THE YEAR IN HYPERTENSION 2001
THE YEAR IN HYPERTENSION 2001 HENRY L.ELLIOTT, JOHN M.C.CONNELL and GORDON T.McINNES Department of Medicine and Therapeutics, University of Glasgow Gardiner Institute, Western Infirmary, Glasgow
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[email protected] © Clinical Publishing Services Ltd 2001 First published 2001 This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” 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, without the prior permission in writing of Clinical Publishing Services Ltd A catalogue record for this book is available from the British Library ISBN 0-203-01184-8 Master e-book ISBN
ISBN 0 9537339 4 7 (Print Edition) The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work Project Manager: Rosemary Osmond
Contents
Part I
Contributors
vi
Foreword Peter Sever
vii
Preface Henry Elliott, Gordon McInnes, John Connell
viii
Clinical trials and guidelines 1.
Recent trial results Gordon McInnes
2
2.
Current guidelines Gordon McInnes
35
3.
Ongoing trials Gordon McInnes
76
Part II Interface: hypertension and other cardiovascular risk factors 4.
Hypertension, diabetes and cardiovascular risk Henry Elliott
117
5.
Lipid-lowering treatment: status report Henry Elliott
140
6.
Hormone replacement therapy and cardiovascular risk Henry Elliott
157
Part III Hypertension: emerging concepts 7.
Essential hypertension—the search for specific genetic markers John Connell
171
8.
Insulin resistance, hypertension, and endothelial function Stephen Cleland
187
9.
Mineralocorticoid hypertension: from recent research to clinical developments John Connell and Andrew Kernohan
203
v
Part IV Current practical issues 10.
Selective angiotensin II receptor antagonists Henry Elliott and Peter Meredith
228
11.
24-hour blood pressure measurement: current issues Henry Elliott
244
12.
Surrogate measures in cardiovascular disease Henry Elliott
256
13.
Calcium channel blockers in profile Henry Elliott and Gordon McInnes
277
List of abbreviations
289
Index of papers reviewed
294
General index
305
Contributors
STEPHEN CLELAND, BSc, MRCP, PhD, Lecturer in Clinical Medicine, Department of Medicine & Therapeutics, Gardiner Institute, Western Infirmary, University of Glasgow, Glasgow JOHN CONNELL, MBChB, MD, FRCP, FMedSci, Professor of Endocrinology, Department of Medicine & Therapeutics, Gardiner Institute, Western Infirmary, University of Glasgow, Glasgow HENRY ELLIOTT, MD, FRCP, Senior Lecturer in Medicine and Therapeutics, Department of Medicine & Therapeutics, Gardiner Institute, Western Infirmary, University of Glasgow, Glasgow ANDREW KERNOHAN, BMedSci, MBChB, MRCP, Clinical Research Fellow, Department of Medicine & Therapeutics, Gardiner Institute, Western Infirmary, University of Glasgow, Glasgow GORDON McINNES, BSc, MD, FRCP, FFPM, Senior Lecturer and Honorary Consultant Physician, Department of Medicine & Therapeutics, Gardiner Institute, Western Infirmary, University of Glasgow, Glasgow
Foreword
The authors’ second annual review of the year in hypertension is timely in the light of many new trial outcomes which have recently been reported. As highlighted in the earlier volume, there remains considerable uncertainty as to whether ‘newer’ drugs, such as the angiotensin-converting enzyme inhibitors and calcium channel blocking drugs, confer advantages over older drugs in the treatment of hypertension in general and in important high-risk subgroups such as those with diabetes, existing vascular disease or renal impairment. To have waited almost 20 years without knowledge of the long-term outcomes of these drugs when used as hypertension treatment is a clear indictment of the profession whose responsibility surely should have been to demand that morbidity and mortality studies were set in place long before now. It is against this background that the authors critically review many trials, the results of which have recently been published. They rightly emphasize the many shortcomings of trials such as INSIGHT, NORDIL and CAPPP, which were clearly underpowered to detect potential advantages of the newer drugs in protection against coronary heart disease. The discussion of the HOPE trial is important because of the remaining uncertainty as to whether the benefits observed were related to the drug ramipril, or to blood pressure differences between the groups. Several new meta-analyses have been published this year and deserve mention. The reader is encouraged to be as critical in evaluation of these data as he or she might be in looking at the individual trials. As the Blood Pressure Trialists’ Collaboration were at pains to point out, these are interim analyses and report endpoint numbers that are still too small to allow definitive conclusions to be made on drug-drug comparisons. Many on-going studies are cited and several will report in the next year, guaranteeing the wherewithal for future reviews! The authors reiterate a summary of contemporary guidelines and it is likely that the various bodies will reconvene to review their recommendations in the light of new trial results. The section on genetics and cardiovascular disease leads us through a particularly challenging and difficult field characterized by inconsistent and at times conflicting findings. For the clinician, the book will come as an important and useful reference. Many issues, however, remain unresolved and one hopes that future editions of The Year in Hypertension will provide critical summaries of key outstanding studies aimed to establish the definitive evidence base upon which to establish optimal clinical practice and to reduce the prevailing and unacceptable burden of hypertension-related cardiovascular disease in contemporary society. Peter S Sever, MA, MB, BChir, PhD, FRCP, FESC Professor of Clinical Pharmacology & Therapeutics Imperial College School of Medicine London, UK
Preface
The task of keeping up to date with recent developments is becoming increasingly difficult, even for the specialist, on account of the exponential expansion in medical knowledge and the ever increasing numbers of journals and other publications. For the non-specialist, therefore, especially where time and the relevant resources are restricted, it may prove to be impossible to keep abreast of all recent developments. Accordingly, the principal aim of The Year in Hypertension is to distill and summarize the information contained in recent publications and to present to the reader an abbreviated version of any recent ‘landmark’ clinical trials and illustrative examples of smaller research studies that influence current therapeutic practice, or indicate likely future directions. The Year in Hypertension cannot possibly be a comprehensive and extensive review of every recently published paper. While major studies, which are likely to influence clinical practice directly can readily be identified and commented upon, other smaller studies are selected on the pragmatic basis that they are illustrative of current lines of research. This does not mean that a chosen paper is necessarily definitive, or unique, or unexpected, but it has been selected because it provides the reader with ready access to current directions in terms of both clinical practice and ongoing research. In addition to providing a distillate of the literature published within the last year or so, there is a necessary requirement to maintain a perspective on how these recent findings relate to existing knowledge. For this reason, specific comment and summarizing conclusