% vs. 1.3%, p ⬍ 0.001). There was no difference in intracranial hemorrhage (0.3% each). These

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findings suggest that dual antiplatelet therapy may not be beneficial in all patients at risk for CVD, but that in patients with established CVD, dual therapy may be effective in reducing subsequent events. In the CURE study, 12,562 patients with acute coronary syndromes without ST-segment elevation have received ASA and clopidogrel 300 mg bolus, followed by 75 mg daily, versus ASA and placebo (50). The clopidogrel group had early reduction [within 24 hours of treatment—9.3% vs. 11.4%, RR reduction 20% (p ⬍ 0.001) in the primary endpoint death from cardiovascular cause, nonfatal MI, or stroke], which was sustained at one year, and was observed in all patients with acute coronary syndromes regardless of their level of risk. CURE patients who underwent PCI and were randomized to clopidogrel had a 31% RR reduction in death and MI compared with placebo-treated PCI patients (51). The CREDO trial, which studied an elective population of patients who underwent PCI, showed benefits of clopidogrel (52). Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n ⫽1053) or placebo (n ⫽1063), 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/day, through day 28. The group loaded with clopidogrel was continued on active drug from day 28 through 12 months while the control group received placebo. Both groups received aspirin throughout the study. There was a significant 27% (p ⫽ 0.02) reduction in death, MI, or stroke in patients receiving clopidogrel, suggesting that clopidogrel therapy should be continued in addition to ASA for a minimum of nine months post PCI. There was an increase in major bleeding with clopidogrel in both the CURE and CREDO trials. In CURE, those receiving clopidogrel had bleeding rates of 3.7% versus 2.7% (p ⫽0.001), most notably in those patients requiring CABG. In CREDO, there was only a trend toward more TIMI (thrombolysis in MI) major bleeding (8.8% vs. 6.7%, p ⫽ 0.07) and no excess bleedings among patients undergoing CABG.

side effects, as well as fewer hematologic complications (neutropenia). Ticlopidine use in the United States in patients undergoing PCI is mostly reserved for those patients with allergy or intolerance of clopidogrel.

Smoking cessation Smoking cessation should be encouraged because it slows the progression of PAD to critical leg ischemia and reduces the risks of MI and death from vascular causes (54). Patients with CHD who stopped smoking had a 36% reduction in crude RR of mortality compared with those who continued smoking (RR 0.64, 95% CI, 0.58–0.71) (55). While smoking cessation does not improve maximal treadmill walking distance in patients with claudication based on a meta-analysis from published data (56), smoking cessation is critical in patients with thromboangiitis obliterans, because continued use is associated with a particularly adverse outcome (57). Physician advice coupled with frequent follow-up achieves one-year smoking cessation rates of approximately 5% compared with only 0.1% in those attempting to quit smoking without a physician’s intervention (58). Pharmacologic interventions (nicotine replacement therapy and bupropion) should be encouraged because they achieve higher cessation rates at one year (16% and 30%, respectively) (59).

Treatment for claudication Intermittent claudication decreases exercise capacity and overall functional capacity. Impaired walking ability is coupled with the inability to perform activities of daily living and results in a decrease in overall quality of life (60). Pharmacologic and nonpharmacologic measures aimed in improving mobility and consequently the quality of life is important treatment goals for patients with PAD.

Ticlopidine Although the original stent thrombosis data were obtained with ticlopidine, its use has been virtually abandoned in the United States owing to its increased risk of neutropenia. A meta-analysis demonstrated that clopidogrel was associated with a significant reduction in the incidence of major adverse cardiac events (2.1% in the clopidogrel group and 4.04% in the ticlopidine group). After adjustment for heterogeneity in the trials, the odds ratio (OR) of having an ischemic event with clopidogrel, as compared with ticlopidine, was 0.72 (95% CI, 0.59–0.89, p ⫽ 0.002). Mortality was also lower in the clopidogrel group compared with the ticlopidine group ⫺0.48% versus 1.09% (OR 0.55, 95% CI, 0.37–0.82, p ⫽ 0.003). The safety and tolerability of clopidogrel were superior to that of ticlopidine (53). This includes fewer rashes, gastrointestinal

Exercise In patients with claudication, the most important nonpharmacologic treatment is a formal exercise-training program (61). An exercise program can significantly improve maximal walking time and overall walking ability (62). The optimal exercise program for improving distances walked without claudication pain involves intermittent walking to near-maximal pain over a period of at least six months based on meta-analysis from Gardner et al. (63). ACC/AHA guidelines recommend exercise training in duration for a minimum of 30 to 45 minutes, in sessions performed at least three times per week for a minimum of 12 weeks (ACC/AHA guidelines). Optimal results involve a motivated patient in a supervised setting, which represents a challenge for

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patients and health care providers because supervised exercisetraining programs are not covered by medical insurance, which makes their extensive and long-term use difficult (64). The mechanism by which exercise improves leg symptoms is uncertain, but it does not appear to operate through improvement of the ABI or growth of collateral vessels (65).

Pharmacologic treatment for claudication Cilostazol The primary action of cilostazol is inhibition of phosphodiesterase type 3, which increases intracellular concentrations of cyclic AMP. Cilostazol inhibits platelet aggregation, the formation of arterial thrombi, and vascular smooth-muscle proliferation and causes vasodilatation (66–68). Since vasodilator and antiplatelet drugs do not improve claudication-limited exercise performance, the precise mechanism through which cilostazol exerts its effect in PAD is unknown. After 12 to 24 weeks of therapy patients treated with cilostazol improve maximal walking distance by 40% to 60% (69–73). In addition to improved walking capacity cilostazol improves healthrelated quality of life (74). Administered at the dose of 100 mg twice daily cilostazol is more effective than 50 mg twice daily (71,73). Although no trials have found a significant increase in major cardiovascular events in patients treated with cilostazol (an increased mortality was observed with other phosphodiesterase inhibitors such as milrinone), it remains contraindicated in individuals with coexistent heart failure because of its potential adverse effect in this population. The predominant side effect of cilostazol is headache, which affects 34% of patients taking 100 mg twice daily, as compared with 14% of patients taking placebo.

Pentoxifylline Mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity (75). The recommended dose of pentoxifylline is 400 mg three times daily with meals. Pentoxifylline causes a marginal but statistically significant improvement in pain-free and maximal walking distance (a net benefit of 44 m in the maximal distance walked on a treadmill (95% CI, 0 14 to 0 74) based on meta-analyses of randomized, placebo-controlled, double-blind clinical trials (76). At the same time pentoxifylline does not increase the ABI at rest or after exercise (56). Pentoxifylline may be used to treat patients with intermittent claudication; however, it is likely to be of marginal clinical importance (56,77). Medical therapies

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whose effectiveness is not well established by evidence/opinion (Class IIb – ACC/AHA Guidelines).

L-arginine Infusion of L-arginine produces systemic vasodilatation via stimulation of endogenous nitric oxide (NO) formation, which may improve vascular endothelial function and muscle blood flow in patients with PAD via the NO-cyclic GMP pathway in a dose-related manner (78). In patients with claudication, two weeks of treatment using a food bar enriched with L-arginine and a combination of other nutrients increased the pain-free walking distance 66% while the total walking distance increased 23% in the group taking two active bars per day. Improvements were not observed in the one active bar per day and placebo groups (79).

L-carnitine

and propionyl-L-carnitine

Orally administered L-carnitine and propionyl-L-carnitine may have metabolic benefits by providing an additional source of carnitine to buffer the cellular acyl CoA pool. In this way, carnitine may enhance glucose oxidation under ischemic conditions and improve energy metabolism in the ischemic skeletal muscle. Propionyl-CoA generated from propionylL-carnitine may also improve oxidative metabolism through its anaphoretic actions in priming the Kreb’s cycle, secondary to succinyl-CoA production. After 180 days of treatment there was a significant improvement of 73 ⫾9% (mean ⫾SE) in maximal walking distance in PAD patients treated with propionyl-L-carnitine compared to placebo (80). Propionyl-L-camitine has been shown to improve treadmill performance and quality of life in patients with claudication. After six months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 ⫾ 222 seconds (a 54% increase) as compared with an improvement of 75 ⫾ 191 seconds (a 25% increase) for those on placebo (p ⬍ 0.001) (81).

Ginkgo biloba Ginkgo biloba extract has been reported to improve symptoms of intermittent claudication. Meta-analysis of the efficacy of Ginkgo biloba extract for intermittent claudication based on the results of eight randomized, placebo-controlled, double-blind trials found a significant difference in the increase in pain-free walking distance in favor of Ginkgo biloba (weighted mean difference: 34 m, 95% CI, 26–43 m). Though the results showed statistical superiority of Ginkgo biloba extract compared to placebo in the symptomatic treatment of intermittent claudication, extent of the improvement was modest and of uncertain clinical relevance (82).

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Prostaglandin Vasodilators decrease arteriolar tone; however, numerous controlled trials have found no convincing evidence of clinical efficacy for any of these medications in patients with claudication (83). There are several potential pathophysiologic explanations for the lack of efficacy of these drugs in treating claudication. During exercise, resistance vessels dilate distal to a stenosis or occlusion in response to ischemia. Vasodilators have little effect on these already dilated vessels and may decrease resistance in unobstructed vascular beds, leading to a “steal” of blood flow away from underperfused muscles. Vasodilators can also lower systemic pressure, leading to a reduction in perfusion pressure. Thus, vasodilating medications do not favorably address the pathophysiology of claudication or result in a treatment benefit. The initial trial with oral prostaglandin beraprost showed an improvement of ⬎50% in pain-free walking distance and maximum walking distances at six months compared to placebo (84). A US study, however, showed that administration of beraprost did not improve the pain-free walking distance or the quality-of-life measures between the treatment groups (85).

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Other therapies A systematic review of the literature aimed to assess the effectiveness of any type of complementary therapy for intermittent claudication revealed that there is no evidence of effectiveness of acupuncture, biofeedback therapy, chelation therapy, CO(2)-applications and the dietary supplements of Allium sativum (garlic), omega-3 fatty acids and Vitamin E (86). PAD is particularly common in patients with CAD undergoing PCI. PCI patients affected with PAD have an increased risk of major adverse cardiovascular events in addition to impaired ambulatory capacity and quality of life, compared with PCI patients without PAD. PAD is undertreated, especially in patients with asymptomatic PAD, with consideration to pharmacologic and nonpharmacologic therapies. Therefore it is important to recognize PAD in PCI patients so that they can be aggressively managed with regard to risk factor modification using pharmacologic approach in treating hypertension, hyperlipidemia, diabetes mellitus, and symptoms of PAD. Pharmacologic therapies should be coupled with a supervised exercise program and smoking cessation program.

References 1

2

Nikolsky E, Mehran R, Mintz GS, et al. Impact of symptomatic peripheral arterial disease on 1-year mortality in patients undergoing percutaneous coronary interventions. J Endovasc Ther 2004; 11(1):60–70. Nallamothu BK, Chetcuti S, Mukherjee D, et al. Long-term prognostic implication of extracardiac vascular disease in

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patients undergoing percutaneous coronary intervention. Am J Cardiol 2003; 92(8):964–966. Singh M, Lennon Ryan J, Darbar D. Effect of peripheral arterial disease in patients undergoing percutaneous coronary intervention with intracoronary stents. Mayo Clin Proc 2004; 79(9):1113–1118. Criqui MH, Denenberg JO, Langer RD, et al. The epidemiology of peripheral arterial disease importance of identifying the population at risk. Vasc Med 1997; 2:221–226. Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospitalbased geriatrics practice. J Am Geriatr Soc 1999; 47: 1255–1256. Weitz JI, Byrne J, Clagett GP, et al. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities a critical review. Circulation 1996; 94:3026–3049. Smith SC Jr, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006; 113(19):2363–2372. Leng GC, Price JF, Jepson RG. Lipid-lowering for lower limb atherosclerosis (Cochrane review). In: The Cochrane Library. Oxford, England: Update Software, 2001. Buchwald H, Bourdages HR, Campos CT, et al. Impact of cholesterol reduction on peripheral arterial disease in the Program on the Surgical Control of the Hyperlipidemias (POSCH). Surgery 1996; 120:672–679. Khan F, Litchfield SJ, Belch JJ. Cutaneous microvascular responses are improved after cholesterol-lowering in patients with peripheral arterial disease and hypercholesterolaemia. Adv Exp Med Biol 1997; 428:49–54. Kirk G, McLaren M, Muir AH, et al. Decrease in P-selectin levels in patients with hypercholesterolaemia and peripheral arterial occlusive disease after lipid-lowering treatment. Vasc Med 1999; 4:23–26. Pedersen TR, Kjekshus J, Pyorala K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol 1998; 81: 333–335. Mohler ER III, Hiatt WR, Creager MA. Cholesterol reduction with atorvastatin improves walking distance in patients with peripheral arterial disease. Circulation 2003; 108(12): 1481–1486. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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) final report. Circulation 2002; 106:3143–3421. Cannon CP, Braunwald E, McCabe CH, et al. Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350:1495–1504. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals, a randomised placebo-controlled trial. Lancet 2002; 360:7–22.

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Tsuchikane E, Fukuhara A, Kobayashi T, et al. Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty. Circulation 1999; 100:21–26. Dawson DL, Cutler BS, Meissner MH, et al. Cilostazol has beneficial effects in treatment of intermittent claudication results from a multicenter, randomized, prospective, doubleblind trial. Circulation 1998; 98:678–686. Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg 1998; 27:267–274. Beebe HG, Dawson DL, Cutler BS, et al. A new pharmacological treatment for intermittent claudication results of a randomized, multicenter trial. Arch Intern Med 1999; 159:2041–2050. Dawson DL, Cutler BS, Hiatt WR, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med 2000; 109:523–530. Strandness Jr DE, Dalman RL, Panian S, et al. Effect of cilostazol in patients with intermittent claudication randomized, double-blind, placebo-controlled study. Vasc Endovasc Surg 2002; 36:83–91. Regensteiner JG, Ware Jr JE, McCarthy WJ, et al. Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease meta-analysis of six randomized controlled trials. J Am Geriatr Soc 2002; 50:1939–1946. Jacoby D, Mohler ER III. Drug treatment of intermittent claudication. Drugs 2004; 64(15):1657–1670. ACSM’s Guidelines for Exercise Testing and Prescription. In: Franklin BA, ed. Baltimore, MD, Lippincott: Williams & Wilkins, 2000.Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyla meta-analysis. Arch Intern Med 1999; 159:337⫺345. Hood SC, Moher D, Barber GG. Management of intermittent claudication with pentoxifylline meta-analysis of randomized controlled trials. CMAJ 1996; 155:1053–1059. Schellong SM, Boger RH, Burchert W, et al. Dose-related effect of intravenous L-arginine on muscular blood flow of the calf in patients with peripheral vascular disease: a H2 150 positron emission tomography study. Clin Sci (Lond) 1997; 93(2):159–165. Maxwell AJ, Anderson BE, Cooke JP. Nutritional therapy for peripheral arterial disease: a double-blind, placebo-controlled, randomized trial of Heart Bar. Vasc Med 2000; 5(1):11–19. Brevetti G, Perna S, Sabba C, et al. Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995; 26(6):1411–1416. Hiatt WR, Regensteiner JG, Creager MA, et al. PropionylLcarnitine improves exercise performance and functional status in patients with claudication. Am J Med 2001;110(8): 616–622. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med 2000;108(4):276–281. Coffman JD. Vasodilator drugs in peripheral vascular disease. N Engl J Med 1979; 300:713–717. Lievre M, Morand S, Besse B, et al. Oral beraprost sodium, a prostaglandin I(2) analogue, for intermittent claudication: a

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45 Pharmacotherapy peri-percutaneous coronary intervention Waqas Ullah, Rakesh Sharma, and Carlo Di Mario

Introduction Since Andreas Grüntzig described the first percutaneous coronary intervention (PCI) in 1978 (1), the field has progressed immeasurably in both equipment and pharmacotherapy. The overall trend with regard to the latter has been for improved strategies aimed at inhibition of platelet aggregation and the clotting cascade. This has led to better outcomes by reduction of the ischemic complications associated with the procedure. The current evidence regarding the available agents in a PCI setting is summarized in Table 2. A practical flowchart based on our recommendations is provided in Table 3.

Antiplatelet agents Aspirin Aspirin inhibits platelet aggregation by reducing production of thromboxane A2 through inhibition of the enzyme cyclo-oxygenase-1. Initial studies of aspirin often combined its administration with dipyridamole. Aspirin either with or without dipyridamole was found to reduce the incidence of coronary thrombosis during percutaneous transluminal coronary angioplasty (2), and the combination was found to reduce the incidence of Q-wave infarction compared to placebo (3). The combination of dipyridamole and aspirin has lost favor as the addition of dipyridamole has been found to confer no additional benefit (4). With respect to actual dose of aspirin used peri-PCI, there have not been any randomized trials looking into this issue. Subgroup analysis based on aspirin dosing (range 75 to 325 mg) of patients with non-ST elevation myocardial infarction (NSTEMI) acute coronary

syndrome (ACS) in the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) trial has demonstrated that higher doses of aspirin do not confer additional benefit but are conversely associated with an increased risk of bleeding complications (5).

Thienopyridines Thienopyridines reduce platelet aggregation by inhibiting the activity of the adenosine diphosphate receptor. The addition of ticlopidine to aspirin has been shown to have a synergistic effect on the inhibition of platelet aggregation after stent insertion (6), and this combination has also been found to be superior in terms of prevention of in-stent thrombosis to both aspirin alone and aspirin combined with warfarin (7). However, due to the rare but serious side effect of agranulocytosis associated with ticlopidine (8), and its slow onset of action, ticlopidine is no longer used in most countries. The combination of clopidogrel and aspirin has been proved to be as effective as aspirin and ticlopidine in the prevention of intrastent thrombosis (9). The PCI-clopidogrel as adjunctive reperfusion therapy trial was a randomized control trial of the use of clopidogrel in patients treated with fibrinolysis for an ST-segment elevation myocardial infarction (STEMI) who went on to have a PCI (10). In this trial, patients given clopidogrel prior to PCI had better indices of infarct-related artery patency. These patients also had lower rates of preprocedural recurrent myocardial infarction (MI) and a significantly decreased incidence of the combined endpoint of recurrent MI, cardiovascular death or cerebrovascular accident at 30 days. PCI-CURE studied NSTEMI patients who were randomized to receive either placebo or a 300 mg loading dose of clopidogrel, followed by regular doses, with PCI carried out a

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median of 6 days later (11). Those in the treatment group had lower rates of preprocedure MI and refractory ischemia. These patients also had a significant reduction in the combined endpoint of cardiovascular death, MI, and urgent target vessel revascularization at 30 days, and this was extended to the longer period of follow-up (the median length of the latter being eight months). Clopidogrel has also been studied among elective patients. The Clopidogrel for the Reduction of Events During Observation (CREDO) trial found no significant benefit at 28 days from preloading patients with clopidogrel a range of 3 to 24 hours prior to PCI (12). In this study, clopidogrel was continued for a year, leading to a significant decrease in the combined endpoint of stroke, MI, and death at this time point. There was also a suggestion that there may be additional benefit from clopidogrel given greater than six hours prior to PCI, with a nonsignificant improvement in the combined endpoint (p ⫽ 0.51). The three trials above all used a 300-mg loading dose followed by 75-mg maintenance dose, yet CREDO (12) failed to demonstrate the same shorter term benefits. While this may be because of the higher risk patients studied in the other trials (10,11), the results relating the outcome to the timing of clopidogrel administration may be the key. In the Atorvastatin for Reduction of MYocardial Damage during Angioplasty-2 (ARMYDA-2) trial, comparison was made of a 300 mg to a 600 mg loading dose of clopidogrel given four to eight hours prior to PCI (13). This trial showed a significantly lower incidence of peri-procedural MI in the latter group. These results demonstrate the faster onset of action of the higher loading dose of clopidogrel. Kandzari et al. examined the pharmacokinetics after administration of a 600 mg dose given at different time points (from two to three hours or earlier) pre-PCI in elective patients (14). They found that there was no difference, at 30 days, in the combined endpoint of death, MI or urgent revascularization between patients given clopidogrel two to three hours pre-PCI and those who started it sooner. These trials therefore suggest an advantage from the higher loading dose of clopidogrel when PCI is to be performed within eight hours. It is with respect to clopidogrel that there is a significant point of variance in the pharmacotherapeutic management between bare-metal stents and the newer, drug-eluting stents. In the case of the former, no benefit has been found to a course of clopidogrel longer than one month in elective cases, on direct comparison of a one month and six-month course (15). With drug-eluting stents, there is a concern that delayed endothelialization will lead to an increased risk of stent thrombosis. For this reason, trials have empirically used longer clopidogrel regimens, three months for sirolimuseluting stents (16) and six months for paclitaxel-eluting stents (17). While no trials are available where comparison has been made between different lengths of treatment, the importance of uninterrupted antiplatelet therapy is propounded by the association between discontinuation of

clopidogrel and stent thrombosis (18,19). A longer course of clopidogrel treatment is recommended in the ACS setting on the basis of the PCI-CURE trial; in this study, patients with NSTEMI-ACS were given clopidogrel for up to 12 months (11). Our own practice in terms of the length of treatment with clopidogrel is to prescribe a one month course of clopidogrel for bare metal stents and a one year course for drug-eluting stents. In the case of all ACS, a one year course is given. These practices are concordant with the current European guidelines, where a month is also recommended for bare metal stents, 6–12 months for drug-eluting stents and 9–12 months of clopidogrel for ACS cases (20).

Cilostazol Cilostazol is a phosphodiesterase inhibitor that reduces platelet aggregation, vascular smooth muscle proliferation and also has vasodilatory effects. Earlier studies comparing cilostazol and aspirin to ticlodipine and aspirin identified no significant increase in the subacute stent thrombosis rate (21–23). Indeed, the latter has been supported by comparison of this combination to clopidogrel and aspirin (24). Two recent trials, however, have demonstrated that a much higher proportion of patients develop subacute stent thrombosis when taking cilostazol as compared with ticlodipine (25,26). The data from these trials are summarized in Table 1.

Glycoprotein IIb/IIIa inhibitors Glycoprotein IIb/IIIa receptors are present on the surface of activated platelets. Fibrinogen and von Willebrand Factor are able to cross link platelets through these receptors, leading to their aggregation (Fig. 1). Glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibitors are the most potent and fastest acting anti-platelet agents available. After the unfavorable results of trials with oral agents, only three commercially available drugs (all given parenterally) are presently available in this class: abciximab (ReoPro), eptifibatide (Integrilin), and Tirofiban (Aggrastat). Abciximab use peri-PCI has been well studied in the setting of STEMI. A meta-analysis of 8 trials using abciximab in the context of primary-PCI has demonstrated a significant reduction in mortality in the context of primary PCI at both 30 days and longer term (6 or 12 month) follow-up (27). In this analysis there was also a reduced reinfarction rate at 30 days with abciximab and no increased risk of bleeding complications. Data also suggests that an early infusion (in the ambulance or immediately after admission) can be beneficial when compared to administration at the time of the procedure. The Chimeric 7E3 Antiplatelet Therapy in Unstable Angina REfractory to Standard Treatment (CAPTURE) trial was the first to demonstrate the benefit of abciximab among patients with unstable angina, with a lower rate of the

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Table 1 A comparison of the rates of subacute stent thrombosis in trials comparing cilostazol with ticlodipine or clopidogrel Patients with subacute stent thrombosis (%) Clopidogrel

Ticlodipine

Cilostazol

Park 1999 (21)

N/A

0/243

2/247

Tanabe 2000 (22)

N/A

0/50

0/54

Kamishirado 2002 (23)

N/A

2/65

0/65

Sekiguichi 2004 (25)

N/A

1/138

8/144

Takeyasu 2005 (26)

N/A

1/321

8/321

Total (Ticlodipine trials)

N/A

4/817 (0.49%)

18/831 (2.17%)

Lee 2005 (24)

2/345

3/344

Total (Thienopyridine trials)

6/1162 (0.52%)

21/1175 (1.79%)

The first total is a comparison of ticlodipine and aspirin to cilostazol and aspirin; the second total compares the results for thienopyridines and aspirin to cilostazol and aspirin.

combined endpoint of death, MI and urgent intervention (driven by a lower rate of non-Q wave MI), but a higher bleeding rate (28). In the evaluation of platelet IIb/IIIa inhibitor for stenting (EPISTENT) trial, abciximab was shown to be of benefit in a wider range of patients following stent implantation (elective and urgent cases), with the incidence of bleeding reduced by the use of weight-adjusted, low-dose heparin administration. This trial showed that abciximab reduced the incidence of the combined endpoint of mortality, MI and urgent revascularization (major adverse cardiovascular events, MACE). EPISTENT (29) had the merit of replicating in the era of universal stent usage the

results obtained in the earlier CAPTURE and EPIC (30) trials (which were conducted in the balloon angioplasty era). Unfortunately, no attempt was made to explore whether the 12 hour infusion shown to be more beneficial than the bolus alone in the EPIC study was still necessary when the risk of postprocedural abrupt occlusion was nearly abolished through the use of stents. Mortality benefit for Gp IIb/IIIa inhibitors during PCI has been demonstrated on meta-analysis for abciximab (31) and this class of agents as a whole (32). These agents have also been shown, on meta-analysis, to reduce rates of MI and urgent revascularization post-PCI (33).

Figure 1 Fibrinogen and von Willebrand Factor are able to cross link platelets through binding to glycoprotein IIb/IIIa receptors present on the surface of activated platelets, leading to their aggregation. Abbreviations: Gp, glycoprotein; RGD, Arg-Gly-Asp.

activated endothelium vWF

Gp Ib receptor

Gp IIb/IIIa receptor

Fibrino

Platelet

gen

RGD

dimeric

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Platelet RGD

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Some of the results with abciximab were duplicated using the small molecules eptifibatide and tirofiban. These are intrinsically cheaper than abciximab which is produced using recombinant DNA technology for its production. The enhanced suppression of platelet receptor IIb/IIIa using integrilin therapy (ESPIRIT) trial of nonurgent PCI demonstrated a significant reduction in the incidence of postPCI MI at 30 days but not death or urgent target vessel revascularization using eptifibatide in terms of MACE (34). However, this trial randomized patients to receive placebo in the control arm. To date, of the Gp IIb/IIIa inhibitors, only abciximab and tirofiban have been compared directly. The Do Tirofiban and ReoPro Give Similar Efficacy (TARGET) trial, a randomized double-blind trial of urgent and elective PCI (excluding patients in cardiogenic shock or with STEMI), demonstrated that abciximab significantly reduced the incidence of MACE at 30 days compared to tirofiban (35). In further analysis it was noted that the only point of significant difference was in the incidence of nonfatal MI, and that the benefit of abciximab in terms of MACE at 30 days was only present in ACS patients. No mortality benefit has been found at one year among those patients treated with abciximab instead of tirofiban (36). The tirofiban dosing regimen used in the TARGET trial (10 µg/kg bolus followed by 0.15 µg/kg/ min infusion) has been found to be suboptimal for platelet inhibition in one small study (37). This issue has been addressed further in a recent observational trial which demonstrated no difference compared to abciximab in MACE incidence at six months when a higher tirofiban dosing regimen was used (25 µg/kg bolus followed by 0.15 µg/kg/min infusion) (38). The main concern with the use of Gp IIb/IIIa inhibitors is the risk of hemorrhage and thrombocytopenia. On meta-analysis, major hemorrhage was significantly more likely with abciximab than with either tirofiban (standard regimen) or eptifibatide (33). The TARGET trial demonstrated abciximab to predispose to thrombocytopenia when compared to tirofiban (35). Regardless, thrombocytopenia (platelet count ⬍20,000/µl) is rare (⬍3%) and can often be treated conservatively, without the need for platelet transfusions. Clopidogrel use peri-PCI has gained popularity and its interaction with Gp IIb/IIIa inhibitors has been investigated for all three agents. The intracoronary stenting and antithrombotic regimen–rapid early action for coronary treatment (ISAR-REACT) trial studied low/intermediate risk patients given clopidogrel 600 mg at least two hours before the PCI along with aspirin, and randomized them to receive abciximab or placebo (39). This trial showed that patients receiving abciximab had a significantly higher incidence of profound thrombocytopenia (less than 20,000 platelets per mm3) and required more blood transfusions than the placebo group. In terms of 30 day MACE incidence, there was no difference between the two groups. This lack of benefit was further

confirmed by Claeys et al., who demonstrated that these results were achieved despite abciximab’s addition resulted in greater inhibition of platelet aggregation (40). A re-evaluation of the ISAR-REACT patients at one year continued to show a lack of advantage conferred by abciximab (41). It should be noted however that these trials did not include high-risk patients and so it may not be appropriate to extrapolate these results to this group which has been investigated separately in the ISAR-REACT 2 trial. The combination of tirofiban with clopidogrel and aspirin on the other hand, in the small (109 elective patient) troponin in planned PTCA/stent implantation with or without administration of the glycoprotein IIb/IIIa receptor antagonist tirofiban study, has been shown to significantly reduce MACE incidence at nine months compared to clopidogrel and aspirin alone (42). This was associated with significantly lower levels of Troponin release at 12 and 24 hours in the tirofiban group although differences that were not maintained at 48 hours. In comparison to the two abciximab/clopidogrel combination studies this study did use a slightly lower dose of clopidogrel [375 mg loading as opposed to the 600 mg ISAR-REACT (39) loading or 300 mg plus 150 mg loading (40)] but the influence of this on the results is unclear. In view of the widespread use of clopidogrel peri-PCI, it is important to elucidate the interaction between this and Gp IIb/IIIa inhibitors. A lack of synergistic benefit would not be unexpected as clopidogrel ultimately exert its effects on platelet aggregation through the Gp IIb/IIIa receptor (43). Still, Gp IIb/IIIa antagonists do have a more potent and consistent inhibitory action platelet aggregation than clopidogrel.

Anticoagulants Heparin The two forms of heparin available are unfractionated heparin (UFH) and low molecular weight heparin (LMWH). Both exert their anticoagulant effect on the clotting cascade by enhancing the activity of antithrombin. In the case of LMWH this is by enhancing the binding of antithrombin to factor Xa and so inhibiting the function of the latter; UFH not only shares this effect but also enhances the inhibition of thrombin through antithrombin (44). UFH is the most commonly employed anticoagulant peri-PCI. UFH suffers from several shortcomings as reviewed by Kokolis et al. (45) and Rebeiz et al. (8). These drawbacks include the variability of its anticoagulant effect necessitating monitoring of clotting indices, its ability to activate platelets causing a paradoxical pro-coagulant effect, and the possibility of inducing heparin-induced thrombocytopenia (HIT).

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The main cause of debate at present with regard to UFH centers on the amount used peri-PCI. The level of anticoagulation produced by UFH is measured by the activated partial thromboplastin time and activated clotting time (ACT), the latter being available in the cardiac catheter laboratory as a near-patient test. A meta-analysis of earlier trials found the risk of complications associated with PCI to be closely related to the ACT, with a target ACT of 350–375 suggested (45). Higher ACTs were associated with increased bleeding risks. ACTs above and below this range were both associated with an increased incidence of death, MI and urgent revascularization at 7 days. The reason for the association between ischemic complications and elevated ACTs is believed to be a consequence of heparin’s platelet activating properties at higher doses. The trials summated in this meta-analysis were from an era prior to the widespread adoption of stents, thienopyridines, and Gp IIa/IIIb inhibitors. A more recent meta-analysis of four trials involving 9974 patients demonstrated different relationships, most likely due to the change in practices in the interim (46). In this meta-analysis, a lack of correlation was found between the ACT and ischemic complications at 48 hours. A correlation was found with the total heparin dose, with doses above 5000 units associated with increased ischemic complications. With the heparin dose adjusted for weight, every 10 U/kg increase in dose, up to 90 U/kg, was associated with a significant increase in the risk of ischemic complications. There was no significant association between ACT and rates of major bleeding. For a combination of major and minor bleeding, increasing ACTs up to 365 were associated with an increasing rate of major/minor bleeding but above this the rate actually decreased. When looking from a dosing point of view, there was a relationship between increasing heparin dose and rates of major/minor bleeding. With regard to weight-indexed dosing, there was a significant increase in the bleeding risk with every 10 U/kg increase in dose. Based on these findings, in the context of oral and intravenous antiplatelet therapies and stenting, the suggestion is that lower heparin doses may not compromise efficacy and may in fact be safer. Moreover, the ACT itself may not be as useful a marker of optimal UFH use peri-PCI compared to the actual UFH dose given. LMWHs mainly inhibit factor Xa through antithrombin, although they have varying degrees of associated indirect thrombin inhibiting activity. In the latter respect they share the disadvantage of UFH of being unable to inhibit clot-associated thrombin. The advantages of LMWH over UFH include a more predictable anticoagulant effect requiring less monitoring, and reduced incidence of HIT. Of the LMWH, the most extensively studied with regard to PCI is enoxaparin. The National Investigators Collaborating on Enoxaparin (NICE) trials examined the use of intravenous enoxaparin peri-PCI in elective and urgent patients (47). These trials were observational studies without a control

529

group: patients from other trials served as historical controls for comparison. NICE-1 examined 828 patients treated with 1 mg/kg of intravenous enoxaparin at the time of PCI (47). Similar efficacy and safety was found to equivalent patients treated with UFH in the previous EPISTENT trial. NICE-4 investigated patients treated with 0.75 mg/kg of intravenous enoxaparin and concomitant abciximab (47). The results also compared favorably with respect to death, infarction and urgent revascularization at 30 days as well as bleeding complications on comparison to patients treated with abciximab and UFH from the EPISTENT and evaluation of PTCA to improve long-term outcome by c7E3 GP IIb/IIIa receptor blockade trials (48). Among elective patients, trials have also examined the combination of enoxaparin with eptifibatide (49,50) or tirofiban (50) and similarly found no significant differences between UFH and 0.75 mg/kg intravenous enoxaparin. The above trials have investigated intravenous enoxaparin. The pharmacokinetics of enoxaparin in PCI (PEPCI) study found that anti-Xa levels, a measure of LMWH activity, were within target range two to eight hours after a dose of subcutaneous enoxaparin (51). Anti-Xa levels could be kept in the target range for a further two hours by an additional intravenous bolus of 0.3 mg/kg. The SYNERGY (52) trial of ACS patients compared UFH to an enoxaparin regimen as suggested by the PEPCI (51) trial. Among these patients, those who had received their last dose of subcutaneous enoxaparin over eight hours prior to PCI were given an additional intravenous bolus. In the SYNERGY trial, no difference in the incidence of ischemic events during PCI was noted between UFH and subcutaneous LMWH, and there was an increased incidence of major bleeding in the LMWH group (52). The observation that an increased bleeding risk compared to UFH was noted in this trial rather than those investigating intravenous enoxaparin may be indicative of a less predictable bioavailability of this route of administration, or perhaps a need for dose reduction. On the whole, while not demonstrating superiority of LMWH with regard to bleeding complications, death, infarction, and urgent revascularization over UFH, the above results do support its noninferiority. In view of LMWH’s simplicity of use in ACS, which makes most centers prefer it to UFH, it is important to recognize it as an acceptable alternative to UFH when the patient must be treated soon after their last subcutaneous dose.

Fondaparinux Fondaparinux is a pure inhibitor of factor Xa, which exerts its effect through antithrombin. This compares with UFH and LMWH both of which have additional activity against thrombin to a greater and lesser degree, respectively. To date one trial has been published investigating fondaparinux use

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peri-PCI. Compared to UFH, no significant increase in bleeding complications or a composite of all cause mortality, MI, urgent revascularization, and need for bailout Gp IIb/IIIa antagonist was demonstrated (53). Whether this agent will have any advantage over LMWH or UFH is to be established.

Direct thrombin inhibitors Direct thrombin inhibitors (DTIs) inhibit thrombin directly rather than through the indirect, antithrombin-mediated pathway utilized by UFH and LMWH. Unlike heparin, they can inhibit clot-bound thrombin and do not induce HIT. While heparin-based anticoagulation can be reversed using protamine, there is no such agent for DTIs: this is especially a concern for lepirudin which, unlike bivalirudin, binds to thrombin irreversibly and so has a longer half life. With bivalirudin, the effect almost disappears after two hours which helps planning the timely removal of arterial sheaths. Bivalirudin has been the subject of a large trial, randomized evaluation in PCI linking angiomax to reduced clinical events-2 (REPLACE-2), involving 6010 patients (54). Randomization was either to UFH and Gp IIb/IIIa (abciximab or eptifibatide) or to bivalirudin with the option of Gp IIb/IIIa use if there were procedural or angiographic complications. Patients with unstable ischemic syndromes or acute-MI were excluded. There was no difference in the combined endpoint of death, MI, and urgent repeat revascularization at 30 days. While the latter suggested equivalence in efficacy with UFH, a reduced incidence of major and minor bleeding with bivalirudin suggested that it held safety advantages over UFH. At six months, the rates of death, MI, and revascularization were no difference between the two groups and this lack of difference in mortality was also present at one year (55). A meta-analysis of DTIs compared to UFH in ACS has shown that there is a significant decrease in the combined endpoint of death and MI at 30 days, with the significance driven by the improvement in MI incidence in the former group (56). There was no significant decrease in mortality itself. The benefit of DTIs compared to heparin was only found in those patients undergoing early (within 72 hours) PCI as opposed to those managed conservatively or treated with PCI after this. There was also significantly less major bleeding in patients receiving DTIs rather than UFH. These results suggest that DTI may have increased safety and efficacy for those undergoing early PCI for ACS. The results from REPLACE-2 (54) would seem to extend this benefit to a wider group of patients and additionally suggests that a more parsimonious use of Gp IIb/IIIa agents may be possible. The acute catheterization and urgent intervention triage strategy trial has explored the use of bivalirudin in highly unstable syndromes, also in combination with LMWH, with results just presented. The harmonizing outcomes with revascularization

and stents trial will answer the same question in STEMI patients undergoing primary PCI.

Lipid-lowering medication In a small (81 patients) retrospective analysis, patients on lipidlowering medication (statins, fibrates, or niacin derivatives) at the time of PCI had a significantly lower incidence of adverse events during the procedure, such as emboli and dissections, as compared to those not taking such agents (57). A high-total cholesterol, low-density lipoprotein, or ratio of low to highdensity lipoprotein were also associated with increased adverse events. A prospective trial of ACS patients undergoing PCI (119 patients) showed that those on statins at the time of PCI had significantly reduced incidence of peri-procedural myocardial necrosis as determined by CK or CK-MB level (58). At six months, these patients also had a lower incidence of the combined endpoint of death, MI, target vessel revascularization, and hospital admission for unstable angina. The patients who were on statins were significantly less likely to have hyperlipidemia at the time of PCI. The incidence of the combined endpoint was not increased by patients being hyperlipidemic at six months, or reduced by patients being on statin therapy at six months. Instead the relationship was with being on a statin prior to PCI, suggesting the importance of pretreatment. he ARMYDA study of 153 low-risk elective PCI demonstrated that pretreatment of patients with a week of atorvastatin prior to PCI resulted in significantly less release of markers of myocardial damage such as Troponin, myoglobin, and CK-MB compared to placebo (59). This was associated with a decrease in the rate of peri-procedural MI. It is postulated that this effect of atorvastatin may relate to its anti-inflammatory properties.

Conclusions A summary of the discussions above regarding the various trials can be found in Table 2. Table 3 details our recommendations with regard to pharmacotherapy peri-PCI, which includes an attempt to offer advice in the cases where trial evidence is lacking. There is a wealth of data currently available regarding different agents to use peri-PCI and yet, as with any field, there remain unanswered questions particularly concerning long term treatment after drug eluting stents. It is the task of the physician to tailor these therapies to the specific clinical situations with which they are presented. In this article, as well as reviewing the currently available evidence, we have also provided our own recommendations for the use of the

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Conclusions

Table 2

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A comparison of the different drugs used peri-percutaneous coronary intervention

Drug

Patient type

Dosing

Main findings and conclusions

Aspirin

All PCI

75–325 mg

Dipyridamole

No longer recommended Only if intolerant to clopidogrel

No longer recommended At least 250 mg bd

Reduced incidence of coronary thrombosis (2) and Q-wave infarct (3) No additional benefit when given with aspirin (4)

Clopidogrel

STEMI (10), NSTEMI (11), Elective PCI (12)

Cilostazol

Elective (21–25) and emergency (22–26) PCI See below

300 mg loading dose (10–12) unless PCI to be performed within eight hours in which case 600 mg recommended 100 mg twice daily

Ticlopidine

Gp IIb/IIIa inhibitors Abciximab

STEMI (27), unstable angina (28),elective PCI (29)

Epitifibatide

ACS (not including STEMI) (60), nonurgent PCI (34) ACS (not including STEMI) (61)

Tirofiban

UFH

All PCI

LMWH

Elective and urgent PCI (47,49,50)

Fondaparinux

Urgent and elective PCI (53) Elective PCI (54), ACS (56) past HIT

DTI

Lipid lowering medication

Elective PCI (59)

See below

0.25 mg/kg followed by 0.125 µg/kg/min infusion Benefit in low/intermediate risk patients following clopidogrel pretreatment debated (39,40) Two 180 µg/kg boluses 10 min apart and 2 µg/kg/min infusion (34) 25 µg/kg bolus and 0.15 µg/kg/min infusion—may be more effective than standard regimen of 10 µg/kg bolus and 0.15 µg/kg/min infusion (37,38) Dose of UFH more predictive of complications than ACT value (46) 1 mg/kg intravenous enoxaparin (0.75 mg/kg if used with Gp IIb/IIIa) (47,49,50) Optimal dosing still being determined Dependent on agent used

Dependent on agent used

Synergistic with aspirin in reducing platelet aggregation (6) and reducing instent restenosis (7) Concern over associated incidence of agranulocytosis (8,9), frequent gastric intolerance and skin rashes Sequential FBC required at follow-up As effective as ticlodipine in preventing stent thrombosis (9) Reduced incidence of adverse hematologic reactions compared to ticlodipine (9) Possibility of increased subacute stent thrombosis rate (21–26) Mortality benefit in the context of PCI (32) Decreased MI and urgent revascularization rates post-PCI (33) Significant benefit (27–29) especially with respect to mortality (27) and reinfarction (27,28) Increased risk of major bleeding and thrombocytopenia compared to other Gp IIb/IIIa inhibitors (33)

Studies comparing efficacy to other members of this class awaited Beneficial in one trial evaluating use in patients with non-STEMI ACS, but no benefit in another investigating patients with ACS including STEMI Abciximab associated with more favorable outcome at 30 days (35) [no mortality benefit at one year (36)]. This superiority may be abrogated by the higher tirofiban dosing regimen (38) Variable anticoagulant effect (needing monitoring), platelet activation causing paradoxical pro-coagulant effect, HIT, unable to bind clot-bound thrombin (8,44) Similar efficacy to UFH with no increase in adverse events (47,49,50) Unable to bind clot-bound thrombin (8,44) Similar efficacy and safety to UFH (53) Able to bind clot-bound thrombin, do not induce HIT (8,44) May have benefit compared to UFH among ACS patients (56) Pretreatment with atorvastatin associated with decreased peri-PCI myocardial infarction (59)

Abbreviations: ACS, acute coronary syndrome; DTI, direct thrombin inhibitor; Gp IIb/IIIa, glycoprotein IIb/IIIa; HIT, heparin induced thrmobocytopenia; LMWH, low molecular weight heparin; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST elevation myocardial infarction; UFH, unfractionated heparin.

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Practical tips for drug administration peri-percutaneous coronary intervention

Drug

Dose

Recommendation

Pre-PCI Aspirin

75–100 mg

Start at least 48 hours before procedure Consider 250 mg i.v. if PCI to be performed sooner than this 300 mg loading dose if not already on treatment, with 600 mg loading if PCI expected to occur within eight hours In the case of unstable angina or NSTEMI, the preferred agents are epitifabatide/tirofiban. Abciximab is the preferred agent in the cases of STEMI Avoidance of doses inducing respiratory sedation and hypotension is recommended Agents such as midazolam with a rapid onset and offset of action are preferred Low threshold in the cases of previous gastric problems (e.g., ulcers, diaphragmatic hernias) and in the cases of microcytic anemia of unknown cause

Clopidogrel

75 mg

Glycoprotein IIb/IIIa inhibitors Sedation

Proton pump inhibitors

During PCI Heparin

50–75 mg/kg Avoid additional boluses ⬎ 30 mg/kg

Enoxaparin

0.5 mg/kg i.v.

Bivalirudin

0.75 mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI

Glycoprotein IIb/IIIa inhibitors

Abciximab 0.25 mg/kg or high dose bolus epitifibatide or tirofiban

Nitrates

Preferred agents: isosorbide dinitrate 1–3 mg and nitroglycerine 100–300 µg

Sodium nitroprusside

40–100 µg in three minutes

Preferred agent in the cases of chronic total occlusion Recommend checking ACT after five minutes and then every hour Target ACT of 200–250 s Keep as close as possible to 200 s if used in conjunction with Gp IIb/IIIa inhibitors Higher target (250–300 s) recommended if filters are used Avoid routine infusion after PCI (associated with increased bleeding events with little benefit) No additional boluses if within four to six hours of subcutaneous injection Excellent alternative to heparin in elective cases Trial results pending for unstable syndromes Adjust dose according to renal function Not enough data in acute MI and after enoxaparin Stop after removal of intracoronary wires Remove sheath after two hours unless closure devices are used If infusion already started, continue same Gp IIb/IIIa inhibitor started pre-PCI. Low threshold for administering in the cases of thrombus containing lesions in the context of unstable angina; no reflow/slow reflow after PCI; treatment of diffuse disease, and in diabetes mellitus Caution (not needed or risky) for treatment of SVGs, CTO or lesions at risk of perforation In the case of abciximab, consider withholding infusion if normal flow is obtained with a good result after stenting and the patient is fully loaded with clopidogrel Use intracoronarily to appropriately size the balloons and stent, and to prevent coronary spasm during wire/balloon manipulation Not effective/contraindicated in the treatment of secondary spasm Avoid pressure drop in no reflow/slow flow Preferred agent in the cases of no reflow/slow reflow. Always selective infusion (or better subselective infusion via intracoronary catheter) Strict BP monitoring required during administration Needs to be available for the cases of degenerate SVG or lesions containing thrombus (Continued)

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Conclusions

Table 3

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Practical tips for drug administration peri-percutaneous coronary intervention (Continued )

Drug

Dose

Recommendation

Adenosine

20–100 µg

Verapamil

1–2 mg

Have the same indications as sodium nitroprusside Can cause sinus arrest/AV block when high doses are used, especially in the RCA (an effect which is reversible within seconds) Same indications as sodium nitroprusside and adenosine but associated with more prolonged hypotension/bradycardia

Post-PCI Aspirin

Clopidogrel

Lipid lowering agents, beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, other antihypertensives, antihyperglycemic medications Warfarin

75–100 mg od

75 mg od

Lifelong Higher doses are advantageous only to prolong the effect in the cases of withheld doses, but are associated with increased bleeding complications with no reduction in the incidence of thrombotic events Continue for 28–30 days after bare metal stent insertion but 9 to 12 months in the cases of ACS In the cases of proven resistance (⬍50% in vitro platelet inhibition) consider doses of 150 mg od. Also consider higher dose in the cases of previous stent thrombosis For drug-eluting stents, continue for six months (but consider stopping after two to three months for sirolimus eluting stents for simple lesion treatment). For indications outside major drug eluting/sirolimus eluting stent trials (Sirius/Taxus IV, long lesions, bifurcations, ostial, SVGs, CTO etc.) the most frequent empirical approach is to prolong treatment for 9–12 months Where thrombosis would be catastrophic, such as in left main or single remaining vessel intervention, a more prolonged treatment—perhaps even lifelong—can be considered until the risk of late stent thrombosis is better defined Titrate according to most recent guidelines

If systemic anticoagulation is strongly indicated based on high thrombo-embolic risk (cases of mechanical valve prosthesis, left ventricular thrombus, active deep vein thrombosis, high-risk atrial fibrillation), stop warfarin three to four days pre-PCI and anticoagulate with unfractionated heparin or enoxaparin. Warfarin can be restarted the evening after the procedure with a loading dose Consider the possibility of stopping clopidogrel (or aspirin) after one month in the case of nondrug eluting stents, or two to three months in drug eluting stents. If the indication for warfarin is less robust, such as AF at low embolic risk, consider stopping warfarin permanently or until double antiplatelet treatment is no longer required

Abbreviations : ACS, acute coronary syndrome; ACT, activated clotting time; BP, blood pressure; CTO, chronic total occlusion; i.v., intravenous; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery; STEMI, ST-segment elevation myocardial infarction; SVGS, saphenous vein grafts.

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various agents available: in doing so it is hoped this will facilitate the decision making process.

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Schomig A, Schmitt C, Dibra A, et al. Intracoronary stenting and antithrombotic regimen-rapid early action for coronary treatment study investigators. One year outcomes with abciximab vs. placebo during percutaneous coronary intervention after pretreatment with clopidogrel. Eur Heart J 2005; 26(14):1379–1384. Bonz AW, Lengenfelder B, Strotmann J, et al. Effect of additional temporary glycoprotein IIb/IIIa receptor inhibition on troponin release in elective percutaneous coronary interventions after pretreatment with aspirin and clopidogrel (TOPSTAR trial). J Am Coll Cardiol 2002; 40(4):662–668. Geiger J, Brich J, Honig-Liedl P, et al. Specific impairment of human platelet P2YAC ADP receptor—Mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 1999; 19(8):2007–2011. Kokolis S, Cavusoglu E, Clark LT, Marmur JD. Anticoagulation strategies for patients undergoing percutaneous coronary intervention: Unfractionated heparin, low-molecular-weight heparins, and direct thrombin inhibitors. Prog Cardiovasc Dis 2004; 46(6):506–523. Chew DP, Bhatt DL, Lincoff AM, et al. Defining the optimal activated clotting time during percutaneous coronary intervention: Aggregate results from 6 randomized, controlled trials. Circulation 2001; 103(7):961–966. Brener SJ, Moliterno DJ, Lincoff AM, Steinhubl SR, Wolski KE, Topol EJ. Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention. Circulation 2004; 110(8):994–998. Kereiakes DJ, Grines C, Fry E, et al. NICE 1 and NICE 4 investigators. National investigators collaborating on enoxaparin. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invasive Cardiol 2001; 13(4):272–278. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336:1689–1696. Bhatt DL, Lee BI, Casterella PJ, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention: results of the coronary revascularization using integrilin and single bolus enoxaparin study. J Am Coll Cardiol 2003; 41(1):20–25. Madan M, Radhakrishnan S, Reis M, et al. Comparison of enoxaparin versus heparin during elective percutaneous coronary intervention performed with either eptifibatide or tirofiban (the ACTION Trial). Am J Cardiol 2005; 95(11): 1295–1301. Martin JL, Fry ET, Sanderink GJ, et al. Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention: the pharmacokinetics of enoxaparin in PCI (PEPCI) study. Catheter Cardiovasc Interv 2004; 61(2):163–170. Ferguson JJ, Califf RM, Antman EM, et al. SYNERGY trial investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004; 292(1):45–54. Mehta SR, Steg PG, Granger CB, et al. ASPIRE investigators. Randomized, blinded trial comparing fondaparinux with

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unfractionated heparin in patients undergoing contemporary percutaneous coronary intervention: Arixtra Study in percutaneous coronary intervention: a randomized evaluation (ASPIRE) pilot trial. Circulation 2005; 111(11):1390–1397. Lincoff AM, Bittl JA, Harrington RA, et al. REPLACE-2 investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289(7):853–863. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. REPLACE-2 investigators. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004; 292(6):696–703. Sinnaeve PR, Simes J, Yusuf S, et al. Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention. Eur Heart J 2005; 26(22):2396–2403. Ferguson MA, Romick BG, Carter LI, De Geare VS. Relation of the use of lipid-lowering medications prior to

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percutaneous coronary intervention to the incidence of intraprocedural adverse angiographic events. Am J Cardiol 2005; 95(8): 978–980. Chang SM, Yazbek N, Lakkis NM. Use of statins prior to percutaneous coronary intervention reduces myonecrosis and improves clinical outcome. Catheter Cardiovasc Interv 2004; 62(2):193–197. Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G; ARMYDA investigators. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2004; 110(6):674–678. The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998, 339:436–443. The PRISM-PLUS Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338(21):1488–1497.

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46 Pharmacologic management of patients with CTO interventions David R. Holmes, Jr

Patients with chronic total occlusion (CTO) represent a significant problem for interventional cardiology. Interest in this group dates back to the earliest days of the field (1–4). The presence of a chronic total occlusion identified patients in whom the chances of a successful procedure were decreased compared with those patients who treated for a subtotal stenosis. In addition, failure was not necessarily benign because of the potential for coronary perforation which can lead to tamponade or compromise of collaterals to the distal vessel which could lead to infarction. Because of these issues, the presence of a chronic total occlusion was the most common reason for deferral of percutaneous coronary intervention (PCI) in early studies instead patients with chronic total occlusions were preferentially treated with coronary artery bypass graft surgery (CABG). In a more recent single-center registry series of 8004 consecutive patients undergoing diagnostic catheterization from 1990 to 2000, a chronic total occlusion was found in 52% of patients with significant coronary artery disease. Patients with a chronic total occlusion had more frequent hypertension and peripheral vascular disease. The ejection fraction was significantly less 53 ⫾ 16% versus 60 ⫾ 14% (p ⬍ 0.001), and multivessel disease was significantly more common 66% versus 42% (p ⬍ 0.001). Twelve percent of patients had more than one chronic total occlusion. Typically, the occlusion involved the RCA (64%) followed by the circumflex (35%) and then the LAD (28%). In this more recent series, using multivariate analysis, the presence of a chronic total occlusion remained the strongest predictor against selection of PCI (OR 0.26, 95% CI 0.22–0.31, p ⬍ 0.0001) (5). Because of the frequency with which chronic total occlusion occurs, there has been intense interest in developing and studying new approaches. These efforts have been spurred on by the finding in multiple series that successful PCI of a chronic occlusion is associated with a survival benefit as well as improvement in LV function. In an early study, Suero et al. (6) evaluated in-hospital and longer-term outcome in 2007 consecutive patients undergoing PCI for a CTO from 1980 to 1999 (Fig. 1A and 1B). These were matched with patients

treated for a subtotal stenosis using a propensity analysis. For both cohorts, the 10-year survival was similar —71.2% for CTO patients and 71.4% for non-CTO patients. In patients with a CTO, the outcome of the procedure was a very important determinant of survival; in those patients with successful CTO treatment, 10-year survival was 73.5% compared with patients with a failed procedure in whom the 10-year survival was only 65.1% (p ⫽ 0.001). More recent series have also documented a survival advantage (7–9). Hoye et al. in 874 consecutive patients with a CTO found a five-year survival in 93.5% of patients with successful revascularization versus 88.0% in these patients with failed revascularization (p ⫽ 0.02). In a Canadian registry of 1458 patients at seven year, successful recanalization of a chronic total occlusion was associated with improved survival as well as lower rates of PCI and/or CABG (9). In addition to survival advantage, both regional and global left ventricular function is improved in patients with successful treatment of a chronic total occlusion (10). This improvement may depend on whether the patient had a prior infarction in the distribution of the occlusion (11). If prior infarction resulted in frank myocardial necrosis, then recanalization may not improve the function; however, many patients with chronic occlusion have preservation of regional wall function. Despite the potential for improved outcome in patients treated percutaneously for chronic total occlusion, in many laboratories, these procedures are undertaken sparingly. Abbott et al. (12) analyzed 2000 patients undergoing PCI in four sequential waves of patients from 1997 to 2004. In this group, 5173 lesions were attempted. In the first cohort treated from 1997 to 1998, 9.6% of treated lesions were chronic total occlusions; in the last cohort from 2004, the percentage of lesions treated that were chronic total occlusions had decreased to 5.7% (p ⬍ 0.0001) (Fig. 2). Procedural success declined from 79.7% to 71.4% during those same time periods. Procedural success rates such as this may be an over estimate because series of chronic total occlusion cases contain only patients in whom the

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638/ 79.2 811/ 76.6 221/ 68.8

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1,393/ 1,145/ 88.0 83.1 1,347/ 1,104/ 87.9 82.2

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1,491 1,208/ 93.7 1,888 1,497/ 93.2 514 396/ 89.0

1,033/ 852/ 89.4 85.5 1,256/ 1,028/ 88.0 82.7 360/ 293/ 84.4 76.5

Figure 1 A ) Outcome of chronic total occlusion versus Long-term outcome of patients undergoing attempted PCI of a chronic total occlusion. (A B ) Outcome of successful versus unsuccessful treatment of a chronic total occlusion. Successful non-chronic total occlusion patients, (B treatment is associated with a survival advantage. Abbreviation : CTO, chronic total occlusion.

interventional cardiologist thought that successful recanalization was possible. There are multiple reasons for the decrease in frequency of performing procedures for CTO at the centers, but among the most prominent are the low success rates, procedural complexity, and time and resource utilization. In addition, recently because of the duration of procedures, excess radiation exposure has been documented (13,14). The most common reason for failure of a chronic total occlusion is inability to cross with a guidewire. The pathologic basis for this has been studied (15–17). Srivatsa et al. (15) evaluated the histologic correlates of angiographic total coronary artery occlusion in an autopsy series of 61 patients with

96 angiographic chronic total occlusions. They analyzed the occlusion segments for histologic composition and for the presence of neovascular channels. They identified that fibrocalcific intimal plaque increased with increasing age of the occlusion and that neovascular channels were related to the extent of inflammation. Micro channels particularly advential channels may make entry into the true lumen difficult (Fig. 3). Entry into and dilatation of these advential collaterals could result in vessel perforation. Another finding in chronic total occlusion is a fibrotic hard cap which is sometimes calcified. These hard caps may be difficult or even impossible to cross. A final large component is collagen-rich extracellular matrix (17). The entire longitudinal picture is often underlying plaque

Figure 2 Dynamic wave registry of four separate time intervals. Attempts at CTO recanalization have been decreased. Abbreviation: CTO, chronic total occlusion.

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Figure 3 A) large central neovascular channels (arrow ) or (B B ) extensive Histologic specimens of chronic coronary arterial occlusions with (A media/adventitial collaterals.

and then multiple layers of matrix and thrombus which build up to form the occlusion (16). The specific anatomy of the occlusion has a major impact on outcome of attempted percutaneous revascularization. Correlates of decreased success rates include older age of the occlusion, the presence of an abrupt cut off, the presence of a large patent side branch at the site of occlusion, and the presence of bridging collaterals. There are some patients in whom there are central intraplaque vessels (15,18,19). These may be associated with improved success rates. These problems have led to the development and testing of new approaches, both mechanical and pharmacologic

Table 1 New mechanical approaches for CTO revascularization New approaches Double wire Anchoring balloon Retrograde via collaterals Re-entry techniques

(Table 1). The mechanical approaches are very variable and range from new stiffer and/or coated guidewires, lasers, forward-looking ultrasound and ablative catheters. In addition, new guide catheter techniques and totally new approaches such as retrograde approaches through collaterals have been tested in specialized expert centers. These new catheter techniques have been reviewed elsewhere and are not the scope of this chapter on pharmacology (20). One item for emphasis is the use of drug-eluting stents. As the field has evolved, bare metal stents for chronic total occlusion were found to be substantially superior to conventional PTCA in reducing restenosis and reducing subsequent recurrent occlusion. More recently, there has been great interest in drug-eluting stents (21–27). This has culminated in a randomized trial which has been reported to show improvement in outcome compared with bare metal stents (26). Pharmacologic approaches are also evolving. Some of these approaches are aimed at making the procedure safer and avoiding complications; others are aimed at improving initial success rates or preventing reocclusion or restenosis.

Dedicated guidewires Hydrophilic guidewires Tapered tip guidewires Stiff guidewires with variable stiffness (3–12 gms) New devices Frontrunner blunt microdissection catheter Radiofrequency ablation with optical Coherence reflectometry guidance Laser guidewire High frequency ultrasound New visualization adjuncts Preprocedural multislice CT Forward looking ultrasound

Abbreviations : CT, computed tomography; CTO, chronic total occlusion.

Pharmacologic approaches to optimize initial safety The most important safety concerns are the potential for perforation which could result in tamponade or compromise of collaterals which can result in infarction. In current PCI practice with its reliance on drug eluting stent (DES), dual antiplatelet therapy with aspirin (ASA) and a thienopyridine (usually clopidogrel) is standard. These should be used in all patients. Pre-procedure administration of the thienopyridine should be given, if possible. IIb/IIIa platelet glycoprotein inhibitors are widely used in some institutions, particularly in the setting of complex interventions. However, in the setting of chronic total occlusion, these agents should not be used until the occlusion has

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successfully been crossed. This minimizes the potential for bleeding should perforation occur. In addition if guidewire perforation does occur, even if the procedure is eventually successful and the guidewire can be seen entering the distal vessel, IIb/IIIa agents should be avoided. If crossing a complete occlusion is achieved without complications, a IIb/IIIa agent can then be administered particularly if the vessel is small or has other complex features. Heparin is the standard treatment for conventional PCI. Recently, bivalirudin has been promoted extensively as an alternative. The latter has several advantages; it can be given as a single bolus, ACTs are not measured, and the half life is very short. In the setting of chronic total occlusion, bivalirudin has some significant disadvantages, namely although the half life is short, it cannot be reversed; in addition, chronic total occlusion cases are often long and would require additional dosing of bivalirudin which can increase costs substantially. Accordingly, unfractionated heparin should remain as the standard.

Pharmacologic agents to optimize initial success Recognition that the usual reason for failure with chronic total occlusions is inability to cross with a guidewire; there has been interest in softening the occlusion. This is based on a robust experience in the treatment of peripheral arterial occlusions with thrombolytic therapy (29–33). In that setting, intravenous thrombolytic therapy was used initially to soften the occluded segment and make subsequent PTA easier and more successful. The field soon migrated to using intra arterial infusions of urokinase to decrease hemorrhagic complications and improve success rates. This has widely been used for iliac, femoral, and poplitial occlusions. The specific dose and duration of therapy have varied, but even for long chronic total occlusions, it has been found to be effective although bleeding remains a problem particularly during longer duration of occlusion; the bleeding may be in part related to the need for heparin. Application of this concept has been expanded to the treatment of coronary arterial chronic total occlusion, the aim being the same as in the periphery to soften the occlusion and facilitate guidewire passage (34–37). Zidar et al. (36) reported on a randomized trial of prolonged intracoronary urohinase for chronic total occlusion of native coronary arteries. This study included 101 patients with an occlusion ⬎3 mo. Patients were pre-treated with ASA and then given 10,000 U of IV heparin. Urohinase was infused after initial attempts at crossing the occlusion with a guidewire. The urohinase was administered for approximately eight hour with a split dosing through the guide catheter and the infusion catheter which were positioned proximal to the site of

occlusion. One of three doses was used for a total of 800,000 U, 16 million U or 3.2 million U over the eight hour. Following infusion, the patient was returned to the catheterization laboratory for an additional attempt at guidewire passage. After urohinase infusion, angioplasty was successful in 53%. Patients receiving higher doses of urohinase had more bleeding although the numbers were too small to reach statistical significance. Follow up angiographic rates were low but the target vessel was patent in 91%; however, restenosis rates were high. Subsequent to this study, Abbas et al. (37) reported on 85 patients who had a history of failed attempt at recanalization of a chronic coronary occlusion in whom at the time of repeat intervention, pre-procedural intracoronary fibrinspecific lytic therapy was used. In this group, either weightadjusted alteplase (tPA, Genentech, San Francisco, CA; 0.025–0.05 mg/kg/hr; 2 mg/hr for weight ⱕ60 kg, 3 mg/hr for weight 61 to ⱕ80 kg, 4 mg/hr for weight 81 to ⱕ105 kg, and 5 mg/hr for weight ⱖ105 kg) or standard dose tenecteplase (TNK) (Genentech; 0.5 mg/hr) was administered for eight hour with an infusion catheter positioned at the face of the chronic total occlusion (Fig. 4). All of the occlusions were greater than three month in duration and 62% involved the right coronary artery. Despite the fact that all of the patients had had a previous failed attempt at recanalization, the procedure after lytic therapy was successful in 54%. Among the failed cases, inability to cross the occlusion with a guidewire was the most common reason for failure (97%). Procedural complications were relatively infrequent and included 5% with dissections that did not result in perforation or tamponade, groin hematoma in 8%, and positive biomarkers with elevation of total CK with an increase in MB fraction seen in 5%. This approach appears promising in these patients with previously failed attempts and will be tested in a larger trial. Recently, there has been in the use of other pharmacologic agents to modify the chronic total occlusion and render it more suitable for treatment (38–40). An animal model has been developed for testing these new approaches. In this rabbit model, thrombin is injected into an isolated portion of the femoral artery. After recovery, during the next two to four month, the thrombus is replaced by collagen which results in a chronic total occlusion. Using this rabbit model, a purified human grade collagenase was tested (39). Similar to the human situation, an over-the-wire balloon angioplasty catheter was advanced and positioned immediately proximal to the part of occlusion. The collagenase was administered through the central lumen for 24 hour. Following this, guidewire recanalization was attempted using conventional coronary guidewires. In the series of 10 CTO treated in this way, passage of the guidewire was successful in all 10. A wire-induced dissection was identified in two animals; despite that the wire eventually crossed into the distal vessel. For this study, multiple doses of collagenase were used. The author studied the effect of the collagenase on subcutaneous

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Figure 4 Approach used for subselective infusion prior to attempted PCI of a RCA. (Left ) The RCA has been intubated with a guiding catheter, and a small infusion catheter advanced to the beginning of the occlusion. (Right ) Both guide catheter and infusion catheter are used to deliver material. Both must be secured to avoid displacement. Ostial occlusion lesions are not suitable for this approach.

bruising. With higher doses, there was more extensive bruising but no significant differences in hemoglobin at 24 hours. Vessel wall structure remained intact. This approach has considerable potential in the human arena although multiple details need to be worked out including the optimal duration of local arterial therapy. This detail has major implications for patient care. Infusions for up to six hour may be reasonably well tolerated; beyond this window, they become increasingly complicated. Prolonged heparin if required to maintain guide and sub-selective catheter patency may be associated with increased bleeding.

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Conclusions Chronic total occlusions remain one of the last great problems (or opportunities) for interventional cardiology. Despite their frequency, current success rates are still quite low even in selected patients; the dominant reason for failure is inability to cross with a guidewire. New mechanical approaches continue to be evaluated. In addition to these, new pharmacologic strategies are being developed to facilitate initial safe passage of the guidewire. These have the potential to improve success rates. Resolution of this problem will open up the doors for many patients with chronic coronary artery disease to undergo a percutaneous revascularization procedure rather than CABG.

References 1 2

3

Holmes DR Jr, Vlietstra RE, Reeder GS, et al. Angioplasty in total coronary artery occlusion. JACC 1984; 3:845–849. Bell MR, Berger PB, Bresnahan JF, et al. Initial and long term outcome of 354 patients after coronary balloon angioplasty of total coronary artery occlusion. Circulation 1992; 85: 1003–1011. Safian RD, McCabe CH, Sipperly ME, et al. Initial success and long-term follow-up of percutaneous transluminal coronary

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angioplasty in chronic total occlusions versus conventional stenoses. Am J Cardiol 1988; 61:23G–28G. Ivanhoe RJ, Weintraub WS, Douglas JS Jr., et al. Percutaneous transluminal coronary angioplasty of chronic total occlusions. Primary success, restenosis and long-term clinical follow-up. Circulation 1992; 85:106–115. Christofferson RD, Lehmann KG, Martin GV, et al. Effect of chronic total coronary occlusion on treatment strategy. Am J Cardiol 2005; 95:1088–1091. Suero JA, Marso SP, Jones PG, et al. Procedural outcomes and long term survival among patients undergoing percutaneous coronary intervention of a chronic total occlusion in native coronary arteries: a 20 year experience. JACC 2001; 38:409–414. Noguchi T, Miyazaki S, Morii I, et al. Percutaneous transluminal coronary angioplasty of chronic total occlusions. Determinants of primary success and long-term clinical outcome. Catheter Cardiovasc Inter 2000; 49:258–264. Hoye A, van Domburg RT, Sonnenschein K, Serruys, PW. Percutaneous coronary intervention for chronic total occlusions: the Thoraxcenter experience 1992–2002. Eur Heart J 2005; 26:2630–2636. Ramanathan K, Gao M, Nogareda GJ, et al. Successful percutaneous recanalization of a non acute occluded coronary artery predicts clinical survival and outcome. Circulation 2001; 104:415A. Ermis C, Boz A, Tholakanahalli V, et al. Assessment of percutaneous coronary intervention on regional and global left ventricular function in patients with chronic total occlusions. Can J Cardiol 2005; 21:275–280. Chung CM, Nakamura S, Tanaka K, et al. Effect of recanalization of chronic total occlusions on global and regional left ventricular function in patients with or without previous myocardial infarctions. Catheter Cardiovasc Interv 2003; 60:368–374. Abbott JD, Kip KE, Vlachos HA, et al. Recent trends in the percutaneous treatment of chronic total artery occlusions. Am J Cardiol 2006; 97:1691–1696. Suzuki S, Furui S, Kohtake H, et al. Radiation exposure to patient’s skin during percutaneous coronary intervention for various lesions including chronic total occlusion. Circulation 2006; 70:44–48. Kuon E, Empen K, Rohde D, Dahm JB. Radiation exposure to patients undergoing percutaneous coronary

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interventions: are current reference values too high. Herz 2004; 29: 208–217. Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary occlusion. JACC 1995:29:955–963. Meier B. Chronic total occlusions. In Topol EJ editor Textbook of Interventional Cardiology 4th Edition Philadelphia PA Saunders 2003; 303–316. Katsuda S, Okada Y, Minamoto T, et al. Collagens in human atherosclerosis: immunohistochemical analysis using collagen type specific antibodies. Arterioscler Thromb 1992; 12:494–502. Katsuragawa M, Fujiwara H, Miyamae M, et al. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: comparison of tapering and abrupt types of occlusion and short and long occluded segments. JACC 1993; 21:604–611. Strauss BH, Segev A, Wright GA, et al. Microvessels in chronic total occlusions: pathways for successful guidewire crossing? J Interv Cardiol 2005; 18:425–436. Fung A, Hamburger JN. The chronic total occlusion In Ellis S and Holmes 3rd Edition Strategic Approaches in Coronary Interventions. 2005:366–373. Ge L, Iakovou I, Cosgrove J, et al. Immediate and mid-term outcomes of Sirolimus eluting stent implantation for chronic total occlusions. Eur Heart J 2005; 26:1056–1062. Rohel BM, Suttorp MJ, Laarman GL. Primary stenting of occluded native coronary arteries: final results of the primary stenting of occluded native coronary arteries (PRISON) study. Am Heart J 2004; 147:H1–H5. Hoye A, Tanabe K, Lemos A, et al. Significant reduction in restenosis after the use of Sirolimus eluting stents in the treatment of chronic total occlusions. JACC 2004; 43:1954–1958. Olivari Z, Rubertelli P, Piscione F, et al. TOAST-GISE Investigators. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE). J Am Coll Cardiol 2003; 41: 1672–1678. Migliorini A, Moschi G, Vergara R, et al. Drug-eluting stent supported percutaneous coronary intervention for chronic total coronary occlusion. Catheter Cardiovasc Interv 2006; 67:344–348. Rahel BM, Laarmen GJ, Suttorp MJ, et al. Primary stenting of occluded native coronary arteries II—rationale and design of the PRISON II study: a randomized comparison of bare metal stent implantation with Sirolimus-eluting stent implantation for the treatment of chronic total coronary occlusions. Am Heart J 2005; 149:e1–e3.

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Olivari Z, Rubartelli P, Piscione, F, et al. Immediate results and one-year clinical outcome after percutaneous coronary interventions in chronic total occlusions: data from a multicenter, prospective, observational study (TOAST-GISE). J Am Coll Cardiol 2003; 41:1672–1678. Braim MR, Gert JL, Maarten JS, et al. Primary stenting of occluded native coronary arteries II—rationale and design of the PRISON II Study: a randomized comparison of bare metal stent implantation with sirolimus-eluting stent implantation for the treatment of chronic total coronary occlusions. Circulation 2006; 114:921–928. Poliwoda H, Alexander K, Buhl V, et al. Treatment of chronic arterial occlusions with streptokinase. N Engl J Med 1969; 280:689–692. Martin M, Schoop W, Weitler E. Streptokinase in chronic arterial occlusive disease. JAMA 1970; 211:1169–1173. Verstraete M, Vermlen J, Donati MB. The effect of streptokinase infusion on chronic arterial occlusions and stenoses. Ann Intern Med 1971; 74:377–382. Lupattelli L, Barzi F, Corneli P, et al. Selective thrombolysis with low-dose urokinase in chronic arteriosclerotic obstructions. Cardiovasc Intervent Radiol 1988; 11:123–126. Motarjeme A, Gordon G, Bodenhagen K. Thrombolysis and angioplasty of chronic iliac artery occlusions. J Vasc Intervent Radiol 1995; 6:665–725. Ajluni SC, Jones D, Zidar FJ, et al. Prolonged urokinase infusion for chronic total native coronary occlusions: clinical, angiographic, and treatment observations. Cathter Cardiovasc Diagn 1995; 34:106–110. Razavi MK, Wong H, Kee ST, et al. Initial clinical results of tenecteplase (TNK) in catheter-directed thrombolytic therapy. J Endovasc Ther 2002; 9:593–598. Zidar FJ, Kaplan BM, O’Neill WW, et al. Prospective randomized trial of prolonged intracoronary urokinase infusion for chronic total occlusions in native arteries. J Am Coll Cardiol 1996; 27:1406–1412. Abbas AE, Brewington SD, Dixon SR, et al. Intracoronary fibrin-specific thrombolytic infusion facilitates percutaneous recanalization of chronic total occlusion. JACC 2005; 46:793–798. Segev A, Strauss BH. Novel approaches for the treatment of chronic total occlusions. J Interv Cardiol 2004; 17:411–416. Segev A, Nili N, Qiang B, et al. Human-grade purified collagenase for the treatment of experimental arterial chronic total occlusion. Cardiovasc Revasc Med 2005; 6:65–69. Strauss BH, Goldman L, Qiang B, et al. Collagenase plaque digestion for facilitating guidewire crossing in chronic total occlusions. Circulation 2003; 108:1259–1262.

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47 Newer pharmacologic approaches targeting receptors and genes Omer M. Iqbal, Debra Hoppensteadt, and Jawed Fareed

Introduction The emergence of pharmacogenomic-guided drug development has led to novel approaches in the effective management of patients and ensured individualized therapy tailored to the needs of one and all, at the right dosage and right time. The entire human genome is now completely mapped. Gene expression profiling and identification of the single nucleotide polymorphism (SNP) will enable effective diagnosis of various diseases, and has a role in preclinical phases of drug development, in developing markers for adverse drug interactions and desired pharmacologic effects. Newer drugs can be withdrawn from the drug development pipeline should they exhibit hepatic metabolism requiring CYP450 enzymes known to manifest SNPs resulting in adverse drug reactions. Vogel for the first time introduced the term, pharmacogenetics, in 1959 (1), which refers to the analysis of monogenetic variants that define an individual’s response to a drug, and aims to deliver the right drug at right dosage to a right patient by using DNA information. The variable drug response in different patients may be the result of genetic differences in drug metabolism, drug distribution, and drug target proteins (2). Pharmacogenetics refers to the entire library of genes that determine drug efficacy and safety. There are approximately three billion base pairs in the human genome that code for at least 30,000 genes. Although the majority of basepairs are identical from individual to individual, only 0.1% of the basepairs contribute to individual differences. Three consecutive basepairs form a codon that specifies the amino acids that constitute the protein. Genes represent a series of codons that specifies a particular protein. At each gene locus, an individual carries two alleles, one

from each parent. If there are two identical alleles, it is referred to as a homozygous genotype, and if the alleles are different, it is heterozygous. Genetic variations usually occur as SNPs and occur on an average of at least once every 1000 basepairs, accounting to approximately three million basepairs distributed throughout the entire genome. Genetic variations that occur at a frequency of at least 1% in the human population are referred to as polymorphisms. Genetic polymorphisms are inherited and monogenic; they involve one locus and have interethnic differences in frequency. Rare mutations occur at a frequency of less than 1% in the human population. Other examples of genetic variations include insertion–deletion polymorphisms, tandem-repeats, defective splicing, aberrant splice site, and premature stop codon polymorphisms. Pharmacogenomics, through the discovery of new genetic targets, is expected to improve the quality of life and control the healthcare costs by treating specific genetic subgroups and by avoiding adverse drug reactions and by decreasing the number of treatment failures. The evolution and the concepts of pharmacoeconomic-based pharmacogenomics and pharmacogenetics should be widely known and practiced. Pharmacogenomics and cheminformatics should become a part of the current study designs of prospective clinical trials. Pharmacogenomic and pharmacogenetic data should be included in the investigational new drug (IND) applications, thereby enabling the food and drug administration (FDA) to evaluate its true impact on pharmacoeconomics resulting in drastic reduction in the healthcare expenditure worldwide. Pharmacogenomics provides a significant paradigm shift in the management of patients and provides a means to increase the quality of medical care.

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Single nucleotide polymorphism Pharmaceutical industries are very much interested in pharmacogenomics as a means to reduce the costs and the time involved in conducting the clinical trials and to improve the efficacy of drugs tailored to the individual patient need. Although the genetic association studies are used to establish links between polymorphic variation in the coagulation Factor V gene and deep vein thrombosis (DVT), this approach of “susceptibility genes” that has a crucial role in the likelihood of developing a disease has enabled identification of other genes (3). Variations in a drug metabolizing enzyme gene, thiopurine methyltransferase (TPMT), have been linked to adverse drug reactions (4). Similarly, variants in a drug-target, 5lipoxygenase, (ALOX5) have been linked to variations in drug response (5). Through linkage disequilibrium (LD) or nonrandom association between SNPs in proximity to each other, tens of thousands of anonymous SNPs are identified and mapped. These anonymous genes may fall either within susceptibility genes or in noncoding DNA between genes. Through LD, the associations found that with these anonymous SNP markers can identify a region of the genome that may harbor a particular susceptibility gene. Through positional cloning, the gene and the SNP can be revealed conferring the underlying associated condition or disease (6). Numerous companies have now developed DNA

Table 1

microarrays (biochips) of different genes of interest that could be used in high-throughput sequencing in a population to detect common or uncommon genetic variants. These DNAbased diagnostic microarrays, which are targeted for patient care, must be accurate, high-throughput, reproducible, flexible, and inexpensive. Efforts should be made to improve the sensitivity as well as to reduce the costs of identifying polymorphisms by direct sequencing. It is important to understand the genetic variability in genes in relation to the safety and efficacy of any drug. The functional consequences of nonsynonymous SNPs can be predicted by a structurebased assessment of amino acid variation (7).

Pharmacogenomics in coagulation disorders According to the SNP Map Working Group (Nature 2001), there are 1.42 million SNPs; one SNP per 1900 bases; 60,000 SNPs within exons; two exonic SNPs per gene (1/1080 bases); 93% of genetic loci contain two SNPs. Because each person is different at one in 1000–2000 bases, SNPs are responsible for human individuality. A list of genes involved in coagulation disorders is given in Table 1. The various polymorphisms in different coagulation proteins are discussed subsequently.

List of genes involved in coagulation disorders

Clone ID

Name

Gene title

22040

MMP9

Matrix metalloproteinase 9 (gelatinase B, 92-Kd gelatinase, 92-Kd type IV collagenase)

26418

EDG1

Endothelial differentiation, sphingolipid G-protein-coupled receptor

32609

LAMA4

Laminin, alpha 4

34778

VEGF

Vascular endothelial growth factor

40463

PDGFRB

Platelet-derived growth factor (PDGF) receptor, betapolypeptide

41898

PTGDS

Prostaglandin D2 synthase (21 Kd, brain)

44477

VCAM1

Vascular cell adhesion molecule 1

45138

VEGFC

VEGF factor C

49164

VCAM1

Vascular cell adhesion molecule 1

49509

EPOR

Erythropoietin receptor

49665

EDNRB

Endothelin receptor type B

49920

PTDSS1

Phosphatidylserine synthase 1

51447

FCGR3B

Fc fragment of IgG, low affinity IIIb, receptor for Z(CD16)

66982

PLGL

Plasminogen-like

67654

PDGFB

PDGF-betapolypeptide [Simian sarcoma viral (v-sis) oncogene homolog]

71101

PROCR

Protein C receptor, endothelial (EPCR)

71626

ZNF268

Zinc finger protein 268 (Continued )

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Table 1

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List of genes involved in coagulation disorders (Continued )

Clone ID

Name

Gene title

768246

G6PD

Glucose-6-phosphate dehydrogenase

85678

F2

Coagulation factor II

85979

PLG

Plasminogen

120189

PSG4

Pregnancy-specific beta-1-glycoprotein 4

121218

PF4

Platelet factor 4

127928

HBP1

HMG-box containing protein 1

130541

PECAM1

Platelet/endothelial-cell adhesion molecule (CD31 antigen)

131839

FOLR1

Folate receptor 1 (adult)

135221

S100P

S100 calcium-binding protein P

136821

TGFB1

Transforming growth factor, beta 1

137836

PDCD10

Programmed cell death 10

138991

COL6A3

Collagen, type VI, alpha 3

139009

FN1

Fibronectin 1

142556

PSG2


143287

PSG11


143443

TBXAS1

Thromboxane A synthase 1

149910

SELL

Selectin E (endothelial adhesion molecule 1)

151662

P11

Protease, serine, 22

155287

HSPA1A

Heatshock 70Kd protein 1A

160723

LAMC1

Laminin, gamma 19 formerly LAMB2

179276

FASN

Fatty acid synthase

180864

ICAM5

Intercellular adhesion molecule 5, telencephalin

184038

SPTBN2

Spectrin, beta, nonerythrocytic 2

191664

THBS2

Thrombospondin 2

194804

PTTPN

Phosphatidylinositol transfer protein

196612

MMP12

Matrix metalloproteinase 1 (interstitial collagenase)

199945

TGM2

Transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase)

205185

THBD

Thrombomodulin

210687

AGTR1

Angiotensin receptor 1

212429

TF

Transferrin

212649

HRG

Histidine-rich glycoprotein

234736

GATA6

GATA-binding protein 6

240249

APLP2

Amyloid beta (A4) precursor-like protein 2

241788

FGB

Fibrinogen, B betapolypeptide

243816

CD36

CD36 antigen (collagen type 1 receptor, thrombospondin receptor)

245242

CPB2

Carboxypeptidase B2 (Plasma, carboxypeptidase U)

260325

ALB

Albumin

261519

TNFRSF5

TNF-receptor (superfamily, member 5)

292306

LIPC

lipase, hepatic (Continued )

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Clone ID

Name

Gene title

296198

CHS1

Chediak-Higashi syndrome 1

310519

F10

Coagulation factor X

340644

ITGB8

Integrin, beta 8

343072

ITGB1

Integrin, beta 1 (finronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12)

345430

PIK3CA

Phosphoinositide 3 kinase, catalytic, alpha polypeptide

589115

MMP1

Matrix metalloproteinase 1 (interstitial collagenase)

666218

TGFB2

Transforming growth factor, beta 2

712641

PRG4

Proteoglycan 4 (megakaryocyte-stimulating factor, articular superficial zone protein)

714106

PLAU

Plasminogen activator, urokinase

726086

TFPI2

Tissue factor pathway inhibitor (TFPI) 2

727551

IRF2

Interferon regulatory factor 2

753211

PTGER3

Prostaglandin E receptor 3 (subtype EP30)

753418

VASP

Vasodilator-stimulated phosphoprotein

753430

ATRX

Alpha Thalassemia/mental retardation syndrome X-linked RAD54 (S. cerevisiae) homolog

754080

ICAM3

Intercellular adhesion molecule 3

755054

IL18R1

Interleukin 18 receptor 1

758266

THBS4

Thrombospondin 4

770462

CPZ

Carboxypeptidase Z

770670

TNFAIP3

Tumor necrosis factor (TNF), alpha-induced protein 3

770859

ITGB5

Integrin, beta 5

776636

BHMT

Betaine-homocysteine methyltransferase

782789

AVPR1A

Arginine vasopressin receptor 1A

785975

F13A1

Coagulation factor XIII, A1 polypeptide

788285

EDNR A

Endothelial receptor type A

809938

TACSTD2

Matrix metalloproteinase 7 (matrilysin, uterine)

810010

PDGFRL

PDGF-receptor-like

810017

PLAUR

Plasminogen activator, urokinase receptor

810117

ANXA11

Annexin A11

810124

PAFAH1B3

Platelet-activating factor acetylhydrolase, isoform 1b, gamma subunit (29 Kd)

810242

C3AR1

Complement component 3a receptor 1

810512

THBS1

Thrombospondin 1

810891

LAMA5

Laminin, alpha 5

811096

ITGB4

Integrin, beta 4

811792

GSS

Glutathione synthetase

812276

SNCA

Synuclein, alpha (non-A4 component of amyloid precursor)

813757

FOLR2

Folate receptor 2 (fetal)

813841

PLAT

Plasminogen activator, tissue serine (or cysteine) proteinase inhibitor, Clade E (nexin, plasminogen activator inhibitor type 1), member 1

814378

SPINT2

Serine protease inhibitor, kunitz type 2 (Continued )

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Table 1

547


Clone ID

Name

Gene title

814615

MTHFD

Methylene tetrahydrofolate dehydrogenase (NAD-dependent), methylenetetrahydrofolate cyclohydrolase

825295

LDLR

low-density lipoprotein-receptor (familial hypercholesterolemia)

840486

vWF

von Willebrand factor

842846

TIMP2

Tissue inhibitor of metalloproteinase-2

1813254

F2R

Coagulation factor II (thrombin) receptor

Fibrinogen Various polymorphisms have been identified in all the three genes located on the long arm of chromosome 4 (q23–32). However, the two dimorphisms in the ␤-chain gene, namely the HaeIII polymorphisms (a G→A substitution at position –455 in the 5⬘ promoter region and the BcII polymorphism in the 3⬘ untranslated region, are of major importance and are in LD with each other. The –455G/A substitution in different investigations was found to be a determinant of plasma fibrinogen levels (8,9) and linked the fibrinogen gene variation to the risk of arterial disease. Because of conflicting reports from different studies, this association between fibrinogen gene variation and arterial disease is controversial. The ␣-chain Thr-312 AIa polymorphism has been reported to increase the stability of the clot (10). Specific factor XIIIa inhibitors may play an important role in decreasing clot stability.

Prothrombin The coagulation Factor II (prothrombin) G20210A mutation occurring in 2% of the population is located in the 3⬘ UTR of the coagulation Factor II propeptide near a putative polyadenylation site (11). It is associated with increased levels of prothrombin resulting in DVT, recurrent miscarriages, and portal vein thrombosis in cirrhotic patients (13–16). Anticoagulant drugs, such as Factor Xa inhibitors or tissue factor pathway inhibitor (TFPI), should be developed to prevent thrombosis in these conditions. The interactive role of hormone replacement therapy and prothrombotic mutations has been reported to cause the risk of nonfatal myocardial infarction in postmenopausal women (17).

Factor V Leiden R506Q This mutation (G1691A), occurring in 8% of the population and referring to specific G→A substitution at nucleotide 1691 in the

gene for Factor V, is cleaved less efficiently (10%) by activated protein C. This results in DVT, recurrent miscarriages, portal vein thrombosis in cirrhotic patients, early kidney transplant loss, and other forms of venous thromboembolism (12,14,15,17). A dramatic increase in the incidence of thrombosis is seen in women who are taking oral contraceptives. Both prothrombin G20210 and Factor V Leiden in the presence of major risk factors may contribute to atherothrombosis. Antithrombin drugs may play a crucial role in the management of these thrombotic disorders. The Factor V Leiden allele is common in Europe, with a population frequency of 4.4%. The mutation is very rare outside Europe with a frequency of 0.6% in Asia Minor (18).

Factor VII Polymorphisms in the Factor VII gene, especially the Arg-353Gln mutation in exon 8 located in the catalytic domain of Factor VII, influence plasma Factor VII levels. The Gln-353 allele caused a strong protective effect against the occurrence of myocardial infarction (19). Further research in this area is warranted to understand the role of Factor VII in determining arterial thrombotic risk. Since the Factor VIIa/tissue factor (TF) is the initial coagulation pathway, much attention has been given in blocking this pathway by developing Factor VIIa inhibitors and TFPI (20). NAPc2 and NAP-5 are two of the anticoagulant proteins isolated from the hookworm nematode, Ancylostoma caninum. NAPc2 is currently undergoing Phase II clinical trials for prevention of venous thromboembolism in patients with elective knee arthroplasty. NAPc2 binds to a noncatalytic site on Factor X or Xa and inhibits Factor VII. NAP-5 inhibits Factor Xa and the Factor VII/TF complex after prior binding to Factor Xa.

Factor VIII Increased Factor VIII activity levels are associated with increased risk of arterial thrombosis. However, no specific polymorphisms in the Factor VIII gene have been determined.

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Von Willebrand factor Although increased plasma von Willebrand factor (vWF) levels have been attributed to increased risk of arterial thrombotic events, no gene polymorphisms in vWF have been identified.

Factor XIII Factor XIII SNP G→T in exon 2 causes a Val/Leu change at position 34. The Val34Leu polymorphism increases the rate of thrombin activation of Factor XIII and causes increased and faster clot stabilization (21,22). The Leu34 allele has been shown to play a protective role against arterial and venous thrombosis (23,24). Specific Factor XIIIa inhibitors, such as tridegin and others mentioned earlier, may provide an interesting and novel approach to preventing fibrin stabilization. It is important to identify this polymorphism since the Leu34 variant associated with increased Factor XIIIa activity reduces the activity of thrombolytic therapy (21,22).

The Val264Met mutation causes decreased TFPI levels (29). It is reported that the Pro-151Leu replacement is a risk factor for venous thrombosis (30). A polymorphism in the 5⬘ UTR of the TFPI gene (–287 T/C did not alter the TFPI levels and did not influence the risk of coronary atherothrombosis (31). It has been recently reported that the –33T→C polymorphism in the intron 7 of the TFPI gene influences the risk of venous thromboembolism, independently of the Factor V Leiden and prothrombin mutations, and its effect is mediated by increased total TFPI levels (32).

Endothelial protein C receptor A 23 bp insertion in exon 3 of the endothelial protein C receptor (EPCR) gene has been reported to predispose patients to the risk of coronary atherothrombosis (33). Further studies are needed to relate the polymorphisms in the EPCR gene to thrombotic diseases.

Polymorphisms in the natural anticoagulant system

Platelet surface gene polymorphisms

Genetic defects in the antithrombin, protein C and protein S in arterial diseases are not completely understood and may not contribute to the risk of arterial thrombosis.

Various polymorphisms of the platelet surface proteins, such as glycoprotein (GP) Ia-IIa, GPIb-V-IX, and GPIIb/IIIa have been reported. Afshar-Kharghan et al. (34) have recently reported a gene polymorphism in the Kozac sequence of the GpIb␣ receptor. Definition of the role of these polymorphisms in arterial diseases is warranted. Platelet receptor GPIb␣ and immobilized vWF interactions cause rolling of platelets on the damaged endothelium facilitating platelet activation. These interactions in occluded atherosclerotic arteries or ruptured atherosclerotic plaques cause arterial thrombosis (35). Mutations of GPIb␣ and vWF cause four different types of bleeding disorders enhancing or reducing complex formation. The receptor complex consists of GPIb␣, GPIb␤, IX, and V. Through GPIb␣, the complex is anchored to the cytoskeleton. The vWF protein forms large multimers, which are found in plasma and subendothelial cell matrix and are released from the storage granules upon activation of platelets and endothelial cells. GPIb␣ and vWF have two contact sites and may serve as primary useful targets for the development of drugs for the treatment or prophylaxis of arterial thrombosis (36,37).

Thrombomodulin Thrombomodulin mutations are more important in arterial diseases than in venous diseases. The thrombomodulin polymorphism, G→A substitution at nucleotide position 127 in the gene, has been studied regarding its relation with the arterial disease. The 25 Thr allele has been reported to be more prevalent in male patients with myocardial infarction than the control population (25). Polymorphism in the thrombomodulin gene promoter (–33 G/A) influences the plasma soluble thrombomodulin levels and causes increased risk of coronary heart disease (26). Carriership of the –33A allele was also reported to cause increased occurrence of carotid atherosclerosis in patients less than 60 years (27).

Tissue factor pathway inhibitor Sequence variation of the TFPI gene has been reported. The four different polymorphisms reported are: pro-151Leu, Val-264Met, T384C exon 4, and C-33T intron 7 (28,29).

Methylene tetrahydrofolate reductase gene A common polymorphism C677T, seen in the methylenetetrahydrofolate reductase (MTHFR) gene causing

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hyperhomocysteinemia is considered to be a potential risk factor for both venous and arterial thrombotic diseases.

Cardiovascular genomics Cardiovascular healthcare can be personalized. The complete mapping of the human genome has brought out novel technologies that allow genome-wide interrogation of SNPs. Several other technologies such as transcriptomics (gene expression profiles), proteomics (proteomes), metabolomics (metabolomes) would go hands in gloves with genomics (human genome sequence), in making the personalized healthcare possible. The first autosomal dominant gene for coronary artery disease and myocardial infarction, reported recently, was a deletion mutation in a member of the myocyte enhancer Factor 2 transcription factor family (MEF2A), discovered in a single large family of which 13 members had coronary artery disease, and nine had myocardial infarction (38). Large case control association studies of candidate genes for myocardial infarction or premature coronary artery disease have been carried out. The various candidate genes include the gap junction protein, alpha 4, 37 kDa gene (GJA4) or connexin 37, p22 (phox) (39); plasminogen activator inhibitor1, stromelysin-1 (39); lymphotoxin-alpha (40); alpha-adducing (ADD1), cholesteryl ester transfer protein (CETP), paraoxonase-1,2, apolipoprotein C-III (41); 5-lipoxygenase activating protein (FLAP), apolipoprotein E (42); low-density lipoprotein-related protein-1, matrix metalloproteinase 3 gene (MMP3), angiotensin-1 converting enzyme, methylene tetrahydrofolate reductase, Factor VII, P-selectin (SELP, fibrinogen-beta, thrombopoietin, GP-Ib alpha, interleukin-1 receptor antagonist, thrombospondin 2 and 4, and plasminogen activator inhibitor 2 (43).

Expression profiling of RNA Gene variants may be associated with the disease; however, it does not specify that a disease phenotype will be present. While the information in the DNA may not be altered, RNA, an intermediate gene product from DNA transcription, might change in response to environmental, intracellular, and extracellular stimuli. Using microarrays the entire transcriptome comprising 25,000 transcripts can be interrogated. The RNA profile can help to subclassify disease, for example heart failure (44,45), and predict response to different therapies or to identify genes associated with a clinical outcome.

Genomics and sudden cardiac death Although cardiac arrhythmias involve the electrical conduction system of the heart including the sinus node, atrioventricular

549

node and bundle of His and the Purkinje system and eventually the electrical current has to pass in the cardiomyocytes. In order to facilitate such a transmission to the cardiomyocytes, it involves the functional roles of ionic currents, ion channels, structural proteins, and gap junctions. Genetic defects are known to involve the subunits of the ion channels. So far 429 genes encoding ion channel proteins in humans have been identified (46). Of the 429 genes, 170 encode potassium channels, 38 calcium channels, 29 sodium channels, 58 chloride channels, and 15 encode glutemate receptors (47). Ion channels have quite a complex functional network and are known to not only regulate membrane potentials but also regulate cell volume and hormone secretion (48,49). Sudden cardiac death in younger patients (⬍35 years) is mainly due to genetic causes. Atrial fibrillation has been mapped to nine chromosomal loci involving four genes. The adenosine monophosphate-activated protein kinase gene is responsible for the Wolff-Parkinson-White syndrome. The long QT syndrome and the Brugada syndrome are due to the involvement of other genes defects primarily in sodium and potassium channels in the heart (50).

Eradication of cardiovascular disease and future prospects Eradication of cardiovascular disease is the long-term goal of cardiovascular genomics. As the aging population continues to grow, the actual number of persons who die from cardiovascular disease remained nearly constant at about three quarters of a million per year during the period 1970–1998 (51,52). However, the cardiovascular death in women has declined less than men. Furthermore, the growing incidence of obesity worldwide would lead to diabetes and metabolic syndrome and should sound a major alarm for heightened risk of cardiovascular morbidity and mortality.

Cardiovascular genomics and biomedical engineering Keeping pace with the pharmacogenomics and metabolomics, the advances in molecular imaging have contributed significantly to the understanding of cardiovascular system. The display and quantification of the molecular and cellular targets have become possible with the development of chemical and biologic probes to monitor the activity of molecular pathways, and development of molecular imaging techniques. For example, the optical coherence tomography (OCT) helps in measuring the macrophage content of arterial plaques enabling prognosis and guiding therapy (53), radiolabeled antibodies against epitopes on low-density lipoproteins such as I-125 MDA2 used in animals to assess disease severity (54), magnetic

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resonance imaging, fluorescence imaging, bioluminescence imaging, positron emission/single photon emission computed tomography (PET/SPECT) and ultrasound techniques to image enzymes (e.g., cathepsins B,D,K,S, and MMPs), receptors (e.g., GPCRs, integrins), and endothelial cells (e.g., E-selectin, VCAM) apoptosis (phosphatidylserine), angiogenesis (VCAM), and thrombosis (fibrin, thrombin) (55). Furthermore, visualization of clot formation and angiogenesis may be possible through application of magnetic resonance nanoparticles targeting directly to fibrin and integrins (56). Other applications of molecular imaging are in the fields of cancer and inflammatory diseases as well as atherosclerosis, heart failure, and thrombosis for early detection of disease, monitoring of disease progression, and to monitor response to therapy (55). Polymorphisms in candidate genes related to hemostasis, thrombosis, lipid metabolism, inflammation, and cell matrix adhesion have been known to be useful in risk assessment of cardiovascular diseases. However, recent report on multilocus candidate gene polymorphisms and risk of myocardial infarction, a population-based, prospective genetic analysis concluded that after correction for multiple comparisons, the addition of genetic information observed had a little impact on myocardial infarction risk prediction models (57). Realizing the fact that the analyses in this study were not designed to directly address the potential for gene⫺environmental interactions, further studies need to be done to better understand the haplotypic effect, gene–gene interactions, and gene–environment interactions in the pathophysiology of athero-thrombosis. This would be a potential focus of intense research in the postgenomic era. Analyzing Zee et al.’s study, Reitsma commented that the study although based on the very large Physicians Health Study lacks power and includes data on about 500 cases and 2000 controls, which is too little to detect small but clinically relevant genetic risk factors or a combination of risk factors (58). Reitsma further commented that study performed by Zee et al. did not include a variant gene encoding leukotriene A4 hydrolase, which has recently been reported to confer the risk of myocardial infarction particularly in Africans and Americans (59). Furthermore, Lysenko et al reported that future Type 2 diabetes, a major risk factor for cardiovascular disease, could be detected by a combination of peroxisome proliferator-activated receptor gamma (PPARG) and CALPAIN (CAPN) genotypes in susceptible individuals with high plasma glucose and body mass index (60). Interestingly, even though the PPARG polymorphism came up positive in Zee et al’s study, this result was rejected after correction for multiple testing (58).

Pharmacogenetic-based dosing of oral anticoagulants Improved prediction of maintenance warfarin dose is linked to SNPs in the vitamin K epoxide reductase complex subunit

1 gene (VKORC1) (61–63). The different high- and low-dose haplotypes can be identified by screening for haplotype tag SNPs (61). Warfarin dose can also be predicted by CYP2C9 genotype (64,65). While VKORKC1 haplotype accounts for 21–25% of the variation and by the addition of CYP2C9*2 and 3 genotype improved the prediction model to 31% (64), considering the narrow therapeutic range and life-threatening thrombotic and bleeding complications, prior screening of VKORKC1 and CYP2C9 enables dose selection and monitoring strategies. Considering some studies that have reported population differences in VKORKC1 and CYP2C9 haplotypes, Marsh et al identified the frequency of genotype combinations across world populations of four haplotype tag SNPs for VKORKC1 (861, 5808, 6853, and 9041) and CYP2C9 (*2 and *3) (61,64,66,67) using prosequencing (61,64). Using Rieder et al.’s criteria to determine high- and low-dose VKORKC1 haplotype groups (61) and incorporating Gage et al.’s dose-limiting CYP2C9 genetic variation (64), Marsh et al concluded that Asians and Caucasian populations had the highest incidence (86% and 55%, respectively) of “low-dose” individuals from either VKORKC1 or CYP2C9 variants (from at least one VKORKC1 or haplotype A or CYP2C9 variant allele) (67). Eighteen percent of the Caucasian population had a combination of at least one VKORKC1 haplotype A and at least one CYP2C9 variant (67). Hence, caution is required to identify the predictive SNPs and haplotypes in all populations before proposing pharmacogenetic-based warfarin dosing regimens (67).

Dual functionality of factor V Factor V through its APC resistant properties is well known to have a strong prothrombotic effect (68). Factor V also has anticoagulant properties, as it participates in the degradation of Factor VIIIa by APC and Protein S (69,70). Cleavage of FV by APC at position 506 is essential for FV to function as a cofactor. Thus, FV Leiden, lacking the APC cleavage site at position 506, is not capable of inactivating FVIII and hence procoagulant through yet another mechanism. The APC cofactor function of FV and the FXa cofactor role of FVa are the two opposing functions, which render FV-derived proteins manifest dual functions, viz., more procoagulant and less anticoagulant functions. This dual functionality of FV is important since there is a relatively high frequency of FV Leiden mutations in Caucasian population. Interestingly, heterozygous carriers of FV Leiden were reported to be protected against death from sepsis (71) although the survival benefits in both humans and mice are not as strong as initially reported (72,73). Besides FV Leiden variation at Arg 506, variations at Arg306, the other major cleavage sites in FV include FV Hong Kong (R306G, Arg306Gly, A1090G) and FV Cambridge (R306T, Arg306Thr, G1091C) (74,75) and were shown to have mild form of APC resistance in vitro (76,77). Factor V

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References

Liverpool is a variant displaying APC resistance (78). The dual function of FV, the thrombotic function (79,80), and the anticoagulant side (81) need further research, especially because of the polymorphic nature of protein V-derived proteins.

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COL4A1 Mutations and predisposition to hemorrhagic stroke It has recently been reported that mutation in the mouse Col4a1 gene, encoding procollagen type IV ␣1, a basement membrane protein, predisposes both newborn and adult mice to intracerebral hemorrhage. A COL4A1 mutation was identified in a human family with small-vessel disease (82). It was concluded that persons with COL4A1 mutations might be predisposed to intracerebral hemorrhage especially after environmental stress (82).

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Conclusions Pharmacogenomic-based personalized practice of medicine is expected to reduce the number of adverse drug effects, and drug failure rates thereby dramatically reducing the total healthcare costs. Ethical concerns with gene therapy requiring transgenic manipulations of germline cells may be minimized by focusing on somatic gene transfer instead of the germline. Advances in pharmacogenomics, metabolomics, transcriptomics, and molecular imaging techniques will revolutionize the practice of medicine in the future, provided these advancements are embraced and adapted by the physicians. Those days are not too far off, when a physician will first see the genetic profile of the patient before examining the patient and then providing personalized medical care (83).

References 1 2 3

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Vogel F. Moderne probleme der Humangenetik. Ergebn Inn Med Klinderheilk 1959; 12:52–125. Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286:481–491. MacCarthy JJ, Hilfiker R. The use of single nucleotide polymorphisms maps in pharmacogenomics. Nat Biotechnol 2000; 18:505–508. Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis of individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharm Res 1999; 16:342–349. Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to asthma treatment. Nat Genet 1999; 22:168–170.

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48 Carotid artery stenting Amir Halkin, Sriram S. Iyer, Gary S. Roubin, and Jiri Vitek

Introduction Carotid artery stenting (CS), a less invasive intervention than carotid endarterectomy (CEA), has emerged as a safe and effective method for revascularization of extra-cranial carotid artery stenosis. Recent observational (1–4) and randomized (5,6) trials in well-defined patient subsets have shown that the risk of major procedure-related complications, i.e., stroke and death, is comparable when these interventions are performed in skilled hands. In patients at high risk for CEA, carotid stenting has been established as the revascularization strategy of choice (4). Multicenter, randomized trials [carotid revascularization endarterectomy vs. stent trial (CREST); asymptomatic carotid stenosis stenting versus endarterectomy trial (ACT 1)] are in progress to assess the applicability of carotid stenting in a broader clinical spectrum, i.e., asymptomatic patients with severe carotid artery stenosis and patients at low surgical risk with CEA. With the ongoing refinement of endovascular devices and techniques for carotid revascularization, catheter-based therapy has become technically feasible in most patients. Notwithstanding, appropriate case selection is required to ensure procedural safety. Here within we review new concepts pertaining to patient selection and technical procedural considerations that we consider crucial for enhancing clinical outcomes following carotid stenting.

The evolution of endovascular carotid revascularization: historical perspectives Carotid revascularization, initially by CEA, was introduced in early 1950s as a method to prevent stroke due to atherosclerosis of the carotid bifurcation and internal carotid artery (ICA). At least four prospective randomized trials have demonstrated

that CEA compared with medical therapy reduces the risk of stroke in patients with carotid artery stenosis (7–10), with the magnitude of clinical benefit dependent on symptom status, lesion severity, and the risk of surgery-related complications. While perioperative death and stroke rates were low in the highly selected patients enrolled in these trials, the risk for other complications causing significant morbidity was not negligible. For example, in the North American Symptomatic Carotid Endarterectomy trial (NASCET) cranial nerve damage and serious medical complications occurred in 5.6% and 8.1% of patients, respectively (11,12). Effective application of carotid angioplasty began in the mid 1970s (13,14) and rapidly developed during the following two decades (15–19). The first rigorous, prospective study of carotid stenting entailing independent neurologic evaluation at baseline and at 30 days post procedure was instigated in 1994 (20). This study, as well as the experience of others (21,22), demonstrated that in the hands of experienced operators carotid stenting resulted in acceptable outcomes. While stenting compared with balloon angioplasty significantly enhanced the safety and late outcomes (primarily the risk of restenosis) of endovascular carotid revascularization, atherembolism from the intervention site remained the Achilles heel of catheterbased interventions. The development of embolic protection methods has in large provided an answer to this problem. From Vitek’s early description of innominate artery angioplasty with occlusive balloon protection of the common carotid artery (CCA) (23), through pioneering work by Theron (24) and Henry (25), distal (26) and proximal (27) antiembolic protection technology has developed with impressive rapidity. The availability of multiple embolic protection systems has been shown in many single and multicenter registries to confer a remarkably low risk of embolic complications following carotid stenting (28–32). Thus, the technical feasibility of carotid stenting, its simplicity compared with CEA and the low morbidity afforded by distal protection devices and refinements in the process of case selection have accelerated the acceptance and utilization of this procedure.

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Clinical outcomes and the impact of embolic protection devices Procedural neurologic complications are due primarily to embolization of atheromatous material from the aortic arch or the carotid intervention site (31,33,34). Embolic protection devices (EPDs) that eliminate liberated atheromatous debris from the circulation have had a significant impact on the safety of carotid stenting, and a number of such protection devices have recently been introduced and are under clinical evaluation (26). In the European Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte (ALKK; n ⫽ 1483) registry (35), use of an EPD (n ⫽ 668) compared with no such use (n ⫽ 815) was associated with significantly lower in-hospital rates of stroke (1.7% vs. 4.1%, p ⫽ 0.007) and stroke or death (2.1% vs. 4.9%, p ⫽ 0.004). Our own group’s experience in more than 1300 carotid stent procedures has recently been presented (36). In a prospective registry, carotid stenting procedures with (n ⫽ 538) versus without (n ⫽ 775) embolic protection were associated with lower 30-day rates of any stroke (1.9% vs. 5.8%, respectively, p ⫽ 0.0003) and stroke or death (2.4% vs. 6.5%, respectively, p ⫽ 0.001). Utilization of embolic protection was the strongest multivariate predictor of freedom from periprocedural stroke. The impact of EPD use on stroke risk was most pronounced in patients ⬎80 years (n ⫽ 220), in whom 30-day rates of any stroke or major stroke were significantly lowered by EPD use (6.6% vs. 15.4%, p ⫽ 0.02; 0.8% vs. 2.3%, p ⬍ 0.001, respectively). A meta-analysis of earlier studies has reported similar findings (37). Most recently, the stent-supported percutaneous angioplasty of the carotid artery versus endarterectomy (SPACE) randomized controlled trial, comparing carotid stenting with CEA in symptomatic patients (n ⫽ 1200) has been published (5). With EPDs used in only 27% of patients randomized to endovascular therapy, the rates of the 30-day composite endpoint (all-cause mortality or any ipsilateral stroke) was 6.84% in carotid stenting patients (vs. 6.34% in CEA patients, p ⫽ NS, OR ⫽ 1.09, 95% CI, 0.69–1.72). Randomized trial data suggest that unprotected carotid angioplasty can be performed with results comparable to those of CEA (5,6), and some authors have suggested that filter-type EPDs use might be associated with an increased propensity to embolism (38). Nevertheless, we believe that utilization of embolic protection should be considered the standard of care in carotid stenting. When use of an EPD is precluded by anatomical factors, alternative treatment strategies (CEA, medical therapy) must be strongly considered. Late neurologic events (occurring more than 30 days following angioplasty) and restenosis complicating carotid stenting are rare. In the stenting and angioplasty with protection in patients at high risk for endarterectomy (SAPPHIRE) trial, the one-year rate of major ipsilateral stroke following carotid stenting was 0.0% (vs. 3.5% with CEA, p ⫽ 0.02) (4). In the prospective carotid stenting registry reported by Roubin

et al. follow-up, available in 99.6% of 528 patients, ranged from six months to five years (mean 17 months) (1). Freedom from any ipsilateral stroke after the first postprocedural month was ⬇99% and the rate of restenosis requiring reintervention was only 3%. Gray et al. performed clinical follow-up and serial imaging studies in 136 patients after carotid stenting, demonstrating angiographic restenosis in four patients (3.1%) at six-month follow-up, an additional two cases between six and twelve months, with no further restenosis or any major ipsilateral strokes at two-year follow-up (39). Bosiers et al. recently reported the long-term outcomes of 2167 patients undergoing successful carotid angioplasty (stenting rate in ⬇95%). At five-year follow-up, approximately 85% of patients were alive and free from ipsilateral stroke, with restenosis rates ⬍4% (40). Other centers have also witnessed low rates of late adverse events, with long-term freedom of death, ipsilateral major stroke, or restenosis in excess of 95% (41). The available data thus demonstrate that in a broad spectrum of patients, the excellent early results of carotid stenting are durable in the long term.

Indications Candidates for carotid revascularization include patients with symptomatic carotid lesions and asymptomatic patients, usually diagnosed as the result of a screening procedure. In general, the indications for carotid revascularization are dependent on the symptomatic status of the patient and on lesion severity, and are similar for the endovascular and surgical strategies (Table 1) (42–45). Carotid stenting is particularly useful in the presence of specific clinical and/or anatomical features indicative of a high risk for perioperative complications after CEA. The randomized SAPPHIRE trial compared CEA with carotid stenting with use of an EPD in 334 patients considered at high risk for open surgical intervention due to coexistent vascular disease or medical comorbidities (4). Enrollment required lesion severity ⱖ50% in symptomatic patients, or ⱖ80% in asymptomatic patients (the latter accounting for ⬇71% of the trial population). Though by intention to treat the differences in one-year rates of the individual major adverse events rates favoring carotid stenting over CEA did not attain statistical significance [death (7.4% vs. 13.5%, p ⫽ 0.08), any stroke (6.2% vs. 7.9%, p ⫽ 0.60), major ipsilateral stroke (0.6% vs. 3.3%, p ⫽ 0.09), myocardial infarction (3.0% vs. 7.5%, p ⫽ 0.07)], the composite endpoint occurred significantly less frequently with carotid stenting than with CEA (12.2% vs. 20.1%, respectively, 0.053). At one year, the requirement for repeated carotid revascularization procedures was lower in patients treated with stenting versus CEA (0.6% vs. 4.3%, p ⫽ 0.04). Notably, carotid stenting was entirely devoid of cranial nerve injury, which occurred in 5.3% of CEA patients. Recent prospective registries of carotid stenting in patients at high risk for CEA are consistent with the SAPPHIRE trial, reporting

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Table 1

557

Indications for carotid artery revascularization

Indication level

Symptomatic stenosis

Asymptomatic stenosis

Proven

70–99% stenosis

⬎60% stenosis

Periprocedural complication risk ⬍6%

Periprocedural complication risk ⬍3% Life expectancy ⬎5 yrs

Acceptable

⬎60% stenosis

50–69% stenosis Periprocedural complication risk ⬍3%

Periprocedural complication risk ⬍3% Simultaneous CABG

Unacceptable

⬍29% stenosis

⬍60% stenosis

Or

Or

Periprocedural complication risk ⬎6%

Periprocedural complication risk ⬎5% No indication for CABG

Abbreviation: CABG, coronary artery bypass graft surgery. Source: From Refs. 42–45.

30-day major adverse event rates ⬍8% (2,3). Thus, patients who have serious comorbid medical and/or anatomical conditions that increase the risk from an open surgical approach or general anesthesia should be primary candidates for carotid stenting. These conditions include advanced age, significant cardiac and pulmonary disease, prior neck irradiation or radical surgery, restenosis following endarterectomy, contralateral carotid occlusion, high lesions behind the mandible and low lesions that would require thoracic exposure. Randomized trials comparing carotid stenting and CEA in patients at low surgical risk are in progress. Carotid stenting has a number of notable relative contraindications. In patients who are intolerant of or noncompliant with antiplatelet agents, CEA should be strongly considered. Similarly, in patients planned for a major surgical procedure within three to four weeks that will require the cessation of antiplatelet therapy, CEA may be a better option than carotid stenting. A large thrombus burden as well as specific angiogrpahic findings discussed in detail below should be excluded prior to carotid stenting. Intracranial arterial stenoses, arteriovenous malformations, or stable aneurysms are not necessarily contraindications for CS. However, in the latter case, stringent control of blood pressure and careful modulation of anticoagulation is mandatory. While contrast nephropathy is an important consideration in all patients exposed to radiographic dye, this seldom represents a contraindication to carotid stenting since experienced operators should rarely require ⱖ75 cc of contrast material to complete the procedure.

Patient selection The risk of stroke due to carotid artery stenosis treated conservatively is primarily dependent on two features: (i) Angiographic lesion severity; (ii) patient symptom status

(7,9,45,46). In this regard, it is important to note that the methods for the measurement of the degree of carotid stenosis have varied among trials, so that application of the ECST methodology results in greater degrees of stenosis for a given lesion than the NASCET methodology (44,47). It is also noteworthy that the risk of periprocedural complications following CEA appears to be largely independent of the degree of the stenosis (10), and the available data suggest that the same holds true for carotid stenting (unless the lesion contains a large thrombus load) (1,40,48).

Symptomatic patients Given the demonstrated benefit of revascularization over medical therapy in the management of severely stenotic lesions [70 –99% diameter stenosis by the NASCET criteria (44,47,49)] associated with recent ipsilateral symptoms (⬍6 mo), CEA in these patients has been considered indicated when the periprocedural risk of death or stroke is ⬍6% (43). The same is applicable to carotid stenting. Available data demonstrate that the rates of periprocedural death or disabling stroke following carotid stenting are generally below 6%, even without the universal use of EPDs (1,5,50) and in patients high risk for CEA (2–4). The risk of recurrent ipsilateral neurologic events with medical management is much lower for moderate (50–69% by the NASCET criteria) compared with severe carotid lesions (10). Since the potential benefit of any revascularization procedure is dependent on lesion severity (45) in patients with moderate or borderline stenoses the risk-benefit ratio of carotid stenting should carefully be weighed.

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Asymptomatic patients Stroke prevention in asymptomatic patients requires special consideration. The risk of stroke in the territory of an asymptomatic carotid stenosis is closely related to angiographic lesion severity (46). In the European Carotid Surgery Trial (ECST), the three-year rates of ipsilateral stroke with asymptomatic lesions less or greater than 70% stenosis were approximately 2% and 5.7%, respectively (46). In the medical treatment arms of ACAS and ACST, five-year rates of death or ipsilateral stroke were similar at ⬇12% (7). Thus, for clinical benefit to be derived by an asymptomatic patient with a severely stenotic carotid lesion, periprocedural rates of death or stroke following carotid revascularization must not exceed 3% (9). Given the high prevalence of asymptomatic carotid disease (51,52), the Lesion severity, Symptom status

(A)

Carotid Revascularization Indicated No

Yes

Medical therapy • Co-morbidities • Hostile neck • post CEA restenosis • High/low lesions

Evaluate CEA risk

High

Low

CEA or stenting vs. CEA trial (B)

Carotid stenting

Lesion severity, Symptom status

Carotid Revascularization Indicated

No

Medical therapy

Yes

Evaluate carotid stent risk Low

Carotid stenting or stenting vs. CEA trial

High

• Age • Cerebral reserve • Tortuosity • Calcification

Evaluate CEA risk Low

CEA

High

Medical therapy?

Figure 1 Decision-making in the management of carotid artery stenosis based upon symptom status, lesion severity, and estimated procedural risks. The conventional paradigm for treatment assignment is depicted in the top panel. The proposed new paradigm in the bottom panel. Abbreviation: CEA, carotid endarterectomy.

optimal application of carotid stenting in this patient subset must be rigorously defined (see “3% Rule” below). Due to the very low event rates in patients with asymptomatic lesions of moderate severity (⬍60% diameter stenosis), it is unknown whether currently available interventional techniques can improve long-term outcomes over those achievable with optimal medical management. Also unresolved are the indications for carotid stenting in asymptomatic individuals with contralateral carotid occlusion (53) and those undergoing major cardiac or vascular surgery (54).

The 3% rule As explained above, arotid artery revascularization can be justified in the asymptomatic patient only if the procedure can be accomplished with a complication rate ⱕ3% (9), a principle underlying the “3% Rule” coined by one of the authors (SI). With the widespread availability of CEA and carotid stenting, candidates for carotid revascularization have generally been selected for either procedure based on the presumed surgical risk (the “conventional paradigm”, depicted in Fig. 1, top panel). Low-risk surgical patients would usually be referred for CEA or be enrolled in a randomized clinical trial of surgery versus stenting. Patients considered at high risk for open surgery were often referred for carotid stenting, arbitrarily considered a low-risk intervention since little attention had been given to definition of the risks associated with the latter procedure. However, it is of crucial importance to recognize the risks of carotid stenting and to realize that in certain patients (easily identified by readily available clinical and angiographic features), particularly those with asymptomatic lesions, the risks of procedure-related major adverse events might exceed the long-term risk of ipsilateral stroke with medical therapy. We believe that for the full clinical potential of carotid stenting to be realized, a paradigm shift needs to be implemented in the process of procedural-risk stratification and selection of patients for revascularization. This applies both to clinical practice and to the design and inclusion criteria of randomized trials. Clinical decision-making based upon these principles is outlined in the lower panel of Figure 1.

Implementing the 3% rule In determining the risk of death or stroke associated with carotid stenting it is of critical importance to recognize four factors that have been associated with increased procedural complications following carotid stenting (Table 2). The most important of these factors is advanced age. In the lead-in phase of the multicenter CREST trial, the risk of 30-day stroke or death among 749 patients was directly related to age (⬍60 years, 1.7%; 60–69 years, 1.3%; 7079, 5.3%; ⬎80 years, 12.1%, p ⫽ 0.006). Though the risk attributable to advanced age in this analysis appeared to be independent

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Table 2 Clinical and angiographic features associated with increased risk for peri-procedural complications following CS T

Risk factor

Features

Clinical

Advanced age

ⱖ80 yrs

Decreased cerebral reserve

Dementia Prior (remote) stroke Multiple lacunar infarcts Intracranial microangipathy

Angiographic

Excessive tortuosity

ⱖ2 90°-bends within 5 cm of the lesion

Heavy calcification

Concentric circumferential calcification, width ⱖ3 mm

Abbreviation: CS, carotid stenting. Source: From Refs. 42–45.

of other clinical (e.g., gender, symptom status), angiographic (e.g., lesion severity), or procedural (e.g., use of distal protection devices) factors (55), it is likely that increasing prevalence of the other factors listed in Table 2 with advanced age accounts, at least partly, for this association. Decreased cerebral reserve is another important factor when considering the risk of carotid stenting. Carotid revascularization (carotid stenting or CEA) is usually associated with some degree of cerebral embolization that is generally well tolerated in patients with good cerebral reserve. However, patients with prior strokes, lacunar infarcts, microangiopathy, or dementia of varying stages are much more likely to experience neurologic deficits after carotid stenting. This risk is markedly amplified in the presence of an isolated hemisphere with lack of good collateral support. While some lesion characteristics (e.g., degree of stenosis, length) indicate potential technical difficulties, the two most important anatomic findings portending an increased procedural risk are vascular tortuosity and heavy concentric calcification. Excessive tortuosity is defined as two or more bend points exceeding 90°, within a 5 cm segment spanning the lesion, including the takeoff of the ICA from the CCA (Fig. 2). Excessive tortuosity increases the difficulty of access to the lesion, may not permit device delivery, and can prevent distal positioning of an EPD with a “landing zone” sufficient for stent placement. These factors expose the patient to the risks of atheroembolism from the arch, air embolism, excessive contrast administration, bifurcation plaque disruption, and ICA dissection. Importantly, tortuosity should be assessed after the sheath (or guide catheter) has been placed in the CCA, since forces by the catheter directed toward the unyielding base of the cranium tend to exaggerate ICA tortuosity. Finally, heavy calcification is an important predictor of complications. This is defined as concentric calcification, ⱖ3 mm in width and deemed by at least two orthogonal views to be circumferentially situated around lesion (Fig. 3).

Figure 2 Vascular tortuosity predicting adverse events following carotid stenting. (See text for definition.)

Heavy calcification, especially in combination with arterial tortuosity, causes difficulties in tracking devices, lesion dilation, stent positioning, and achieving adequate stent expansion. In our experience, the presence of two or more of the risk factors listed in Table 2 is an important adverse prognosticator in patients undergoing carotid stenting. Although special techniques generally result in a satisfactory angiographic outcome, the risk of neurologic adverse events exceeds the “3% Rule” and is thus prohibitive.

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Figure 3 Heavy lesion calcification predicting adverse events following carotid stenting. (See text for definition.)

Procedural considerations The protocol for carotid stenting has been described in detail previously (56). The following technical and procedural factors have proved important in ensuring a facile and complication-free carotid stenting procedure.

Periprocedural monitoring and management With respect to preprocedural therapy, adequately dosed dual antiplatelet therapy is key. Patients must receive either a combination of clopidogrel 75 mg and aspirin 325 mg for five days prior to carotid stenting, or alternatively, loading doses of clopidogrel (600 mg) and aspirin (650 mg) at least four hours prior to the procedure. On the day of the procedure oral antihypertensive therapy is withheld and adequate volume status is ensured. Mild sedation may be offered to anxious patients but for the vast majority reassurance and adequate local anesthesia are all that is necessary. Avoiding sedatives enhances neurologic monitoring and limits hypotension. Continuous monitoring of pulse oximetry, intra-arterial pressure, and heart rhythm are essential as is meticulous control of hemodynamics. Intravenous atropine (0.6–1.0 mg) should be administered following placement of the sheath in the CCA to suppress bradycardic responses to balloon inflation

and stent implantation. Hypotension is invariably noted after balloon dilatation of the stent, particularly in elderly patients with heavily calcified stenoses, and is generally benign. However, aggressive volume expansion, intravenous phenylephrine, and occasionally dopamine infusions are sometimes necessary. Blood pressure elevation after the relief of the stenosis can also occur and should be treated using intravenous nitroglycerine, nitroprusside, or labetalol. If distal protection is with an occlusion-aspiration system, blood pressure should be lowered before deflating the occlusive balloon to prevent the potential consequences of hyperperfusion (57). Anticoagulation therapy with carotid stenting is vital, but it is equally important to note that modest anticoagulation levels should be targeted. Either heparin (70 IU/ kg initial bolus, targeting an activated clotting time of 200–250 sec) or bivalirudin (0.75 mg/kg bolus, followed by a maintenance infusion of 1.75 mg/kg/hr) are administered immediately with sheath insertion. Prolonged infusion of anticoagulant drugs is unnecessary and these are stopped immediately following stent deployment. Glycoprotein IIb/IIIa antagonists are not routinely used (58). The use of 6Fr femoral sheaths and arteriotomy closure devices allows for early ambulation. This counteracts the bradycardia and hypotension commonly associated with carotid stenting. Postprocedural intensive care monitoring is unnecessary although patients should be followed in a monitored environment by staff familiar with the postprocedural course and groin access site management. Remaining sheaths should be removed as early as possible, once the activated clotting time has fallen below 150 sec. Hypotension should be treated aggressively and causes unrelated to baroreceptor responses (e.g., retroperitoneal hemorrhage) should be considered and managed promptly.

Procedural stages The extent of diagnostic angiography is determined by the anatomic information obtained by preprocedural noninvasive studies, but should at the very least include an accurate evaluation of lesion severity; the carotid bifurcation, ipsilateral intracranial anatomy, and the anatomy of the CCA. If a balloon-occlusive EPD is to be used, it is mandatory to ensure adequate collateral flow from the contralateral carotid or posterior circulations. For diagnostic angiography, a double-curved 5Fr catheter (VTK, Cook Inc.) and a 0.038inch angled-tip hydrophilic-coated wire are used (59). In ⬎98% of patients this system enables safe selective catheterization of the CCA, ICA and ECA, both subclavian arteries and at least one vertebral artery. The same catheterization technique is used to introduce a 6F 90 cm sheath (Shuttle, Cook Inc.) into the CCA, generally delivered over a softtipped, stiff 0.035-inch guidewire (e.g., Supracore, Guidant Inc.) positioned in the ECA. The tip of the sheath is

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positioned in the distal CCA. “Guiding-shots” of the lesion immediately following sheath placement are performed, since ICA tortuosity might be more pronounced by the sheath (Fig. 3, top panel). Next, the lesion is crossed with a 0.014-inch guidewire, usually that of the EPD. The EPD is deployed in a distal segment of the cervical ICA. Next, the lesion is dilated with an undersized coronary balloon (“predilatation”). The stent is the deployed and subsequently “postdilated” with a conservatively sized, low profile balloon. Finally, the EPD is removed and final angiography is performed. Using contemporary rapid exchange (“monorail”) systems the entire process should take as little as 10 to 15 minutes.

Special considerations Catheter placement Modifications of the catheter placement technique may be required when the lesion is located in the distal segments of the CCA or if the ECA cannot be catheterized. In these cases, the tip of the 5Fr catheter and guidewire (Amplatz Super Stiff J-wire, MediTech) assembly over which the 6Fr sheath is placed in the CCA is kept below the lesion or bifurcation. In cases of significant aortic arch elongation or CCA tortuosity, inability to access the ECA might result in insufficient support for sheath placement. Placing guidewires and catheters at or across the lesion to provide adequate support markedly increases the risk of embolic complications.

Crossing the lesion Wiring the lesion and device delivery can be technically challenging. It is critical to minimize the number and volume of contrast injections into the brain, since this alone predisposes to neurologic events. At times, due to extreme angulation at its takeoff, the ICA might not be amenable to wiring. In more complex and calcified lesions, a 7Fr sheath will provide superior support. At all times the position of the sheath should be monitored to prevent its prolapse back into the arch. Appropriately shaped 5Fr catheters (125 cm right Judkin’s or internal mammary catheters) can be advanced through the guiding sheath so that the tip points into the ostium of the ICA, facilitating wire entry. The EPD has to be placed at least ⱖ2 cm cephalad to the stenosis to accommodate the tip of the stent delivery system and satisfactory coverage of the lesion. With heavy calcification, it can be technically difficult or even impossible to advance the EPD beyond the lesion. In these situations, placement of a second (“buddy”) wire and gentle dilatation of the lesion with an undersized balloon can facilitate delivery of the system. Anticipating this situation

561

and having the necessary equipment available minimizes cerebral ischemia. Frequently used for this purpose are 0.014-inch coronary guidewires (e.g., Balance, Guidant Inc.) through an over-the-wire low profile angioplasty balloon (e.g., Maverick, 2.0 ⫻ 40 mm, Boston Scientific). Following inflation, the balloon catheter is used to exchange the wire for a more supportive type (e.g., Stabilizer-Plus, Cordis Inc.). This guidewire will usually straighten the ICA permitting delivery of the EPD beyond the lesion, though it might result in significant spasm reducing flow. The tip of any wire used is placed close to the skull base so the operator must ensure its control in order to avoid distal vessel trauma. Depending on the severity of ICA tortuosity, “buddy wires” can be removed after the protection device has been placed. Alternatively, the “buddy wire” can be withdrawn after the stent has been positioned, following stent deployment and postdilated (“jailed buddy wire”), or even after retrieval of the protection device. This can be important since resistance to stent delivery might cause the sheath to prolapse into the arch, a problem that can be eliminated by the “buddy wire.”

Predilatation Lesion dilation prior to stenting is strongly recommended. Experimental work has shown that less debris is liberated from the lesion site when pre dilation is performed (29), and clinical experience suggests that this strategy is associated with a reduction in lower rates of neurologic complications (40). Atherembolism is increased when predilation is performed with large (0.035-inch compatible) balloons, so low-profile coronary balloons should be selected. When full deflation is ensured, these balloons “re-wrap” well without residual winging so that the risk of vessel wall trauma during balloon withdrawal is reduced. If the lesion is preocclusive, it is preferable to gradually step up the balloon size to minimize plaque disruption and distal embolization. In these situations, predilatation is first performed using a 2.0 mm balloon followed by a second inflation of a 3.5–4.0 mm balloon. In rare cases, mainly in heavily calcified lesions, a 5 mm balloon might be required to enable stent delivery. Long balloons (30–40 mm in length) are preferred to avoid “watermelon seed effect.”

Stent selection and deployment Self-expanding stents are routinely used because balloonexpandable stents are prone to deformation by external compression. The nominal diameter of the self-expanding stent chosen should be at least 1–2 mm larger than the largest diameter of the treated segment, usually the CCA, and 10 mm stents are used in almost all cases (oversizing the stent relative to the diameter of the ICA produces no adverse effects and provides effective trapping of plaque, thereby reducing the risk for embolization). Stent length should be

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adequate to cover the entire lesion, typically located at the origin or proximal segment of the ICA, such that it usually extend from the distal CCA to a healthy segment of the ICA, covering the origin of the ECA. For the large majority of cases, a stent 30 mm in length by 10 mm in diameter will provide complete lesion coverage and facilitates facile, accurate placement using “road mapping,” or bone landmarks. Though randomized trial data are not available, some have suggested that in symptomatic patients stents of the closed cell design might afford superior clinical outcome (60). Clearly, such observational data must be considered hypothesis generating and further research is necessary before device design can be selected based upon clinical and/or angiographic features. The use of contrast injections for stent positioning should be avoided, since embolic events from air trapping may occur. Positioning the distal end of the stent in kinks and tortuosities of the ICA should be avoided. These tortuosities can be rarely eliminated, and tend to be displaced distally and exaggerated by the stiff stent. Covering the origin of the ECA with the stent is not associated with adverse clinical consequences. Follow-up arteriograms have shown that the ECA remains patent with only few exceptions.

Postdilatation This is a critical step and requires careful attention since it is at this stage that embolic events are most likely to develop. The risk of embolization is minimized by conservative sizing of the balloon (5 mm) and by performing a single inflation. The balloon should be deflated slowly. Mild residual stenoses (ⱕ20%) or persistence of an ulcer at the lesion site should be accepted, since aggressive stent dilatation can produce cerbral embolization.

with filter-based devices. It is not unusual to encounter spasm and kinks in ICA segments distal to the site of intervention, particularly in tortuous vessels. These are generally alleviated by guidewire removal and withdrawal of the guiding sheath to the proximal. A small dose of intra-arterial nitroglycerine (100–200 ␮g) is occasionally needed. Stent-related distal edge dissections are rare.

Postdischarge therapy and surveillance In our practice, most patients are discharged on clopidogrel (75 mg daily) for one month. Patients treated for lesions related to prior neck irradiation are prescribed clopidogrel for one year. In the absence of contraindications, aspirin (100–325 mg daily) is prescribed indefinitely. Patients should have a baseline postprocedural ultrasound duplex study within one month following carotid stenting. This serves as a reference for later follow-up evaluations for potential restenosis. Not infrequently, flow velocities within the stent are elevated immediately after the procedure, despite documented good angiographic results. Evidence to date suggests that this finding neither predicts excessive progression of neointimal proliferation nor restenosis (61). Magnetic resonance angiography is not useful for follow-up purposes because of signal dropout due to the metallic stent. Computed tomographic angiography has shown some promise (62) and may prove to be the modality of choice for follow-up post carotid stenting. Significant angiographic restenosis (⬎80%) is an uncommon finding, occurring in 3–6% of patients (1,40,63). Restenosis is more common in patients initially treated for radiation-induced or post-CEA lesions, and can usually be managed by balloon dilatation or repeated stenting (Fig. 4).

EPD removal Removal of balloon-occlusive EPDs is preceded by aspiration of 50–60 ml of blood using a dedicated catheter. Filter-based EPDs are removed using a dedicated retrieval catheter. Difficulties in advancing the retrieval catheter through the stent are at time eliminated by having the patient rotate his/her neck. Rarely, the filter can become obstructed by large amounts of embolic material and blood flow in the ICA is interrupted. Facile technique and optimal antiplatelet therapy prevent this complication in most cases.

Final angiographic assessment Careful attention must be paid to the segment of the ICA that contained the EPD. Rarely, the embolic protection device causes a dissection in the distal ICA. The risk of this complication is probably greater with balloon-occlusive devices then

Procedural complications Potential complications of carotid stenting are listed in Table 3. Bradyarrhythmias (including asystole) and/or hypotension are frequent in CS, usually occur during balloon inflations and generally respond promptly to balloon deflation. Prevention is by adequate hydration, conservative balloon sizing, premedication with atropine and early ambulation. Although some advocate the routine prophylactic use of temporary transvenous pacemakers in CS (64,65), we consider the risks of this procedure to outweigh any potential benefit. In one series (n ⫽ 114), a transvenous pacemaker was required in 9.6% (66), though in our experience this is needed far less frequently. Permanent pacemaker requirement is exceptionally rare. Occasionally, patients require short-term treatment

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Figure 4 Cartoid in-stent restenosis. This patient underwent stenting of the right internal carotid artery (ICA) in 2000 and was followed by serial doppler studies. A scan performed in 2002 did not indicate significant obstruction within the stent. A repeat doppler study in 2005 indicated a severe stenosis of the proximal ICA, a finding confirmed by angiography (A), revealing a severe discrete lesion within the stent in the proximal ICA (arrow), with mild irregularities of its distal portion (arrowheads). Using a filter-based EPD (Accunet, Guidant) (B, arrowhead), the lesion was dilated with a 3.5 ⫻ 20 mm (Maverick2, Boston Scientific), followed by deployment of a 7–10 ⫻ 30 mm self-expanding nitinol stent (Acculink, Guidant Corp.) and post-stent dilatation with a 5.0 ⫻ 20 mm balloon (Gazelle, Boston Scientific) (B, arrow). The procedure resulted in the elimination of the severe proximal lesion (C, arrow). The mild distal irregularities within the stent were intentionally left untreated.

with ephedrine for symptomatic bradycardia. Hypotension may last from hours to days dependent on baroreceptors sensitivity, the stent used, and whether bilateral carotid stenting was performed. The degree of hypotension tends to be more pronounced following treatment of heavily calcified lesion. Although some reports differ (67), we find that with

Table 3

the aforementioned preventive measures postprocedural hypotension usually requires no specific intervention. Bed rest, sedation, or narcotics exacerbate hypotension and interfere with rapid ambulation and recovery. Importantly, alternative causes of hypotension including bleeding complications should be sought.

Potential peri-procedural complications in CS

Vascular access

Minor

Major

Groin hematoma

Retroperitoneal hemorrhage

Femoral artey pseudoaneurysm Hemodynamic/arrhythmic

Hypotension Transient bradycardia

Cerebrovascular

Carotid spasm

Carotid dissection

Compromise of ECA ostium

Carotid perforation

Hyperfusion syndrome

Hyperperfusion syndrome

Contrast encephalopathy

Acute stent thrombosis

Transient symptomatic cerebral ischemia

Major ischemic stroke

Global Focal Abbreviations: CS, carotid artery stenting; ECA, external carotid artery.

Cerebral hemorrhage

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Hyperperfusion syndrome, characterized by headache, a confusional state, and at times focal neurological deficits, occurs in some patients, particularly those with a history of hypertension or those treated for high-grade stenoses (⬎90%) with concomitant severe contralateral carotid disease (68). This condition may not be associated with angiographic abnormalities, although CT or MR imaging will often show mild hemispheric swelling with effacement of sulci or suggest “luxury perfusion.” With meticulous blood pressure control, symptoms usually resolve within 24 hours. However, some patients develop life-threatening cerebral hemorrhage. Management involves blood pressure control (preferably avoiding direct vasodilators) and reversal of anticoagulation. Contrast encephalopathy is a rare syndrome in which the ipsilateral hemisphere is overexposed to contrast material resulting in profound neurological deficits. CT characteristically shows marked contrast staining in the basal ganglia and the cortex. Angiography is normal. With good hydration and control of blood pressure, patients usually recover within 24–48 hours. Transient cerebral ischemia is a syndrome caused by cerebral deprivation of blood flow during occlusion of the carotid artery with the balloon or EPD in patients with an isolated hemisphere or in those with occlusion of the contralateral ICA (the contralateral hemisphere supplied through the anterior communicating artery). Sudden loss of consciousness, pseudo-seizures and paresis are common and completely reverse on prompt balloon deflation and restoration of blood flow. In these anatomical situations balloon-occlusive EPDs are contraindicated. Though rare, major complications can occur even when carotid stenting is meticulously performed with an EPD. Carotid dissection or perforation is usually technique-related complications. Carotid dissection is most serious when it involves the ICA distal to the stent. This generally occurs when the distal edge of the stent is deployed near a severe kink but can also develop when the a balloon is infalted beyond the distal edge of the stent, when stiff peripheral balloons or stent delivery systems are advanced through bends points, or by the EPD at the site of its deploymeny. Distal dissections are best treated with appropriately sized flexible stents. A less common dissection site is in the CCA and is caused by the tip of the guiding sheath. This complication can be treated, if necessary, with another stent. Carotid perforation is an extremely rare event caused by balloon oversizing, usually in a misguided attempt to optimize the final angiographic appearance. Perforation can be sealed with heparin reversal, inflation of a soft balloon or a covered stent. Stent thrombosis is a potentially catastrophic event that is uncommon (⬍0.005%) with appropriate doses of antiplatelet agents and adherence to stenting techniques (elimination of significant inflow or outflow obstruction, ensuring that the proximal and distal edges of the stent are anchored in normal arterial segments, proper sizing of self-expanding stents and ensuring apposition to the vessel wall).

Major ischemic stroke due to distal embolization is the commonest serious complication of carotid stenting. Neurologic monitoring throughout the procedure is imperative (69). Changes in neurological status should initiate immediate measures to optimize blood pressure, volume status, and oxygenation as well as an evaluation of the cervical and intracranial vasculature to identify alternative causes of neurologic status changes (e.g., lesion recoil, guidewire-induced spasm, dissection). The stenting procedure should be quickly and efficiently completed. If a change in neurological status does not resolve and there are no signs of embolism on intracranial angiography, a CT scan should be performed immediately to rule out intracerebral hemorrhage. If intracranial embolus is detected, appropriate steps are taken to recanalize the occluded vessel as soon as possible. Cerebral hemorrhage is a devastating complication of CS. Cerebral hemorrhage has been associated with at least one, but usually a combination, of the following factors: treatment of a preocclusive lesion with severe contralateral disease (in the setting of the hyperperfusion syndrome); excessive anticoagulation; poorly controlled hypertension; stentingng after a recent (⬍2 wk) ischemic stroke; and presence of a vulnerable aneurysm. If a cerebral hemorrhage is suspected, the procedure should be terminated. Sudden loss of consciousness preceded by a headache in the absence of intracranial vessel occlusion and presence of moderate mass effect should alert the operator to this devastating event. Anticoagulation should be reversed if possible and an emergency CT scan should be performed. Blood pressure control and supportive measures are generally the only therapeutic options.

Conclusion Carotid stenting with the use of an EPD has evolved as a safe and effective method for revascularization of the extracranial carotid bifurcation. In patients at high risk for complications due to CEA, carotid stenting has proven the intervention-of-choice. Randomized trials comparing the endovascular and open surgical methods in standard-risk CEA patients and asymptomatic individuals are continuing active enrollment. Until the results of these trials are available, careful patient selection, based on readily available clinical and angiographic features, must be exercised for this procedure to fulfill the potential it holds for stroke prevention. Individuals not considered ideal candidates for carotid stenting, especially asymptomatic patients and those with a low-CEA operative risk, should be offered well-validated surgical or medical alternatives.

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Weisz G. Distal protection devices improve the safety of carotid artery stenting. Analysis of Over 1350 Procedures. Circulation 2003; 108 (suppl IV):IV-605. [Abstract]. Kastrup A, Groschel K, Krapf H, Brehm BR, Dichgans J, Schulz JB. Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke 2003; 34:813–819. Vos JA, van den Berg JC, Ernst SM, et al. Carotid angioplasty and stent placement: comparison of transcranial Doppler US data and clinical outcome with and without filtering cerebral protection devices in 509 patients. Radiology 2005; 234:493–499. Gray WA, White HJ, Jr, Barrett DM, Chandran G, Turner R, Reisman M. Carotid stenting and endarterectomy: a clinical and cost comparison of revascularization strategies. Stroke 2002; 33:1063–1070. Bosiers M, Peeters P, Deloose K, et al. Does carotid artery stenting work on the long run: 5-year results in high-volume centers (ELOCAS Registry). J Cardiovasc Surg (Torino) 2005; 46:241–247. Wholey MH, Tan WA, Eles G, Jarmolowski C, Cho S. A comparison of balloon-mounted and self-expanding stents in the carotid arteries: immediate and long-term results of more than 500 patients. J Endovasc Ther 2003; 10:171–181. Goldstein LB, Adams R, Becker K, et al. Primary prevention of ischemic stroke: a statement for healthcare professionals from the Stroke Council of the American Heart Association. Circulation 2001; 103:163–182. Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 1998; 29:554–562. Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. AHA Scientific Statement. Supplement to the guidelines for the management of transient ischemic attacks: a statement from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks, Stroke Council, American Heart Association. Stroke 1999; 30:2502–2511. Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998; 339:1415–1425. Risk of stroke in the distribution of an asymptomatic carotid artery. The European Carotid Surgery Trialists Collaborative Group. Lancet 1995; 345:209–212. Rothwell PM, Gutnikov SA, Warlow CP. Reanalysis of the final results of the European Carotid Surgery Trial. Stroke 2003; 34:514–523. Mathur A, Roubin GS, Iyer SS, et al. Predictors of stroke complicating carotid artery stenting. Circulation 1998; 97: 1239–1245. Eliasziw M, Smith RF, Singh N, Holdsworth DW, Fox AJ, Barnett HJ. Further comments on the measurement of carotid stenosis from angiograms. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group. Stroke 1994; 25:2445–2449. Wholey MH, Wholey M, Mathias K, et al. Global experience in cervical carotid artery stent placement. Catheter Cardiovasc Interv 2000; 50:160–167.

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Pujia A, Rubba P, Spencer MP. Prevalence of extracranial carotid artery disease detectable by echo-Doppler in an elderly population. Stroke 1992; 23:818–822. Ellis MR, Franks PJ, Cuming R, Powell JT, Greenhalgh RM. Prevalence, progression and natural history of asymptomatic carotid stenosis: is there a place for carotid endarterectomy? Eur J Vasc Surg 1992; 6:172–177. Baker WH, Howard VJ, Howard G, Toole JF. Effect of contralateral occlusion on long-term efficacy of endarterectomy in the asymptomatic carotid atherosclerosis study (ACAS). ACAS Investigators. Stroke 2000; 31:2330–2334. Paciaroni M, Caso V, Acciarresi M, Baumgartner RW, Agnelli G. Management of asymptomatic carotid stenosis in patients undergoing general and vascular surgical procedures. J Neurol Neurosurg Psychiatry 2005; 76:1332–1336. Hobson RW II, Howard VJ, Roubin GS, et al. Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase. J Vasc Surg 2004; 40:1106–1111. Vitek JJ, Roubin GS, Al-Mubarek N, New G, Iyer SS. Carotid artery stenting: technical considerations. AJNR Am J Neuroradiol 2000; 21:1736–1743. Coutts SB, Hill MD, Hu WY. Hyperperfusion syndrome: toward a stricter definition. Neurosurgery 2003; 53:1053– 1058; discussion 1058–1060. Chan AW, Yadav JS, Bhatt DL, et al. Comparison of the safety and efficacy of emboli prevention devices versus platelet glycoprotein IIb/IIIa inhibition during carotid stenting. Am J Cardiol 2005; 95:791–795. Vitek JJ. Femoro-cerebral angiography: analysis of 2,000 consecutive examinations, special emphasis on carotid arteries catheterization in older patients. Am J Roentgenol Radium Ther Nucl Med 1973; 118:633–647. Hart JP, Peeters P, Verbist J, Deloose K, Bosiers M. Do device characteristics impact outcome in carotid artery stenting? J Vasc Surg 2006; 44:725–730; discussion 730–731. Roffi M, Chan A, Yadav J. Can ultrasound accurately predict restenosis after carotid artery stenting? (Abstract). Circulation 2001; 104:II-583. Leclerc X, Gauvrit JY, Pruvo JP. Usefulness of CT angiography with volume rendering after carotid angioplasty and stenting. AJR Am J Roentgenol 2000; 174:820–822. Bergeron P, Roux M, Khanoyan P, Douillez V, Bras J, Gay J. Long-term results of carotid stenting are competitive with surgery. J Vasc Surg 2005; 41:213–221. Harrop JS, Sharan AD, Benitez RP, Armonda R, Thomas J, Rosenwasser RH. Prevention of carotid angioplasty-induced bradycardia and hypotension with temporary venous pacemakers. Neurosurgery 2001; 49:814–820; discussion 820–822. Bush RL, Lin PH, Bianco CC, Hurt JE, Lawhorn TI, Lumsden AB. Reevaluation of temporary transvenous cardiac pacemaker usage during carotid angioplasty and stenting: a safe and valuable adjunct. Vasc Endovascular Surg 2004; 38:229–235. Wholey MH, Jarmolowski CR, Eles G, Levy D, Buecthel J. Endovascular stents for carotid artery occlusive disease. J Endovasc Surg 1997; 4:326–338.

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following carotid artery stenting: risk factors, prevention, and treatment. J Am Coll Cardiol 2004; 43: 1596–1601. Gomez CR, Roubin GS, Dean LS, et al. Neurological monitoring during carotid artery stenting: the Duck Squeezing Test. J Endovasc Surg 1999; 6:332–336.

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49 Anticoagulants in peripheral vascular interventions Rajesh M. Dave, Azim Shaikh, and Mubin Syed

Introduction There are no anticoagulants with defined indications for use during percutaneous peripheral intervention (PPI). The endovascular treatment of peripheral arterial disease expands from simple procedures such as renal artery stenting to more complex interventions such as those required to treat acute critical limb ischemia (CLI), deep vein thrombosis (DVT), and acute stroke. The disease states range from focal severe atherosclerotic stenosis to thrombus-laden lesions within diffusely diseased large to small lumen arteries. Depending on the complexity of the PPI, total procedure time also varies from relatively short to very long. All these factors must be considered when deciding the optimal choice of anticoagulant for a peripheral vascular intervention. Procedural anticoagulants currently in use are unfractionated heparin (UFH) and bivalirudin. While UFH is the most widely used anticoagulant during PPI, there is no consistent dosing regimen and dose response variability demands diligence in monitoring the therapeutic response and duration. Bivaluridin is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin therapy. PPI is becoming a more frequent first line approach for the treatment of renal, iliac, femoral, femoropopliteal, and tibial vascular diseases. Since the introduction of angioplasty, great progress has been made in technology for use in these procedures. These include laser atherectomy, nitinol stents, thrombectomy devices, and radiation therapy. Despite technological advances, progress in anticoagulant therapy was halted until the availability of direct thrombin inhibitors (DTI).

Indirect thrombin inhibitors Unfractionated heparin UFH is the oldest and most widely utilized agent in PPI. It was discovered by McLean in 1916 (1). It is a mixture of sulfated

monopolysacharrides with molecular weight ranging from 3000 to 30,000 daltons, with a mean molecular weight of 15,000 daltons (2). Standard UFH is derived from porcine or bovine intestinal mucosa or bovine lung. Heparin acts indirectly at multiple points within the coagulation cascade. Its major anticoagulant effect is via interaction with its requisite co-factor, antithrombin III (AT). The heparin–AT complex inactivates factors IXa, Xa, and XIIa, and binds thrombin at its active site to prevent the conversion of fibrinogen to fibrin (3). Heparin also prevents fibrin stabilization through the inhibition of fibrin stabilization factor. Heparin has no fibrinolytic activity and therefore is ineffective as a thrombolytic (4,5). Heparin is administered intravenously at the start of a PPI procedure either as a standard bolus injection or, as more appropriately, a weight-adjusted dose regimen. No consistent dosing regimen has been tested in a well-controlled study. The anticoagulant effect of heparin during PPI should be monitored by the activated clotting time (ACT).

Clinical indications UFH anticoagulation is routinely used during vascular and cardiac surgery, for the prophylaxis and treatment of DVT, for the prevention of pulmonary embolism in surgical patients, and in patients with atrial fibrillation and recent embolization (6).

Adverse reactions Heparin is associated with an increased risk of bleeding either due to over anticoagulation or the occurrence of heparin inducted thrombocytopenia. The risk of major bleeding associated with heparin is reported to be 0% to 7% (7,8). The long-term administration of UFH may also be associated with osteopenia. Other reported adverse effects include skin lesions, priaprism, and elevated liver enzymes.

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The most devastating complication is heparin induced thrombocytopenia (HIT) (1). In contrast with other immune mediated thrombocytopenia, HIT is associated with thrombosis.

Therapeutic limitations The anticoagulant activity of UFH varies among patients and therefore has a narrow therapeutic index, unpredictable pharmacokinetics, and requires frequent monitoring of the ACT. The optimal ACT for minimizing both ischemic and hemorrhagic complications during PPI in patients not treated with a glycoprotein IIb/IIIa inhibitor or thrombolytic is approximately 300 seconds.

Advantages of UFH The primary advantage of UFH as an anticoagulant is the relatively low unit cost and familiarity with its use and monitoring by staff members during the intervention. Another important consideration in the selection of UFH is the availability of a reversal agent, protamine, in an unfortunate event of major bleeding due to a procedural vascular perforation.

Protamine As an endovascular specialist, it is important to be familiar with the use of protamine in an emergent situation. Protamine is a low molecular weight protein that has an anticoagulant effect when administered alone. However when given in the presence of heparin, a stable salt forms to effect a loss of anticoagulant activity of both drugs. Heparin is highly acidic and forms a strong bond with the highly basic protamine molecules, forming an inactive complex. Protamine has a rapid onset of action; within five minutes of administration, it begins to neutralize heparin. It should he administered slowly over 10 minutes, with a goal of one milligram of protamine to neutralize every 90 units of heparin. Further dosing should be guided by coagulation studies. Too rapid of an administration of protamine can have serious side effects, including hypotension and anaphylaxis. Pulmonary hypertension, shortness of breath, flushing, and urticaria have all been associated with rapid administration. Patients with allergies to fish products may be allergic to protamine.

Direct thrombin inhibitors The direct thrombin inhibitor (DTI) is a new class of antithrombotic with the potential for improving outcomes in

endovascular interventions. Thrombin is a central enzyme in hemostasis. Its multiple roles include the conversion of fibrinogen to fibrin, further amplification of the coagulation cascade, and activation of platelets. The treatment of many thrombotic disorders in cardiovascular medicine is directed toward thrombin inhibition. Heparin has historically been used as a primary treatment of such disorders, although there are several limitations that control its clinical utility including extensive protein binding and an inability to inactivate platelet bound Factor Xa and fibrin bound thrombin. The thrombin molecule contains the following three binding sites: 1. A catalytic site responsible for the cleavage of substances (active site); 2. A substrate recognition site that also functions as the binding site for the AT-heparin complex–AT complex (exosite 1); and 3. A heparin binding domain (exosite 2) (10,11). Heparin bound to exosite 2 bridges more fibrin onto thrombin and renders the heparin–fibrin–thrombin complex inaccessible to inhibition by AT. Such fibrin bound thrombin serves as a reservoir of thrombogenic activity capable of converting Factors V and VIII to their activated form, converting fibrinogen to fibrin, activating Factor XIII, and attenuating fibrinolysis (12). Bound thrombin also continues to activate platelets through thromboxane A2 independent mechanisms not inhibited by aspirin (13). Platelet bound Factor Xa is similarly resistant to inactivation by heparin–AT complex, serving as a source of further thrombin generation. Therefore, drugs such as heparin cannot fully attenuate the thrombotic process, a potentially important concern at the site of arterial injury or foreign body placement in the form of a self-expanding or balloon expandable stent. A DTI offers several advantages over conventional heparin. They act independent of AT and are capable of inactivating free and clot-bound thrombin equally well. As a group, these agents inhibit thrombus growth and thrombin-mediated platelet activation. Several direct thrombin inhibitors have now been studied in clinical trials.

Bivalirudin The active substance in bivalirudin (Hirulog), a direct thrombin inhibitor, is a 20-amino acids ynthetic peptide based on the hirudin template. In the Hirulog angioplasty study, 4098 patients with unstable or post infarction angina were randomized to bivalirudin or heparin before PTCA (14). The conclusion of this study was that there was no difference in the 30-day primary endpoint with either treatment. Patients randomized to Hirulog, however, did have a statistically significant reduced incidence of bleeding-related complications.

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Hence, bivalirudin concurrently reduced both ischemiadriven and bleeding complications. In the REPLACE-2 trial, 6010 PTCA patients were randomized to bivalirudin with provisional GP IIb/IIIa inhibitor use versus the current standard of heparin and planned GP IIb/IIIa inhibitor use (15). Patients in both groups were also pretreated with aspirin. Stents were used in approximately 85% of patients, and approximately 86% of patients were pretreated with thienopyridines (ticlopidine or clopidogrel). A 30-day composite endpoint of death, myocardial infarction (MI), urgent revascularization, or major in-hospital bleeding occurred in 9.2% of patients in the bivalirudin arm versus 10% of the patients in the heparin plus GP IIb/IIIa arm. Major bleeding rates were 2.4% in the bivalirudin arm versus 4.1% in the heparin and GP IIb/IIIa arm (p 0.001). The investigators concluded that bivalirudin was effective in reducing the incidence of acute ischemic events with the added advantage of less bleeding.

Bivalirudin use in peripheral interventions The Angiomax Peripheral Procedure Registry of Vascular Events (APPROVE), a prospective, open-label single arm study, evaluated bivalirudin in 505 patients undergoing renal, iliac, or femoral artery intervention (16). Bivalirudin was administered as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/hr infusion for the duration of the produce. The primary endpoint was procedural success defined as 20% residual stenosis. Secondary endpoints included death, MI, unplanned revascularization, or surgical intervention for ischemia, amputation through 30 days and major bleeding. Aspirin was administered in 96.8% of the patients and clopidogrel to 95% of the patients. In-hospital procedural success was achieved in 95% of patients. At 30 days, the incidence of the composite of death/MI/unplanned revascularization/amputation was 1.2%. In-hospital major bleeding occurred in 2.2% of the patients. In this study however, patients with a serum creatinine 4 mg/dl were excluded. No dose adjustment was made for renal insufficiency. There was no correlation between clinical outcome and the degree of renal impairment. In addition to the APPROVE trial, three single center studies have reported successful use of bivalirudin with similar outcomes during PPI (17,18,19). The results of these studies are summarized in Table 1. In summary, bivalirudin use during PPI is safe and may prove to have an advantage over heparin. However, we caution the use of bivalirudin during PPI procedures attempting to cross and treat chronic total occlusions where the risk of perforation is substantial with an indication for immediate reversal of anticoagulation. There is no known antidote to bivalirudin.

571

Thrombolytic agents and antiplatelet therapy, including GPIIb/ IIIa inhibitors, are an important modality in the treatment of peripheral arterial disease. The following section presents the latest published data supporting the use of these relatively new drugs during PPI.

Thrombolytics Thrombolytic agents belong to the family of drugs called plasminogen activators. The mechanism of action of these agents results in the breakdown of plasminogen to form fibrinolytic plasmin. The formed plasmin enzymatically dissolves thrombus and degrades particular coagulation and complement plasma proteins. Direct acting agents are currently under investigation and include alfimeprase and plasmin. These drugs directly degrade fibrin within a blood clot due to their strong proteolytic activity, in contrast to the currently available plasminogen activators, which are dependent on the conversion of clot bound plasminogen to form plasmin. The management of acute arterial and vascular graft occlusions by the intra-arterial local administration of fibrinolytic agents has emerged as an alternative and a frequent adjunct to surgical or endovascular therapy in a select group of patients. It is important to understand that there is no regulatory approval or labeling indication for the use of these drugs in the treatment of peripheral vascular disease. Absolute contraindications for thrombolytic agents include recent stroke or recent transient ischemic attack (TIA) (although low dosage regimens might be considered in desperate cases), active or recent bleeding, and significant coagulopathy. Relative contraindications include recent neurosurgery (3) or cranial trauma, resuscitation or trauma in the last 10 days, uncontrolled high blood pressure (>180 SBP, 110 DBP), recent puncture of noncompressible vessel, and intracranial tumor or recent eye surgery.

Urokinase Urokinase (UK) was the first of the thrombolytic agents to appear in widespread use in the 1990s (20). UK is a naturally occurring thrombolytic produced by renal parenchyma and is therefore found in human urine. It has a plasma half-life of 15 minutes and when administered intravenously, it is rapidly removed from circulation by hepatic clearance. UK is nonantigenic and its mechanism of action is much more direct compared with that of streptokinase. UK cleaves plasminogen, by first-order reaction kinetics, to form plasmin. It is pH and temperature stable. The lack of circulating neutralizing antibodies and its direct mechanism of action allow for a predictable dose response relationship.

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Table 1

In-hospital clinical outcomes with bivalirudin in recent PPI studies Eres A n 150 n (%)

Allie DE n 255 n (%)

Shammas NW n 131 n (%)

Death

3

(2.0)

0

(0.0)

0

(0.0)

MI

0

(0.0)

0

(0.0)

0

(0.0)

Revascularization

1

(0.8)

0

(0.0)

0

(0.0)

Amputation

0

(0.0)

0

(0.0)

0

(0.0)

Major

bleedinga

7

(4.7)

4

(1.6)

2

(4.2)

Minor

bleedinga

3

(2.0)

8

(3.1)

0

(0.0)

aThe definition of bleeding varied between trials.

Abbreviation: PPI, peripheral intervention.

Controversy exists regarding the actual thrombolytic effect of UK when administered in vivo. Experimental studies suggest exogenous fibrinolysis as the main pathway of thrombolysis (21). However, laboratory findings in treated patients have indicated less fibrinolytic response suggesting activity within thrombus also. In clinical practice, UK has produced similar results to streptokinase with less bleeding complications. UK was voluntarily withdrawn by Abbott Laboratories in 1999 when the FDA alerted the company about potential viral contamination in its manufacturing process. In October 2002, the FDA approved the reintroduction of UK (Abbokinase®) to the market after Abbott made significant changes to its quality control and manufacturing practices. Urokinase is intended for intravenous use only and indicated for the treatment of pulmonary embolism, coronary artery thrombosis, and intravenous catheter clearance. Typical dosages in peripheral arterial disease consist of an infusion at a rate ranging from 60,000 IU/ hr to 240,000 IU/ hr infused directly into the thrombus.

Rochester trial Ouriel et al. conducted this important equally randomized trial in which 114 patients presenting with acute lower limb ischemia (7 days) received either catheter-directed UK or underwent surgical revascularization (22). The primary endpoints were limb salvage and survival at 12 months. The amputation-free survival rates at one year were statistically significant at 75% and 52%, respectively. Other results of Rochester Trial are summarized in Table 2. Although there was no statistical difference in limb salvage, 12-month mortality was higher in surgical group. The authors attributed the higher mortality to cardiopulmonary complications. This is an important fact considering that many CLI

patients do have associated morbidities such as coronary heart disease, diabetes, cerebrovascular disease, and renal insufficiency.

Thrombolysis or peripheral arterial surgery (TOPAS) trial The findings of Rochester Trial led to a two-phase randomized prospective multicenter trial known as the TOPAS Trial. Phase 1 was designed as a dose ranging study where 213 patients with lower extremity arterial occlusion of less than 14 days duration were randomized to receive one of three doses of recombinant UK (2000 IU/min, 4000 IU/min, or 6000 IU/min) for four hours followed by 2000 IU/min for 44 hours versus surgical revascularization (23). The 4000 IU/min regimen was found to be the most effective when safety and efficacy was considered. Amputation free survival was similar in both groups but patients who underwent thrombolytic infusion required much less surgical intervention. However, bleeding complications were higher in UK group compared to surgery. In the larger second phase of the TOPAS Trial, 544 patient patients with acute limb ischemia of less than 14 days duration were randomized to receive either catheter-directed recombinant UK or operative revascularization (24). The summary of results is described in Table 3. Amputation-free survival rates in UK group were 72% at 6 months and 65% at one year compared to 75% and 70%, respectively, in the surgical group. By one year the surgical group had undergone 30% more surgical procedures compared to the UK group. However, bleeding complications were again more frequent in UK group compared to surgery (12.5% vs. 5.5%, p 0.005). It is important to note that the bleeding rate was considerably less in patients who did not require concomitant heparin therapy.

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573

Figure 1

Figure 3

Patient presents with acute lower extremity ischemia, thrombotic lesion in common femoral artery with femoropopliteal bypass occlusion.

Crossing of femoropopliteal occlusion and selective angiography of the graft demonstrates large thrombus burden.

Figure 2

Figure 4

Distal reconstitution of popliteal artery via collaterals.

Placement of infusion catheter across the entire length of the occlusion, A critical step in the procedure.

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Figure 5

Figure 7

Post 12 hours lysis with 0.5 mg/hr tPA through infusion catheter and IV heparin.

Post balloon angioplasty and nitinol stent placement at distal end of graft.

Figure 6

Figure 8

After thrombolysis distal anastomotic disease is uncovered.

Post balloon angioplasty and nitinol stent placement at proximal graft occlusion site.

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575

Figure 9

Figure 11

Patient with severe claudication and complex popliteal artery occlusion.

Post laser atherectomy and percutaneous transluminal angioplasty of popliteal artery as well as tibioperoneal trunk, IV heparin used as an anticoagulant with pretreatment with aspirin and clopidogrel.

Figure 10

Figure 12

Post laser atherectomy and percutaneous transluminal angioplasty of popliteal artery as well as tibioperoneal trunk, IV heparin used as an anticoagulant with pretreatment with aspirin and clopidogrel.

Reconstruction of anterior tibial artery with balloon angioplasty and nitinol stent in the proximal segment of anterior tibial artery.

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t-PA is a direct plasminogen activator. Its main advantage is its high affinity for clot-bound fibrin. t-PA specifically binds to fibrin within a formed thrombus and enzymatically converts surface-bound plasminogen to plasmin. Two forms of t-PA are recognized, single- and double-chain, and both are commercially available. Both contain enzymatic activity. The endogenous single-chain molecule is converted by plasmin to a double-chain plasmin molecule. Alteplase was the first commercially available recombinant tissue-type plasminogen activator (rt-PA) (25). It has a plasma half-life of less than five minutes and is metabolized by the liver. This agent was initially hailed as fibrin-specific unlike its precursors (urokinase and streptokinase). It was thought that this would result in a better safety profile, but this has not been born out in either the coronary or the peripheral experience, where actually there may be a higher bleeding risk as infusion time increases. Alteplase is currently indicated for use in the treatment of myocardial infarction, acute ischemic stroke, and pulmonary embolism.

Figure 13 Final result at popliteal occlusion postnitinol stent placement, at follow up complete resolution of symptoms.

During the time that UK was unavailable, increased experience and familiarity were gained with other agents, such as recombinant tissue plasminogen activator (rt-PA) and reteplase.

Alteplase (recombinant tissue plasminogen activator) Tissue plasminogen activator (t-PA) is an endogenous serine protease synthesized and secreted by the vascular endothelium. It is present in all human tissues. With the exception of liver and spleen, tissue concentration correlates directly with vascularity.

Table 2

STILE trial The STILE (Surgery versus Thrombolysis for the Ischemic Lower Extremity) Trial compared catheter-directed lysis to surgery as well as differences in outcome between rt-PA and UK (26). This study enrolled patients with acute limb ischemia as well as chronic limb ischemia. Dosages of rt-PA were initial infusion of 0.1 mg/kg/hr followed by 0.05 mg/kh/hr for 12 hours. UK was given as 250,000 IU bolus followed by 4000 IU/min for four hours and then reduced to 2000 IU/min for 36 hours. Outcomes of this trial are summarized in Tables 4 and 5. Endpoints measured included death, ongoing or recurrent ischemia, major amputation, and major morbidity. The trial was halted early after first interim analysis. This was driven by the failure of catheter-directed lysis in patients with chronic native artery occlusions.

Major observations from the rochester trial Thrombolytic therapy (n 57)

Surgical therapy ( n 57)

p value

Limb salvage at 12 months

82%

82%

1.00

Survival at 12 months

84%

58%

0.01

Hospitalization (median)

11 days

11 days

1.00

Major bleeding

11%

6%

0.06

Intracranial bleed

2%

0

NS

Hospital cost

$15,672

$12,253

0.02

Abbreviation: NS, not significant.

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Table 3

TOPAS trial—summary of results Urokinase px (n 272)

Surgery (n 272)

Recanalization

80%

—

Complete lysis

68%

—

Hospitalization (median)

10 days

10 days

Major hemorrhage

13%

6%b

Intracranial bleed

1.6%

0%

Major amputation

15%

13%

Death

20%

17%

Amputation-free survival

65%

70%

Open surgical procedures

351

590

Percutaneous procedures

135

70

Early

1 year

aPercentages bp

577

a good efficacy and safety profile comparable to alteplase in the peripheral circulation (27,28). Reteplase is indicated for acute myocardial infarction. Due to its longer half-life of 13–16 minutes it can be administered as double bolus injections. This treatment option is of no value in peripheral arterial thrombus, where continuous infusion is the norm. Typical dosage is 0.25 to 0.5 units/ hr.Castaneda et al. evaluated 101 arterial occlusions in 87 patients using three different dosing regimens of reteplase: 0.5 u/ hr, 0.25 u/ hr, and 0.125 u/ hr. Concomitant heparin was administered in all patients. Thrombolytic success was achieved in 86.7%, 83.8%, and 85.3%, respectively. The 0.5 u/hr group received more reteplase and had higher bleeding complications while the 0.125 u/ hr group required longer infusion times to achieve a successful outcome. Kiproff et al. demonstrated efficacy of pulsed spray reteplase in 18 acute ischemic limb patients using 0.5 u/hr dosing (29). Clinical success was achieved in 89% of patients with the average time of lysis reported as 26.9 hr.

rounded except for intracranial bleed.

0.005.

Abbreviation: TOPAS, thrombolysis or peripheral arterial surgery.

In patients with acute limb ischemia, there was a significant reduction in major amputation and significantly improved amputation-free survival in the lysis group. Surgical treatment fared better in chronic limb ischemic group. Detailed analysis did not demonstrate differences in efficacy and safety between UK and rt-PA. However, lysis infusion time was shorter in rt-PA group compared to UK. Once again, bleeding complications were higher with lysis compared to surgery. These complications occur early in the course of thrombolytic infusion. The duration of therapy was not longer in patients who experienced bleeding. One important observation was lower fibrinogen levels (188 mg/dL vs. 310 mg/dL, p 0.01) and the partial thromboplastin time (PTT) was longer (114 seconds vs. 58 seconds; p 0.26) in patients with bleeding complication, suggesting more a severe coagulopathy. Our current clinical practice guidelines include monitoring fibrinogen levels; if it falls below 150 mg/dl we decrease the dose of lytic infusion by 50% and if below 100 mg/dl, we discontinue the lytic infusion.

Reteplase Reteplase is a second-generation recombinant tissue plasminogen activator, which lacks portions of the original alteplase. The chemical structure results in a smaller molecule having less fibrin specificity and a longer half-life than alteplase. Studies from Ouriel et al. and Castaneda et al. demonstrated

Tenecteplase Tenecteplase-tPA (TKNase™) is a bioengineered mutant of rt-PA. The mutations were directed at three sites on the molecule to affect pharmacological improvements relative to native rt-PA. These alterations created a molecule with a longer half-life, increased fibrin specificity, and increased resistance to plasminogen activator inhibitor-1 (PAI-1) (30). TKNase can be administered by single bolus injection with less systemic plasminogen/plasmin interaction and more rapid reperfusion. These features may be beneficial in reducing bleeding complications. Tenecteplase is currently indicated for use in mortality reduction associated with acute myocardial infarction. Early experience with this lytic in the treatment of peripheral arterial disease has been promising with equivalent safety and efficacy to alteplase (31,32). Burkart et al. published their initial experience in 13 patients with arterial occlusion and five with venous thrombosis. TNK-tPA was administered at a rate of 0.25 mg/ hr with restoration of flow in all patients. The clinical success with respect to limb salvage or symptom relief was achieved in 11 of 13 (85%) patients and four out of the five patients with venous thrombosis. There were no intracranial bleeding complications.

Glycoprotein IIb/IIIa inhibitors The use of GPIIb/IIIa inhibitors has been extensively studied in numerous large randomized controlled trials involving percutaneous coronary intervention (PCI). The advantages of their use in the coronary circulation that can theoretically

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STILE trial–outcome at one month duration of ischemia (53-3) (intention-to-treat analysis)

Event Duration of Ischemia: 0 –14 days (count)

Surgery (n 135)

Thrombolysis (n 240)

No.

No.

%

39

P Value

%

73

Composite clinical outcome

21

53.8

43

61.4

0.459

Death

2

5.1

3

4.3

0.810

Major amputation

7

17.9

4

5.7

0.061

Ongoing/recurrent ischemia

15

38.5

34

48.6

0.328

Major morbidity

10

25.6

15

21.4

0.598

Life-threatening hemorrhage

0

0

4

5.7

0.157

Perioperative complications

8

20.5

7

10

0.098

Renal failure

0

0

0

0

—

Anesthesia complications

0

0

0

0

—

Vascular complications

1

2.6

5

7.1

0.293

Post intervention wound complications

1

2.6

5

7.1

0.293

Duration of Ischemia 14 days (count)

96

170

Composite clinical outcome

28

29.2

107

62.9

0.001

Death

4

4.2

5

2.9

0.617

Major amputation

2

2.1

9

5.3

0.218

Ongoing/recurrent ischemia

20

20.8

99

58.2

0.001

Major morbidity

13

13.5

34

20

0.169

Life-threatening hemorrhage

1

1.0

9

5.3

0.080

Perioperative complications

5

5.2

7

4.1

0.712

Renal failure

1

1

3

1.8

0.618

Anesthesia complications

1

1

0

0

—

Vascular complications

4

4.2

18

10.6

0.063

Postintervention wound complications

3

3.1

8

4.7

0.526

crossover into the peripheral circulation include decreased distal microembolization, decreased vascular thrombus formation, decreased abrupt closure at the site of intervention, increased efficacy of thrombolytic therapy, and decreased long-term target vessel revascularization in diabetic subjects. Glycoprotein IIb/ IIIa receptor inhibitors include abciximab, eptifibatide, and tirofiban. These drugs disrupt the platelet aggregation cascade by inhibiting the binding of fibrinogen to the platelet membrane. The use of these drugs is established in the coronary vasculature through large randomized controlled trials. However, in peripheral disease no large studies have been conducted to prove their efficacy. It has been suggested that in peripheral vascular interventions their use may be justified when heparin is likely to be inadequate in

preventing acute intraprocedural thrombosis. Such examples would include infrapopliteal angioplasty or long segment superficial femoral artery stenosis or occlusion. The current practice of administering dual-platelet function inhibitors (i.e., aspirin and clopidogrel) prior to any PPI may obviate any clinical benefit to the administration of a GPIIb/ IIIa inhibitor.

Abciximab Abciximab was the first commercially available GPIIb/ IIIa receptor inhibitor. Abciximab is a monoclonal Fab immunoglobulin fragment that binds to the glycoprotein receptor on the platelet membrane. The half-life of abciximab

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Table 5

579

STILE trial—death and amputation outcome at six months by duration of ischemia (53-4) 14 Days

0–14 Days Surgery No.

%

Lysis No.

%

Surgery p value

72

No.

%

101

Lysis No.

%

p value

Intent-to-treat (count)

40

Death/amputation

15

7.5

11

15.3

0.01

10

9.9

31

17.8

0.08

Death

4

10

4

5.6

0.45

8

7.9

12

6.9

0.81

Major amputation

12

30

8

11.1

0.02

3

3

21

12.1

0.01

Per-protocol (count)

36

Death/amputation

13

36.1

7

14

0.02

9

10.1

30

21

0.03

Death

4

11.1

3

6

0.45

7

7.9

12

8.4

0.99

Major amputation

10

27.8

5

10

0.04

3

3.4

20

14

0.01

50

174

89

is less than 10 minutes with a second phase half-life of 30 minutes. The antiplatelet effect lasts for up to 48 hours and low levels of GPIIb/ IIIa inhibition may last for up to 15 days. Abciximab is indicated for PCI and ACS (acute coronary syndrome) if PCI is planned within 24 hours. It is infused intravenously as a weight-based bolus of 0.25 mg/kg (about 17 mg). This is followed by a continuous IV infusion at 0.125 mcg/kg/min (max 10 mcg/min) for 12 hours. The adverse reaction of mild thrombocytopenia occurs in 4.2% of patients versus 2.0% of patients receiving placebo. Severe thrombocytopenia (50,000 per microliter) occurs in 1.0% of patients versus 0.4% of patients receiving placebo (33). Abciximab binds to other integrins (a class of cell surface receptors involved in platelet aggregation) such as avB3 (vitronectin receptor) and the leukocyte integrin MAC-l (34). This could theoretically reduce the inflammatory response from vessel wall injury and the resulting intimal hyperplasia. This has not been proven in any large scale clinical trial. One randomized control trial involving the use of abciximab during PPI demonstrated no long-term benefit in stent patency for complex superficial femoral lesions (35). However, a larger prospective, double-blind, placebocontrolled designed study that involved 98 patients showed that adjunctive administration of abciximab had a favorable effect on patency and clinical outcome in patients undergoing complex femoropopliteal catheter interventions not hampered by serious bleeding (36).

Eptifibatide Eptifibatide is a lower molecular weight molecule than abciximab. It is derived from a peptide constituent of venom from

143

the southeastern pigmy rattlesnake. This agent binds competitively to the GPIIb/IIIa receptor. It therefore has a much shorter receptor blockade and plasma half-life of 2.5 hr. This drug is eliminated by the kidney and the dosage must be adjusted in renal insufficiency. Eptifibatide is indicated for PCI. Dosing is 180 mg/kg bolus followed by a 2.0 mg/kg/min infusion with a second 180 mg/kg bolus 10 minutes after the first bolus for 18–24 hr. Eptifibatide has been shown to be safe and feasible for peripheral interventions (37). The INFLAME trial showed that markers of inflammation are reduced by using eptifibatide when performing peripheral interventions (38). There has been no data yet to suggest improved clinical outcomes or patency.

Tirofiban Tirofiban is another low molecular weight nonpeptide drug, which was designed using X ray crystallography. It is a competitive inhibitor of the GPIIb/ IIIa receptor. The drug plasma half-life is one to six hours. Tirofiban is excreted by the kidney. Tirofiban is indicated for use in ACS. Dosing is 0.10 mg/kg followed by 0.15 mg/kg for 18–24 hr. Renal insufficiency patients with a creatinine clearance 30 mL/min should receive half the dose. Adverse reactions could include thrombocytopenia (100,000) in 0.5% of patients (39). In the peripheral circulation there has been no large study demonstrating the benefit of tirofiban as stand alone therapy. A trend toward improved outcomes was demonstrated in a study using combined therapy with bivalirudin and tirofiban for CLI (40).

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Combination therapy Combination therapy with a thrombolytic agent and GPIIb/ IIIa inhibitor has been studied in acute MI. Various randomized trials (TAMI-8, IMPACT, INTRO AMI, TIMI-14, SPEED, GUSTO V) in the coronary literature have shown that combination therapy reduced thrombolysis time and permitted a reduction of thrombolytic doses by 25% to 50% of the normal dose. This is explained by the fact that thrombus is composed of both fibrin and platelets. Thrombolytics only address the fibrin component of acute thrombus. Furthermore, thrombolytics may actually activate platelets directly resulting in additional thrombus formation. Therefore, the addition of GPIIb/ IIIa inhibition facilitates the efficiency of the thrombolytic agent. It is also known that GPIIb/ IIIa inhibition alone can actually dissolve platelet rich clot (41,42,43). There are several small studies examining this concept of thrombolytic infusion with GPIIb/ IIIa inhibition to reduce lytic infusion time and improve efficacy as summarized below. This concept is not universally proven in these studies. A larger randomized trail is needed to examine this concept before a clinical practice recommendation can be made. Tepes et al. reported the first clinical experience with abciximab and urokinase combination therapy in the peripheral circulation (44). Schweizer et al. used abciximab and rt-PA versus rt-PA with ASA in an 84 patient trial and found a significantly shorter duration of thrombolytic infusion was required to achieve lytic success in the combination group as well as improved clinical endpoints of less re-hospitalization, re-intervention, and amputation compared to ASA and heparin (45). Duda et al. prospectively studied 70 patients in the PROMPT trial of UK and abciximab versus UK alone. The trial showed the combination therapy resulted in a decreased infusion time, improved amputation free survival, and improved open surgery free survival at 90 days (46). Interestingly, a post hoc economic analysis of the PROMPT trial found an economic benefit to combination therapy at 90 days based on endpoints of amputation free survival, survival without open surgery, lack of major amputation and lack of major complications. The extra cost of abciximab was more than offset by the decreased costs through improved patient outcomes (47). Yoon et al. retrospectively compared the clinical outcomes of 17 patients who received eptifibatide and rt-PA to an agematched group of patients who received only rt-PA. The study demonstrated a significantly decreased thrombolytic dose in the combination group (9.0 /– 4.4 mg vs. 38.9 /– 30.7 mg) (48). Syed et al. reported that intra-arterial eptifibatide infusion with reteplase can be successful in restoring blood flow in the presence of chronic arterial thrombus (49). With combination therapy using reteplase and abciximab, a prospective double center study of 50 patients was reported by Drescher et al (50). Recently, however, the 74 patient

RELAX trial comparing reteplase and abciximab combination therapy to reteplase monotherapy found no significant difference in safety and efficacy in all major clinical end points (death, amputation, PTA/stent, surgical revascularization). The trial did demonstrate a decreased rate of distal embolic event in the combination group (51). Very limited clinical data is available for tenecteplase and eptifibatide combination therapy. A small 16 patient study did show feasibility of combining these agents with positive efficacy and safety (52). However, there was a negative safety correlation with the use of abciximab with tenecteplase in a recent 37 patient study (53). A 60 patient study comparing treatment with abciximab and rt-PA to treatment with tirofiban with rt-PA found no difference in bleeding complications, re-hospitalization, reintervention, or amputation rate. The duration of lysis was only slightly shorter in the abciximab group but this was not clinically relevant (149.7 18 vs. 139.3 31.3 min) (54). The 50 patient APART trial recently compared reteplase plus abciximab or urokinase plus abciximab and found overall no significant differences except a decreased thrombolysis time in the urokinase and abciximab group (120 min vs. 200 min, p 0.001) (55).

References 1 2 3

4

5 6 7

8

9 10 11

McLean J. The thromboplastic action of cephalin. Am J Physiol 1916; 41:250–257. Johnson EA, Mulloy B. The molecular weight range of mucosal heparin preparations. Carbohydr Res 1976; 51:119–127. Rosenberg RD, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci USA 1979; 76:1218–1222. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119(1 suppl):64S–94S. Weitz JI, Crowther M: Direct thrombin inhibitors. Thromb Res 2002; 106:V275–V284. Hirsh j, Anand SS, Halperin JL, Fuster V. Guide to Anticoagulant therapy: heparin. Circulation 2001; 103:2994–3018. Levine MN, Raskob G, Landefeld S, Kearon C. Hemorrhagic complications of anticoagulant treatment. Chest 2001; 119(1 suppl):108S–121S. Wester JP, de Valk HW, Nieuwenhuis HK, et al. Risk factors for bleeding during treatment of acute venous thromboembolism. Thromb Haemost 1996; 76:682–688. Gupta AK, Kovacs MJ, Sauder DN. Heparin-induced thrombocytopenia. Ann Pharmacotherapy 1998; 32:55–59. Weitz JI, Crowther M: Direct thrombin inhibitors. Thromb Res 2002; 106:V275–284. Wiggins BS, Spinler S, Wittkowsky AK, Stringer KA. Bivalirudin. a direct thrombin inhibitor for percutaneous transluminal coronary angioplasty. Pharmacotherapy 2002; 22:1007–1018.

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28

Bates SM, Weitz JI. Direct thrombin inhibitors for treatment of arterial thrombosis: Potential differences between bivalirudin and hirudin. Am J Cardiol 1998; 82:12–18. Direct thrombin inhibitors in acute coronary syndromes: Principal results of a meta-analysis based on individual patients’ data. Lancet 2002; 359:294–302. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med 1995; 333:764–769. Lincoff AM, Bittl JA, Harrington RA, et al. and for the REPLACE-2 Investigators. bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289:853–863. Alle D, Hall P, Shammas N, et al. The Angiomax peripheral procedure registry of vascular events trial (APPROVE): In hospital and 30-day results. J Invas Cardiol 2004; 16:651–656. Eres A. Use of bivalirudin as the foundation anticoagulant during percutaneous peripheral interventions. J Invas Cardiol 2006; 18:125–128. Allie D, Lirtzman M, Watt DH, et al. Bivalirudin as a foundation anticoagulant in peripheral vascular disease: a safe and feasible alternative for renal and iliac interventions. J Invasive Cardiol 2003; 15:334–342. Shammas N, Lemke J, Dippel E et al. Bivalirudin in peripheral vascular interventions: A single center experience. J Invas Cardiol 2003; 15:401–404. Comerota AJ, Rao AK, Throm RC, et al. A prospective, randomized, blinded, and placebo-controlled trial of intraoperative intraarterial urokinase infusion during lower extremity revascularization: Regional and systemic effects. Ann Surg 1993; 218:534. Varadi A, Patthy L. Location of plasminogen-binding sites in human fibrin(ogen). Biochemistry 1983; 22:2240–2246. Ouriel K, Shortell C, DeWeese J, et al. A comparison of thrombolytic therapy with operative revascularization in the initial treatment of acute peripheral arterial ischemia. J Vasc Surg 1994; 19:1021. Ouriel K, Veith FJ, Sasahara AA, et al. Thrombolysis or peripheral artery surgery: phase 1 results. J Vasc Surg 1996; 23:64–75. Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. N Engl J Med 1998; 338:1105–1111. Goldhaber SZ, Kessler CM, Heit J, et al. Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2:293–298. The Stile Investigators. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. Ann Surg 1994; 220:251–268. Ouriel K, Katzen B, Mewissen M, et al. Reteplase in the treatment of peripheral arterial and venous occlusions: a pilot study. J Vasc Interv Radiol 2000; 11(7):849–854. Castaneda F, Swischuk JL, Li R, Young K, Smouse B, Brady T. Declining-dose study of reteplase treatment for lower extremity arterial occlusions. J Vasc Interv Radiol 2002; 13(11):1093–1098.

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Kiproff PM, Yammine K, Potts JM, et al. Reteplase infusion in the treatment of acute lower extremity occlusions. J Thromb Thrombolysis 13:75–79, 2002. McCluskey ER, Refino CJ, Zioncheck TF, et al. Tenecteplase: Biochemistry, pharmacology, and clinical experience. In Sasahara AA, Loscalzo J (eds): New Therapeutic Agents in Thrombosis and Thrombolysis, 2nd ed. New York: Marcel Dekker, 2003:501–511. Razavi MK, Wong H, Kee ST, Sze DY, Semba CP, Dake MD. Initial clinical results of tenecteplase (TNK) in catheter-directed thrombolytic therapy. J Endovasc Ther 2002; 9(5):593–598. Burkart DJ, Borsa JJ, Anthony JP, Thurlo SR. Thrombolysis of occluded peripheral arteries and veins with tenecteplase: a pilot study. J Vasc Interv Radiol 2002; 13(11):1099–1102. Dasgupta H, Blankenship JC, Wood GC, Frey CM, Demko SL, Menapace FJ. Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis. Am Heart J 2000; 140(2):206–211. Scarborough RM, Kleiman NS, Phillips DR. Platelet glycoprotein IIb/IIIa antagonists. What are the relevant issues concerning their pharmacology and clinical use? Circulation 1999; 100(4):437–444. Ansel GM, Silver MJ, Botti CF Jr, et al. Functional and clinical outcomes of nitinol stenting with and without abciximab for complex superficial femoral artery disease: a randomized trial. Catheter Cardiovasc Interv 2006; 67(2):288–297. Dorffler-Melly J, Mahler F, Do DD, Triller J, Baumgartner I. Adjunctive abciximab improves patency and functional outcome in endovascular treatment of femoropopliteal occlusions: initial experience. Radiology 2005; 237(3):1103–1119. Rocha-Singh KJ, Rutherford J. Glycoprotein IIb-IIIa receptor inhibition with eptifibatide in percutaneous intervention for symptomatic peripheral vascular disease: the circulate pilot trial. Catheter Cardiovasc Interv 2005; 66(4):470–473. Shammas NW, Dippel EJ, Lemke JH, et al. Eptifibatide in peripheral vascular interventions: results of the Integrilin Reduces Inflammation in Peripheral Vascular Interventions (INFLAME) trial. J Invasive Cardiol 2006 18(1):6–12. Merlini PA, Rossi M, Menozzi A, et al. Thrombocytopenia caused by abciximab or tirofiban and its association with clinical outcome in patients undergoing coronary stenting. Circulation 2004; 109(18):2203–2206. Epub 2004 Apr 26. Allie DE, Hebert CJ, Lirtzman MD, et al. A safety and feasibility report of combined direct thrombin and GP IIb/IIIa inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention: treating critical limb ischemia like acute coronary syndrome. J Invasive Cardiol 2005; 17(8):427–432. Gold HK, Garabedian HD, Dinsmore RE, et al. Restoration of coronary flow in myocardial infarction by intravenous chimeric 7E3 antibody without exogenous plasminogen activators. Observations in animals and humans. Circulation 1997; 95(7):1755–1759. Rerkpattanapipat P, Kotler MN, Yazdanfar S. Images in cardiovascular medicine. Rapid dissolution of massive intracoronary thrombosis with platelet glycoprotein IIb/IIIa receptor inhibitor. Circulation 1999; 99(22):2965. No abstract available. Berkompas DC. Abciximab combined with angioplasty in a patient with renal artery stent subacute thrombosis. Cathet Cardiovasc Diagn 1998; 45(3):272–274.

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Tepe G, Duda SH, Erley CM, Schott U, Huppert PE, Claussen CD. [The adjuvant use of the monoclonal antibody c7E3 Fab in peripheral arterial thrombolysis] Rofo 1997; 166(3):254–257. German. Schweizer J, Kirch W, Koch R, Muller A, Hellner G, Forkmann L. Short- and long-term results of abciximab versus aspirin in conjunction with thrombolysis for patients with peripheral occlusive arterial disease and arterial thrombosis. Angiology 2000; 51(11):913–923. Duda SH, Tepe G, Luz O, et al. Peripheral artery occlusion: treatment with abciximab plus urokinase versus with urokinase alone—a randomized pilot trial (the PROMPT Study). Platelet receptor antibodies in order to manage peripheral artery thrombosis. radiology 2001; 221(3):689–696. Duda SH, Tepe G, Luz O, et al. Peripheral artery occlusion: treatment with abciximab plus urokinase versus with urokinase alone–a randomized pilot trial (the PROMPT Study). platelet receptor antibodies in order to manage peripheral artery thrombosis. Radiology 2001; 221(3):689–696.

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Yoon HC, Miller FJ Jr. Using a peptide inhibitor of the glycoprotein IIb/IIIa platelet receptor: initial experience in patients with acute peripheral arterial occlusions. AJR Am J Roentgenol 2002; 178(3):617–622. Syed, MI, Shaikh, A. Combination thrombolysis/GPIIbIIIa inhibition in chronic peripheral thrombosis- A case report. New Deve- lopments in Vascular Disease. Vol 1, (4) Spring 2003: 12–17. Drescher P, McGuckin J, Rilling WS, Crain MR. Catheterdirected thrombolytic therapy in peripheral artery occlusions: combining reteplase and abciximab. AJR Am J Roentgenol 2003; 180(5):1385–1391. Ouriel K, Castaneda F, McNamara T, et al. Reteplase monotherapy and reteplase/abciximab combination therapy in peripheral arterial occlusive disease: results from the RELAX trial. J Vasc Interv Radiol 2004; 15(3):229–238. Burkart DJ, Borsa JJ, Anthony JP, Thurlo SR. Thrombolysis of acute peripheral arterial and venous occlusions with tenecteplase and eptifibatide: a pilot study.

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50 Repair of AAAs Alexandra A. MacLean and Barry T. Katzen

Introduction Fifteen years ago, the only option for patients with large abdominal aortic aneurysms (AAA) that required either elective or emergent repair was an open surgical approach using a transperitoneal or retroperitoneal incision. Now with the advent of endovascular approaches to aortic diseases, many patients, especially those in the high-risk groups, have a minimally invasive option to permit repair of aortic aneurysms, dissections, pseudoaneurysms, and ruptures. The endovascular procedure is most frequently used to treat infrarenal AAAs that are a leading cause of death in the older population. As our population ages, we will encounter AAAs more frequently than ever before. An aneurysm is defined by a size greater than 5 cm or 2.5 times the normal diameter of the native artery. Most aneurysms begin below the renal arteries and end close to the iliac bifurcation. More complicated AAAs exist involving the suprarenal aorta and visceral vessels and extending into the iliac arteries. The prevalence of AAAs is 3% to 10% for patients older than 50 years (1). They occur more frequently in men and reach a peak incidence close to the age of 80 years. AAA rupture is associated with an 80% to 90% mortality rate and therefore the focus of AAA treatment is on intervening before the aneurysm ruptures; elective repair has mortality rate of less than 5%. The first endovascular repair of an AAA in a human was performed by Parodi in 1991. He made an endograft by combining a prosthetic vascular graft with expandable Palmaz stents (2). Since this milestone, the field has undergone immense growth and has benefited from many technologic advances that have permitted a wider application of this treatment modality. The patient population that has benefited most has been the population at high risk for open surgical repair. These patients have severe comorbidities including and not limited to old age, renal, heart, and pulmonary diseases. Endovascular aneurysm repair (EVAR) of AAAs, results in a quick recovery, can be done under local anesthesia and has fewer systemic complications than open surgical repair. The goal of this chapter is to describe patient and aneurysm

selection factors, the procedure and endografts, review clinical trials, outcomes and complications and address some of the controversial and challenging areas of EVAR with a view to the future.

Patient selection factors Abdominal aortic aneurysms can present as an incidental asymptomatic finding on imaging or with symptoms, most prominently, back and abdominal pain. The asymptomatic aneurysms can be detected during routine physical examination but are more likely found during workup for other complaints or as part of a screening program for patients who are at high risk for developing AAAs (positive family or personal history of aneurysms). Intervention is indicated for symptomatic aneurysms regardless of size, and asymptomatic aneurysms with a size greater than 5 cm in diameter or with an increase in size greater than 10% per year as these groups have the greatest chance of rupture. Controversy exists as to when to intervene in females with aneurysms less than 5 cm diameter. Given smaller native aorta in this group, the aneurysmal dilatation can be greater than 2.5 times the diameter of the native aorta and less than 5 cm in diameter. Given the smaller native aorta in this group, the aneurysmat dilatation can be greater than 2.5 times the diameter of the native aorta and less than 5 cm in diameter. This smaller size of aneurysm may put the patient at equivalent risk of rupture. There are patient selection factors for EVAR of AAAs that set this procedure apart from open repair. The durability of the open repair is well known and has been demonstrated in multiple clinical studies. EVAR on the other hand requires routine and frequent follow-up with ultrasound examination and or CT scans to evaluate the repair for the development of complications that require secondary interventions. The patient must be able to commit to this follow-up routine in order to be eligible for the procedure. In general, patients who are young with few comorbidites are still advised to undergo open surgical repair because of the demonstrated

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Repair of AAAs

longevity of the repair and ease of follow-up. EVAR has become the procedure of choice for patients at high risk for open repair given an older age and other morbidities (3).

Aneurysm assessment The aneurysm and aorta are assessed with a 3D reconstruction CT scan or aortography with a calibrated catheter (Table 1, Fig. 1). The fitness of the femoral arteries is evaluated as the access route. They should be greater than 7 mm in diameter and free from extensive atherosclerotic or stenotic disease. The anatomy of the proximal neck is important; the length of aneurysm free aorta from the most caudal renal artery to the beginning of aneurysmal dilatation must be at least 15 mm to permit adequate seal of the device to a segment of normal aorta. In addition, the angulation of the neck is ideally less than 60°. The placement of an endovascular device is not possible when the neck is too large. The size limitation comes from the need to have device sizes that can be packaged into sheaths deliverable through the femoral artery. The shape of the neck is described as tapered, reverse tapered, or straight, with the latter being ideal. The distal landing zone is evaluated for the location of the hypogastric artery and presence of iliac aneurysms. Once again, an area adequate for seal of the device to the iliac artery is located, usually 20 mm in length. If a common iliac aneurysm precludes landing the device proximal to the takeoff of the hypogastric artery, then the patient’s circulation is evaluated for preoperative embolization of the hypogastric artery. This will permit the device to land distal to the hypogastric artery and backflow from this artery is eliminated by the embolization.

Table 1

Assessment and contraindications

CT scan assessment for EVAR eligibility Proximal neck: diameter, length, angle, Presence or absence of thrombus Distal landing zone: diameter and length Iliac arteries: presence of aneurysms and occlusive disease Access arteries (common, external and femoral arteries): Diameter, presence of occlusive disease Contraindications for EVAR Short proximal neck Thrombus presence in proximal landing zone Conical proximal neck Greater than 120° angulation of the proximal neck Critical inferior mesenteric artery Significant iliac occlusive disease Tortuosity of iliac vessels Abbreviation: EVAR, endovascular aneurysm repair.

Figure 1 (Left) Angiogram of infrarenal abdominal aortic aneurysms (AAA) with marker catheter in place; (Right) 3D CT reconstruction of an infrarenal AAA.

The visceral vessels are evaluated for patency because the required coverage of the inferior mesenteric artery mandates that blood supply to the viscera be adequate from other sources (celiac and superior mesenteric arteries). With experience, some of these contraindications can be overcome with suprarenal attachment devices, additional cuffs, and limbs, but for the nascent EVAR physician the contraindications should be acknowledged and adherence to the fundamental principles of endovascular device implantation will permit good outcomes.

EVAR technology Endograft design is derived directly from the traditional grafts used in open aortic surgery. The endograft body comes in one piece (unibody) or as a bifurcated graft (Fig. 2). The unibody endograft is designed to land into one of the iliac arteries, thereby necessitating contralateral iliac occlusion and a femoro-femoral bypass graft. Most of the procedures carried out today use a bifurcated graft that comes with extensions into the limbs and additional cuffs. This design provides greater flexibility for matching the device to the particular aneurysm features. The early endografts were unsupported throughout the body with stents at the proximal and distal ends. Today, the endografts have a metal skeleton throughout the graft providing a supported structure. The metal skeleton is covered with a fabric [polyester or polytetrafluoroethylene (PTFE)]. To prevent slippage of the endograft, it is secured either by radial force or additional hooks and barbs. The majority of the endografts are designed to fixate and seal to a 15 mm segment of normal infrarenal native aorta. The device is deployed with either a selfexpanding or balloon-expanding mechanism.

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Endograft challenges

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The many permutations of these features have led to the generation of multiple devices employing a variety of concepts and approaches ( Table 2). Two devices are no longer available (Ancure and Vanguard/Stentor) but are mentioned because some patients had these implanted and these may be encountered in the clinical setting. Four devices are currently FDA approved for commercial use in the United States (AneuRx, Excluder, Zenith, and PowerLink); the other devices are in clinical trials or in use in Europe. With multiple devices available and increased clinical and technical experiences, it is apparent that each device has its own advantages and disadvantages. The best results can come from optimizing the type of endograft to specific anatomy of a given patient. This is less important in patients with ‘ideal’ anatomic features, but when features such as neck angulation, calcification, access tortuosity are encountered, one device may to superior to another for dealing with the challenging anatomy. On some occasions supraprenal attachment may be necessary and desirable, in others infrarenal fixation may be sufficient.

locate the renal and hypogastric arteries. The main body is then inserted through either femoral arteriotomy but the largest and most disease free femoral artery is preferred. The patient is anticoagulated as at this point in the procedure blood flow to the legs is interrupted by the size of the sheath; heparin or a direct thrombin inhibitor (e.g., bivalirudin) may be used (5). The location of the renal arteries with respect to the top of the endograft is reassessed. The endograft is then deployed. Next the limbs are inserted through each groin into the respective leg of the endograft. Once again the location of the hypogastric arteries is verified before the limbs are landed just proximal to their orifices or distally if the hypogastric was embolized preoperatively. A completion angiogram is performed and examined for the development of complications, especially Type I endoleaks. If further intervention is required, it is done at this point. Finally, the groins are closed either with sutures or with the aid of one of many percutaneous closure devices. The distal pulses are examined and documented for further vascular monitoring.

The procedure: start to finish

Endograft challenges Ruptured aneurysm

Once the patient is selected and the appropriate device is in hand to deal with the particular aneurysm morphology, the patient is brought into the interventional or operating room suite for the procedure. The procedure is now performed by interventional radiologists, cardiologists, and vascular surgeons with the patient under general, regional, or local anesthesia (4). The femoral arteries are accessed by either open surgical incisions or percutaneously. An aortogram is performed to

Table 2

Endo devices

Available or in trials/development AneuRx (Medtronic, Santa Rosa, CA, U.S.A.) Excluder (W.L. Gore, Flagstaff, AZ, U.S.A.) Zenith (Cook Inc., Bloomington, IN, U.S.A.) PowerLink (Endologix, Irvine, CA, U.S.A.) Talent (Medtronic, Santa Rosa, CA, U.S.A.) Fortron (Cordis Corp., Johnson and Johnson, Miami, FL, U.S.A.) Lifepath (Edwards Lifesciences, Irvine, CA, U.S.A.) Quantum (Cordis Corp., Johnson and Johnson, Miami, FL) Enovus (Trivascular, Santa Rosa, CA, U.S.A.) No longer available Ancure (Guidant Corp., Indianapolis, IN, U.S.A.) Vanguard/Stentor (Boston Scientific Corp., Natick, MA, U.S.A.)

A ruptured AAA is a devastating event with an overall mortality rate of greater than 90% and 40% to 70% of those patients who make it to the hospital alive die (1). An endovascular approach to ruptured aneurysms has been developed and involves the rapid deployment of a proximal occlusion balloon through the brachial artery to sit in the descending thoracic aorta. Some of the key maneuvers include permissive hypotension, placement of the brachial wire under local anesthesia, performance of a diagnostic angiogram, and of course, readiness for conversion to an open procedure if necessary (6,7). The patients who undergo endovascular repair have to be stable enough to have a CT scan performed preoperatively. In one study, the thirty day mortality rate was 10.8% for this approach and the late conversion rate was 9% and was attributed to mainly infection issues and device migration (8). Survival was 89.1% at one year and 69.9% at four years. This was compared with a thirty-day mortality rate of 35% for patients undergoing open repair of ruptures.

Difficult neck The difficult neck comes in a variety of types: angulated, conical, stenotic (Fig. 3). The angulated neck makes wire passage challenging, but this can be overcome with the use of flexible sheaths and if necessary brachial artery insertion of the initial wire for retrieval from the femoral artery. In addition, the angulation often straightens during endograft placement and

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Figure 2 Abdominal aortic aneurysms bifurcated supported stent graft (Excluder, Gore).

therefore the ability to judge the exact postprocedure location of the graft is difficult, especially with respect to the renal arteries. The conical neck can be viewed as a cone with an increasing diameter from the renals to the aneurysm sac. This neck is a challenge for endograft sizing and achievement of graft seal to nonaneurysmal aorta. The first issue is often dealt with by decreasing the amount of the usual graft oversizing from the normal 20% to 10% to 15%; this reduces stretching the narrower portion of the conical neck. Endografts that require balloon expansion, as opposed to radial force, may facilitate graft seal when dealing with the conical neck. The third type of challenging neck is the stenotic neck. Once again, the issue centers on the importance of sizing the graft correctly. If the graft is oversized for the stenotic portion, graft infolding may occur. On the other hand, if the graft is undersized, then the neck may seal but the remainder of the repair does not fit properly, leading to endoleak and possible graft migration.

Figure 3 (Left) Angulated proximal aortic neck; (Right) tortuous iliac arteries.

Small iliac arteries are encountered in 8% of the population and most are found in women (II). Some arteries can be dilated but not without risk of dissection and rupture. Therefore, a patient with an external iliac artery smaller than 7 mm should undergo either open repair or have the endograft inserted through the larger common iliac artery or aorta. Stenotic iliac arteries can also be dilated but with the same risks of dissection and rupture. Aneurysmal iliac disease is a challenging anatomical feature especially for adequate endograft distal landing and sealing and may require coverage of the hypogastric artery.

EVAR complications

Difficult iliac arteries Access to the aorta is usually obtained through the femoral arteries, either by percutaneous methods or by surgical exposure. The presence of tortuous or atherosclerotic iliac arteries makes the insertion of wires and sheaths through the arteriotomy difficult and potentially risky (Fig. 3). CT scan imaging techniques often do not adequately show iliac artery anatomy. Even arteriography cannot reliably measure areas of stenosis. 3D CT scan reconstructions with the ability to insert a virtual sheath help tackle the challenge of preoperative imaging and measuring of iliac arteries. Sometimes it is necessary to access the brachial artery to pass the initial wire into the femoral artery (9) or access the iliac artery or aorta through a retroperitoneal incision with the addition of a conduit to facilitate endograft insertion (10).

One of the distinguishing differences between EVAR and open repair is the higher rate of graft related complications with EVAR (12). Some occur during or soon after the procedure whereas others are only noticed during the graft surveillance period (Table 3). Reporting standards have been established to permit comparison of complications (13). The analysis of the Lifeline Registry (2664 EVAR cases and 334 open surgical cases) showed that the thirty-day operative mortality rates for the two groups were similar at 1.7% for EVAR and 1.4% for open surgical. The freedom from rupture was also similar for the two groups at one year: 99.8% and 100% and there was no difference in AAA-related death rates (14). Greenhalgh in the report from the EVAR 1 trial noted that complication rate was 41% for EVAR patients and 9% for open surgical patients within four years of the procedure (15). The aneurysm-related death rate was 4% for EVAR patients and 7% for open surgical patients. The all-cause mortality rates were similar for the two groups (28%).

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Table 3

Complications

Early Type I proximal and distal endoleaks Type IV endoleak Device related complications Inability to deploy stent Arterial complications Systemic complications Cardiac Cerebral Pulmonary Renal Access site and lower limb complications Bleeding, hematoma, false aneurysm Arterial thrombosis Death Conversion Rupture Late Endoleaks: I (a, b), II, III Aneurysm growth greater than or equal to 8 mm Late AAA-related death Death Conversion Rupture Classification of endoleaks Attachment site leaks Proximal end of endograft Distal end of endograft Iliac occluder (plug)

Branch leaks (without attachment site connection Simple or to-and-fro (from only one patent branch) Complex or flow-through (with two or more patent branches) Graft defect Junctional leak or modular disconnect Fabric disruption (midgraft hole) Minor (⬍2 mm; e.g., suture holes) Major (ⱖ2 mm) Graft wall (fabric) porosity (⬍30 days after graft placement)

Access complications Access problems occur with either the percutaneous approach or open surgical approach to the vessels for endograft insertion. The femoral artery may be injured and require immediate repair with a patch or replacement of a segment. In addition, distal thrombosis may occur from the blockage of the flow into the lower extremities by the sheath and

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inadequate anticoagulation. This highlights the importance of noting the preoperative pulse examination, so that the postoperative findings can be correctly interpreted. As with any groin procedure, lymph leaks, wound infections and hematomas can occur and vary from the benign that resolves to the serious that requires further intervention (re-exploration, evacuation, muscle flaps, etc.).

Device problems Device design evolves to remedy problems associated with structural integrity. There have been reports of fabric erosion (16), hook fractures (17), and component separation (18).

Surgical conversion Primary surgical conversion occurs within the first postoperative 30 days and secondary surgical conversion occurs any time after that. In an examination of the EUROSTAR (European Collaborators on Stent/graft Techniques for aortic Aneurysm Repair) registry, 2.6% of the 1871 patients required conversion and in 38 patients this occurred in the first postoperative month (primary conversion) (19). Eleven patients underwent open surgical repair during a mean follow-up period of eight months (secondary conversion) and rupture was the most frequent reason for this. Kong et al. examined secondary conversion for the 594 patients in the Excluder clinical trials and noted that 2.7% of the patients underwent late open conversion; no conversions occurred in the first year after the procedure. Freedom from conversion was 96.7% at forty-eight months postoperative. The major indication noted was the development of endotension in the absence of a demonstrable endoleak.

Endoleaks Endoleaks are a major concern for those engaged in EVAR (Table 3, Fig. 4). This phenomenon describes the continuation of blood flow into the extragraft portion of the aneurysm (20). Endoleaks are related to the graft itself or other factors such as the presence of large patent lumbar arteries (21). The presence of an endoleak increases the chance of rupture. Diagnostic imaging plays an important role in the detection of endoleaks: intraprocedural angiograms, surveillance CT scans, or duplex ultrasounds. The management of endoleaks varies according to the type: type I and III endoleaks should be addressed expediently, and type IV endoleaks usually resolve. The treatment algorithm for

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extremity loss (23). Small limb diameter and graft extension to the external iliac artery, as opposed to the common iliac, is a risk factor for the development of limb occlusion. Fifty percent of the thromboses occurred within 30 days of the procedure and almost 70% required intervention: surgical (femorofemoral, axillary-femoral, axillary-bifemoral bypasses) and/or endoluminal techniques (rheolytic and pharmacologic thrombolysis).

Graft kinks Stent-graft kinks are more often seen when unsupported endografts are used (24). This complication occurred in 3.7% of the patients in the EUROSTAR registry and was associated with type I and III endoleaks, graft stenosis, graft limb thrombosis, graft migration, and conversion to open repair (25). In addition, women with angulated AAA necks were atmost risk for stent-graft kink. This problem is usually managed with stenting of the kink.

Sac enlargement Figure 4 Type IA endoleak noted on completion angiogram.

type II endoleaks is not straightforward as these endoleaks may resolve on their own over time. If a type I endoleak is noted on the completion angiogram, a stent-graft cuff or extension is immediately placed to facilitate better seal. A similar treatment plan is undertaken if the type I endoleak is noted in the postoperative period. Type II endoleaks can be followed and intervention planned if the endoleak does not resolve; some physicians suggest a follow-up CT scan at six months and if the endoleak is present, then the patent artery is either embolized or surgically ligated. Other physicians will only treat type II endoleaks if it is accompanied with sac enlargement. Gelfand et al. examined the clinical significance of type II endoleaks by analyzing data from 10 EVAR trials (22). The authors found that approximately half of the endoleaks disappeared within 12 months. This paper delineated situations when type II endoleak intervention is warranted: AAA sac enlargement after six months, increased sac pressure (⬎20% of systolic BP), presence of leak greater than 12 months after procedure.

Endograft limb occlusion This is an infrequently encountered problem, occurring in less than 5% of patients, but its morbidity is serious leading to

The AneuRx clinical trial was analyzed by Zarins to describe the phenomenon of aneurysm sac enlargement (26). Twelve percent of the patients experienced aneurysm sac enlargement and these patients were older and usually had an endoleak. When patients with endoleaks were analyzed, 17% had sac enlargement whereas only 2% of patients without endoleaks had the same finding. Elevated pressure within the aneurysm sac, also known as endotension, has been reported as one mechanism that is responsible for sac enlargement (27). This finding is documented when the intraaneurysm pressure is measured during follow-up angiography. Endotension can exist without an endoleak.

Device migration The AneuRx trial has also been analyzed to determine the frequency of stent migration and identify risk factors (21,28). Ninety-four of 1119 patients had evidence of stent migration that occurred a mean of 30 months after EVAR. Low initial deployment, below the renals, and short proximal fixation length are the identifiable risk factors. In this study, 68% of the patients required no treatment whereas 23 patients had extender modules placed and seven patients underwent surgical conversion. Surgical conversion was examined in a single center study of 640 patients by Verzini (29). This group found that early conversion (within 30 days) was performed in nine patients and late conversion was carried out in 29. At

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six years after EVAR the risk of undergoing a conversion was 9%. A study by Tonnessen et al. examined device migration at mid- and long-term timepoints with the AneuRx and Zentih endografts (30). The AneuRx device had a significantly higher incidence of migration than the Zenith device. At three and four years out from the procedure, the migration rate was 22% and 28%, respectively, for AneuRx and only 2.4% for Zenith. In addition, a greater proportion of the migrated AneuRx endografts had dilated necks compared with the nonmigrated AneuRx endografts. One of the conclusions was that devices with active fixation design (e.g., Zenith) may be protective against migration. Also, a significant proportion of patients with endograft migration required intervention and so this one again highlights the importance of long-term surveillance.

Extremity and visceral ischemia Ischemia to the viscera and extremities can also occur and the signs can be subtle (decreased pulses, mild abdominal pain, buttock claudication) or alarmingly obvious (lower extremity mottling, severe abdominal pain, elevated creatinine phosphokinase levels, or gastrointestinal bleeding) (31). Lower extremity ischemia can result from problems at the femoral access site (dissection, atheroembolization) or from issues with the endograft (limb occlusion, kinking). The former often requires surgical intervention whereas the latter can be managed by interventional techniques like placing additional stents. The endograft covers the inferior mesenteric artery and if the remainder of the visceral and hypogastric circulation is poor or compromised can lead to colonic ischemia. In addition, spinal cord ischemia can manifest in paresis or paralyis due to the coverage of intercostals arteries; this complication is rare but serious.

Surveillance The recommended surveillance routine is for a CT scan at 1, 6, and 12 months and annually thereafter. If an endoleak is detected, the frequency of the scans increases to every six months until resolution of the endoleak is detected. Investigators have compared duplex ultrasound with CT scan for surveillance and found that CT scan is superior for endoleak detection (32). Since endoleaks are an important complication with therapeutic implications, CT scans should be used rather than duplex examination for repair surveillance. MRI has been investigated as a useful way to follow these patients. It has advantages over CT scan surveillance because it does not put renal function at risk in this older population. It should especially be entertained in patients with preexisting renal insufficiency (33). Endograft surveillance methods now

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include the use of an implanted sensor to measure sac pressure to assess for the development of endotension (34,35). The advances in EVAR technology have been accompanied by a greater understanding of the basic science of aneurysmal disease and cross-fertilization has occurred. For example, Curci has been studying the relationship between the secretion of matrix metalloproteinases (MMPs) and AAAs (36). He has measured increased levels in the aneurysmal rather than the normal arterial wall. This finding led physicians to develop a new method for endograft surveillance: the lack of a decrease in MMP-3 and MMP-9 levels should alert the physician to possibility of a failing endograft repair (37). Advances in the basic science of aneurysm disease are helping us better manage this disease.

EVAR outcomes and trial results Examination of outcomes of endovascular AAA repair comes from mainly two sources: databases and clinical trials.

Eurostar registry The EUROSTAR Registry was started in 1996 and has continued to provide a substantial amount of data especially for outcome analyses. Data come from 135 vascular centers in Europe (38–40). Outcomes in patients greater than or equal to eighty years old have been analyzed and compared to those less than 80 years (41). The octogenarians more frequently had heart, kidney, and lung disease preoperatively and a greater proportion was deemed not fit for surgery compared with the younger group of patients. The thirty-day and in-house mortality rate for octogenarians was significantly higher than the younger group: 5% versus 2%. In addition, this group of patients had higher device-related and systemic complication rates. Finally, aneurysm related and all cause mortality rates were significantly higher for this older group of patients.

Dream trial The Dream trial examined outcomes two years following open or endovascular repair of AAAs (42). The cumulative survival rates for the two groups were similar: 89.6% (open), 89.7% (endovascular). There was no significant difference in aneurysm related mortality. The study concluded that the early advantage of EVAR is no longer present after one year following intervention.

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EVAR 1 and 2 trials Results of the EVAR trial 1 were recently published and describe the outcomes of 543 patients who were anatomically suitable for EVAR and fit for open repair but ultimately underwent EVAR and 539 patients who had open repair (15). The authors found that EVAR is more expensive, had a higher number of complications and reinterventions but it resulted in a 3% better aneurysm survival rate. The EVAR trial 2 then examined those patients who were unfit for open repair and underwent either EVAR or no intervention (43). The 30-day operative mortality rate in the EVAR group was 9% and in the no intervention group the rupture rate was nine per 100 person years. There was no significant difference in either aneurysm-related mortality or all-cause mortality.

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EVAR future directions and controversies The future of EVAR is not fully determined; many questions remain unanswered. Some help will come from the results of ongoing clinical trials. The impact of endotension and the viability of pressure monitoring will become clearer once more intragraft sensor data becomes available. In addition, the utility of fenestrated transrenal endografts is an area of great interest. We will soon see if this is a solution to short proximal aortic necks and suprarenal aneurysms (44). With this new technology and low mortality rate physicians are investigating whether we should be treating smaller aneurysms and clinical trials are being conducted to address this issue (45,46). As the design of EVAR devices evolves and our facility using them improves, the one thing that will not change is the importance of appropriate patient selection.

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Rutherfor RB, ed. Vascular Surgery, 6th ed. Amsterdam, Netherlands: Elsevier, 2005. Parodi JC, Palmaz JC, Barone HD. Transfemoral intraluminal graft implantation for abdominal aortic aneurysms. Ann Vasc Surg 1991; 5(6):491–499. Hua HT, Cambria RP, Chuang SK, et al. Early outcomes of endovascular versus open abdominal aortic aneurysm repair in the National Surgical Quality Improvement Program-Private Sector (NSQIP-PS). J Vasc Surg 2005; 41(3):382–389. Parra JR, Crabtree T, McLafferty RB, et al. Anesthesia technique and outcomes of endovascular aneurysm repair. Ann Vasc Surg 2005; 19(1):123–129. Katzen BT, Ardid MI, MacLean AA, et al. Bivalirudin as an anticoagulation agent: safety and efficacy in peripheral interventions. J Vasc Interv Radiol 2005; 16(9):1183–1187; quiz 7.

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Lee WA, Hirneise CM, Tayyarah M, et al. Impact of endovascular repair on early outcomes of ruptured abdominal aortic aneurysms. J Vasc Surg 2004; 40(2):211–215. Ohki T, Veith FJ. Endovascular therapy for ruptured abdominal aortic aneurysms. Adv Surg 2001; 35:131–151. Hechelhammer L, Lachat ML, Wildermuth S, et al. Midterm outcome of endovascular repair of ruptured abdominal aortic aneurysms. J Vasc Surg 2005; 41(5):752–757. Criado FJ, Wilson EP, Abul-Khoudoud O, et al. Brachial artery catheterization to facilitate endovascular grafting of abdominal aortic aneurysm: safety and rationale. J Vasc Surg 2000; 32(6):1137–1141. Carpenter JP. Delivery of endovascular grafts by direct sheath placement into the aorta or iliac arteries. Ann Vasc Surg 2002; 16(6):787–790. Wolf YG, Arko FR, Hill BB, et al. Gender differences in endovascular abdominal aortic aneurysm repair with the AneuRx stent graft. J Vasc Surg 2002; 35(5):882–886. Elkouri S, Gloviczki P, McKusick MA, et al. Perioperative complications and early outcome after endovascular and open surgical repair of abdominal aortic aneurysms. J Vasc Surg 2004; 39(3):497–505. Chaikof EL, Blankensteijn JD, Harris PL, et al. Reporting standards for endovascular aortic aneurysm repair. J Vasc Surg 2002; 35(5):1048–1060. Lifeline registry of endovascular aneurysm repair: long-term primary outcome measures. J Vasc Surg 2005; 42(1):1–10. Greenhalgh RM, Brown LC, Kwong GP, et al. Endovascular aneurysm repair versus open repair in patients with abdominal aortic aneurysm (EVAR trial 1): randomised controlled trial. Lancet 2005; 365(9478):2179–2186. Teutelink A, van der Laan MJ, Milner R, et al. Fabric tears as a new cause of type III endoleak with Ancure endograft. J Vasc Surg 2003; 38(4):843–846. Najibi S, Steinberg J, Katzen BT, et al. Detection of isolated hook fractures 36 months after implantation of the Ancure endograft: a cautionary note. J Vasc Surg 2001; 34(2): 353–356. Maleux G, Rousseau H, Otal P, et al. Modular component separation and reperfusion of abdominal aortic aneurysm sac after endovascular repair of the abdominal aortic aneurysm: a case report. J Vasc Surg 1998; 28(2):349–352. Cuypers PW, Laheij RJ, Buth J. Which factors increase the risk of conversion to open surgery following endovascular abdominal aortic aneurysm repair? The EUROSTAR collaborators. Eur J Vasc Endovasc Surg 2000; 20(2):183–189. White GH, Yu W, May J. Endoleak—a proposed new terminology to describe incomplete aneurysm exclusion by an endoluminal graft. J Endovasc Surg 1996; 3(1):124–125. Veith FJ, Baum RA, Ohki T, et al. Nature and significance of endoleaks and endotension: summary of opinions expressed at an international conference. J Vasc Surg 2002; 35(5):1029–1035. Gelfand DV, White GH, Wilson SE. Clinical significance of type II endoleak after endovascular repair of abdominal aortic aneurysm. Ann Vasc Surg 2006; 20(1):69–74. Carroccio A, Faries PL, Morrissey NJ, et al. Predicting iliac limb occlusions after bifurcated aortic stent grafting: anatomic and device-related causes. J Vasc Surg 2002; 36(4):679–684. Carpenter JP, Neschis DG, Fairman RM, et al. Failure of endovascular abdominal aortic aneurysm graft limbs. J Vasc Surg 2001; 33(2):296–302; discussion 3.

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Fransen GA, Desgranges P, Laheij RJ, et al. Frequency, predictive factors, and consequences of stent-graft kink following endovascular AAA repair. J Endovasc Ther 2003; 10(5): 913–918. Zarins CK, Bloch DA, Crabtree T, et al. Aneurysm enlargement following endovascular aneurysm repair: AneuRx clinical trial. J Vasc Surg 2004; 39(1):109–117. Lin PH, Bush RL, Katzman JB, et al. Delayed aortic aneurysm enlargement due to endotension after endovascular abdominal aortic aneurysm repair. J Vasc Surg 2003; 38(4):840–842. Zarins CK, Bloch DA, Crabtree T, et al. Stent graft migration after endovascular aneurysm repair: importance of proximal fixation. J Vasc Surg 2003; 38(6):1264–1272; discussion 72. Verzini F, Cao P, De Rango P, et al. Conversion to open repair after endografting for abdominal aortic aneurysm: causes, incidence and results. Eur J Vasc Endovasc Surg 2006; 31(2):136–142. Tonnessen BH, Sternbergh WC, 3rd, Money SR. Mid- and long-term device migration after endovascular abdominal aortic aneurysm repair: a comparison of AneuRx and Zenith endografts. J Vasc Surg 2005; 42(3):392–400; discussion-1. Maldonado TS, Rockman CB, Riles E, et al. Ischemic complications after endovascular abdominal aortic aneurysm repair. J Vasc Surg 2004; 40(4):703–709; discussion 9–10. Raman KG, Missig-Carroll N, Richardson T, et al. Color-flow duplex ultrasound scan versus computed tomographic scan in the surveillance of endovascular aneurysm repair. J Vasc Surg 2003; 38(4):645–651. Engellau L, Albrechtsson U, Hojgard S, et al. Costs in followup of endovascularly repaired abdominal aortic aneurysms. Magnetic resonance imaging with MR angiography versus EUROSTAR protocols. Int Angiol 2003; 22(1):36–42. Baum RA, Carpenter JP, Cope C, et al. Aneurysm sac pressure measurements after endovascular repair of abdominal aortic aneurysms. J Vasc Surg 2001; 33(1):32–41. Ellozy SH, Carroccio A, Lookstein RA, et al. First experience in human beings with a permanently implantable intrasac pressure transducer for monitoring endovascular repair of abdominal aortic aneurysms. J Vasc Surg 2004; 40(3): 405–412.

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Curci JA, Thompson RW. Adaptive cellular immunity in aortic aneurysms: cause, consequence, or context? J Clin Invest 2004; 114(2):168–171. Sangiorgi G, D’Averio R, Mauriello A, et al. Plasma levels of metalloproteinases-3 and -9 as markers of successful abdominal aortic aneurysm exclusion after endovascular graft treatment. Circulation 2001; 104(12 suppl 1):I288–1295. Berg P, Kaufmann D, van Marrewijk CJ, et al. Spinal cord ischaemia after stent-graft treatment for infra-renal abdominal aortic aneurysms. Analysis of the Eurostar database. Eur J Vasc Endovasc Surg 2001; 22(4):342–347. Fransen GA, Vallabhaneni SR Sr, van Marrewijk CJ, et al. Rupture of infra-renal aortic aneurysm after endovascular repair: a series from EUROSTAR registry. Eur J Vasc Endovasc Surg 2003; 26(5):487–493. Peppelenbosch N, Buth J, Harris PL, et al. Diameter of abdominal aortic aneurysm and outcome of endovascular aneurysm repair: does size matter? A report from EUROSTAR. J Vasc Surg 2004; 39(2):288–297. Lange C, Leurs LJ, Buth J, et al. Endovascular repair of abdominal aortic aneurysm in octogenarians: an analysis based on EUROSTAR data. J Vasc Surg 2005; 42(4):624–630; discussion 30. Blankensteijn JD, de Jong SE, Prinssen M, et al. Two-year outcomes after conventional or endovascular repair of abdominal aortic aneurysms. N Engl J Med 2005; 352(23):2398–2405. Endovascular aneurysm repair and outcome in patients unfit for open repair of abdominal aortic aneurysm (EVAR trial 2): randomised controlled trial. Lancet 2005; 365(9478): 2187–2192. Verhoeven EL, Prins TR, Tielliu IF, et al. Treatment of short-necked infrarenal aortic aneurysms with fenestrated stent-grafts: shortterm results. Eur J Vasc Endovasc Surg 2004; 27(5): 477–483. Cao P. Comparison of surveillance vs Aortic Endografting for Small Aneurysm Repair (CAESAR) trial: study design and progress. Eur J Vasc Endovasc Surg 2005; 30(3):245–251. Zarins CK, Crabtree T, Arko FR, et al. Endovascular repair or surveillance of patients with small AAA. Eur J Vasc Endovasc Surg 2005; 29(5):496–503; discussion 4.

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51 Interventions for structural heart disease Ralph Hein, Neil Wilson, and Horst Sievert

Transcatheter ablation of septal hypertrophy Approximately 25% of all patients with hypertrophic cardiomyopathy (HCM) have latent left ventricular outflow obstruction with an intraventricular gradient (1). Pathophysiologic features are asymmetric hypertrophy of the septum and a systolic anterior movement of the anterior leaflet. Medical treatment includes betablockers, and calcium antagonists of the verapamil type. Approximately 5–10% of the patients with outflow obstruction are refractory to such negative inotropic therapy (2). Positive inotropic drugs such as digitalis or sympathomimetics are strictly contraindicated. In the presence of atrial fibrillation, anticoagulation therapy should be started. Since endocarditis is more common in patients with HCM because of turbulence in the left ventricle, prophylactic antibiotics should be administered for periods of potential bacteraemia. Subvalvular myectomy has a reported success of more than 90% with a mortality rate of less than 2%, but this therapy is not applicable to every patient. Transcatheter ablation of septal hypertrophy has been performed since 1994 as a reasonable option for obstructive HCM patients. An increasing number of reports claim efficacy comparable to that of the surgical approach (3). Patients with a high risk of surgical morbidity and mortality and those who suffer from pharmacologic side effects under conservative treatment should be considered for transcatheter alcohol ablation. NYHA classification, left ventricular gradient, and a septal thickness exceeding 16 mm are indications for intervention. NYHA or CCS class II patients with a minimum resting gradient of 50 mmHg are candidates for this procedure as well as class III and IV patients with a resting gradient of more than 30 mmHg or a provoked gradient greater than 60 mmHg (4,5). The initial stage of the procedure entails measurement of the peak to peak intraventricular gradient at rest. Induced extrasystolic beats can unmask a potentially higher gradient.

Stepwise application (until a heart rate of about 110 bpm is achieved) of isoproterenol 200 mcg in 50 cc of saline can be used to increase the pressure gradient in sedated patients. Following administration of heparin, the target vessel for alcohol dilution is probed by catheter. The target vessel is almost always the first septal branch of the left anterior descending artery. Balloon inflation isolates the vessel, occluding blood flow. Retrograde leakage of alcohol back into the left anterior descending has to be avoided. An echo contrast study is performed to confirm effective occlusion and thus obviate this complication. Intravenous analgesia should be administered before alcohol injection to diminish chest pain. Slow application of 0.2–1.5 mL of alcohol through the inflated balloon catheter induces necrosis of the myocardium, which is seen as an obvious contrast enhancement on echocardiography. If the gradient post instillation of alcohol remains above 30 mmHg, the balloon may be positioned more proximally in the vessel or a second septal perforating artery may be treated in the same way. In some cases, tissue edema of the affected myocardium may temporarily increase the outflow gradient during the early days of follow-up. During subsequent months remodeling of the outflow tract is usually observed, resulting in a progressive reduction in gradient. Several studies have documented the efficacy of alcohol septal ablation (6⫺8), demonstrating improvement in functional class and exercise capacity. Possible complications include massive myocardial infarction due to retrograde flow around the occlusion balloon, complete heart block, ventricular fibrillation, stroke, dissection of the left anterior descending artery, and right coronary artery thrombosis. Though high grade atrioventricular blockage occurs relatively frequently, procedural mortality rate is low (0–4%) and severe complications are rare and often avoidable (7⫺10). Creatinine kinase levels should be assessed frequently during the stay in the coronary care unit and may rise up to 1500 U/ l. After the procedure there may be some risk

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of thrombus formation in the area of ablation. Some operators prescribe aspirin (100 mg/day, p.o.) for four weeks postinterventionally.

LAA occlusion The left atrial appendage (LAA) is a muscular cavity discharging into the left atrium. It is the prevalent location for intracardiac thrombus (11). If atrial fibrillation cannot be eliminated with medical therapy or an ablation procedure then life-long anticoagulation is necessary. Usually patients with chronic atrial fibrillation are anticoagulated with coumadin type drugs. Many patients however have contraindications to anticoagulation like intracerebral aneurysms, hemorrhagic diathesis, gastrointestinal lesions, and liver dysfunction. For such patients interventional closure of the LAA may be a therapeutic alternative, and has been performed now for almost five years. There are currently three devices under investigation: 1. PLAATO device (ev3, Inc., Plymouth, MN) 2. Amplatzer occluder (AGA Medical Corporation, Golden Valley, MN) 3. Watchman device (Atritech, Inc., Minneapolis, MN) 1. The PLAATO device (Fig. 1) was the first device to be implanted in a human LAA in August 2001. Its nitinol framework features a tissue-anchoring system on the struts to maintain the correct position once deployed. The orifice of the LAA is sealed

Figure 1 PLAATO left atrial appendage device.

by a nonthrombogenic polytetrafluoroethylene membrane excluding the appendage from the blood circulation and allowing tissue adhesion. The morphology and diameter of the appendage are very variable; hence, detailed preinterventional imaging with transesophageal echocardiography (TEE) and angiography is important. Thrombus in the appendage is obviously a strict contraindication to the procedure and should be excluded by transesophageal echo before attempting closure. The orifice diameter of the appendage should range between 13 and 27 mm to achieve a stable device position. To access the LAA transseptal puncture is necessary. Angiography is performed for further morphologic measurements. The PLAATO system is engaged via a delivery catheter and unfolded in the appendage. Compression of 10% is mandatory and at least two rows of anchors should be engaged into the surrounding tissue. In July 2005, the PLAATO Feasibility Study reported good implantation results with this device with an acceptable complication rate (12). For premedication aspirin 300 mg twice a day 48 hours prior to the procedure and a loading dose of clopidogrel 300 mg (or ticlopidine 250 mg) is recommended. Endocarditis prophylaxis with a first generation cephalosporin (e.g., cefuroxime, 1, 5 g, i.v.) should be administered before and after intervention. After transseptal puncture, 10,000 units of heparin are administered. An activated clotting time of 200–300 seconds is desirable. Postprocedure, clopidogrel (75 mg/day, p.o.) and endocarditis prophylaxis for the first six months is suggested. Aspirin (300–325 mg/day, p.o.) should be prescribed indefinitely. 2. A variety of Amplatzer devices are applicable for LAA occlusion including the atrial and ventricular septal defect devices, the patent foramen ovale devices, the patent ductus arteriosus devices, and other arteriovenous fistulae devices. A special fabric-free LAA plug is currently under investigation (Fig. 2). The characteristic feature of all Amplatzer devices is the nitinol wire mesh. There are two possible methods of implantation. Either the device is placed entirely into the appendage or the distal disc is expanded in the neck and the proximal disc in the left atrium. The risk of residual shunting around the device is increased when it is totally inserted into the LAA with no part protruding into the atrium. The Amplatzer occluder series holds the widest spectrum of device sizes (4 to 40 mm). The device is attached to a delivery cable and can simply be opened or recollapsed into the delivery catheter. Release is by unscrewing the device after first testing stability with simple traction. Intravenous antibiotics are given before and after the procedure. Five thousand to ten thousand units of heparin should be administered after transseptal puncture. Aspirin (100–300 mg/day, p.o.) and clopidogrel (75 mg/day, p.o.) is prescribed for the following six months as well as endocarditis prophylaxis. A TEE is performed at six months. If the LAA is completely occluded, no further anticoagulation is required.

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Intravenous antibiotics are given before and after the procedure. Endocarditis prophylaxis is recommended for six months. Coumadin type drugs should be administered at least for 45 days after the Watchman implantation procedure with an INR between two and three in combination with 100 mg aspirin. When complete endothelialization is likely with no or only little flow through the device, coumadin can be discontinued and clopidogrel 75 mg/day is given until six months follow-up examination. In the absence of thrombus or flow in the appendage at TEE at six months, clopidogrel is stopped and aspirin therapy 100 mg/day is continued indefinitely. If thrombus formation is seen, obviously coumadin therapy is restarted.

Valvuloplasty

Figure 2 Amplatzer left atrial appendage plug.

Aspirin therapy should be continued to prevent thrombus formation outside the LAA. 3. The Watchman implant (Fig. 3) is the latest device to be used for occlusion of the LAA. The nitinol frame structure incorporates a permeable 160 micron PET filter on the proximal face of the device to encourage endothelialization. Fixation barbs on the surface anchor the device to the LAA wall. The filter is released distal to the LAA ostium. Clinical experience is limited with this device (13).

Figure 3 Watchman left atrial appendage device.

Percutaneous valvuloplasty was introduced during the early 1980s as a method for treatment of stenotic valves (14). Since then, with the improvement in wire and balloon technology and expertise, it is the method of choice for almost all patients with severe pulmonary stenosis and for younger patients with congenital noncalcified aortic valve stenosis. Mitral balloon valvuloplasty is widely applicable and efficacious in postrheumatic mitral stenosis. Tricuspid valvuloplasty is rarely performed as severe rheumatic stenosis of this valve is rarely seen.

Pulmonary stenosis Congenital abnormalities of pulmonary valve morphology including fused valve commissures, unicuspid and bicuspid valves, leaflet thickening, or valve dysplasia may occur in isolation or combination to cause narrowing of the valve. Without treatment, chronic right ventricular hypertension leads to severe hypertrophy and ultimately right ventricular failure, tricuspid regurgitation, and atrial and ventricular tachyarrhythmias. The first report of percutaneous balloon dilation of a pulmonary valve was published in 1982 (14). Today the transcatheter approach has largely replaced surgical valvulotomy for pure stenosis. Surgery is only necessary when balloon dilatation was not successful or other heart abnormalities demand an open heart procedure. Exercise intolerance and dyspnea are the predominant symptom. Doppler systolic gradient on echocardiography of 50 mmHg or more is generally accepted as a clear indication for intervention, accepting that invasive gradients measured in a sedated or anesthetized patient are likely to be less than the Doppler gradient for reasons of timing and a reduced cardiac output. After puncture of the femoral vein, a multipurpose catheter is used to document right ventricular and pulmonary

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artery pressures, with a pullback across the pulmonary valve to measure the peak-to-peak systolic gradient. A right ventricular angiogram is performed in an right anterior oblique (RAO) and/or lateral projection to localize the valve and to measure the size of the valve annulus. A multipurpose catheter is then advanced to one of the branch pulmonary arteries and an exchange length guidewire positioned in a distal branch. An appropriate sized balloon catheter is advanced into the right ventricle and positioned across the pulmonary valve. The balloon diameter should measure about 1.2–1.5 times the size of the valve annulus. Balloon inflation is performed until the waist is abolished, signaling effective disruption of the stenotic valve leaflets. After dilation, the pressure gradient across the valve is measured; a reduction to less than half the predilation gradient is accepted as an effective result. However, some patients, especially those with the more severe obstruction, display a “reactive” infundibular dynamic obstruction after valvuloplasty. In this case, the initial fall in gradient may seem disappointing, but providing the operator is confident that an appropriate sized balloon was used, the gradient will fall further in the weeks following valvuloplasty as the right ventricular hypertrophy regresses. Complications reported with this type of intervention are rare. Rupture of the annulus is reported. The tricuspid valve may also be damaged if a large diameter balloon catheter has been passed inadvertently through the tricuspid valve chordae. After inflation, the balloon is relatively bulky and as it is removed the tricuspid valve apparatus may be disrupted causing regurgitation. A procedure-associated death rate of 0.24% and a major complication rate of 0.35% were found in a large study comprising 822 balloon pulmonary valvuloplasty procedures (15).

Aortic stenosis The commonest cause of stenosis in patients below 60 years of age is a congenitally bicuspid aortic valve with fused commissures and/or dysplastic leaflets. Over time calcification and fibrosis may cause the valve to become rigid and obstructive. Coexisting regurgitation of these valves is common. The number of patients with a rheumatic type of stenosis has decreased in recent years. Rheumatic valve disease causes fusion and thickening of the commissures, which in turn accelerates calcification and fibrosis. A third type of stenosis of a degenerative nature occurs in patients above 70 years of age in whom the commissures stay separated but the valve excursion is impeded at the base of the leaflets. Clinical symptoms may include syncope, dyspnea, or angina. Advanced stages of this disease can cause heart failure and sudden death. Surgery has been the preferred option for patients with severe stenosis. The options are either a commissurotomy or, in patients with significant regurgitation or severe calcification,

valve replacement or a pulmonary autograft procedure, the Ross operation. After successful experience with pulmonary balloon valvuloplasty, aortic balloon valvuloplasty has gained acceptance (16⫺18). The aim of aortic valvuloplasty is to reduce the transvalvular gradient to a subintervention level. An efficacious result is generally accepted as a pressure gradient less than 50 mmHg and an increase in valve area of 100%. The acute results of dilation are comparable to pulmonary procedures though the complication rate is considerably higher. Aortic regurgitation, embolic events, arrhythmias, and progressive heart failure have all been reported during intervention or follow-up. Recurrent stenosis is the highest among patients with severe calcification (19), which has been addressed by the development of transcutaneous valve replacement (for further information see the section “valve replacement”).

Mitral stenosis Mitral stenosis is seen typically as a consequence of chronic rheumatic fever. Isolated congenital mitral stenosis is very rare and not suitable for balloon valvuloplasty. Clinical symptoms depend on the degree of obstruction. Dyspnea, atrial fibrillation, embolic events, pulmonary edema, and right heart decompensation may occur and are all indications for treatment. Surgery and catheter intervention provide similar results. Balloon valvuloplasty produces best results in patients with little or no calcification of the mitral leaflets (20⫺23). Since the first steps in transluminal balloon dilation of mitral valves in 1982 (24) numerous techniques have been described. One method is to access the left atrium with a transseptal puncture from the venous side (antegrade). Another way is to advance the catheter via the aorta into the left ventricle and perform the valvulotomy from the arterial side (retrograde). The use of two dilation balloons introduced via the transseptal approach is a common technique described by Bonhoeffer using a monorail-type system over a single guidewire (25). Minor degrees of mitral regurgitation are relatively common after valvuloplasty of the mitral valve. More severe regurgitation requiring early surgical repair or replacement may also occur. Restenosis is seen after both surgical and interventional valvuloplasty on the mitral valve in longer-term follow-up (26,27). The valve area usually increases approximately from 1 to 1.8⫺2.2 cm2 (28).

Tricuspid stenosis Isolated tricuspid stenosis is very rare and almost always associated with chronic rheumatic fever. Techniques to dilate this valve are based on those for mitral dilation.

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During all valvuloplasty interventions antibiotics (e.g., cefuroxime, 1, 5 g, i.v.) are administered. Patients allergic to penicillin should receive vancomycin 1 g intravenously. Most physicians perform transcatheter valvuloplasty in the fasting state under mild sedation. Substances that are frequently used are meperidine, promethazine, and chlorpromazine, given intramuscularly or intermittent doses of midazolam (0.05 to 0.1 mg/kg, i.v.) and/or fentanyl (0.5 to 1.0 µg/kg, i.v.). Some operators also apply ketamine or general anesthesia for all interventional cases. Following transseptal left heart catheterization, systemic anticoagulation is achieved by the intravenous administration of 100 U/kg of heparin.

Mitral valve repair Transcutaneous mitral valve repair has been developed for patients with significant valve regurgitation. A frequent etiology of regurgitation is myocardial infarction causing ventricular dilation, rupture of chordae, or dysfunctional papillary muscles. Additionally mitral valve prolapse, dilated cardiomyopathy, or rheumatic/bacterial endocarditis can result in a regurgitant mitral valve. Chronic regurgitation is tolerated by many patients for quite a long time but eventually symptoms of dyspnea, palpitations, edema, and severe arrhythmias emerge. Indications for surgical intervention include regurgitation with NYHA III–IV symptoms or NHYA ⬎II with atrial fibrillation refractory to conservative treatment. Several surgical techniques are effective. The “Alfieri stitch” or “edge to edge” technique is of interest because one of the percutaneous mitral valve repair techniques is based on an equivalent principle (29,30). Currently two methods for transcatheter mitral valve repair are investigated in clinical trials: 1. Edge-to-edge repair 2. Transcatheter annuloplasty 1. In 1991, the surgical variant of the edge-to-edge repair technique was first tried in patients that were not suitable for complex mitral valve repair (29). This procedure is still performed with the intention of sewing together part of the free edges of the anterior and posterior valve leaflets in such a way as to construct a double orifice valve to decrease regurgitation. The edge-to-edge transcatheter mitral valve repair system consists of a steerable guide catheter and a steerable clip or suture delivery system. From a venous approach, a transseptal puncture is employed to access the left atrium. The delivery system is maneuvered through the mitral valve into the left ventricle and aligned perpendicular to the line of valve coaptation. The EVEREST I trial featured first data on transcatheter mitral repair with this technique using a clip (31). In 89% the implantation procedure was successful reducing

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mitral regurgitation in 67% of the patients to levels under II°. However, 25% of these patients required surgery within two months after the intervention. 2. The concept of percutaneous transvenous mitral annuloplasty is to place a relatively stiff rod or stent into the coronary sinus (CS) to achieve a configuration change of the dilated mitral annulus. This procedure is feasible due to the fact that the posterior mitral annulus is separated from the CS and great cardiac vein (GCV) only by a thin band of atrial muscle and connective tissue. Preinterventional assessment of the anatomical relationships between the CS and mitral annulus by magnetic resonance imaging, CT scan, or 3D echocardiography is helpful for this procedure. The rod is positioned under fluoroscopic guidance through the CS and GCV to an appropriate position. By straightening the venous vessels, the posterior leaflet converges to the anterior leaflet thereby reducing regurgitation. A new CS probe, which applies heat energy to the mitral annulus, is being developed to denaturize collagen fibers in the adjacent mitral annulus producing a shrinkage effect that decreases the valve dilation, potentially reducing regurgitation. Perforation and tamponade, coronary occlusion, sinus thrombosis, or device migration are all potential complications of this procedure. Short- and midterm follow-up results are expected (32,33). With annuloplasty procedures heparin and endocarditis prophylaxis should be administered before the procedures. When the edge-to-edge technique is performed, heparin should not be administered until the transseptal puncture has been performed. Regular follow-up examination, anticoagulation, and endocarditis prophylaxis are recommended after mitral repair procedures.

Valve replacement Currently transcatheter replacement of heart valves is limited to the aortic and pulmonary valves. Hywel Davies reported of temporarily treatment of aortic regurgitation with a parachute valve mounted onto a catheter tip in 1965 (34). Twenty-seven years later Andersen and his colleagues described the first experience with a bioprosthetic valve attached to a wire-based stent and mounted on a balloon valvuloplasty catheter (35). In 2002, Alain Cribier performed the first transcatheter valve implantation in an elderly patient with inoperable aortic stenosis using a prototype of a stentmounted, pericardial, tricuspid aortic valve (36). Approaching the aortic valve with a catheter can be achieved via the venous (antegrade, transseptal) or the arterial routes (retrograde) (37,38). The delivery assembly is positioned within the diseased native valve. Before expansion of the valve mounted balloon rapid pacing (⬎200 beats/min) is performed to lower stroke volume during the implantation sequence. The balloon is inflated fixing the stented valve to the implantation site. Immediately after balloon deflation

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pacing is discontinued and the balloon removed leaving the valve in position. Reported complications in this group of patients with very high comorbidity are renal failure, pericardial tamponade, stroke, injury to the mitral valve and atrial septum, paravalvular regurgitation, valve migration and cardiogenic shock. Residual regurgitation after reparative surgery of congenital heart disease is the most frequent indication for pulmonary valve replacement. Bonhoeffer reported early results in 2000 (39,40). Since then, over 100 patients have undergone this procedure. Extensive diagnostic imaging is performed before pulmonary valve implantation to delineate anatomy, and quantify the regurgitation and right ventricular function. The pulmonary valve is a bovine jugular vein valve mounted within a platinum iridium stent. It is advanced on a double-balloon delivery system via the femoral vein into the right atrium, through the tricuspid valve and into the right ventricular outflow tract. Once the correct position of the valve-stent assembly is identified angiographically, the inner and outer balloons are inflated sequentially, and subsequently deflated and removed. Occasionally, it is necessary to perform further deployment of the valve using a high pressure, noncompliant balloon system. The procedures may be performed under local anesthesia and mild sedation or general anesthesia with heparin anticoagulation. Aspirin (160 mg, p.o.) and a loading dose of clopidogrel (300 mg, p.o.) are administered 24 hours before intervention for the aortic valve. Antibiotics (e.g., first generation cephalosporin, i.v.) are given before the procedure and continued for 48 hours. After the procedure aspirin is continued for three to six months.

membranous, and the new perimembranous device (Fig. 4) are by far the most widely applied. The CardioSEAL-STARflex occluder or Nit-Occlud Coils may also be used for this purpose. Before intervention clinical condition often warrants intraaortic balloon pump and revascularization or stenting of the infarct-related artery. For VSD closure either the transvenous or the transarterial approach can be used to access the defect. Commonly an arteriovenous circuit is established. This increases wire stability and thus facilitates positioning of the delivery sheath. The appropriate device size is selected and positioned within the defect. Care is taken that the device does not impinge on important related structures such as the aortic, mitral, and tricuspid valves. The morphology of the post infarction VSDs is complex thus residual shunting is often seen and mortality remains high. While the procedure may be life saving in some circumstances, procedural failure and residual flow are commoner than with congenital defects (for further information on congenital VSD closure see chap. 62). Post infarction patients need to be treated with long-term antiplatelet therapy. Aspirin (100 mg/day, p.o.) reduces the mortality rate within one year post infarction by 15% and the risk for reinfarction by 30%. Additionally, clopidogrel (75 mg/day, p.o.) may be administered. Supplementary clopidogrel therapy for at least nine months also improves prognosis (45). The risk of thrombus formation in the affected myocardium is high. Anticoagulation for three months with a target INR of 2.0–3.0 is recommended by some operators.

Patent foramen ovale Persistence of patent foramen ovale (PFO) into adulthood carries a risk of paradoxical embolization. This risk is accentuated

Post-surgical and postmyocardial infarction ventricular septal defect The vast majority of ventricular septal defects (VSD) are congenital. Acquired VSDs are almost always a consequence of septal rupture following myocardial infarction, traumatic VSDs as a consequence of sharp or blunt chest trauma are exceptionally rare. Typically the post myocardial infarction ventricular septal defect (PMIVSD) occurs within the first week after the event (41). In the current era of thrombolysis about 0.2% of patients develop a VSD as a result of septal necrosis. Medical management of these patients is limited and carries a 30-day mortality of 94% compared with 47% who were treated surgically (42). A residual VSD following surgical closure occurs in 10% to 40% of patients depending on its location (43). Selected patients are suitable for a transcatheter approach. Interventional closure of selected muscular VSD has been possible for some years using the Rashkind (44) and subsequent generation devices (Clamshell, CardioSEAL). Currently the Amplatzer muscular,

Figure 4 Amplatzer post myocardial infarction ventricular septar defects (VSD) occluder.

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if the PFO is associated with an atrial septal aneurysm (46). Therapeutic options to prevent embolism are a lifelong application of anticoagulant drugs, surgical closure, or catheter intervention. Despite efficacious new generation antiplatelet and anticoagulation drugs there is nevertheless a risk of recurrent embolic events. Additionally, 2–5% of the patients on anticoagulant drugs will encounter significant bleeding complications per year (47). Surgery for PFO closure lowers the rate of cerebrovascular events per year and carries a mortality of less than 1%, but is associated with significant morbidity. Transcatheter closure of PFO is a standard technique for many interventional cardiologists. Low morbidity, efficacy approaching 100% at follow-up, and the avoidance of scar, make transcatheter closure the procedure of choice. All double disc devices (see later) are introduced via the femoral vein and advanced within a delivery catheter through the PFO into the left atrium. Here the distal disc of the occluder is released and carefully withdrawn to the left side of the atrial septum. The proximal disc is deployed on the right side of the septum. Effective positioning is confirmed on fluoroscopy and transesophageal or intracardiac echo and the device subsequently released from its delivery system. Following devices are either standard PFO devices or constitute emerging methods for PFO closure: 1. Amplatzer PFO occluder (AGA Medical Corporation, Golden Valley, MN) 2. Helex occluder (W.L. Gore & Associates, Flagstaff, AZ) 3. Premere occluder (St Jude Medical, Maple Grove, MN) 4. CardioSEAL-STARflex occluder (NMT Medical, Inc., Boston, MA) 5. BioSTAR (NMT Medical, Inc., Boston, MA) 6. PFX Closure System (Cierra, Inc., Redwood City, CA) 1. The Amplatzer occluder (Fig. 5) is probably the most widely used device in this indication. This double disc device

Figure 5 Amplatzer PFO occluder.

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Figure 6 Helex PFO occluder.

consists of self-expandable nitinol wire mesh. Both discs contain patches of polyester fabric for enhanced defect occlusion. Compared to other Amplatzer devices, the PFO occluder features a thinner connection waist and is available in sizes of 18, 25, and 35 mm. Most frequently the 18 and 25 mm devices are implanted, but the 35 mm occasionally is useful in patients with a large ASA. Before insertion the device needs to be evacuated from air by expanding and refolding the wire mesh in saline. Once accomplished, the device is loaded into the delivery catheter and percutaneously introduced. Self-expansion of the left and right atrial discs is achieved by pushing the delivery cable and retrieving the catheter stepwise. After checking for proper device position and configuration, the device is released. 2. The Helex device differs from the common double umbrella concept (Fig. 6). Expanded polytetrafluoroethylene (ePTFE) patch material is bonded to a single strand of nitinol wire. When fully constituted the device conforms in a circular fashion with two discs held together by an integrated eyelet mechanism. This mechanism also provides visibility under fluoroscopy and ensures flat alignment of the discs to the left and right aspects of the atrial septum. Due to its round edges, ePTFE material and the fine nitinol wire, this device has a low rate of complications. The device remains elongated in a linear form when loaded in the catheter and forms 11/4 turns on each side of the septum after deployment. A security suture is attached to the proximal eyelet allowing device retrieval even after release. 3. The Premere PFO occluder (Fig. 7) is another selfexpanding double disc device specifically designed for PFO closure. The right-sided anchor is constructed of nitinol between two layers of knitted polyester fabric connected by a flexible polyester braided tether to the left atrial anchor. The left atrial anchor consists of four radiating arms without polyester layers to improve tissue absorption and to minimize thrombus formation. Since the distance between the anchors

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Figure 7 Premere PFO occluder.

Figure 9 adapts to the tunnel length, this device is suitable for longtunnel type PFOs. Until the abovementioned tether is cut, the anchors are fully retrievable. This device was first used in November 2003. 4. The CardioSEAL occluder features eight wire spring arms that form two rectangular discs. Each disc is covered with a knitted polyester patch. The CardioSEAL-STARflex septal repair system (Fig. 8) is an advanced version, which has nitinol coil microsprings connecting the opposing arms of the left and right atrial discs. These springs enable self-centering of the device to obtain improved adjustment to the septal anatomy.

Figure 8 CardioSEAL-STARflex device.

BioSTAR persistence of patient foramenovale (PFO) occluder.

5. The BioSTAR occluder (Fig. 9) evolved from the CardioSEAL-STARflex design. It is a prototype of a bioactive device that uses tissue-engineered collagen matrix derived from the submucosal layer of the porcine small intestine (Organogenesis Inc., Canton, MA) as its “fabric”. The device is 90% absorbable and has a very low profile encouraging tissue overgrowth and decreased thrombogenicity. The BioSTAR occluder features drug eluting capabilities for heparin or growth factors. This device is currently in clinical trials. 6. The PFX Closure system (Fig. 10) does not involve the implantation of a device. The method of action involves the sealing of the flap valve of the foramen ovale to the atrial septum. The distal end of the catheter consists of an electrode composed of a metallic wire framework and covered by an elastomeric vacuum housing. A retractable outer sleeve confines the electrode from the surrounding blood. The system is introduced transvenously and positioned in the right atrium. The electrode is guided toward the overlapping septum primum and secundum. Both parts of the atrial septum are engaged by inducing a vacuum within the elastomeric housing. After confirming the position of the electrode by TEE or ICE, a monopolar radiofrequency energy impulse is triggered, welding the tissues of septum primum and septum secundum together. This procedure was first performed in 2005 and is currently under procedural and technical evaluation (48). It has become recognized that PFO device closure not only significantly decreases the incidence of paradoxical embolism (47), but can also reduce the incidence of migraine in susceptible patients. Fifty-five percent of patients with aura and 62% of those without aura experienced a reduction of

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4

5

6

Figure 10 PFX electrode. 7

headache frequency after PFO closure (49). The MIST study (http://www.migraine-mist.org) found out that PFO closure might achieve a mean reduction in headache burden of 50 hours per month. In this study, 42% of the patients with migraine experienced a 50% reduction in headache. Reported major procedural and post procedural complications include frame fracture, device embolization, or the need for surgical retrieval. Depending on the operator experience, the method and the morphology of the PFO, the procedure time constitutes approximately 20–40 minutes. The hospital stay is rarely more than a single overnight stay; many patients undergo PFO closure as a day case procedure. Before intervention heparin is administered (100 U/kg) in addition to endocarditis prophylaxis (e.g., cefuroxime, 1,5 g, i.v.). Endocarditis prophylaxis is repeated after the procedure. Aspirin (100 mg, p.d.) and clopidogrel (75 mg/day, p.o.) are prescribed for six months after implantation. The incidence of thrombus formation varies between devices (50). If thrombus is seen during follow-up, coumadin therapy should be commenced.

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References 1

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Maron MS, Olivotto I, Betocchi S, et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003; 348: 295–303. Maron BJ, Bonow RO, Cannon RO III, et al. Hypertrophic cardiomyopathy. Interrelations of clinical manifestations, pathophysiology, and therapy (2). N Engl J Med 1987; 316 (14):844–852. Review. Gietzen FH, Leuner CJ, Obergassel L, et al. Role of transcoronary ablation of septal hypertrophy in patients with hypertrophic cardiomyopathy, New York Heart Association functional class III or IV, and outflow obstruction only under provocable conditions. Circulation 2002; 106:454–459.

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Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002; 106(24):3006–3008. Cribier A, Eltchaninoff H, Tron C, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004; 43(4):698–703. Webb JG, Chandavimol M, Thompson CR, et al. Percutaneous aortic valve implantation retrograde from the femoral artery. Circulation 2006; 113(6):842–850. Bonhoeffer P, Boudjemline Y, Saliba Z et al. Transcatheter implantation of a bovine valve in pulmonary position. A lamb study. Circulation 2000; 102:813–816. Bonhoeffer P, Boudjemline Y, Saliba Z et al. Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction. Lancet 2000; 356:1403–1405. Topaz O, Taylor AL. Interventricular septal rupture complicating acute myocardial infarction: from pathophysiologic features to the role of invasive and noninvasive diagnostic modalities in current management. Am J Med 1992; 93(6):683–688. Review. Crenshaw BS, Granger CB, Birnbaum Y, et al. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) Trial Investigators. Circulation 2000; 101(1):27–32. Killen DA, Piehler JM, Borkon AM, et al. Early repair of postinfarction ventricular septal rupture. Ann Thorac Surg 1997; 63(1):138–142. Lock JE, Block PC, McKay RG, et al. Transcatheter closure of ventricular septal defects. Circulation 1988; 78:361–368. Fox KA, Mehta SR, Peters R, et al. Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004; 110(10):1202–1208. Mas JL, Arquizan C, Lamy C. Patent Foramen Ovale and Atrial Septal Aneurysm Study Group: recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm or both. N Eng J Med 2001; 345:1740–1746. Khairy P, O’Donnell CP, Landzberg MJ. Transcatheter closure versus medical therapy of patent foramen ovale and presumed paradoxical thromboemboli: a systematic review. Ann Intern Med 2003; 139(9):753–760. Skowasch M, Hein R, Buescheck F, et al. Non-Implant Closure of Patent Foramen Ovale: First-in-Man Results. Am J Cardiol 2005; 96(suppl 7A):101H. Schwerzmann M, Wiher S, Nedeltchev K, et al. Percutaneous closure of patent foramen ovale reduces the frequency of migraine attacks. Neurology 2004; 62(8):1399–1401. Krumsdorf U, Ostermayer S, Billinger K, et al. Incidence and clinical course of thrombus formation on atrial septal defect and patient foramen ovale closure devices in 1,000 consecutive patients. J Am Coll Cardiol 2004; 43(2):302–309. Review.

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52 Pharmacologic use of ethanol for myocardial septal ablation George D. Dangas, Edwin Lee, and Jeffrey W. Moses

Hypertrophic cardiomyopathy, a primary myocardial disorder of sacromeric proteins with an autosomal dominant pattern of inheritance is characterized by asymmetric hypertrophy of the septum with or without dynamic obstruction of the outflow tract (1,2). The prevalence in the general population is estimated as 1:500 and it is the most common monogenic cardiac disorder. Annual mortality in an unselected population is reported to be about 1% to 2%, and sudden death is the most common cause. Sudden death is assumed to be due to idiopathic ventricular arrhythmias, but hemodynamic factors and myocardial ischemia may be involved as well.

The dynamic outflow obstruction leads to the characteristic spike-and-dome arterial pressure waveform seen most evidently in the proximal aorta (Fig. 1). The early spike is due to a rapid ventricular ejection from the hypercontractile myocardium, and the pressure dip and subsequent doming of the pulse reflect the dynamic outflow obstruction. This is seen following conditions that increase the dynamic gradient, such as an extrasystole, the Valsalva maneuver, or administration of beta-adrenergic agonists or vasodilators. The narrowing in pulse pressure of the spike-and-dome arterial waveform following an extra-systole is known as the BrockenbroughBraunwald sign. Associated diastolic dysfunction is common with increased diastolic filling pressure evident in the contour of the left ventricular diastolic pressure tracing.

Hemodynamics The most characteristic hemodynamic feature of hypertrophic cardiomyopathy is the dynamic intraventricular pressure gradient (3). Obstruction to left ventricular ejection occurs in the left ventricular outflow tract due to the contraction of the basal aspect of an asymmetrically hypertrophied interventricular septum resulting in a subaortic pressure gradient. As the ventricle contracts the subaortic flow velocity increases. The acceleration of blood flow through the narrowed outflow tract causes a pressure drop that draws the anterior leaflet of the mitral valve towards the ventricular septum due to a Venturi effect, exacerbating the outflow obstruction and contributing to mitral incompetence. Outflow obstruction is a dynamic phenomenon. Patients with hypertrophic cardiomyopathy may not have a systolic pressure gradient at rest but can have one provoked with the Valsava maneuver or an extrasystole. There is a variability and heterogeneity of hemodynamics among affected patients and even within the same patient over time.

Treatment options The treatment strategy in patients with severe symptoms unresponsive to maximum medical management and a significant outflow tract obstruction is the reduction of the myocardial septum either by surgery or alcohol ablation (4–6).

Surgery Surgical myectomy involves incision into and resection of small portions of the hypertrophied septum resulting in a significant reduction or abolition of intramyocardial gradients and reduction in mitral incompetence. Patients report a significant reduction in disabling symptoms and improvement in exercise capacity, and the benefit is usually sustained. The complications are few and the postoperative mortality is

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Pharmacologic use of ethanol for myocardial septal ablation

Figure 1 Demonstration of the typical hemodynamic evaluation of hypertrophic cardiomyopathy. Equipment used: single end-hole pigtail catheter, a femoral arterial sheath at least one size larger than the catheter, and two pressure transducers (one at the femoral sheath side port and the other at the pigtail catheter). The catheter is initially seated beyond the stenosis and a pressure gradient is documented, as well as the spike-and-dome configuration during systolic ventricular pressure rise can be observed while the arterial systolic pressure upstroke is steep (single black arrow). While the catheter is pulled back, the gradient essentially disappears while the catheter is still inside the left ventricular cavity as documented by the diastolic part of the pressure curve. Finally, the catheter is pulled outside the ventricle and the two transducers document essentially identical pressures (small differences are due to the aortic to femoral pressure wave potentiation). This pullback maneuver is pathognomonic for subaortic obstruction and needs to be performed very slowly and taking special care to avoid provoking a series of ventricular extra-systoles that will obviate the above-described evaluation.

1–3% when myectomy are performed by experienced surgeons in a comprehensive care setting. Long-term survival in patients with obstructive hypertrophic cardiomyopathy and severe symptoms postsurgical myectomy was equivalent to that of the general population (7). Surgical myectomy patients had reduced all cause mortality and sudden cardiac death compared to nonoperated obstructive hypertrophic cardiomyopathy patients (7), suggesting that myectomy may reduce mortality risk in severely symptomatic patients with obstructive hypertrophic cardiomyopathy.

Septal Ablation Septal alcohol ablation, first reported in 1995 (4), has evolved to become a relatively common procedure with ⬎4000 patients having been treated. This procedure consists of injecting absolute alcohol into a septal perforator to create necrosis and permanent myocardial infarction (MI) in the proximal septum. Subsequent intramyocardial scarring (8) leads to progressive left ventricular wall thinning, restricted septal excursion, enlargement of the outflow tract and consequent reduction in obstruction and mitral regurgitation, thus mimicking the remodeling that results from surgical myectomy.

Selection of patients Selection of patients for septal ablation includes those with severe symptoms (i.e., New York Heart Association functional class III or IV) despite appropriately adjusted medical therapy, with a documented resting left ventricular outflow tract gradient ⬎30 mmHg or a provocable gradient ⱖ60 mmHg and septal thickness of at least 18 mm. Patients at high risk of surgical morbidity or mortality, including patients of advanced age or with insufficient motivation for surgery, and those with other important comorbidities or other conditions that will likely limit long-term survival are candidates for septal ablation (Table 1). Patients who have not obtained a satisfactory result after surgical myectomy may also be candidates for septal ablation. Selected patients with advanced function class II with obstructive symptoms that interfere with their occupation may also be candidates for intervention. Patients with the non-obstructive form of hypetrophic cardiomyopathy should not undergo septal ablation. Patients with congential anomalies of the mitral valve apparatus, associated heart lesions (e.g., advanced multivessel coronary artery disease) requiring surgical correction, unfavorable distribution of septal hypertrophy with mild proximal thickening, basal septal wall thickness ⬍18 mm, or anatomically unsuitable septal perforators should not be candidates for septal ablation.

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Ablation techniques

Table 1

605

Patient selection criteria for septal alcohol ablation

Severe symptoms (NYHA or CCS class III or IV) despite appropriate drug therapy NYHA or CCS class II with a resting gradient of ⬎50 or ⬎30 mmHg and ⱖ100 mmHg with physiological exercise Symptoms resulting from left ventricular obstruction after discontinuing medication because of intolerable side effects Resting left ventricular outflow gradient of ⬎30 mmHg or a provocable gradient ⱖ60 mmHg Previous unsatisfactory surgical myectomy or pacemaker therapy Septal thickness ⬎18.5 mm Abbreviations: CCS, Canadian Cardiovascular Score; NYHA, New York Heart Association.

Ablation techniques Detailed baseline coronary angiography, left ventriculography, hemodynamic measurements, and measurement of resting/provocable gradients should precede any attempt at septal ablation. Angiography allows for identification of suitable target septal perforators, preferably a large first septal perforator. Ventriculography is useful for demonstrating the degree of mitral regurgitation and location of the dynamic outflow obstruction. Initial hemodynamic assessment assures that the level of obstruction is subaortic. Contrast echocardiography is essential as it enhances the effectiveness and safety of septal ablation (9). Left ventricular pressure measurements are monitored continuously by use of a 5F end-hole pig-tail catheter in the left ventricular apex and a 6F femoral sheath in order to be able to assess the gradient. If the outflow gradient is absent or small under the basal conditions, the magnitude of provocable obstruction is most appropriately assessed with maneuvers (Valsalva, ventricular pacing, extrasystoles, physiological exercise, amyl nitrate). The inability to elicit any provocable gradient is a contraindication to the procedure. Dobutamine, an inotropic and catecholamine-inducing drug and a powerful stimulant of subaortic gradients in normal hearts and cardiac conditions other than hypertrophic cardiomyopathy, is not recommended to provoke outflow gradients for assessing the appropriateness of septal ablation (1). If the gradient is indeed confirmed, a 6 or 7Fr sheath is placed in the left coronary artery from the contralateral femoral artery, in order to reliably assess the ascending aortic pressure even in the presence of intracoronary wires and a balloon inside it (Fig. 2). A guidewire and subsequently a balloon catheter (2.0–2.5 mm in diameter) are advanced into the septal perforator. Identification of the target territory is performed by contrast echocardiography to determine the most appropriate septal perforator for ethanol infusion by showing echo

contrast localization in the area of maximal septal bulge when the target septal is injected with contrast (preferably at the point of mitral leaflet near-contact with the septum). The guidewire is then removed and dilute Optison (1:10) is injected through the inflated balloon lumen to echocardiographically visualize the septal territory perfused by the target septal perforator. The appropriate area of outflow obstruction should be opacified with little spillover to other areas. Once Optison injection confirms appropriate placement, a small amount of angiographic contrast is infused through the inflated balloon to confirm stasis in the septal perforator and also to document the absence of reflux into the left anterior descending artery during balloon inflation. One to two milliliters of ethanol (100% dehydrated ethanol) is then injected slowly into the target septal artery through the balloon lumen in 0.5–1.0 milliliter amounts at a rate of approximately 1 ml/min, under continuous fluoroscopy in order to surveil for possible balloon displacement (Fig. 2). Throughout the course of balloon inflation, the patency of the downstream left anterior descending artery should be monitored with occasional contrast injection through the guiding catheter. Following the outflow tract gradient response, the coronary balloon remains inflated for 5–10 minutes after the final administration of ethanol to insure that no alcohol refluxes into the left anterior descending artery. After the procedure, repeated hemodynamic and angiographic studies should be performed. “No-flow” at the site of the injected target septal perforator indicates successful alcohol ablation. Hemodynamic measurements are repeated 10 minutes after balloon deflation. Because of the possibility of developing bradycardia from high-degree atrioventricular block as a consequence of the procedure, a temporary pacemaker should be placed. If the gradient is not adequately reduced, consideration then can be given to repeating the injection or injecting alcohol in an adjacent septal perforating branch, bearing in mind that each additional amount of alcohol increases the risk of atrioventricular block.

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1

2

3

4

Figure 2 A) Four stop-frames of an alcohol septal ablation have been captured. Note the presence of a pigtail catheter in the left ventricle and a (A temporary pacemaker in the right ventricle. Spot-1 depicts the dominant proximal septal perforator. Spot-2 shows the selective catheterization of this septal branch with a 0.014 inch wire and an “over-the-wire balloon,” while another wire has been placed in the left anterior descending artery. Spot-3 depicts the way slow, selective injections are delivered selectively in the septal branch through the balloon, after the septal perforator wire has been removed. A test injection with contrast is first performed to ensure absence of back-flow in the left anterior descending artery; contrast echocardiography is then performed after selective contrast injection in order to verify the myocardial distribution of this septal branch in relation to the hypertrophied septal area; another radiographic contrast injection is then performed to verify continued absence of back-flow (spill) in the left anterior descending artery; finally, ethanol injections are performed in 0.5 to 1 ml increments with B) Hemodynamic documentation of the pre- and post-procedure pressure verification of absence of back-flow before any repeat injection. (B tracings in this case. On the left side, the pressure scale is up to 400 mmHg and a gradient ⬎60 mmHg is documented; the spike-and-dome configuration of the left ventricular pressure tracing is observed, as well as a steep upstroke of the arterial pressure. On the right side, a small residual gradient is observed (⬍20 mmHg); note that the pressure scale is now up to 200 mmHg.

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Implications on arrhythmogenicity

Postprocedure care Following septal ablation, patients should be monitored in a coronary care unit for 24 to 48 hours and the temporary pacing wire should be removed at the end of this period in the absence of atrioventricular block. Patients may then be transferred to a telemetry unit for monitoring of arrhythmias. Total hospitalization is usually for three to five days to monitor for occurrence of complete heart block that would require a permanent pacemaker. A sizeable infarction is induced with alcohol ablation and causes creatinine phosphokinase to peak at 1000 to 1500 one day after the ablation. Patients should be maintained on aspirin indefinitely.

Various drugs In preparation for chest discomfort during alcohol injection, prophylactic analgesic medication (eg. fentanyl 25 mm IV) is administered. Antithrombotic prophylaxis with intravenous, weight-adjusted heparin is given to maintain an activated clotting time of 200 to 250 seconds.

607

benefits from two-year follow-up studies (17,18) and more recently up to five-year follow-up (Table 2) (19). Patients with increased outflow gradients prior to discharge after initial success of septal ablation that improves at threemonth follow-up and that remains less than 50% at one-year follow up have been reported (20). At present, it is not known whether the timing of maximal outflow gradient reduction after surgical myectomy or septal ablation is important in reducing morbidity and mortality. The small mean differences in reduction of the LV outflow gradient between surgery and septal ablation may be important, as the severity of left ventricular outflow tract gradient is an independent risk factor for functional deterioration (21). Predictors of an unsatisfactory outcome after septal ablation (persistent symptoms with a less than 50% reduction in the left ventricular outflow tract gradient) includes baseline higher outflow tract gradients, fewer septal arteries injected with alcohol, lower peak creatine kinase, smaller septal area opacified by contrast echocardiography, and higher residual gradient in the catheterization laboratory after septal ablation. Of note, age, New York Heart Association, or Canadian Cardiovascular Score functional class, exercise capacity, septal thickness, left ventricular filling pressures, mitral regurgiation severity, and ventricular function were not determinants of unsuccessful outcome (22).

Acute results Procedural success is defined by an acute reduction in resting and/or provoked left ventricular outflow gradient by 50% or to ⬍20 mmHg, which can be achieved in the short term in approximately 90% of treated patients (Tables 2 and 3) (10,11). The immediate post-ablation gradient reduction is probably due to alcohol-mediated septal necrosis and stunning. Progressive decrease in the gradient across the outflow on long-term follow-up is secondary to septal thinning and ventricular remodeling.

Long-term results Successful septal ablation leads to significant improvement in objective tests of exercise performance in terms of treadmill exercise time and peak oxygen consumption in follow-up studies over 3 to 18 months (Table 2) (11–15). Significant and sustained improvement in echocardiographic measures of diastolic function are seen up to two years which may account for the improved functional status after septal ablation (16). The three-month (11) and one-year (10) results of both surgical myomectomy and alcohol septal ablation were comparable, however, surgical myomectomy was superior to ablation in terms of improved exercise test parameters (Table 1) (14). Studies indicate maintenance of clinical and hemodynamic

Implications on arrhythmogenicity Conduction system defects, a common complication of septal ablation can be associated with a incidence of complete heart block ranging from 10% to 33% (23) compared to a ⬍1% incidence of complete heart block after surgical myectomy (6,24) (Table 4). Because specific, but different, portions of the ventricular septum are affected by each procedure, patients with baseline right bundle branch block are more likely to need long-term pacing after surgical myectomy, whereas those with baseline left bundle branch block are more likely to need pacing after septal ablation (25). Patients who develop acute complete heart block or new intraventricular conduction defects during septal ablation are at high risk of developing subacute complete heart block and should therefore have temporary pacing support for at least 48 hours after septal ablation (26). Other risk factors for complete heart block were left bundle branch block, first degree atrioventricular block, female gender, volume of alcohol, and number of septal perforators treated (27–29). Concerns of increased ventricular arrhythmias created by scarring remaining from spetal ablation have been raised. However, there is no evidence for increased arrhythmogenicity as assessed by serial electrophysiological studies

43

Ablation

41

Ablation

25

Ablation

20

Ablation

12

3

12

12

F/U months

1.5 ⫾ 0.7a 1.7 ⫾ 0.8a

2.3 ⫾ 0.5

1.9 ⫾ 0.7a

3.5 ⫾ 0.5

2.4 ⫾ 0.6

1.5 ⫾ 0.7a

91 ⫾ 18

83 ⫾ 23

64 ⫾ 39

62 ⫾ 43

8⫾

76 ⫾ 23

3.3 ⫾ 0.5

90%

21 ⫾ 12a

17 ⫾ 12a

24 ⫾ 19a

11 ⫾ 6a

15a

4 ⫾ 7a

78 ⫾ 20

23 ⫾ 19a

17 ⫾ 14a

Post

0%a

101 ⫾ 34

100 ⫾ 20

Pre

2%a

1.5 ⫾ 0.7a

2.4 ⫾ 0.5

78%

1.3 ⫾ 0.4a

Post

2.8 ⫾ 0.4

Pre

Note: Pre indicates preintervention; post indicates postintervention. ap ⬍0.05 versus baseline values. bp ⬍0.05 versus septal ablation. Abbreviation: NYHA, New York Heart Association.

24

Myectomy

Firoozi, 2002 (14)

26

Myectomy

Qin, 2001 (11)

41

Myectomy

Nagueh, 2001 (10)

29

No. of patients

Myectomy

Van der Lee, 2005 (33)

Study

LVOT gradient, mmHg

16.2 ⫾ 5.2

16.4 ⫾ 5.8

18.9 ⫾ 5.7

20.8 ⫾ 4.9

Pre

19.3 ⫾ 6.1a

23.1 ⫾ 7.1a,b

22.2 ⫾ 5.3a

26.2 ⫾ 6.5a

Post

Peak O2 consumption, ml/kg/min

121 ⫾ 53

130 ⫾ 57

Pre

137 ⫾ 51

161 ⫾ 60a,b

Post

Exercise workload, watts

11:50 AM

Mean NYHA or % in NYHA Class III/IV

608

Summary of studies comparing surgical myectomy and septal ablation

3/14/07

Table 2



18

33

50

25

50

25

50

Knight, 1997 (34)

Lakkis, 1998 (35)

Gietzen, 1999 (18)

Ruzyllo, 2000 (36)

Lakkis, 2000 (23)

Faber, 2000 (13)

Boekstegers, 2001 (12)

Gietzen, 2002 (15)

312

242

130

47

Faber, 2004 (9)

Faber, 2005 (38)

Fernandes, 2005 (19)

Yoerger, 2006 (20)

1.7 ⫾ 0.9a

2.9 ⫾ 0.7

12

1.2 ⫾ 0.6a

3.0 ⫾ 0.4

43.2 ⫾ 16.8

1.7 ⫾ 0.7a

2.8 ⫾ 0.7

4.9 ⫾ 2.3

1.5 ⫾ 0.6a

2.9 ⫾ 0.5

3

36.0 ⫾ 15.6

1.5 ⫾ 0.6a

98 ⫾ 48

74 ⫾ 30

57 ⫾ 31

64 ⫾ 36

81 ⫾ 33

44b

b111

80 ⫾ 33 ⫾

22 ⫾ 29a

4⫾ 13a

20 ⫾ 21a

16 ⫾ 15a

16 ⫾ 20a

†24 ⫾ 24a

17 ⫾ 15a

3 ⫾ 6a

322 ⫾ 207

443 ⫾ 200a

600 ⫾ 192a

407 ⫾ 211a

271 ⫾ 160

366 ⫾ 168

703.5 ⫾ 175.4a

421 ⫾ 181a

452 (283–621)

Post

571.9 ⫾ 192.2

286 ⫾ 193

418 (273–563)

Pre

Exercise duration/sec

94 ⫾ 51

73 ⫾ 31

66 ⫾ 29

67 ⫾ 74

69 ⫾ 29

Pre

115 ⫾ 43a

94 ⫾ 37a

85 ⫾ 27a

105 ⫾ 40*

88 ⫾ 34a

Post

Exercise/ Watts

18 ⫾ 4

18.4 ⫾ 5.8

14.8 ⫾ 4.5

13.3 ⫾ 4.6

14.6 ⫾ 5.2

13 ⫾ 4

24.2 (18.4–30.0)

Pre

VO2

21 ⫾ 6a

30.0 ⫾ 4.4a

16.6 ⫾ 6.0a

16.0 ⫾ 5.3

20.5 ⫾ 8.6a

16 ⫾ 6a

26.8 (19.1–34.5)

Post

Implications on arrhythmogenicity

Note: Pre indicates preintervention; post indicates postintervention. aP ⬍0.05 versus baseline values. bProvocable left ventricular outflow tract gradient.

64

3.1 ⫾ 0.2

10 ⫾ 8

84

Shamin, 2002 (37)

3.1 ⫾ 0.3

10 ⫾ 8

45

1.7 ⫾ 0.6a

1.7 ⫾ 0.7a

2.8 ⫾ 0.6

18

60 ⫾ 38

1.2 ⫾ 1.0a

2.8 ⫾ 0.6

30 ⫾ 4

18a

6⫾

5 ⫾ 7a

74 ⫾ 23

1.2 ⫾ 0.5a

45 ⫾ 38

9⫾ 19*

12

2.8 ⫾ 0.5

10.4 ⫾ 1.8

1.7 ⫾ 0.6a

49 ⫾ 33

22 (12–32)a

Post

32.4 ⫾ 25.8

3.0 ⫾ 0.3

10.6 ⫾ 5.6

0.9 ⫾ 0.6a

67 (48–87)

Pre

84.5 ⫾ 31.4

3.0 ⫾ 0.5

1.4

Post

LVOT gradient, mmHg

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3

No. F/U, months or Pre of patients Mean ⫾ SD

Mean NYHA class or percent of patients in NYHA Class III/IV

Summary of septal ablation follow-up studies

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Table 3


609

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Table 4 Study

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Reported complication after surgical myectomy or septal ablation Procedure

No. of patients

F/U, Death, months or n (%) mean ⫾ SD

Late cardiac mortality, n (%)

Acute MI n (%)

Ventricular fibrillation, n (%)

Permanent Reintervention, pacing, n (%) n (%)

Van der Lee, Myectomy 2005 (33) Ablation

29 43

12

0 (0) 2 (5)

0 (0) 1 (2)

0 (0) 6 (14)

0 (0) 4 (9)

Nagueh, 2001 (10)

Myectomy Ablation

41 41

12

0 (0) 1 (2)

1 (2) 9 (22)

Qin, 2001 (11)

Myectomy Ablation

26 25

3

0 (0) 0 (0)

2 (8) 6 (24)

Firoozi, 2002 (14)

Myectomy Ablation

24 20

12

1 (4) 1 (4)

1 (4) 3 (15)

Talreja, 2004 (25)

Myectomy Ablation

117 58

0 (0) 0 (0)

4 (3) 66 (12)

Knight, 1997 (34)

Ablation

18

3

0 (0)

Lakkis, 1998 (35)

Ablation

33

1.4

0 (0)

11 (33)

Gietzen, 1999 (18)

Ablation

50

10.6 ⫾ 5.6

2 (4)

19 (38)

Ruzyllo, 2000 (36)

Ablation

25

10.4 ⫾ 1.8

0 (0)

Lakkis, 2000 (23)

Ablation

50

12

2 (4)

Faber, 2000 (13)

Ablation

25

30 ⫾ 4

1(4)

Boekstegers, Ablation 2001 (12)

50

18

0 (0)

Gietzen, 2002 (15)

Ablation

45 84

10 ⫾ 8 10 ⫾ 8

0 (0) 0 (0)

Shamin, 2002 (37)

Ablation

64

36.0 ⫾ 15.6

Faber, 2004 (9)

Ablation

312

3

4 (1)

Faber, 2005 (38)

Ablation

242

4.9 ⫾ 2.3

3 (1)

Fernandes, 2005 (19)

Ablation

130

43.2 ⫾ 16.8

2(2)

1 (6)

3 (12)

1 (3) 4 (9)

0 (0) 6 (24)

2 (11)

0 (0)

1 (2) 1 (4)

4 (16) 11 (22)

7 (14)

5 (20)

3 (12)

5 (10) 0 (0) 0 (0)

12 (27) 21 (25) 17 (27)

3(2)

17 (13)

Abbreviations: ICD, internal cardiac defibrillator, MI myocardial infarction; SCD, sudden cardiac death.

before and after septal ablation (18). There was also no increase in the incidence of ventricular arrhythmias or sudden cardiac death in all of the follow-up studies of septal ablation (Table 4).

Dose of alcohol The amount of alcohol injected depends on the contrast echocardiographic estimated size of the target area, extent of

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References

septal thickness, as well the hemodynamic effect required (30). Lower doses of ethanol (1 to 2 mi) injected into the target septal branch reduces the size of myocardial necrosis and has comparable hemodynamic reduction and clinical outcome as usual doses (2 to 4 milliliters) (31,32). Injection of smaller doses of ethanol (one to 2 mL) over longer time periods (5 to 10 min) can decrease the higher incidence of CHB after septal ablation (27).

References 1

2

Complications Septal ablation related mortality at experienced centers is currently 1% to 2%, similar to that of surgical myectomy (Table 4). Conduction system abnormalities are relatively common complications of septal ablation. Permanent right bundle branch block occurs in about 50% of patients and transitory complete heart block in 60% and permanent pacemakers required for high grade atrioventricular block in about 5% to 20%. Concerns of late occurrence of complete heart block following septal ablation mandates in-patient monitoring for 4 to 5 days. Chest pain during septal ablation commonly occurs and is effectively managed by analgesic therapy. Intensive care unit monitoring is employed routinely postprocedure in anticipation of ventricular arrhythmias during the initial period of myocardial injury. Prophylactic antiarrhythmic therapy has not been used in our center. A profound complication of septal ablation is anterior MI due to ethanol reflux from the septal perforator down the left anterior descending artery. This can be avoided by careful position of the balloon and angiographic monitoring. Other rare complications include coronary dissection, perforation, thrombosis, and spasm.

3

4 5

6

7

8

9

10

11

Conclusions Ethanol has been used successfully for selective ablation of the hypertrophied septum in hyperthrophic cardiomyopathy patients with refractory symptoms on maximal medical therapy. This technique is less invasive than surgical myomectomy, and patient suitability depends on the angiographic delineation of the septal perforators and the distribution of their myocardial perfusion territory as assessed by contrast echocardiography. Both the interventional and the surgical techniques have not been tested against medical therapy or in a prospective, controlled long-term follow-up study. Although the interventional procedure appears simple, it should be conducted with meticulous technique and great attention to all the details because it could have rare, albeit very serious complications.

611

12

13

14

Maron BJ, McKenna WJ, Danielson GK, et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003; 42:1687–1713. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003; 348:295–303. Fang J, Eisenhauer A. Profiles in cardiomyopathy and congestive heart failure. Textbook: Grossman’s Cardiac Catheterization, Angiography, and Intervention. Seventh Edition. Lippincott Williams & Wilkins, 2005. Sigwart U. Non-surgical myocardial reduction for hypertrophic obstructive cardiomyopathy. Lancet 1995; 346:211–214. Maron BJ, Dearani JA, Ommen SR, et al. The case for surgery in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2004; 44:2044–2053. Nishimura RA, Holmes DR, Jr. Clinical practice. Hypertrophic obstructive cardiomyopathy. N Engl J Med 2004; 350: 1320–1327. Ommen SR, Maron BJ, Olivotto I, et al. Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2005; 46:470–476. Raute-Kreinsen U. Morphology of necrosis and repair after transcoronary ethanol ablation of septal hypertrophy. Pathol Res Pract 2003; 199:121–127. Faber L, Seggewiss H, Welge D, et al. Echo-guided percutaneous septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: 7 years of experience. Eur J Echocardiogr 2004; 5:347–355. Nagueh SF, Ommen SR, Lakkis NM, et al. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2001; 38:1701–1706. Qin JX, Shiota T, Lever HM, et al. Outcome of patients with hypertrophic obstructive cardiomyopathy after percutaneous transluminal septal myocardial ablation and septal myectomy surgery. J Am Coll Cardiol 2001; 38:1994–2000. Boekstegers P, Steinbigler P, Molnar A, et al. Pressure-guided nonsurgical myocardial reduction induced by small septal infarctions in hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol 2001; 38:846–853. Faber L, Meissner A, Ziemssen P, Seggewiss H. Percutaneous transluminal septal myocardial ablation for hypertrophic obstructive cardiomyopathy: long term follow up of the first series of 25 patients. Heart 2000; 83:326–331. Firoozi S, Elliott PM, Sharma S, et al. Septal myotomymyectomy and transcoronary septal alcohol ablation in hypertrophic obstructive cardiomyopathy. A comparison of clinical, haemodynamic and exercise outcomes. Eur Heart J 2002; 23:1617–1624.

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Gietzen FH, Leuner CJ, Obergassel L, et al.. Role of transcoronary ablation of septal hypertrophy in patients with hypertrophic cardiomyopathy, New York Heart Association functional class III or IV, and outflow obstruction only under provocable conditions. Circulation 2002; 106:454–459. Jassal DS, Neilan TG, Fifer MA, et al. Sustained improvement in left ventricular diastolic function after alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Eur Heart J 2006. Mazur W, Nagueh SF, Lakkis NM, et al. Regression of left ventricular hypertrophy after nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy. Circulation 2001; 103:1492–1496. Gietzen FH, Leuner CJ, Raute-Kreinsen U, et al. Acute and long-term results after transcoronary ablation of septal hypertrophy (TASH). Catheter interventional treatment for hypertrophic obstructive cardiomyopathy. Eur Heart J 1999; 20:1342–1354. Fernandes VL, Nagueh SF, Wang W, et al. A prospective follow-up of alcohol septal ablation for symptomatic hypertrophic obstructive cardiomyopathy—the Baylor experience (1996–2002). Clin Cardiol 2005; 28:124–130. Yoerger DM, Picard MH, Palacios IF, et al. Time course of pressure gradient response after first alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Am J Cardiol 2006; 97:1511–1514. Kofflard MJ, Ten Cate FJ, van der Lee C, et al. Hypertrophic cardiomyopathy in a large community-based population: clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration. J Am Coll Cardiol 2003; 41:987–993. Chang SM, Lakkis NM, Franklin J, et al. Predictors of outcome after alcohol septal ablation therapy in patients with hypertrophic obstructive cardiomyopathy. Circulation 2004; 109:824–827. Lakkis NM, Nagueh SF, Dunn JK, et al, Spencer WH III3rd. Nonsurgical septal reduction therapy for hypertrophic obstructive cardiomyopathy: one-year follow-up. J Am Coll Cardiol 2000; 36:852–855. McCully RB, Nishimura RA, Tajik AJ, et al. Extent of clinical improvement after surgical treatment of hypertrophic obstructive cardiomyopathy. Circulation 1996; 94:467–471. Talreja DR, Nishimura RA, Edwards WD, et al. Alcohol septal ablation versus surgical septal myectomy: comparison of effects on atrioventricular conduction tissue. J Am Coll Cardiol 2004; 44:2329–2332. Chen AA, Palacios IF, Mela T, et al. Acute predictors of subacute complete heart block after alcohol septal ablation for obstructive hypertrophic cardiomyopathy. Am J Cardiol 2006; 97:264–269.

27

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29

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31

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33

34

35

36

37

38

Chang SM, Nagueh SF, Spencer WH III, et al. Complete heart block: determinants and clinical impact in patients with hypertrophic obstructive cardiomyopathy undergoing nonsurgical septal reduction therapy. J Am Coll Cardiol 2003; 42:296–300. Faber L, Seggewiss H, Welge D, et al. [Predicting the risk of atrioventricular conduction lesions after percutaneous septal ablation for obstructive hypertrophic cardiomyopathy]. Z Kardiol 2003; 92:39–47. Kern MJ, Holmes DG, Simpson C, Bitar SR, Rajjoub H. Delayed occurrence of complete heart block without warning after alcohol septal ablation for hypertrophic obstructive cardiomyopathy. Catheter Cardiovasc Interv 2002; 56:503–507. Seggewiss H. Medical therapy versus interventional therapy in hypertropic obstructive cardiomyopathy. Curr Control Trials Cardiovasc med 2000; 1:115–119. Veselka J, Prochazkova S, Duchonova R et al. Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: Lower alcohol dose reduces size of infarction and has comparable hemodynamic and clinical outcome. Catheter Cardiovasc Interv 2004; 63:231–235. Veselka J, Duchonova R, Prochazkova S, et al. Effects of varying ethanol dosing in percutaneous septal ablation for obstructive hypertrophic cardiomyopathy on early hemodynamic changes. Am J Cardiol 2005; 95:675–678. van der Lee C, ten Cate FJ, Geleijnse ML, et al. Percutaneous versus surgical treatment for patients with hypertrophic obstructive cardiomyopathy and enlarged anterior mitral valve leaflets. Circulation 2005; 112:482–488. Knight C, Kurbaan AS, Seggewiss H, et al. Nonsurgical septal reduction for hypertrophic obstructive cardiomyopathy: outcome in the first series of patients. Circulation 1997; 95:2075–2081. Lakkis NM, Nagueh SF, Kleiman NS, et al. Echocardiographyguided ethanol septal reduction for hypertrophic obstructive cardiomyopathy. Circulation 1998; 98:1750–1755. Ruzyllo W, Chojnowska L, Demkow M, et al. Left ventricular outflow tract gradient decrease with non-surgical myocardial reduction improves exercise capacity in patients with hypertrophic obstructive cardiomyopathy. Eur Heart J 2000; 21:770–777. Shamim W, Yousufuddin M, Wang D, et al. Nonsurgical reduction of the interventricular septum in patients with hypertrophic cardiomyopathy. N Engl J Med 2002; 347:1326–1333. Faber L, Seggewiss H, Gietzen FH, et al. Catheter-based septal ablation for symptomatic hypertrophic obstructive cardiomyopathy: follow-up results of the TASH-registry of the German Cardiac Society. Z Kardiol 2005; 94:516–523.

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Epilogue: Anticoagulant management of patients undergoing interventional procedures Jawed Fareed

Over the past decade, interest in anticoagulant, antiplatelet, and thrombolytic drugs has grown dramatically, as evident by a continual increase in the number of drugs introduced for both preclinical and clinical development. Several comprehensive reviews have provided a timely coverage of new therapeutic agents in thrombosis and thrombolysis, focusing on such topics as new heparins, synthetic heparinomimetic agents, antithrombin agents, anti-Xa agents, biotechnologyderived antithrombotic proteins, antiplatelet drugs, and novel thrombolytic agents. The developments are so fast that periodic updates on the newly available information on these agents are needed. The outstanding scientific research and development activities in the academic centers and pharmaceutical industry have resulted in a steady flow of new products from various groups. Third-party validation of the products developed and extensive clinical trials has been carried out globally to validate the claims on the safety and efficacy of the newer drugs. The results of these studies also constitute a significant portion of the progress reported at scientific forums. Through their fast track and revised policies, the regulatory bodies such as the European Medicine Evaluation Agency, U.S. Food and Drug Administration (US FDA), and other regional agencies have continually contributed to the timely evaluation and approval of new drugs by providing input at various stages of drug development. Such close interactions have facilitated the clarification of various issues related to drug development and, in fact, have accelerated the approval process of many new drugs such as low molecular weight heparins (LMWs), synthetic heparin pentasaccharide (Arixtra), and newer antithrombin agents. Many new antiplatelet drugs and thrombolytic agents have also gained approval for multiple indications. The concept of polytherapy, including a combination of different drugs, has been introduced. The introduction of stents in interventional cardiology has added a new dimension in the management of acute coronary syndrome and related disorders. Moreover, stents are now commonly used in the management of vascular and

ischemic disorders in expanded indications. Initial attempts to coat stents with anticoagulant drugs have met with limited success; however, such approaches are still carried out. Drug-coated stents have also been introduced and until recently were widely used. Antiproliferative agents such as Taxol and Sirolimus have also been employed; however, their use has resulted with unexpected thrombotic complications. A recent US FDA panel has reviewed this matter and recommended that drug-coated stent implanted patients should be simultaneously treated with antithrombotic agents. Over the past few years, interest in anticoagulant drugs has grown significantly, as evidenced by a constant increase in the number of drugs introduced for both preclinical and clinical development. The excellent scientific research and development activities in the laboratories of the pharmaceutical industry have resulted in a steady flow of new products from various groups. Several new antithrombotics and anticoagulants have been introduced during the past five years for clinical evaluation. Third-party validation of developed products and well-designed clinical trials has been carried out in various academic medical centers. The results of these studies also constitute a significant portion of the progress reported at scientific meetings, and many important results have become available since the inception of this publication. Through its fast-track drug approval and revised policies, the FDA has provided expeditious mechanisms to the pharmaceutical industry, along with open-platform meetings, to discuss regulatory issues in the optimal development of new anticoagulant, antithrombotic, and thrombolytic drugs. The FDA and its representatives have continually contributed to the timely availability of new drugs by providing input at various stages of drug development. This input also has helped to clarify various issues related to new drug development and, in fact, has accelerated the approval process for many newer drugs, such as the LMWHs, ReoPro, and recombinant hirudin. Although heparin remains the sole anticoagulant used for the cardiovascular surgical procedures, the introduction of LMWH has added a new dimension to the overall management of

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thrombotic and cardiovascular disorders. Evidently, the LMWHs have achieved gold standard status in the management of thromboembolic disorders and now challenge other treatments, such as oral anticoagulants, for various indications. At the most recent meeting of the American Heart Association (Chicago, U.S.A., 2006), cardiologists revealed supportive data for the polytherapeutic use of LMWHs in the management of coronary syndromes, thrombotic stroke, and malignancy associated with thrombotic events. Antithrombin agents such as hirudin have also been compared with LMWHs for postsurgical prophylaxis of thromboembolism. Initial reports indicate favorable results with the use of polyethylene glycol-coupled (PEG) hirudin for treatment of coronary syndromes. In addition to the development of LMWHs, understanding the mechanisms of their antithrombotic actions and the relevance of their structural components has led to the development of synthetic analogs of heparin fragments. One remarkable approach based on the elucidation of the structure of heparin has led to the synthesis of oligosaccharides with high affinity for antithrombin III (AT III). Synthetic pentasaccharide is under evaluation in clinical trials for both thromboembolic and coronary indications. Several reports described its uses in various interventional procedures. There is much discussion of how LMWHs mediate their effects. In addition to potentiation of AT III, several other mechanisms have been identified, including the release of tissue factor pathway inhibitor (TFPI), vascular effects, profibrinolytic effects, platelet selectin modulation, and growth factor modulation. Clinical trials in Europe have shown that subcutaneous LMWH, given once or twice daily, is at least as safe and effective as continuous intravenous heparin in the prevention of recurrent venous thromboembolism and is associated with reduced bleeding and lower mortality rates. Several recent studies have shown that home administration of LMWH is as safe and effective as hospital administration of intravenous heparin in patients with proximal venous thrombosis. Initial evidence clearly suggests that LMWH may be a useful alternative to heparin in patients with pulmonary embolism. LMWHs may also be a useful alternative to heparin for arterial indications, such as treatment of unstable angina and stroke maintenance of peripheral arterial grafts. Recognizing the usefulness of LMWHs, the pharmaceutical industry has focused its attention on their use in the management of ischemic and thrombotic stroke. The initial results of clinical trials are promising. Thus, in the near future, the use of LMWH for prevention of thrombotic or ischemic stroke will be an important goal. The success of early clinical trials also suggests that LMWH may be useful in the management of primary and secondary ischemic or thrombotic stroke. Although LMWHs are proving to be as effective as and safer than heparin for various indications, it is important to realize that the differences in the manufacture of various LMWHs lead to differences in their pharmacological profile. Although these differences have not been clinically validated, each of the LMWHs is expected to exhibit its own therapeutic index in a

given clinical setting. Thus, the interchange of LMWHs based on equivalent gravimetric or biologic potency of standardized dosages may not be feasible. Because of the newer indications and the length of therapy, some additional issues related to the optimal use of LMWHs remain to be addressed. Examples include monitoring, control of bleeding, and drug interactions. Clinical trials have been designed to obtain information related to these issues. The differential clinical efficacy of various LMWHs was evident in the trials carried out with Fragmin (FRISC and FRIC) and enoxaparin (ESSENCE) and more recently with EXTRACT and other trials. Economic analyses of the treatment cost of heparin versus LMWH in various clinical settings show that although the cost of LMWH is marginally higher than the cost of heparin ($40–150), the expected reduction in costs for all treatment-related clinical events is much higher for LMWHs ($350–2700) than for heparin. Thus, LMWHs are an attractive alternative in an era of managed care health reform. Individual economic analysis for specific indications may provide additional information about the reduced costs, with the use of LMWHs for long-term outpatient treatment of such syndromes as unstable angina and ischemic cerebral events. In the search for antiplatelet agents to be used as antithrombotic drugs, it was recognized that the platelet glycoprotein IIb/IIIa (GPIIb/IIIa) plays a key role in the final common pathway for platelet aggregation. Several reports have become available recently. Many synthetic GPIIb/IIIa inhibitors are currently under clinical development for various indications. In the European Prospective Investigation in Cancer trial, ReoPro (an anti-GPIIb/IIIa) has been shown to reduce thrombotic events after percutaneous coronary angioplasty (PTCA). In an EPILOG study, the combined effects of ReoPro and heparin resulted in the inhibition of restenosis. Many of the GPIIa/IIIb inhibitors, including ReoPro, have also been found to inhibit the vitronectin receptor (᭙1 ᭚3 integrin), which is implicated in endothelial and smooth muscle cell migration. Thus, these agents exhibit multiple effects in addition to their antiplatelet functions. Another application of GPIIb/IIIa inhibitors is as an alternative agent to aspirin in the management of unstable angina, nonQ wave myocardial infarction, and ischemic or thrombotic stroke. The mechanism of the antiplatelet action of synthetic GPIIb/IIIa inhibitors and antibodies may be the same; however, major differences have been noted in their safety and efficacy. An emerging problem is therapeutic monitoring, which is being addressed with point-of-care systems. Thus, major clinical breakthroughs are expected with the use of these inhibitors in the management of cerebrovascular and cardiovascular disorders. The introduction of novel antiplatelet drugs has added a new dimension to the management of arterial thrombotis—in particular, thrombotic stroke. The availability of specific antagonist of adenosine diphosphate (ADP) receptor (e.g., ticlopidine) has provided a new approach for several cardiovascular and cerebrovascular indications. The second generation ADP receptor-blocking

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agents (e.g., clopidogrel) underwent extensive clinical trials to test their therapeutic efficacy in combined cardiovascular and cerebrovascular endpoints. Understanding the coagulation process has led to the identification of thrombin as a key enzyme in thrombogenic processes. Several direct thrombin inhibitors have been developed over the past few years by different methods. Hirudin, the leech-derived protein, has been compared with heparin for various procedures in numerous clinical settings, including treatment and prophylaxis of venous and arterial thrombotic disorders. The use of hirudin has been reported to be associated with increased risk of bleeding, indicating that better monitoring and dose-adjustment protocols are needed as well as antidotes. So far, clinical trials comparing hirudin and heparin as adjuncts in thrombolytic therapy in myocardial infarction (TIMI 9B) and acute coronary syndromes (GUSTO IIb) have shown hirudin to be marginally (if at all) superior to heparin. Recently, several reports comparing the effects of heparin and hirudin on various parameters have become available. A study comparing heparin and recombinant hirudin for the prophylaxis of deep venous thrombosis (DVT) provided impressive data in favor of hirudin. In a second study, LMWHs also were compared with hirudin for postsurgical prophylaxis of DVT; the results favored hirudin. Both studies emphasize an important point about the validity of well-designed clinical trials. It is important to understand that the efficacy and safety of a new drug may not be determined by trials for a single indication. Therefore, clinical trials are needed for various specific indications. Argatroban, another smaller thrombin inhibitor, is currently under clinical development for various indications. It has been used successfully in Japan for over a decade in the treatment of thrombotic disorders. Several clinical trials in both Europe and the United States have been designed to investigate its use as an alternative to heparin in heparin-compromised patients and as a prophylactic agent to reduce late restenosis after PTCA and coronary directional atherectomy. Argatroban was successfully used for the management of anticoagulation in patients with heparin-induced thrombocytopenia and as a substitute for heparin in PTCA. Since the half-life of argatroban is rather short, it has been administered via infusion protocols. For therapeutic anticoagulation, a level of 1–2 ␮g/mL is indicated, whereas for interventional cardiologic procedures a level of 3–7 ␮g/mL is maintained. Angiomax represents a synthetic antithrombin agent, which is shown to exhibit superior safety profile for anticoagulation in interventional procedures in comparison with heparin. Several studies have compared Angiomax with unfractionated heparin in a monotherapeutic approach and in settings with GPIIb/IIIa inhibitors. However, although the initial results show superiority in terms of efficacy and safety, the long-term outcome results have raised some questions on the mortality outcome and other complications. Like other thrombin inhibitors used parenterally, Angiomax

615

does not release TFPI and may compromise thrombin– thrombomodulin-mediated regulatory functions in blood vessels. Moreover, there is no antidote available for Angiomax. Therefore, heparins remain to be the anticoagulant of choice in interventional indications. Angiomax may be useful in heparin-compromised patients. Because of their weaker anticoagulant effect in global clotting tests, direct factor Xa inhibitors were not considered the desirable anticoagulant and antithrombotic agents for developmental purposes. However, because of the favorable clinical results with pentasaccharide, strong interest in synthetic anti-factor Xa drugs has re-emerged. These agents may be useful in the prophylaxis of both arterial and venous thrombotic disorders and may offer a greater margin of safety than the existing drugs. Additional advantages of direct thrombin and factor Xa inhibitors over heparin include subcutaneous and oral bioavailability. Although their biologic half-life is usually under 30 minutes, coupling to larger agents such as dextran or albumin can prolong their half-life without affecting their pharmacologic actions. Questions about monitoring and antagonism will have to be answered before thrombin and factor Xa inhibitors can be widely explored in clinical settings. Depending on their specificity for thrombin or factor Xa, they may be used as adjuncts with other classes of drugs, such as thrombolytic agents, for treatment of acute myocardial infarction. Low-molecular-weight thrombin and factor Xa inhibitors may also be used for localized delivery, stenting, and transdermal delivery. Because of their better bioavailabilty, a combination of thrombin and factor Xa inhibitors may be more useful in combination than as single agents. Optimal combinations for specific indications may be considered. As in the clinical development of LMWHs, thrombin and factor Xa inhibitors should be compared with heparin in terms of safety, efficacy, and cost. Newer developments in thrombolytic therapy include recombinant tissue plasminogen activators (tPAs). Bolusinjectable Reptilase is an unglycosylated plasminogen activator consisting of the Kirngle 2 and protease domain of tPA with a three- to four-fold longer half-life than tPA. The INECT trial demonstrated that Reptilase is superior to streptokinase for management of heart failure. Different variants of wild-type (wt) tPA, recombinant staphylokinase, and RTSPA*1 (vampire bat tPA) also have undergone clinical trials. Recombinant urokinase and prourokinase are now expressed in mammalian cell lines and are undergoing active clinical development. Molecular engineering of wt recombinant tPA extended the biologic half-life for bolus dosing, whereas staphylokinase and vampire bat plasminogen activator exhibited fibrin specificity. Thrombolytic agents also have found a place in the management of acute thrombotic stroke. Optimal approaches to improve the safety/efficacy index are currently under investigation. The next few years will witness the emergence of longer-acting thrombolytics to facilitate bolus dosing and improved specificity for fibrin and other receptors to target thrombotic sites. New indications for

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Epilogue

thrombolytic therapy, such as stroke and microangiographic syndromes, will be pursued. Restenosis after cardiac interventions remains a major challenge. An optimal therapeutic approach is still unavailable despite major scientific and financial undertakings. Even with the introduction of newer interventional cardiovascular and peripheral vascular procedures, late restenosis is commonly seen at a rate of 10% to 60%. Although the claimed efficacy of cardiovascular interventions exceeds that of medical and surgical approaches, restenosis is a major problem, resulting in angina and myocardial infarction. Several newer anticoagulant and antithrombotic drugs have been used to reduce restenosis. However, these approaches have met with limited success. Initial results with GPIIb/IIIa-targeting antibodies were encouraging. The introduction of bare metal and drug-eluting stents added a new dimension in the management of patients undergoing percutaneous coronary intervention (PCI). However, a significant number of patients treated with stents do develop thrombosis, especially those with drug-eluting stents. With a better understanding of pathophysiology of restenosis, improved drugs can be developed. Anticoagulant drugs such as LMWHs and PEG hirudin may prove useful. Mechanical devices such as stents and localized and programmed delivery of drugs may be expected to improve outcomes. Although monotherapy may be useful in the control of abrupt closure and subchronic occlusion, its role in late restenosis may be limited. Combined pharmacologic and mechanical approaches, coupled with specialized delivery, already have provided favorable results. The remainder of this decade will witness dramatic developments in the management of thrombotic and cardiovascular disorders. Synthetic and recombinant approaches will provide cost-effective and clinically useful drugs. LMWHs and synthetic heparin analogs are expected to have significant effects on the overall management of thrombotic and cardiovascular disorders. Factors such as managed care, regulatory issues, polytherapy, and combined pharmacologic and mechanical approaches will redirect the focus in management of DVT, thromboembolism, myocardial infarction, and thrombotic stroke. The direct thrombin agents hirudin and PEG hirudin will be of great value for surgical anticoagulation and in various acute indications. Postsurgical control of thrombotic processes may require combination therapy and LMWHs. Conventional drugs such as heparin, oral anticoagulants, and aspirin will remain the gold standards despite their known drawbacks. They require further optimization and can be used for various indications in cost-effective manner. The newer drugs and devices, however, provide alternatives that in the next few years may lead to improved, cost-compliant treatments. Owing to these rapid developments, several important issues related to current practices in anticoagulant therapy are recognized. Some of these issues include:

1. The replacement of unfractionated heparin by LMWHs in all indications. Although LMWHs have been used for interventional purposes, these drugs have not still gained the approval of the US FDA for this purpose. This is primarily due to the lack of clinical trial data on specific products and an understanding of the mechanisms of action. Moreover, the pharmacokinetics and pharmacodynamics of these drugs are different from that of unfractionated heparin and require further studies. LMWHs are only partially neutralized by protamine sulfate. Thus, additional data on their safety and efficacy in interventional indications are needed. 2. The potential replacement of heparins by newly developed antithrombin and anti-Xa agents. Antithrombin agents and anti-Xa agents have become the main focus for the development of oral and parenteral forms that can potentially replace heparins and oral anticoagulants. Although it is true that in heparin-compromised patients, such as those who develop heparin-induced thrombocytopenia, these agents can be used for acute anticoagulant management, there have, however, been several problematic issues related to the development of these agents. This has sensitized both the clinical and regulatory community to be cautious in recommending their unqualified use in all situations where heparins and warfarin are indicated. This is partly due to the single target effect of the two classes, which results in a relatively narrow therapeutic spectrum for these agents. Unlike heparins and oral anticoagulants, the drugs being currently developed and those undergoing trials do not have polytherapeutic effects, such as the modulation of the endothelium and interaction with endogenous proteins, growth factors, and cellular processes. Moreover, most of these agents, with the exception of the synthetic pentasaccharide, are synthetic peptidomimetics agents, with some unexplained effects on the vasculature and elevation of liver enzymes. This is particularly the case with the oral thrombin inhibitors. Thrombin inhibitors also interfere in the regulatory role of thrombin and indiscriminately inhibit the thrombin–thrombomodulin-mediated activation of protein C and thrombin activatable fibrinolysis inhibitor. In contrast, factor Xa inhibitors, being peptidomimetics, may result in the elevation of liver enzymes and produce other side effects. Currently, there is no antidote available to neutralize the effect of antithrombin and anti-Xa agents. Thus, it is unlikely that these agents will have broad indications such as the use of heparin and LMWH-s. Parenteral antithrombin agents such as argatroban, bivalirudin, and hirudins have been used in the anticoagulant management of heparin-induced thrombocytopenia. Bivalirudin has also been used in percutaneous interventions in several trials. As compared to heparin, although bleeding complications are reportedly less with the use of bivalirudin, long-term mortality outcome is less favorable. Moreover, like other thrombin inhibitors, it does not release TFPI from vascular

Epilogue

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11:51 AM

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Epilogue

sites. Oral thrombin inhibitors have been developed as potential replacement for warfarin in extended antithrombotic management in such indications as atrial fibrillation, DVT, and stroke. However, the current data on the safety and efficacy are unsatisfactory. Several anti-Xa agents are also being developed for both oral and parenteral use for specific indications. The safety of these drugs is reportedly somewhat better; however, conclusive data are not available at this time. Both the anti-Xa and IIa agents may be useful in acute anticoagulant settings; however, their longterm use for extended antithrombotic management of thrombotic and cardiovascular disorders is questionable at this time. 3. The feasibility of oral anti-Xa and anti-IIa agents as potential substitutes for oral anticoagulant and heparin-related drugs. There is major interest in developing anti-Xa and-IIa agents as potential substitutes for oral anticoagulants and heparins. In this regard, synthetic agents such as argatroban and Angiomax are used currently as an anticoagulant substitute for heparin in patients with heparin-induced thrombocytopenia (HIT). These drugs are monotherapeutic, and though they may be useful in acute settings, they may not be as suitable as heparin or oral anticoagulant substitutes for long-term usage. Parenteral anti-Xa drugs have also been developed with limited amount of success. At this time, several companies are developing anti-Xa agents, mostly in the DVT and related indications with oral formulations. The usefulness of the antithrombin and anti-Xa agents in interventional cardiology has not yet been fully validated. It may be that these drugs can be used for acute settings; however, safety considerations and their inhibition of the regulatory functions of thrombin and Xa may limit their use. The claim that oral antithrombin and anti-Xa drugs will eventually replace warfarin is based on limited studies, and the clinical data are not convincing. Thus, in both the parenteral and oral formulations, the anti-Xa and -IIa drugs will be of limited value for anticoagulation in interventional cardiology and postinterventional management of patients. As heparins are polytherapeutic, it would be difficult to mimic their effect with a single target agent; thus, it is prudent to be cautious in endorsing these agents. 4. The development of synthetic heparinomimetics representing specific actions of heparins and their relative bioequivalence to heparin. The synthetic heparinomimetics represented by pentasaccharide (Arixtra) are designer heparin-derived oligosaccharides, which mimic one of the many pharmacologic actions of heparin. In interventional cardiology, their use is limited and, unless given in combination with other drugs, there effectiveness as anticoagulant may be questionable. Arixtra is a sole anti-Xa agent, which only produces this effect after interacting with antithrombin III. The therapeutic spectrum of this drug is nowhere near as broad as that of heparin and LMWHs. Arixtra has no effect on thrombin

617

and does not produce any anticoagulation, even at very high concentrations. This agent was developed for DVT prophylaxis and, at best, can be used for this indication. Additional derivatives of pentasaccharide are also of limited value and their use in interventional cardiovascular setting is somewhat limited. Therefore, it is reasonable to project that these heparin-derived oligosaccharides will be of limited value in interventional cardiology. 5. The development of recombinant antithrombotic agents such as activated protein C (APC), tissue factor pathway inhibitors, recombinant equivalent of serpins, and thrombomodulin, with reference to their relative applications in specific disorders. Recombinant technology offers a unique opportunity to develop anticoagulant drugs of natural origin, which are based on knowing the structure of proteins from plants and animals. One of the most widely investigated anticoagulant proteins is hirudin that is obtained from the leech, Hirudo medicinalis. Although initially slated for multiple indications, this agent has faced several developmental difficulties including safety issues. Moreover, like with all proteins, the development of antibodies has hampered its use in specific indications. Such may be the case with many proteins, such as the protein inhibitors of coagulation factors. Recombinant TFPI has been used in interventional cardiology; however, due to safety issues, its development has stopped. Although recombinant APC may be useful in specific hematologic indications, its use in interventional cardiology is very limited. Moreover, the cost of these proteins is rather high. Thus, the recombinant equivalent products of anticoagulant proteins will be of limited value in any interventional purposes. 6. The development of newer antiplatelet drugs such as the ADP receptor inhibitors, glycoprotein IIb/IIa receptors, phosphodiesterase inhibitors, and specific COX-1 and COX-2 inhibitors and their relevance in the management of various disorders. The relevance of on board aspirin for the therapeutic index of each of these agents also requires additional investigations. Interventional cardiology has gone through several transitions during the past 10 years for the use of antiplatelet drugs. The introduction of glycoprotein IIb/IIIa inhibitors such as the ReoPro, Integrelin, and Aggrastat were initially slated to be the standard of care and were recommended for unqualified use. Moreover, their use resulted in reducing the dosage of heparin for anticoagulation in interventional procedures. With the unexpected impact of clopidogrel on the anticoagulation management of patients undergoing PCIs, the use of GPIIb/IIIa inhibitors has undergone a reevaluation. Currently, these drugs are only used in qualified indications with PCI. The front-loading of clopidogrel remains an open question along with the interactions of drugs with this agent. Together with the newer approaches to using LMWH, antithrombin drugs,

Epilogue

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Epilogue

and possibly anti-Xa drugs, there will be complex drug interactions and safety and efficacy issues, which will require clear recommendations for the optimization of these drugs. Taking into consideration the additional effects of such drugs as statins, this polytherapeutic approach will require close monitoring. 7. The design of newer thrombolytic agents, with specific reference to their endogenous interaction and pharmacodynamic differences in terms of their relative clinical effects in stroke and myocardial infarction. The newer thrombolytic agents represent drugs with significant differences in the biochemical and pharmacologic actions. Besides dissolving the clot, these drugs also have additional effects, which are not completely understood at this time. Moreover, thrombolytic agents exhibit profound interactions with anticoagulant and antiplatelet drugs. The margin of safety in these agents is rather narrow, and although the efficacy of newer agents may be attractive, their safety consideration remains to be resolved. With the widespread use of stenting and other procedures, the use of thrombolytic drugs is reduced. Despite all of these limitations, the conventional thrombolytic agents such as the tPA and streptokinase may be useful in some indications. 8. The recent recognition of the antithrombotic actions of statins, nitric oxide donors, and other nonanticoagulant drugs, and their impact on overall therapeutic approaches. Patients who require interventional procedures are treated with multiple drugs. These drugs include statins, nitrates, calcium channel blockers, betablockers, and many other drugs. The use of anticoagulant and antiplatelet drugs is challenging from the standpoint of achieving desirable anticoagulation for the intended duration without safety compromise. At the present time, there are no guidelines or recommendations that take into account these interactions and adjust dosage for different drugs. There are pharmacokinetic and pharmacodynamic interactions. Moreover, because of the individual differences (pharmacogenomics) and population kinetic variations among patients, optimization of anticoagulation is not an easy task. Collective data from large clinical trials may be applicable, and clinical judgment on the basis of individual patient responses will be more important in achieving satisfactory results. Such interactions have not even been taken into account by some of the most recent trials on newer drugs. 9. Risks associated with drug-coated stents. The initial attempts to coat anticoagulant and antiplatelet drugs on stents have met with limited success, and results have been unsatisfactory. Because of the instant fibrosis and other occlusive lesion development, metal stents were coated with small amounts of antiproliferative (anticancer) drugs such as Paclitaxel and Sirolimus. Although these drugcoated stents have been widely used in interventional procedures, new data suggest that there is a significant

increase in stent thrombosis in patients who have drugeluting stents. The pathogenesis of the thrombotic complications associated with drug-eluted stents is not known and may be multifactorial. The CYPHER Sirolimuseluting Coronary Stent is indicated for improving coronary luminal diameter in patients with symptomatic ischemic disease due to discrete de novo lesions of length ⬍30 mm in native coronary arteries, with reference vessel diameter of 2.5 mm–3.5 mm. The TAXUS Express Paclitaxel-Eluting Coronary Stent System is indicated for improving the luminal diameter for the treatment of de novo lesions of ⬍28 mm length in native coronary arteries 2.5–3.75 mm in diameter. These devices have resulted in significant reduction in the incidence of restenosis. However, because of the stent thrombosis, the US FDA has convened a panel of advisors to discuss the potential risk associated with drugeluting stents. It is now known that cancer patients who are treated with anticancer drugs such as Sirolimus or Taxol develop therapy-associated thrombosis, requiring anticoagulant therapy. Therefore, drug-eluting stents may also produce similar effects in patients implanted with these devices. Although clopidogrel is recommended, the dosage and duration of this drug may vary with patient populations. Moreover, in complicated cases, such as patients with diabetes, acute myocardial infarction, multiple vessel decisions, or lesions involving arterial bifarcations, the left main coronary artery and long arterial segments may require individualized management. The observed thrombotic complications with drug-eluting stents are real, and clopidogrel may not be the only medication needed. In individualized risk groups, it may be that simultaneous use of oral anticoagulant drugs and/or LMWH may be warranted. The current debates on the future of drugeluting stents and associated therapies will continue for some time to come. Additional approaches to keep the vascular patency, structural integrity, and antithrombotic functions, especially in the coronary arteries, have also utilized stem cells and other molecular approaches. At this time, the observations based on these techniques have not provided any conclusive information. The number of drugs and devices will continue to expand for interventional procedures and postinterventional care of patients. Together with the introduction of newer devices and development of additional procedures, this entire field will continue to expand for some time. Because of these dramatic developments, additional approaches will be needed to develop newer approaches to understand the complex interplay between drugs and devices and to balance the optimized use of drugs in this field. Regardless of these remarkable developments, the basic principles behind vascular pathophysiology must be considered prior to the development of complex approaches, which may provide obscure messages and directions.

Dose-dependent; 0.65 mcg/mL for 5 mg dose (17)

Cmax

Halflifea

For warfarin: mean of 40 hrs (1); dose-dependent, 47 hrs for 5 mg dose (17) for vitamin K dependent clotting factors: II-60 hrs, VII-4–6 hrs, IX-24 hrs, X48–72 hrs (1)

AC effect in 2 days (12); AT effect in 6 days (12); 1 hr (9,17) for Cmax

T Cmax

15–20 min (9)

5.51 mcg/mL (after 650 mg dose) (16)

30–40 min (9); 60.4 min (after 650 mg dose) (16)

Aspirin

8 hrs (2,14)

3 mg/L (2,14)

1 hr (2,14)

PLAVIX® Clopidogrel

12 hrs (3,15) 4.5 hrs (3), 4.3 hrs for 40 mg (15); 4.4 hrs for 40 mg (19)

0.42 IU/mL for 40 mg (15); 0.57 IU/ml for 40 mg (19)

3-5 hrs (3); ~3 hrs (15); 2.9 hrs for 40 mg (19)

LOVENOX® Enoxaparin 4–5 hrs (5); 2 hrs ~3 hrs (15)

INNOHEP® Tinzaparin

~12 hrs (15) 3–5 hrs (4); 2.4 hrs for 5000 IU (15); 2.8 hrs for 2500 IU (19)

~12 hrs (15) 3-4 hrs (5); 3 hrs for 50 IU/ kg (15)

Dose dependent; 0.18 IU/mL 0.49 IU/mL for 50 IU/kg for 5000 IU(15); (15) 0.22 IU/mL for 2500 IU (19)

4 hrs (4); ~3 hrs (15); 2.8 hrs for 2500 IU (19)

FRAGMIN® Dalteparin

12 hrs (20)a 30–150 min; dose- and infusion time-dependent; 77 min for 5000 IU s.c. (20)a

0.039 IU/mL for 5000 IU s.c. (20)a; 0.09 IU/mL for 5000 IU s.c. (15)a

~immediate with IV administration; 2.5 hrs for 5000 IU s.c. (15)a

Heparin

17–21 hrs (6,10)

After 2.5 mg s.c., 0.34 mg/L (6,10)

2 hrs after 2.5 mg s.c. (6,10)

ARIXTRA® Fondaparinux

25 min (11,21)

Dose dependent; 12.3 mcg/ ml after 1 mg/kg bolus and 4 hour 2.5 mg/kg/h IV infusion (11)

Within 5 min post 15 min IV bolus of 0.05–0.6 mg/ kg and within 2 min after 0.3 mg/kg bolus inj (21)

ANGIOMAX® Bivalirudin

2–3 hrs (7,8)

EXANTA™ Ximelagatran

~2.5 hrs (18) 46.2 min (18)

(Continued )

2–3 hrs (7.8)

568 ng/ml 0.2 µmol/L steady-state (7) after 125 mcg/kg bolus and 2.5 mcg/kg/min infusion (18)

~1 hr to steady-state after 125 mcg/ kg bolus and 2.5 mcg/kg/ min infusion (18)

Argatroban

11:21 AM

T Cmin

COUMADIN® Warfarin

3/14/07

Agent

Pharmacokinetic comparison of various anticoagulants

Appendix A

1180 AppendixA Page 619

Protamine (3)

Protamine (4)

Residual antiXa activity 24 hrs (19)

Protamine (5)


Protamine

Heparin

None (6)


None (11)


None

Argatroban

None

EXANTA™ Ximelagatran

Abbreviations: AC, anticoagulation; AT, antithrombotic; Cmax, maximum concentration; Cmin, minimum concentration; T Cmax, time to maximum concentration; T Cmin, time to minimum concentration.

platelet-inhibitory effects of aspirin last the lifetime of the platelet, due to irreversible inactivation of platelet COX-1; the average platelet lifespan is 10 days; 50% of platelets function normally 5–6 days after aspirin ingestion (9).

Platelet transfusion (2)

Persistent antiXa activity for 12 hrs after 40 mg (3); Residual anti-Xa activity 24 hrs (19)


LMWH and UFH, half-life refers to half-life of anti-Xa activity following SC injection.

Vitamin K1 (1)

Antidote

7 days (9,13)

10 days (9)b

LOVENOX® Enoxaparin

bThe

4–5 days for INR in range 2–3 to decrease to ⬍1.2 (22)

Return to baseline/ duration of activity

PLAVIX® Clopidogrel

Asprin

aFor

COUMADIN® Warfarin

11:21 AM

Agent

620

3/14/07

Pharmacokinetic comparison of various anticoagulants (Continued )

1180 AppendixA Page 620

Appendix A

1180 AppendixA

3/14/07

11:21 AM

Page 621

References

References 1 2 3 4 5 6 7

8

9

10

11 12

Coumadin Prescribing Information, Bristol-Myers Squibb, June 2002. Plavix Prescribing Information, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, May 2002. Lovenox Prescribing Information, Aventis Pharmaceuticals, January 2003. Fragmin Prescribing Information, Pharmacia, June 2002. Innohep Prescribing Information, LEO Pharmaceutical Products, January 2003. Arixtra Prescribing Information, Sanofi-Synthelabo, December 2002. Sarich TC, Teng R, Peters GR, et al. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003; 42:485–492. Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003; 42:381–392. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationship among dose, effectiveness, and side effects. Chest 2001; 119:39S–63S. Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002; 41 Suppl 2:1–9. Angiomax Prescribing Information, The Medicines Company, June 2002. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119:8S–21S.

13

14 15

16

17

18

19

20

21 22

621

Weber AA, Braun M, Hohlfeld T, et al. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Pharmacol 2001; 52:333–336. Caplain H, Donat F, Gaud, C, et al. Pharmacokinetics of clopidogrel. Semin Thromb Hemost 1999; 25(Suppl 2):25–28. Eriksson BI, Soderberg K, Widlund L, et al. A comparative study of three low-molecular weight heparins (LMWH) and unfractionated heparin (UH) in healthy volunteers. Thromb Haemost 1995; 73:398–401. Muir N, Nichols JD, Clifford JM, et al. The influence of dosage form on aspirin kinetics: implications for acute cardiovascular use. Curr Med Res Opin 1997; 13:547–553. King SYP, Joslin MA, Raudibaugh K, et al. Dose-dependent pharmacokinetics of warfarin in healthy volunteers. Pharm Res 1995; 12:1874–1877. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20:318–329. Collignon F, Frydman A, Caplain H, et al. Comparison of the pharmacokinetic profiles of three low molecular mass heparins-dalteparin, enoxaparin and nadroparin-administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 1995; 73:630–640. Bara L, Billaud E, Gramond G, et al. Comparative pharmacokinetics of a low molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39:631–636. Sciulli TM, Mauro VF. Pharmacology and clinical use of bivalirudin. Ann Pharmacotherapy 2002; 36:1028–1041. White RH, McKittrick T, Hutchinson R, et al. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med 1995; 122:40–42.

1180 AppendixA

3/14/07

11:21 AM

Page 622

Dose-dependent; 0.65 mcg/mL for 5 mg dose (15)

Cmax (Maximum concentration)

4–5 days for INR in range 2–3 to decrease to ⬍1.2 (20)

Vitamin K1 (1)

Antidote

For vitamin K dependent clotting factors: II-60 hr, VII-4–6 hr, IX-24 hr, X-48-72 hr (1)

Return to baseline/ duration of activity

Half-lifea

For warfarin: mean of 40 hrs (1); dose-dependent, 47 hr for 5 mg dose (15)

AC effect in 2 days (10); AT effect in 6 days (10); 1 hr (7,15) for Cmax

T Cmax (Time to maximum concentration)

10 days (7)b

15–20 min (7)

5.51 mcg/mL (after 650 mg dose) (16)

30–40 min (7); 60.4 min (after 650 mg dose) (14)

ASPIRIN

Platelet transfusion (2)

7 days (7,11)

8 hr (2,12)

3 mg/ L (2,12)

1 hour (2,12)

PLAVIX ® AZD6140

Prasugrel

AGGRASTAT ® Tirofiban

INTEGRILIN ® Eptifibatide

(Continued)

REOPRO ® Abciximab

12:14 PM

T Cmin (Time to minimum concentration)

COUMADIN ® Warfarin

Agent

3/14/07

Pharmacokinetic comparison of Warfarin and various antiplatelet drugs

Appendix B

1180 AppendixB Page 623

Persistent anti-Xa activity for 12 hr after 40 mg (3); Residual anti-Xa activity 24 hr (17)

Protamine (3)

Return to baseline/duration of activity

Antidote

Protamine (4)

Residual anti-Xa activity 24 hr (17)

3–5 hr (4); 2.4 hr for 5000 IU (13); 2.8 hr for 2500 IU (17)

Protamine (5)

3–4 hr (5); 3 hr for 50 IU/kg (13)

~12 hr (13)

Protamine

30–150 min; dose- and infusion time-dependent; 177 min for 5000 IU s.c. (18)a

12 hr (18)a

0.039 IU/mL for 5000 IU s.c. (18)a; 0.09 IU/mL for 5000 IU s.c. (13)a

None (6)

17–21 hr (6,8)

After 2.5 mg s.c., 0.34 mg/L (6,8)

Two hrs after 2.5 mg s.c. (6,8)

None (9)

25 min (9,19)

Dose dependent; 12.3 mcg/mL after 1 mg/kg bolus and 4 hr 2.5 mg/kg/hr IV infusion (9)

Within 5 min post 15 min IV bolus of 0.05–0.6 mg/kg and within 2 min after 0.3 mg /kg bolus inj (19)


None

46.2 min (16)

~2.5 hr (16)

568 ng/mL steady-state after 125 mcg/kg bolus and 2.5 mcg/kg/min infusion (16)

~1 hr to steady-state after 125 mcg/kg bolus and 2.5 mcg/kg/min infusion (16)

ARGATROBAN

Abbreviations: AC, anticoagulation; AT, antithrombotic; LMWH, low molecular weight heparin; UFH, unfractionated heparin.

after aspirin ingestion (9).

platelet-inhibitory effects of aspirin last the lifetime of the platelet, due to irreversible inactivation of platelet COX-1; the average platelet lifespan is 10 days; 50% of platelets function normally five to six days

4.5 hr (3), 4.3 hr for 40 mg (13); 4.4 hr for 40 mg (17)

Half-lifea

~12 hr (13)

0.18 IU/mL for 50 IU/kg (13)

~immediate with IV administration; 2.5 hr for 5000 IU s.c. (13)a


LMWH and UFH, half-life refers to half-life of anti-Xa activity following SC injection.

12 hr (3,13)

T Cmin (Time to minimum concentration)

Dose dependent; 0.49 IU/mL for 5000 IU (13); 0.22 IU/mL for 2500 IU (17)

4–5 hr (5); ~3 hr (13)

HEPARIN

bThe

0.42 IU/mL for 40 mg (13); 0.57 IU/mL for 40 mg (17)

Cmax (Maximum concentration)

4 hr (4); ~3 hr (15); 2.8 hr for 2500 IU (17)


12:14 PM

aFor

3–5 hr (3); ~3 hr (13); 2.9 hr for 40 mg (17)

T Cmax (Time to maximum concentration)


624

LOVENOX® Enoxaparin

3/14/07

Agent

Pharmacokinetic comparison of various anticoagulant drugs (Continued)

1180 AppendixB Page 624

Appendix B

1180 AppendixB

3/14/07

12:14 PM

Page 625

References

References 1 2 3 4 5 6 7

8

9 10

11

12

Coumadin Prescribing Information, Bristol-Myers Squibb, June 2002. Plavix Prescribing Information, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, May 2002. Lovenox Prescribing Information, Aventis Pharmaceuticals, January 2003. Fragmin Prescribing Information, Pharmacia, June 2002. Innohep Prescribing Information, LEO Pharmaceutical Products, January 2003. Arixtra Prescribing Information, Sanofi-Synthelabo, December 2002. Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationship among dose, effectiveness, and side effects. Chest 2001; 119:39S–63S. Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002; 41(suppl 2):1–9. Angiomax Prescribing Information, The Medicines Company, June 2002. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 2001; 119:8S–21S. Weber AA, Braun M, Hohlfeld T, et al. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Pharmacol 2001; 52:333–336. Caplain H, Donat F, Gaud C, et al. Pharmacokinetics of clopidogrel. Semin Thromb Hemost 1999; 25(suppl 2):25–28.

13

14

15

16

17

18

19 20

625

Eriksson BI, Soderberg K, Widlund L, et al. A comparative study of three low-molecular weight heparins (LMWH) and unfractionated heparin (UH) in healthy volunteers. Thromb Haemost 1995; 73:398–401. Muir N, Nichols JD, Clifford JM, et al. The influence of dosage form on aspirin kinetics: implications for acute cardiovascular use. Curr Med Res Opin 1997; 13:547–553. King SYP, Joslin MA, Raudibaugh K, et al. Dose-dependent pharmacokinetics of warfarin in healthy volunteers. Pharm Res 1995; 12:1874–1877. Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 2000; 20:318–329. Collignon F, Frydman A, Caplain H, et al. Comparison of the pharmacokinetic profiles of three low molecular mass heparins-dalteparin, enoxaparin and nadroparinadministered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost 1995; 73:630–640. Bara L, Billaud E, Gramond G, et al. Comparative pharmacokinetics of a low molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39:631–636. Sciulli TM, Mauro VF. Pharmacology and clinical use of bivalirudin. Ann Pharmacotherapy 2002; 36:1028–1041. White RH, McKittrick T, Hutchinson R, et al. Temporary discontinuation of warfarin therapy: changes in the international normalized ratio. Ann Intern Med 1995; 122:40–42.

1180 AppendixB

3/14/07

12:14 PM

Page 626

1180 Index

3/14/07

11:50 AM

Page 627

Index

AAA. See Abdominal aortic aneurysms (AAA) AAV. See Adeno-associated virus (AAV) Abciximab (ReoPro), 41–42, 526, 578–579, 622 peri-percutaneous coronary intervention, 531 pharmacology, 129 Abdominal aortic aneurysms (AAA) assessment, 584 bifurcated supported stent graft, 586 device migration, 588–589 DREAM trial, 589 endograft limb occlusion, 588 endoleaks, 587–588 EUROSTAR Registry, 589 EVAR, 590 complications, 586–588 future directions, 590 outcomes and results, 589 extremity and visceral ischemia, 589 graft kinks, 588 infrarenal, angiogram, 584 patient selection, 583–584 repair, 583–591 contraindications, 584 endograft challenges, 585–586 procedure, 585 sac enlargement, 588 surveillance, 589 Acetylsalicylic acid (ASA) MI, 120–121 Acquired (secondary) hypercoagulable states, 15 ACS. See Acute coronary syndrome (ACS) ACT. See Activated clotting time (ACT) Actinomycin D restenosis, 303 Activated clotting time (ACT), 87, 529, 569 Acute coronary syndrome (ACS), 1, 465–471 antithrombotic therapy, 121 biomarkers, 120, 466–467 clopidogrel, 62–63, 121 lipid-lowering agents, 161–162 LMWH, 121 management, 119 pathophysiology, 119 standard therapy, 120–121 thienopyridines, 62–63 Acute myocardial infarction (AMI) cell transplantation, 423 cellular therapy clinical trials, 444 comparative preclinical studies, 423 HIT, 95 oral DTI, 114

Adeno-associated virus (AAV), 363 growth factor delivery, 411 Adenosine peri-percutaneous coronary intervention, 533 Adenosine diphosphate (ADP), 32, 128 receptor, 622 receptor inhibitors, 59–66 indications, 62–63 pharmacokinetic profile, 60–61 structure, 59–60 TXA2, 35 UFH, 94–95 Adenosine receptor agonist, 395–396 ADP. See Adenosine diphosphate (ADP) Adult stem cells cardiac repair, 401 AF. See Atrial fibrillation (AF) AFM. See Atomic force microscopy (AFM) Aggrastat, 41–42, 526, 579 peri-percutaneous coronary intervention, 531 pharmacology, 129 ALA. See Aminolevulinic acid (ALA) Alcohol injection HCM septal alcohol ablation, 607 Aldosterone antagonists heart failure, 453–454 adverse effects, 454 clinical effects, 454 clinical trials, 454 indications, 454 pathophysiology, 453–454 Alloimmune thrombocytopenia, 10–11 Alpha-tocopherol (ART), 219–220 Alteplase (recombinant tissue plasminogen activator), 576–577 AMI. See Acute myocardial infarction (AMI) Aminolevulinic acid (ALA), 383 Aminophylline CIN, 498 Amiodarone AF, 486–488 heart failure, 459 Amlodipine heart failure, 459 Amplatzer devices LAA, 594, 595 Amplatzer PFO occluder, 598 Androgens ED, 511 Anesthesia neuraxial and anticoagulation, 18–19 Aneurysms. See Abdominal aortic aneurysms (AAA)

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11:50 AM

Page 628

Index

Angina autologous bone marrow cells cellular therapy clinical trials, 443–445 Angiogenesis, 339, 393–401. See also Therapeutic angiogenesis atheromatosis, 339–340 bioabsorbable materials, 398 cellular therapy clinical trials, 447 DES, 398 disease, 394 FGF, 340, 397, 409–410 gene therapy, 399 myocardial growth factors, 407–410 preclinical studies, 396–397 protein therapy, 398 thrombosis, 398 Angiogenic agents, 340 local delivery with stents, 341–342 Angiography HCM septal alcohol ablation, 605 Angiomax, 623 Angiopeptin restenosis, 301 Angiopoietin angiogenesis, 339 Angiotensin-converting enzyme inhibitors LVSD, 451–452 adverse effects, 452 clinical effects, 451–452 hemodynamic effects, 451 pathophysiology, 451 trials, 452 peri-percutaneous coronary intervention, 533 Angiotensin receptor blockers peri-percutaneous coronary intervention, 533 Angiotensin II receptor blockers after MI, 457 heart failure and 454–455 adverse effects, 457 clinical trials, 456 indications, 457 mortality and hospitalization, 456–457 pathophysiology, 454–455 Anthocyanidins, 226 Antiangiogenic agents, 340 heart failure, 459–460 Anticoagulant drugs, 528–530 with antiplatelet therapy, 127–133 clinical use, 130–132 combination therapy, 580 current practices, 624 heart failure, 460 natural system polymorphisms, 542 peripheral vascular interventions, 569–580 pharmacokinetic comparison, 613–614, 617–618 pharmacology, 128–129

Anticoagulants oral, 544 current practices, 624 Anticoagulation interindividual difference, 93 Anti-inflammatory agents restenosis, 185–186, 195–196 Antimigratory drugs, 325–337 Antineoplastic drugs systemic and restenosis, 195–207 Antioangiogenetic drugs, 339–344 Antioxidants, 211–233 clinical definition, 218–219 combinations, 228–232 healing, 190 network, 215–216, 218 Antiplatelet drugs, 31–39, 516–518, 525–526 heart failure, 460 pharmacology, 130 rationale, 139–140 resistance, 139–150 sites of action, 127 Antiproliferative drugs restenosis, 188 Antirestenotic agents systemic therapy, 299–300 Antirestenotic drugs systemic clinical trials, 185–192 Antisense oligonucleotides, 371–377 chemistry, 371–372 complications, 373 contraindications, 372–373 gene expression, 373–374 intimal hyperplasia, 373–374 limitations, 375 mechanism of action, 372 restenosis, 374–375, 376 vascular proliferative disease, 375–377 delivery system, 375–376 Antithrombin, 6 parenteral direct, 93–104 Antithrombin drugs oral, 109–115 Antithrombin-III (AT-III), 94 Antithrombotic drugs, 516–518 ACS history, 127–128 future, 133 Antithrombotic prophylaxis HCM septal alcohol ablation, 607 Antrin, 383 Aortic stenosis, 596 Arachidonic acid, 34–35 Argatroban, 87, 623 ACS, 121–122 AMI, 97–99 clinical trials, 99 characteristics, 97

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Page 629

Index

[Argatroban] clinical evidence, 88–89 HIT, 11 monitoring, 99 parenteral, 96–98 PCI, 96–97 HIT, 98–99, 103–104 pharmacokinetics, 87, 96, 98 pharmacology, 129 Arixtra, 621 ART. See Alpha-tocopherol (ART) ASA. See Acetylsalicylic acid (ASA); Aspirin (ASA) Ascorbate, 224 Aspirin premedication LAA, 594 Aspirin (ASA), 517, 525 vs. ADP receptor inhibitors, 21 current practices, 624 heart failure, 460 implantation, 601 mechanism of action, 140–141 newer formulations, 22 peri-percutaneous coronary intervention, 531, 532, 533 pharmacology, 129 PMIVSD, 598 resistance, 141–144 clinical relevance, 142–144 laboratory evaluation, 142 mechanism, 142 studies, 143 therapeutic intervention, 144 restenosis, 301 AT-III. See Antithrombin-III (AT-III) Atheromatosis angiogenesis, 339–340 Atherosclerosis cell transplantation, 428–430 DFO, 244, 245 platelets, 37–38 Atherosclerotic neovascularization, 340 Atomic force microscopy (AFM) TAXUS stent, 284, 285 Atorvastatin ACS clinical trials, 161–162 diabetes, 159 PCI, 162 RCT, 164 target low-density lipoprotein cholesterol levels, 160 Atrial fibrillation (AF) algorithm, 487 during catheterization, 483–490 anticoagulation, 483–484 AV node conduction, 488–490 cardioversion, 485 electrical cardioversion, 485 incidence and prevalence, 483 oral anticoagulation, 484 pharmacologic cardioversion, 485–488 radiofrequency ablation anticoagulation, 484–485

[Atrial fibrillation during catheterization] rate control, 488–490 rhythm control, 485 therapeutic options, 483 interventions, 483 oral DTI, 114 Atrial flutter during catheterization radiofrequency ablation anticoagulation, 484–485 Atypical chest pain, 465 Autologous bone marrow stem cells intracoronary injections cellular therapy clinical trials, 440–443 AVI-4126, 371, 376, 377 AZD6140, 60, 149 Bare metal stents (BMS), 398 Basic fibroblast growth factor (BFGF) angiogenesis, 339 Batimastat, 304 chemical structure, 327 long-term studies, 330 mode of action, 327 preclinical study, 328 restenosis, 303 Bernard-Soulier syndrome, 12 Beta blockers AV node conduction, 488–489 HCM, 593 heart failure adverse effects, 452–453 clinical effects, 452 clinical trials, 453 hemodynamic effects, 452 pathophysiology, 452 peri-percutaneous coronary intervention, 533 Beta-carotene, 221–224 clinical/epidemiological studies, 222–224 Beta-thromboglobulin, 32 Bevacizumab, 342–344 Bevacizumab-eluting stents, 343 BFGF. See Basic fibroblast growth factor (bFGF) Bioabsorbable polymers DES, 291 Biodivysio batimastat stent studies baseline clinical characteristics, 334 clinical follow-up, 333 clinical results, 335 angiographic outcome, 335 six-month follow-up, 335 clinical studies, 330–333 definitions and statistics, 333 demographic characteristics, 333 medication, 333 preclinical assessment, 327–328 quantitative coronary angiographic analysis, 333 results, 333–334 short-term clinical results, 335 Biodivysio stents, 341, 342

629

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630

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Page 630

Index

Bioengineered stents lipid-lowering agents PCI, 166 Biomedical engineering cardiovascular genomics, 543–544 Biostable polymers DES, 291 BioSTAR, 599, 600 Bivalirudin, 86–87, 569, 570–571 ACS, 121–122 AMI, 102 clinical trials, 102 characteristics, 97 clinical outcomes, 572 dose, 102–103 parenteral, 100–101 PCI, 101–102 alternative anticoagulants, 104 peri-percutaneous coronary intervention, 532 pharmacokinetics, 87 pharmacology, 129 Black-hole phenomenon, 270 Bleeding abnormal hemostasis, 10–11 Blood pressure control before and after surgery or angiography, 173 electronic device accuracy, 171–172 sequential readings, 172–173 simultaneous readings, 172 rapid control in hospital or clinic, 175–176 BM-MNC. See Bone marrow mononuclear cells (BM-MNC) BMS. See Bare metal stents (BMS) BNP. See Brain natriuretic peptide (BNP) Bone marrow cell-induced capillary and neovessel formation, 440 Bone marrow mononuclear cells (BM-MNC), 423–424 Bone marrow stem cells, 439–440 Brachytherapy, 267–273. See also Intracoronary brachytherapy (ICB) clinical applications, 268 DES, 268–269 DTI, 90 physics, 267 Bradyarrhythmias carotid artery stenosis, 562 Brain natriuretic peptide (BNP), 466 ACS, 470 Branch retinal vein thrombosis (BRVT), 17 Budd-Chiari syndrome, 17 Bumetanide, 457 Calcium, 32 Calcium antagonists AV node conduction, 489 HCM, 593 heart failure, 459 nondihydropyridine AV node conduction, 489 CAM. See Cell adhesion molecules (CAM) cAMP. See Cyclic adenosine monophosphate (cAMP)

Cangrelor, 60, 149 Cardiac risk sexual activity and 504–505 CardioSEAL-STARflex occluder, 598, 599, 600 Cardiovascular disease eradication, 543 future, 543 homocysteine, 178 iron, 241–242 risk reduction, 515 sexual activity and 507–508 Cardiovascular system genetic manipulation, 363–369, 543 biomedical engineering, 543–544 clinical therapy, 367–368 combination and synergistic use, 367 complications, 367 future, 368–369 gene therapy targets, 364–365 indications, 364–367 interventional cardiology, 367–368 ischemia, 365–366 mechanism of action, 363–365 vectors, 364 Carotid artery dissection, 564 in-stent restenosis, 563 perforation, 564 revascularization asymptomatic patients, 558 historical perspectives, 555 indications, 556–556 patient selection, 557–558 symptomatic patients, 557 stenosis angiographic assessment, 562 bradyarrhythmias, 562 catheter placement, 561 EPD removal, 562 lesion wiring, 561 management decision-making, 558 periprocedural monitoring and management, 560 postdilatation, 562 postdischarge therapy and surveillance, 562 predilatation, 561 procedural complications, 562–564 procedural considerations, 560–562 procedural stages, 560–561 stent selection and deployment, 561–562 vascular tortuosity, 559 stents, 555–564 Catheter ablation NASPE policy statement, 485 CDD. See Controlled drug delivery (CDD) CDK. See Cyclin-dependent kinase (CDK) cDNA. See Complementary DNA (cDNA) Cefuroxime tricuspid stenosis, 597

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Page 631

Index

Cell adhesion molecules (CAM), 37 Cell death PDT, 381–382 Cell migration restenosis, 325 Cell transplantation AMI comparative preclinical studies, 423 atherosclerosis, 428–430 cardiovascular repair, 419–434 cell type selection, 421–422 cell types, 432–433 comparative preclinical studies, 421 creative thinking, 431 data, 430–431 gold rush, 431–432 hurdles and opportunities, 430–433 mechanistic understanding, 431 multicenter trials, 432 optimal delivery, 425–426 premise, 420–430 prevention, 428–430, 432 process, 419–420 tools, 432 unanticipated outcomes, 426–428 heart failure comparative preclinical studies, 422 peripheral vascular disease, 430 prevention ischemic heart disease, 428–430 Cell types, 439–440 Cellular therapy defined, 439 delivery methods and procedures, 440 Cellular therapy clinical trials, 439–448 AMI, 444 angiogenesis and cytokine clinical trials, 447 autologous bone marrow cells for chronic stable angina and ischemic cardiomyopathy, 443–445 autologous bone marrow stem cell intracoronary injections, 440–443 future, 447–448 skeletal myoblast intramyocardial injection for ischemic myocardial dysfunction, 445–447 Central retinal vein thrombosis (CRVT), 17 CEP. See Circulating endothelial precursor (CEP) Cerebral hemorrhage, 564 Cerebral venous thrombosis, 17 Chest pain atypical, 465 Chronic coronary arterial occlusions histologic specimens, 551 Chronic total occlusion (CTO), 549 PCI, 550 pharmacological approach optimizing initial safety, 551–552 optimizing initial success, 552–553 pharmacologic management, 549–553

[Chronic total occlusion] recanalization wave registry, 550 revascularization mechanical approaches, 551 Cilastozole restenosis, 187, 191 Cilazapril restenosis, 301 Cilostazol, 69–75, 526 chemical structure, 72 claudication, 519 clinical experience, 74–75 drug issues, 73 effects, 72 mechanisms of action, 73 peri-percutaneous coronary intervention, 531 restenosis, 190 SMC migration inhibition, 190 CIN. See Contrast-induced nephropathy (CIN) circulating endothelial precursor (CEP), 401 CK. See Creatinine kinase (CK) Claudication treatment, 518–520 CLI. See Critical limb ischemia (CLI) clinical pulmonary embolism frequency, 20 Clopidogrel, 59, 60–61, 144–149, 517–518 ACS, 62–63, 121 chemical structure, 60 coronary artery disease secondary prevention, 64–65 coronary stenting, 64 cytochrome P 450, 61 diabetic CAD, 474, 475 dose, 61 heart failure, 460 implantation, 601 indications, 65 LAA, 594 long-term treatment, 64 mechanism of action, 144–145 neurology, 65 nonresponsiveness, 146 clinical relevance, 148–149 pharmacodynamic mechanisms, 147–148 pharmacokinetic mechanisms, 146–147 therapeutic interventions, 149 PAD, 65 PCI pretreatment, 64 peri-percutaneous coronary intervention, 531, 532, 533 pharmacology, 129 platelet response laboratory evaluation, 145–146 PMIVSD, 598 resistance, 62 studies, 148 response variability clinical studies, 146 side effects, 62

631

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632

11:50 AM

Page 632

Index

[Clopidogrel] STEMI, 525 synergistic action, 61–62 CM. See Contrast media (CM) Coagulation endogenous inhibitors, 6 extrinsic pathway, 3 homocysteine, 179 intrinsic pathway, 3 schematic, 2 Coagulation disorders genes, 538–541 pharmacogenomics, 538–542 Coagulation factor deficiencies, 14 Coagulation factor Xa ACS, 122 inhibitors clinical data, 123–124 preclinical data, 122–123 Coital sudden death, 505 Colchicine restenosis, 301, 303 Collagen, 34–35 Collagenases batimastat inhibition, 327 Comorbidity heart failure, 460 Complementary DNA (cDNA), 363 Congenital disorders hemostasis, 18 Conical neck AAA, 586 Contraceptives oral, 15 Contrast encephalopathy, 564 Contrast-induced nephropathy (CIN) agent administration, 497–498 clinical outcomes, 495–496 clinical recommendations, 498 diabetic CAD, 477–478 forced diuresis, 498 hemodialysis, 498 hemofiltration, 498 osmolality, 494–495 pathogenesis, 493–494 PCI, 493–499 survival, 497 prevention, 496–498 risk evaluation, 496 risk factors, 495 validation model, 497 volume expansion/fluid administration, 496–497 Contrast media (CM), 493 osmolality, 494–495 physiologic and chemical characteristics, 494 Controlled drug delivery (CDD), 277 restenosis pathophysiology, 279 types, 278–279 vascular setting, 279 Controlled drug-eluting stents polymers, 279–280

Coronary artery disease chronic occlusions histologic specimens, 551 clopidogrel, 64–65 diabetes angioplasty vs. surgery, 473–474 PCI, 473 homocysteine, 178 lipid-lowering agents, 158–159 peri-procedural complications, 563 risk factors, 505 Coronary stents clopidogrel, 64 Corticosteroids restenosis, 185–186 stents, 253 CoStar, 295 COX. See Cyclooxygenase (COX) C-reactive protein (CRP), 161 ACS, 466, 468 PTCA, 317 restenosis, 185 Creatinine kinase (CK), 120, 593–594 ACS, 466 MB, 120 Critical limb ischemia (CLI), 569 CRP. See C-reactive protein (CRP) CRVT. See Central retinal vein thrombosis (CRVT) CTO. See Chronic total occlusion (CTO) Cyclic adenosine monophosphate (cAMP), 69 formation, 70 Cyclic nucleotides, 69–70 generation, breakdown, actions, 70 Cyclin-dependent kinase (CDK) inflammation, 316 Cyclooxygenase (COX), 33 restenosis, 188 Cyclooxygenase-2 (COX-2), 38 CYPHER sirolimus-eluting stents, 294 clinical experience, 283 polymers, 282–283 Cytochrome P 450 clopidogrel, 61 Cytokines clinical trials cellular therapy clinical trials, 447 Dabigatran chemical structure, 111, 113 clinical studies, 113 pharmacodynamics, 113 pharmacokinetics, 87, 113 DAG. See Diacylglycerol (DAG) Deep vein thromboembolism (DVT), 538, 569 frequency, 20 incidence, 19 oral DTI, 114 Deferoxamine (DFO), 241 acute iron intoxication, 244 administration, 244 atherosclerosis, 244, 245 cardioprotective effect evidence, 245

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Page 633

Index

[Deferoxamine] chelatable iron access, 242–243 chronic overload, 244 clinical pharmacology, 242 contraindications, 243 dosage, 244 experimental data, 244 future chelation therapy, 245 heart disease reversal, 245 indications, 243 mechanism of action, 243 muscle tissue ischemia, 244 overdosage, 243–244 pharmacology, 242–243 plasma pharmacokinetics, 242 plasma pharmacology, 242–243 precautions and drug interactions, 243 reperfusion protection, 244–245 structure and chemistry, 242 warnings, 243 Dermatan sulfate, 22 DES. See Drug-eluting stents (DES) Desmopressin, 7, 13, 14 DFO. See Deferoxamine (DFO) Diabetes cardiac morbidity and mortality pathogenesis, 473 cardiovascular interventional pharmacology, 473–479 coronary artery disease angioplasty vs. surgery, 473–474 PCI, 473 pharmacology, 474–476 DTI, 90 lipid-lowering agents, 159 treatment, 516 Diacylglycerol (DAG), 34 platelet metabolism, 33 DIC. See Disseminated intravascular coagulation (DIC) Dietary polyphenols epidemiological studies, 227 Differential scanning calorimetry (DSC) TAXUS stent, 284 Difficult iliac arteries AAA, 586 Difficult neck AAA, 585–586 Digitalis HCM, 593 heart failure, 458–459 adverse effects, 458–459 clinical effects, 458 clinical use, 458 mortality and hospitalization, 458 pathophysiology, 458 Digoxin AV node conduction, 488, 489–490 Diltiazem AV node conduction, 489 restenosis, 301

Dipyridamole, 69–75 adenosine uptake, 72 antioxidant properties, 72 chemical structure, 71 clinical experience, 73–74 drug issues, 72–73 eicosanoid effects, 72 mechanism of action, 71–72 peri-percutaneous coronary intervention, 531 phosphodiesterase inhibition, 71 purines, 74 restenosis, 301 Direct factor Xa inhibitors ACS, 119–124 Direct thrombin inhibitors (DTI), 530, 570–576. See also Oral direct thrombin inhibitors bleeding rate differences, 103 brachytherapy, 90 characteristics, 97 clinical evidence, 88 decreased renal function, 89–90 DES, 90 diabetes, 90 heparin-induced thrombocytopenia syndrome, 90 interventional cardiology, 90 oral AMI, 114 vs. vitamin K antagonists, 110 PCI, 85–91 indications, 87–88 peri-percutaneous coronary intervention, 531 peripheral intervention, 90 special groups, 89–90 Disseminated intravascular coagulation (DIC), 16 Diuretics heart failure, 457 adverse effects, 458 clinical effects, 457 indications, 457 pathophysiology, 457 Dobutamine HCM septal alcohol ablation, 605 Dofetilide AF, 486 Dopamine CIN, 498 Doxazosin ED with cardiovascular disease, 510 D-Roms test, 215 Drug-eluting stents (DES), 75, 267 angiogenesis, 398 antirestenotic drug, 289–290, 302–310 bevacizumab, 343 components, 289–290 controlled polymers, 279–280 diabetic CAD, 478 diffusion control, 292 drug compatibility, 290

633

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634

11:50 AM

Page 634

Index

[Drug-eluting stents] drug delivery principles, 277–286 systems, 281–282 drug elution, 290 control, 291–293 future trends, 295 hydrogel matrix, 294 matrix degradation, 292–293 neointimal hyperplasia, 253–258 nonpolymeric paclitaxel clinical experience, 284–285 physical stability, 290 poly-ester-amide, 295 polymers, 289–296, 291 bioabsorbable, 295 carrier, 290 carrying biomolecules, 295 coating designs, 293–294 component, 294–295 matrix, 294 tailored, 295 processing techniques, 291 protective or diffusion barrier polymer layer, 294 rationale, 289 restenosis, 185 stent platform, 290 sterilization compatibility, 290 thin layer coating, 293 thromboresistant, 249–251, 252–253 vascular tissue compatibility, 290–291 Drug induced thrombocytopenia, 11 DSC. See Differential scanning calorimetry (DSC) DTI. See Direct thrombin inhibitors (DTI) DVT. See Deep vein thromboembolism (DVT) EC. See Endothelial cells (EC) ecarin clotting time (ECT), 11, 87 ED. See Erectile dysfunction (ED) EDRF. See Endothelial derived relaxing factor (EDRF) Efegatran ACS, 121–122 EGF. See Endothelial growth factors (EGF) Elderly ED, 503 Electronic blood pressure device accuracy, 171–172 sequential readings, 172–173 simultaneous readings, 172 Embolic disorders, 17 Embolic protection devices impact, 556 Embolic stroke oral DTI, 114 Encephalopathy contrast, 564 Endeavor, 294 Endocarditis heparin, 601 nonbacterial thrombotic, 16 Endo devices, 585

Endogenous glycosaminoglycans, 8 Endogenous serine protease inhibitors, 9 Endothelial cells (EC), 347–348 gene transfer stents, 258–260 Endothelial derived relaxing factor (EDRF), 3 Endothelial growth factors (EGF) re-endothelialization, 190 Endothelial nitric-oxygen synthase (eNOS) endothelium, 347 Endothelium, 5–6 dysfunction, 15 physiology, 127–128 restenosis, 347–348 eNOS. See Endothelial nitric-oxygen synthase (eNOS) enoxaparin, 529 peri-percutaneous coronary intervention, 532 enzymes oxygen quenching, 213 EO. See Ethylene oxide (EO) Epinephrine platelets, 35 Eptifibatide (Integrilin), 41–42, 526, 529, 579 peri-percutaneous coronary intervention, 531 pharmacology, 129 Erectile dysfunction (ED), 503–511 assessment algorithm, 509 cardiac symptoms absence, 506 cardiovascular disease, 505–506 treatment, 507–510 hyperlipidemia, 506 lifestyle factors, 510–511 risk factors, 505 vascular disease, 506–507 vasculogenic, 505 E-selectin, 15 Esmolol AV node conduction, 488–489 Estradiol, 349 endothelium, 348–349 restenosis RCT, 350–351 Estradiol, 17 beta chemistry, 348 pharmacology, 349 prohealing, 351 Estrogen stents restenosis, 349–350 Ethacrynic acid, 457 Ethanol myocardial septal ablation, 603–611 Ethylene oxide (EO), 290 Everolimus restenosis, 188, 196–197 Exanta, 21, 22, 109–110 chemistry, 109–110 clinical studies, 111–113 pharmacodynamics, 110 pharmacokinetics, 87, 110–111 vs. vitamin K antagonists, 110

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Page 635

Index

Exercise claudication, 518–519 Exercise testing sexual intercourse, 504 Fatal pulmonary embolism frequency, 20 Felodipine heart failure, 459 Fenofibrates diabetic CAD, 477 Fentanyl prophylactic HCM septal alcohol ablation, 607 tricuspid stenosis, 597 FGF. See Fibroblast growth factors (FGF) Fibrates PCI restenosis, 166 Fibrinogen, 32 coagulation disorders, 541 platelets, 527 thrombin, 3 Fibrinolysis indications, 135–136 mechanism, 135 risks, 136 Fibrinolytic agents cost, 136 Fibrinolytic therapy, 135–137 alternatives to, 136–137 Fibrinopeptide A (FpA), 120 Fibrinopeptide B (FpB), 120 Fibrin solid phase thrombin inhibition, 94 Fibroblast growth factors (FGF) angiogenesis, 340, 397 myocardial angiogenesis, 409–410 re-endothelialization, 190 Fibronectin, 32 Flavanols, 226 monomeric, 226 Flavones, 226 Flavonoids, 224–225 Flecainide AF, 485–486 Fluvastatin ACS clinical trials, 161 Folic acid restenosis, 187, 191 after coronary angioplasty, 180–181 Fondaparinux, 22, 529–530 peri-percutaneous coronary intervention, 531 pharmacology, 129 Fosinopril restenosis, 301 FpA. See Fibrinopeptide A (FpA) FpB. See Fibrinopeptide B (FpB) Free radicals, 211 Furosemide, 457 CIN, 498

635

Gelatinases batimastat inhibition, 327 Gemfibrozil target low-density lipoprotein cholesterol levels, 160 Gene expression ODN, 373–374 Gene therapy angiogenesis, 399 intimal hyperplasia, 373 Gene transfer EC stents, 258–260 Genes coagulation disorders, 538–541 receptors pharmacologic approaches, 537–545 Genomics. See also Cardiovascular system profiling, 369 GIK. See Glucose insulin potassium infusion (GIK) Ginkgo biloba claudication, 519 Glanzmann’s thrombasthenia, 5, 12 Glucose insulin potassium infusion (GIK) diabetic CAD, 475–476 Glutathione (GSH), 216 Glycoprotein IIb/IIIa inhibitors, 41–55, 526–528, 577–579, 622 ACC/AHA guidelines, 54 ACS, 121 alternatives, 53–54 benefits, 51 clinical evaluation, 42–45 clinical practice, 50–51 comparison, 43 conjunctive heparin therapy, 52 coronary artery bypass graft, 52 coronary intervention vs. medical management, 46–48 differences, 50–51 efficacy and safety, 50 NSTEMI, 43–45 RCT, 45 optimal timing, 51 oral, 49–50 PCI, 42–43 cardiac biomarkers after, 48–49 RCT, 44 peri-percutaneous coronary intervention, 531, 532 pharmacology, 41–42, 130 platelet inhibition monitoring, 52 platelet physiology, 41 reperfusion therapy RCT, 46 restenosis, 52–53 STEMI, 49 survival, 53 UFH, 94–95 unstable angina, 43–45 RCT, 45 Glycoproteins hemostasis, 4 histidine-rich, 9

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Page 636

Index

Glycosaminoglycans, 8, 396 non-heparin, 22 GR32191 B restenosis, 301 Growth factor delivery viral vectors, 410–411 Growth factors myocardial angiogenesis, 407–410 therapeutic angiogenesis, 407–415 therapy, 407–415 GSH. See Glutathione (GSH) HC-II. See Heparin cofactor II (HC-II) HCM. See Hypertrophic cardiomyopathy (HCM) HDL. See High-density lipoprotein (HDL) cholesterol Healing promotion, 190 sarprogrelate, 190 Heart failure, 451–461 aldosterone antagonists, 453–454 angiotensin II receptor blockers, 454–455 antiarrhythmic drugs, 459–460 anticoagulant drugs, 460 antiplatelet drugs, 460 aspirin, 460 beta blockers, 452–453 cell transplantation comparative preclinical studies, 422 comorbidity, 460 digitalis, 458–459 diuretics, 457 interventional laboratory, 460–461 orthopnea, 460 renal function, 460–461 pharmacotherapy, 451–460 preserved systolic function, 460 Helex PRO occluder, 599 HELLP. See Hemolysis elevated liver enzymes low platelets (HELLP) syndrome Hemodialysis CIN, 498 Hemofiltration CIN, 498 hemolysis elevated liver enzymes low platelets (HELLP) syndrome, 10, 17 Hemolytic uremic syndrome (HUS), 10 Hemophilia A, 13–14 Hemophilia B, 13–14 Hemostasis, 1–23 bleeding, 10–11 congenital disorders, 18 defined, 1 glycoproteins, 4 initiation, 37 Leu-Carns, 4 platelets, 3, 31–35 plug, 36 thrombosis, 10–11 VLA complexes, 4 Heparin, 485, 528–529, 570. See also Unfractionated heparin (UFH)

[Heparin] adverse reactions, 569–570 current practices, 624 diabetic CAD, 477 endocarditis prophylaxis, 601 vs. hirudin, 623 LAA, 594 vs. LMWH, 622 parenteral, 93 peri-percutaneous coronary intervention, 532 pharmacology, 128–129, 129 prophylaxis HCM septal alcohol ablation, 607 tricuspid stenosis, 597 Heparin cofactor II (HC-II), 6–7, 94 Heparin-coated stents, 249 Heparin-induced thrombocytopenia (HIT), 11–12, 128, 528 acute myocardial infarction (AMI), 95 pathogenesis, 94 PCI alternative anticoagulants, 103–104 platelet stimulation, 94–95 Heparin-induced thrombocytopenia/thrombosis (HITTS), 11 HETE. See 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) HIF. See Hypoxia inducible transcription factors (HIF) High blood pressure cardiac patient, 171–173 treatment, 516 High-density lipoprotein (HDL) cholesterol target low-density lipoprotein cholesterol levels, 160 Hirudin AMI, 100 clinical trials, 101 clinical evidence, 88 vs. heparin, 623 parental, 99–100 PCI, 100 alternative anticoagulants, 104 dose, 100 monitoring, 100 pharmacokinetics, 87, 96 pharmacology, 129–130 recombinant HIT, 11 Histidine-rich glycoproteins, 9 HIT. See Heparin-induced thrombocytopenia (HIT) HITTS. See Heparin-induced thrombocytopenia/thrombosis (HITTS) HIV/AIDS-associated thrombocytopenia and thrombosis, 18 Homocysteine cardiovascular disease, 178 coagulation, 179 coronary artery disease, 178 elevated plasma concentrations, 177–178 inflammation, 179 lowering therapy, 516 and restenosis after coronary angioplasty, 180–181 mechanisms of action, 178–179 metabolism, 177 oxidative stress, 178 regulators, 177–181

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Page 637

Index

[Homocysteine] restenosis after PCI, 180 smooth muscle proliferation, 179 Human phosphodiesterase enzyme families, 70 HUS. See Hemolytic uremic syndrome (HUS) Hydralazine-isosorbide dinitrate heart failure, 459 Hydrocinnamic acid, 226 Hydroxy benzoic acid, 226 Hyperfusion syndrome, 564 Hyperlipidemia ED, 506 treatment, 515–516 Hypertension cardiac patient, 171–173 treatment, 516 Hypertrophic cardiomyopathy (HCM), 593, 603 hemodynamic evaluation, 604 hemodynamics, 603 septal alcohol ablation, 604 acute results, 607 alcohol dose, 610–611 arrhythmogenicity, 607–610 complications, 611 drugs, 607 long-term results, 607 patient selection, 604 postprocedural care, 607 techniques, 605 surgery, 603–604 treatment, 603–604 Hypotension carotid artery stenosis, 562 Hypoxia inducible transcription factors (HIF), 340 Ibutilide AF, 486 ICAM-I. See Intracellular adhesion molecule-I (ICAM-I) ICB. See Intracoronary brachytherapy (ICB) IL-1. See Interleukin-1 (IL-1) IL-6. See Interleukin-6 (IL-6) IL-8. See Interleukin-8 (IL-8) Iliac arteries difficult, AAA, 586 Immune thrombocytopenic purpura (ITP), 12 Immunomodulators restenosis, 185–186 Immunosuppressive therapy systemic restenosis, 196–197 Implanon, 278 Indirect thrombin inhibitors, 569–570 Induced nitrogen oxide synthase (iNOS), 214 Inferior venal caval interventions thromboembolic disease, 19 Infrarenal abdominal aortic aneurysms angiogram, 584 INOS. See Induced nitrogen oxide synthase (iNOS) In-stent restenosis (ISR), 267, 279 Insulin resistance ED, 510

Insulin sensitizers diabetic CAD, 476–477 Insulin/glucose insulin potassium infusion (GIK) diabetic CAD, 475–476 Integrilin, 41–42, 526, 529, 579 peri-percutaneous coronary intervention, 531 pharmacology, 129 Integrins platelets, 4–5 Intercourse. See Sexual activity Interleukin-1 (IL-1) restenosis, 185 Interleukin-6 (IL-6) PTCA, 317 restenosis, 185 Interleukin-8 (IL-8) angiogenesis, 339 Interventional procedures anticoagulant, 621–626 Intimal hyperplasia ODN, 373–374 Intracellular adhesion molecule-I (ICAM-I), 15 Intracoronary brachytherapy (ICB), 267, 268–271 coronary artery spasm, 272 delayed dissection healing, 272 dual antiplatelets, 273 edge stenosis, 272 future, 273 limitations and complications, 269–270 pseudoaneurysms, 272 thrombosis, 272–273 Iron acute intoxication, 244 body stores, 241 cardiovascular disease, 241–242 chelatable, 242–243 chelation, 241–245 endothelial function, 241 Ischemia cardiovascular system genetic manipulation, 365–366 transient cerebral, 564 Ischemic cardiomyopathy autologous bone marrow cells cellular therapy clinical trials, 443–445 Ischemic heart disease cell transplantation, 428–430 Ischemic myocardial dysfunction skeletal myoblast intramyocardial injection cellular therapy clinical trials, 445–447 Ischemic stroke clopidogrel, 66 ISR. See In-stent restenosis (ISR) ITP. See Immune thrombocytopenic purpura (ITP) Junctional adhesion molecules (JAM), 36, 37 Ketanserin restenosis, 301 KFA-1982 ACS, 123–124 Kunitz domain, 7

637

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638

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Page 638

Index

LAA. See Left atrial appendage (LAA) Late stent thrombosis (LST), 356–357 Left atrial appendage (LAA) occlusion, 594–595 Left ventricular systolic dysfunction pharmacotherapy, 451–452 Lepirudin, 99–100 characteristics, 97 pharmacology, 129 Leu-Carns hemostasis, 4 Leukocytes inflammation, 316 Lipid-lowering agents, 155–166, 530 ACS, 161–162 clinical trials, 155–158 coronary artery disease, 158–159 diabetes, 159 epidemiology, 155 PCI, 164–165 bioengineered stents, 166 contrast-induced nephropathy, 165 coronary blood flow, 165 coronary endothelial dysfunction after DES, 165–166 endothelial progenitor cells, 166 HMG-CoA reductase inhibitors and clopidogrel, 165 intravascular ultrasound, 164–165 peri-procedural MI, 164–165 RCT, 164 restenosis, 166 peri-percutaneous coronary intervention, 531, 533 stroke and PAD, 158–159 target low-density lipoprotein cholesterol levels, 159–160 LMWF. See Low molecular weight heparin (LMWF) Lovastatin restenosis, 301 Low molecular weight heparin (LMWF), 79–83, 621, 622 ACS, 121 diabetic CAD, 477 vs. heparin, 622 PCI, 80–82 pilot studies, 80–82 peri-percutaneous coronary intervention, 531 pharmacology, 129 LOX. See Lypoxygenase-12 (LOX-12) LST. See Late stent thrombosis (LST) Lupus anticoagulant, 13 Lycopene, 223 Lypoxygenase-12 (LOX-12), 34 Major adverse cardiac events (MACE), 527 PTCA, 317 Major ischemic stroke, 564 Mannitol CIN, 498 Manometer nonmercury device, 172 MAP. See Mitogen-activated protein (MAP) kinases

Matrix metalloproteinases (MMP), 325–326 batimastat inhibition, 327 family, 326 MCP. See Monocyte chemotactic protein (MCP) Melagatran chemical structure, 111 pharmacodynamics, 110 pharmacokinetics, 87, 111, 112 vs. vitamin K antagonists, 110 Metabolic syndrome ED, 510 Metalloproteinases, 38 restenosis, 196 Methotrexate restenosis, 303 Methylprednisolone (MP) restenosis, 301 stents, 253–254 Methyl tetrahydrofolate reductase (MTHFR) gene, 542–543 Metoprolol AV node conduction, 488 MI. See Myocardial infarction (MI) Microangiopathies thrombotic, 10–11 Midazolam tricuspid stenosis, 597 Mitogen-activated protein (MAP) kinases, 325 Mitral valve repair, 597 stenosis, 596 MMP. See Matrix metalloproteinases (MMP) Molecular phenotyping, 369 Monocyte chemotactic protein (MCP), 15 Monomeric flavanols, 226 Mononuclear cell-stimulating factor, 15 MP. See Methylprednisolone (MP) MTHFR. See Methyl tetrahydrofolate reductase (MTHFR) gene Myectomy surgical complications, 610 Myocardial angiogenesis growth factors, 407–410 Myocardial hypertrophy and remodeling cardiovascular system genetic manipulation, 366–367 Myocardial infarction (MI) cardiovascular system genetic manipulation, 365 Myocardial septal ablation ethanol, 603–611 Myogenesis, 401–402 cellular myogenic and angiogenic therapy in limb ischemia, 401–402 Myoglobin ACS, 466 N-acetylcysteine, 478 CIN, 497–498 NAION. See Nonarteritic anterior ischemic optic neuropathy (NAION) Natural anticoagulant system polymorphisms, 542

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Index

Natural polymers DES, 291 NBTE. See Nonbacterial thrombotic endocarditis (NBTE) NCE. See New chemical entities (NCE) Neointimal hyperplasia (NIH), 185 Neovascularization, 341 Nephropathy. See Contrast-induced nephropathy (CIN) Neuraxial anesthesia and anticoagulation, 18–19 New chemical entities (NCE), 278 Nifedipine restenosis, 301 NIH. See Neointimal hyperplasia (NIH) Nit-Occlud Coils, 598 Nitrates peri-percutaneous coronary intervention, 532 Nitric oxide (NO), 36, 127 endothelium, 347 homocysteine, 179 NMR. See Nuclear magnetic resonance (NMR) NO. See Nitric oxide (NO) Non-heparin glycosaminoglycans, 22 Non-ST elevation MI (NSTEMI), 465 glycoprotein IIb/IIIa inhibitors, 43–45 RCT, 45 Nonarteritic anterior ischemic optic neuropathy (NAION) ED, 511 Nonbacterial thrombotic endocarditis (NBTE), 16 Nondihydropyridine calcium antagonist AV node conduction, 489 Nonpolymeric paclitaxel drug-eluting stents clinical experience, 284–285 Nonsteroidal anti-inflammatory agents (NSAID) restenosis, 188 Nonviral vectors growth factor delivery, 410 Novoste beta-cath system, 268 NSAID. See Nonsteroidal anti-inflammatory agents (NSAID) NSTEMI. See Non-ST elevation MI (NSTEMI) Nuclear magnetic resonance (NMR) TAXUS stent, 284 Nutritional paradigm, 232 Obesity ED and 510, 511 Occluder CardioSEAL-STARflex, 598, 599, 600 Helex PRO, 599 Premere PFO, 598–599, 600 OCT. See Optical coherence tomography (OCT) ODN. See Oligonucleotides (ODN) Oligonucleotides (ODN) antisense, 371–377 Omega-3 fatty acids restenosis, 301 Optical coherence tomography (OCT), 543 Optison HCM septal alcohol ablation, 605

Oral agents limitations, 191 restenosis, 185 Oral anticoagulants, 544 current practices, 624 Oral antithrombin drugs, 109–115 Oral contraceptives, 15 Oral direct thrombin inhibitors AMI, 114 clinical indications, 114 clinical studies, 111–112 pharmacodynamics, 110 pharmacokinetics, 110–111 Orthopedic surgery oral DTI, 114 OS. See Oxidative stress (OS) Otamixaban ACS, 123–124 Oxidation, 212 Oxidative stress (OS), 211, 213–215 energetic pathway, 213 equilibrium, 214–215 evaluation, 215–216 homocysteine, 178 metabolic pathway, 214 propagation, 214–215 reactive pathway, 213 redox couples, 216–217 Oxygen, 211 PDT, 386 quenching, 213 unpaired orbitals, 212 Oxyhemoglobin absorption coefficient, 386 Paclitaxel, 304–305 cellular and molecular, 304–307 DES clinical trials, 308 restenosis, 196–197, 303 SMC, 305–306 PAD. See Peripheral vascular disease (PAD) PAI-I. See Plasminogen activator inhibitor-I (PAI-I) Parenteral direct antithrombin, 93–104 Parenteral heparin, 93 Patent foramen ovale (PFO), 598–601 PCI. See Percutaneous intervention (PCI) PCL. See Polycaprolactone (PCL) PDE. See Phosphodiesterase (PDE) PDGF. See Platelet-derived growth factor (PDGF) PDT. See Photodynamic treatment (PDT) Pemirolast healing, 190 restenosis, 187 restenosis rates, 191 Pentoxifylline claudication, 519 Percutaneous intervention (PCI), 1, 624 argatroban, 96–97 HIT, 98–99, 103–104

639

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640

11:50 AM

Page 640

Index

[Percutaneous intervention] atorvastatin RCT, 164 bivalirudin, 101–102 alternative anticoagulants, 104 CIN, 493–499 survival, 497 clopidogrel, 64 CTO, 550 description, 525 DTI, 85–91 indications, 87–88 fibrates, restenosis, 166 glycoprotein IIb/IIIa inhibitors, 42–43 cardiac biomarkers after, 48–49 RCT, 44 hirudin, 100 alternative anticoagulants, 104 dose, 100 monitoring, 100 HIT alternative anticoagulants, 103–104 homocysteine, 180 lipid-lowering agents, 164–165 LMWF, 80–82 probucol restenosis, 166 RCA subselective infusion, 553 UFH, 95–96 Percutaneous peripheral intervention (PPI), 569 Percutaneous stent implantation restenosis systemic antineoplastic drugs, 195–207 Percutaneous transluminal coronary angioplasty (PTCA), 267, 315–316 cardiovascular disease immune mechanisms, 319–320 clinical observations, 319 inflammation activation, 316 inflammation circulating markers, 317 pre-existing inflammation, 317 sirolimus, 317–318 animal models, 319 Peri-percutaneous coronary intervention drug administration, 532–533 drug comparison, 531 Peripheral arterial disease, 515–520 lipid-lowering agents, 158–159 Peripheral vascular disease cell transplantation, 430 Peripheral vascular disease (PAD) thienopyridines, 65 Peroxisome proliferator-activated receptor (PPAR)-gamma restenosis, 187–188 PEVA. See Polyethylene-co-vinyl acetate (PEVA) PF4. See Platelet factor 4 (PF4) PFO. See Patent foramen ovale (PFO) PFX Closure System, 599, 600 PFX electrode, 601 PG. See Prostacyclin (PGI2) Pharmacotherapy peri-percutaneous coronary intervention, 525–530 PHBV. See Polyhydroxybutyrate valerate (PHBV)

Phosphodiesterase (PDE), 69–70 enzyme families human, 70 inhibition, 69–70 inhibitors, 69–75 ED with cardiovascular disease, 507–509 mechanism of action, 509 Phospholipase (PL) platelet metabolism, 33 Phosphorodiamidate morpholino oligomers (PMO), 371, 376 PTCA, 377 Phosphorothioates (PSO), 376 Photodynamic effect, 382 Photodynamic treatment (PDT), 381–389 cell death, 381–382 clinical development, 388–389 clinical experience, 387–388 complications, 388 drug to light activation, 384–385 endovascular intervention, 383–384 light activation, 385–386 oxygen, 386 threshold, 382 Photofrin, 381 Photo Point, 383 Physical activity ED, 510 PIFG. See Placental growth factor (PIFG) Pigment epithelium-derived growth factor (PEDF) angiogenesis, 339 Pioglitazone restenosis, 190, 191 PL. See Phospholipase (PL) PLAATO device, 594 Placental growth factor (PIFG) myocardial angiogenesis, 408 Plaque rupture pathophysiology, 127–128 Plasminogen activator inhibitor-I (PAI-I), 9, 32, 571, 577 Platelet activation cascade, 42 Platelet factor 4 (PF4), 32, 36, 37, 93 Platelet glycoprotein IIb/IIIa inhibitors diabetic CAD, 474–475 Platelet surface gene polymorphisms, 542 Platelet-derived growth factor (PDGF), 15, 32, 36, 37 angiogenesis, 339 Platelets activation, 140 adhesion receptors, 32 ADP receptors, 35 aggregation, 3, 33, 60, 140 agonists, 34–35 atherosclerosis, 37–38 cell-based hemostasis model, 35–36 hemostasis, 3 inflammation, 37–38 inflammatory modulators, 36 integrins, 4–5 normal hemostasis, 31–35

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Index

[Platelets] physiology, 127–128 receptors agonist stimulation, 33 PLGA. See Polyglycolic acid (PLGA) PMIVSD. See Post myocardial infarction ventricular septal defect (PMIVSD) PML. See Polymorphonuclear leukocyte (PML) PMO. See Phosphorodiamidate morpholino oligomers (PMO) PNP. See Pooled normal plasma (PNP) POE. See Polyorthoester (POE) Polycaprolactone (PCL), 280 Polycomponent syndrome, 22 Poly-ester-amide DES, 295 Polyethylene-co-vinyl acetate (PEVA), 282 Polyglycolic acid (PLGA), 280 Polyhydroxybutyrate valerate (PHBV), 280 Polymorphisms natural anticoagulant system, 542 single nucleotide, 537, 538 Polymorphonuclear leukocyte (PML) adhesion, 38 elastase, 95–96 Polyorthoester (POE), 280 Polyphenols (PP), 224–225 dietary, epidemiological studies, 227 types, 226 Poly-styrene-b-isobutylene-b-styrene vascular compatibility, 283 Polyunsaturated fatty acids (PUFA), 217 Pooled normal plasma (PNP), 14 Post myocardial infarction ventricular septal defect (PMIVSD), 598 Post surgical and post myocardial infarction ventricular septal defect, 598 Postphlebitic syndrome, 18 PP. See Polyphenols (PP) PPAR. See Peroxisome proliferator-activated receptor (PPAR)-gamma PPI. See Percutaneous peripheral intervention (PPI) Prasugrel, 59–60 Pravastatin ACS clinical trials, 161–162 clinical trials, 155–158 coronary artery disease, 158 diabetes, 159 PAD, 158–159 restenosis, 187, 191 stroke, 158–159 Prednisolone restenosis, 187, 191, 301 Prednisone restenosis, 187, 196 Pregnancy hemostatic problems, 17 Prekallikrein, 3 Premedication aspirin LAA, 594 Premere PFO occluders, 598–599, 600

641

Probucol restenosis, 187, 191 PCI, 166 Procainamide AF, 488 Propafenone AF, 486 Prophylactic fentanyl HCM septal alcohol ablation, 607 Propionyl-L-carnitine claudication, 519 Propranolol AV node conduction, 488 Prostacyclin (PGI2), 4, 34 endothelium, 347 restenosis, 301 Prostaglandin claudication, 520 Protamine, 570 Protease nexins, 9 Protein C, 32 pathway, 8–9 Protein therapy angiogenesis, 398 Prothrombin, 5 coagulation disorders, 541 Prothrombinase complex, 3 Proton pump inhibitors peri-percutaneous coronary intervention, 532 P-selectin inflammation, 316 P-selectin GP ligand-I (PSGL-I), 38 Pseudoaneurysms ICB, 272 PSGL. See P-selectin GP ligand-I (PSGL-I) PSO. See Phosphorothioates (PSO) PTCA. See Percutaneous transluminal coronary angioplasty (PTCA) PUFA. See Polyunsaturated fatty acids (PUFA) Pulmonary embolism clinical, 20 fatal, 20 Pulmonary stenosis, 595–596 Quinidine AF, 488 AV node conduction, 488 RANTES. See Regulated on activation normal T-cell expressed and secreted (RANTES) Rapamycin, 304 analogs, 189 restenosis, 196–197 protein for immune inflammation intervention, 320–321 restenosis, 187–189, 196–207, 201–208, 303 restenosis rates, 191 TOR, 318 Reactive chlorine species (RCS), 213 Reactive nitrogen species (RNS), 211, 213 Reactive oxygen species (ROS), 211 Reactive substances grouping, 212

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642

11:50 AM

Page 642

Index

Receptors and genes pharmacologic approaches, 537–545 Recombinant hirudin HIT, 11 Recombinant tissue plasminogen activator, 576–577 Recombinant tissue plasminogen activator (rt-PA), 576–577, 623 Re-endothelialization promotion, 190 Regulated on activation normal T-cell expressed and secreted (RANTES), 36, 37 ReoPro, 41–42, 526, 578–579, 622 peri-percutaneous coronary intervention, 531 pharmacology, 129 Reperfusion injury cardiovascular system genetic manipulation, 365–366 Reptilase, 623 Restenosis, 624 after PCI homocysteine, 180 after percutaneous stent implantation systemic antineoplastic drugs, 195–207 anti-inflammatory agents, 185–186 antiproliferative and antimigratory compounds, 299–310 catheter-based drug delivery, 301–302 CDD, 279 cell migration, 325 cilostazol, 190 colchicine, 301, 303 corticosteroids, 185–186 dipyridamole, 301 estradiol RCT, 350–351 everolimus, 188, 196–197 fibroproliferative conditions, 302 folic acid, 187, 191 after coronary angioplasty, 180–181 fosinopril, 301 in-stent, 267, 279 carotid artery, 563 inflammation, 316 MMP, 325–327 nifedipine, 301 ODN, 374–375, 376 pathology, 185–186 pathophysiology, 299, 300 pioglitazone, 190, 191 pravastatin, 187, 191 prednisolone, 187, 191, 301 prednisone, 187, 196 prevention, 185–186 probucol, 191 PCI, 166 sarprogrelate, 187, 191 systemic immunosuppressive therapy, 196–197 systemic therapies clinical studies, 301 thiozolidenediones, 189–190 tranilast, 187, 191 valsartan, 191

[Restenosis] vasculoprotective approach, 347–352 verapamil, 187, 301 Resting platelets morphology, 31 Reteplase, 577 Risperdal, 279 RNA gene expression profiling, 543 RNS. See Reactive nitrogen species (RNS) Rochester trial, 572, 576 ROS, 213. See Reactive oxygen species (ROS) Rosiglitazone restenosis, 190 restenosis rates, 191 Rt-PA. See Recombinant tissue plasminogen activator (rt-PA) Ruptured aneurysm AAA, 585 SAA. See Serum amyloid A (SAA) Sarprogrelate healing, 190 restenosis, 187 restenosis rates, 191 Secondary hypercoagulable states, 15 Selective estrogen receptor modulators (SERM), 15–16 Selenium, 227–228 Sepsis, 18 Septal ablation complications, 610 follow-up studies, 609 myocardial ethanol, 603–611 vs. surgical myectomy, 608 Septal alcohol ablation HCM, 604 acute results, 607 Septal hypertrophy transcatheter ablation, 593–594 Serine protease inhibitor (SERPIN), 6 SERM. See Selective estrogen receptor modulators (SERM) Serotonin, 32 platelets, 35 SERPIN. See Serine protease inhibitor (SERPIN) Serum amyloid A (SAA) PTCA, 317 Sexual activity cardiac risk, 504–505 cardiovascular disease, 507–508 cardiovascular response, 503–505 exercise testing, 504 MET, 504 MI risk, 504 positions, 504–505 Sildenafil ED with cardiovascular disease, 509–510 Simvastatin, 515 ACS clinical trials, 161–162 clinical trials, 155–158

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Page 643

Index

[Simvastatin] coronary artery disease, 158 stroke and PAD, 158–159 Single nucleotide polymorphism (SNP), 537, 538 Sirolimus (Rapamycin), 304 analogs, 189 restenosis, 196–197 protein for immune inflammation intervention, 320–321 restenosis, 187, 188–189, 196–197, 303 restenosis rates, 191 TOR, 318 Skeletal myoblasts, 440 intramyocardial injection ischemic myocardial dysfunction, 445–447 SMC. See Smooth muscle cells (SMC) Smoking cessation, 518 ED, 510 Smooth muscle cells (SMC), 299 migration inhibition cilostazol, 190 SNP. See Single nucleotide polymorphism (SNP) SOD. See Superoxide dismutase (SOD) Sodium nitroprusside peri-percutaneous coronary intervention, 532 Sotalol AV node conduction, 488 Statins diabetic CAD, 477 lipid-dependent and pleiotropic effects, 162–164 restenosis, 188 ST elevation MI (STEMI), 465 glycoprotein IIb/IIIa inhibitors, 49 risk score, 466 Stem cells bone marrow, 439–440 plasticity, 401 therapeutic angiogenesis, 400–401 STEMI. See ST elevation MI (STEMI) Stent-based drug delivery occlusive coronary artery disease, 277–278 Stent-mediated local drug delivery, 249–260 Stents. See also Biodivysio batimastat stent studies; Drug-eluting stents (DES) bare metal, 398 Bevacizumab-eluting, 343 biodivysio, 341, 342 bioengineered PCI, 166 carotid artery, 555–564 clopidogrel, 64 c-myc antisense phosphorodiamidate morpholino oligomers, 376 coronary clopidogrel, 64 corticosteroids, 253 CYPHER sirolimus-eluting, 294 clinical experience, 283 polymers, 282–283 endothelial cell Seeding and gene transfer, 258–260

643

[Stents] estrogen restenosis, 349–350 heparin-coated, 249 MP, 253–254 percutaneous implantation restenosis, 195–207 selection and deployment carotid artery stenosis, 561–562 subacute thrombosis cilostazol vs. ticlodipine or clopidogrel, 527 TAXUS, 294 AFM, 284 thromboresistant, 249 thrombosis, 564 VEGF, 358 STILE. See Surgery versus Thrombolysis for the Ischemic Lower Extremity (STILE) trial Stroke embolic oral DTI, 114 ischemic clopidogrel, 66 lipid-lowering agents, 158–159 major ischemic, 564 Stromelysins batimastat inhibition, 327 Structural heart disease interventions, 593–601 Styrene-b-isobutylene-b-styrene vascular compatibility, 283 Subvalvular myectomy HCM, 593 Sudden cardiac death genomics, 543 Sudden death coital, 505 Superoxide dismutase (SOD), 213 Surgery versus Thrombolysis for the Ischemic Lower Extremity (STILE) trial, 576–577 death and amputation outcome, 579 outcome, 578 Surgical myectomy complications, 610 Sympathomimetics HCM, 593 Synthetic heparin pentasaccharide (Arixtra), 621 Systemic antineoplastic drugs restenosis after percutaneous stent implantation, 195–207 Systemic antirestenotic drugs clinical trials, 185–192 Systemic immunosuppressive therapy restenosis, 196–197 Tadalafil ED with cardiovascular disease, 510 TAFI. See Thrombin activatable fibrinolytic inhibitor (TAFI) Talaporfin, 383 red fluorescence, 384

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644

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Page 644

Index

Target vessel revascularization (TVR), 473–474 DES, diabetic CAD, 478 Taxus paclitaxel-eluting controlled drug delivery system, 283 clinical experience, 286 clinical trials, 308–310 Taxus stents, 294 AFM, 284 TC-10 ACS, 123–124 TEE. See Transesophageal echocardiography (TEE) TEM. See Transmission electron microscopy (TEM) Tenase complex, 3 Tenecteplase-tPA (TKNase), 577 Testosterone replacement therapy ED, 511 TFPI. See Tissue factor pathway inhibitor (TFPI) TGF. See Tissue growth factor (TGF) TGF-beta. See Transforming growth factor-beta (TGF-beta) Theophylline CIN, 498 Therapeutic angiogenesis, 394–395 FGF, 394–395 growth factors, 407–415 cell-based therapy, 411 delivery, 410–411 delivery strategies, 411 future, 414–415 gene therapy, 410 clinical studies, 413–414 protein therapy, 410 clinical studies, 411–413 interpatient variability, 399 pro-angiogenesis factors, 394–395 stem cells, 400–401 Thienopyridines, 60, 517–518, 525–526 ACS, 62–63 atrial fibrillation, 65 cardiology, 62–63 coronary stenting, 63–64 interventional cardiology, 63–64 neurology, 65–66 PAD, 65 side effects, 62 Thiozolidenediones restenosis, 189–190 Thrombin, 34–35, 38, 623. See also Direct thrombin inhibitors (DTI) fibrinogen, 3 hirudin, 86 indirect inhibitors, 569–570 monitoring direct inhibitors, 87–88 pharmacokinetics, 87 pharmacology, 86–87 physiology, 85 thrombogenesis, 95 vascular injury, 86 Thrombin activatable fibrinolytic inhibitor (TAFI), 9–10 Thrombin-inhibitors pharmacokinetics, 87 pharmacology, 86

Thrombocytopenia alloimmune, 10–11 heparin-induced, 11 HIV/AIDS, 18 Thrombocytosis, 12–13 Thromboembolism deep vein, 538, 569 frequency, 20 incidence, 19 oral DTI, 114 Thrombogenesis leukocytes, 5 thrombin, 95 Thromboglobulin, 32 Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial, 572–576 results, 577 Thrombolytics, 571 Thrombomodulin, 8, 542 Thromboresistant stents, 249 Thrombosis, 1–23 abnormal hemostasis, 10–11 angiogenesis, 398 branch retinal vein, 17 central retinal vein, 17 cerebral venous, 17 heparin-induced, 11 HIV/AIDS, 18 ICB, 272–273 late stent, 356–357 pharmacologic management, 20–22 platelets, 3 risk reduction, 39 stents, 564 cilostazol vs. ticlodipine or clopidogrel, 527 surgery, 19 VEGF re-endothelialization, 356–357 Thrombotic disorders, 14–16, 17 Thrombotic microangiopathies, 10–11 Thrombotic thrombocytopenic purpura (TTP), 10 Thromboxane A2 (TXA2), 32, 128 synthesis, 34 Thyroid hormone analogs, 396 Ticlopidine, 59, 517–518, 525 ACS, 121 chemical structure, 60 coronary stenting, 63–64 peri-percutaneous coronary intervention, 531 restenosis, 301 side effects, 62 TIMP. See Tissue inhibitor metalloproteinases (TIMP) Tirofiban (Aggrastat), 41–42, 526, 579 peri-percutaneous coronary intervention, 531 pharmacology, 129 Tissue factor pathway inhibitor (TFPI), 7–8, 32, 93, 127, 542, 622 Tissue growth factor (TGF) angiogenesis, 340 Tissue inhibitor metalloproteinases (TIMP), 325 Tissue plasminogen activator, 3 TKNase. See Tenecteplase-tPA (TKNase)

1180 Index

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Page 645

Index

TOPAS. See Thrombolysis or Peripheral Arterial Surgery (TOPAS) trial Torsemide, 457 Tranilast restenosis, 187, 188, 191 Transesophageal echocardiography (TEE), 594 Transforming growth factor-beta (TGF-beta), 36, 37 Transient cerebral ischemia, 564 Transient ischemic attack clopidogrel, 66 Transmission electron microscopy (TEM) TAXUS stent, 284 Transurethral alprostadil ED with cardiovascular disease, 510 Trapidil restenosis, 301 Tricuspid stenosis, 596–597 Triglycerides target low-density lipoprotein cholesterol levels, 160 Troglitazone restenosis rates, 191 Tropocollagen, 214–215 Troponin ACS, 466, 470 elevated, 467 TSP, 36. See Thrombospondin (TSP) angiogenesis, 339 TTP. See Thrombotic thrombocytopenic purpura (TTP) Tumor necrosis factor angiogenesis, 339 TVR. See Target vessel revascularization (TVR) TXA2. See Thromboxane A2 (TXA2) UFH. See Unfractionated heparin (UFH) UK. See Urokinase (UK) Unfractionated heparin (UFH), 79–80, 528–529, 569 ACS, 121 ADP, 94–95 advantages, 570 characteristics, 97 clinical indications, 569 glycoprotein IIb/IIIa inhibitors, 94–95 PCI, 95–96 guidelines, 80 peri-percutaneous coronary intervention, 531 platelets, 94–95 STEMI, 121 therapeutic limitations, 570 Unstable angina, 465 glycoprotein IIb/IIIa inhibitors, 43–45 RCT, 45 Urokinase (UK), 571–572 Vacuum pump ED with cardiovascular disease, 510 Valsartan healing, 190 restenosis, 187, 191 Valve repair, 597–598 Valvuloplasty, 595

Vardenafil ED with cardiovascular disease, 510 Vascular cell adhesion molecules (VCAM), 15, 37 Vascular endothelial growth factors (VEGF), 355–361, 395 adverse effects, 360 angiogenesis, 339, 340, 397–398 balloon-delivered, 357–358 and bFGF cardiovascular system genetic manipulation, 367 clinical trials, 359–360 FGF, cardiovascular system genetic manipulation, 367 A isoforms angiogenesis therapy, 400 local infusion, 357 master switch, 400 myocardial angiogenesis, 407–409 promoting angiogenesis, 358–359 re-endothelialization, 190, 356–347 late thrombosis, 356–357 stent-based delivery, 358 structure and regulation, 355–356 systemic effects, 399–400 Vascular SMC (VSMC), 316 Vasculogenic erectile dysfunction, 505 Vasodilator-stimulated phosphoprotein (VASP), 146 VCAM. See Vascular cell adhesion molecules (VCAM) VEGF. See Vascular endothelial growth factors (VEGF) Veno-occlusive disease (VOD), 17 Ventricular septal defect (VSD), 598 post surgical and post myocardial infarction, 598 Verapamil AV node conduction, 489 healing, 190 peri-percutaneous coronary intervention, 533 restenosis, 187, 191, 301 Viral vectors growth factor delivery, 410–411 Visudyne, 381 Vitamin C, 224–225 clinical/epidemiological studies, 225 Vitamin E, 219–221 Vitamin K antagonists vs. melagatran, 110 Vitamin K-dependent zymogen, 8 Vitamins cardiovascular disease, 180 healing, 190 and restenosis after coronary angioplasty, 180–181 Vitronectin, 32 Vivitrol, 279 VLA complexes hemostasis, 4 VOD. See Veno-occlusive disease (VOD) Von Willebrand factor (VSF), 10, 12–13, 32, 127 coagulation disorders, 542 platelets, 527 VSCM. See Vascular SMC (VSMC)

645

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646

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Page 646

Index

VSD. See Ventricular septal defect (VSD) VSF. See von Willebrand factor (VSF)

White blood cells (WBC) PTCA, 317

Warfarin sodium, 22 heart failure, 460 vs. oral DTI, 110 peri-percutaneous coronary intervention, 533 Watchman left atrial appendage devices LAA, 595 WBC. See White blood cells (WBC) Weight loss ED, 511

Ximelagatran 21, 22, 109–110 chemistry, 109–110 clinical studies, 111–113 pharmacodynamics, 110 pharmacokinetics, 87, 110–111 vs. vitamin K antagonists, 110 ZOLADEX, 279 ZoMaxx, 294 Zymogen, 8

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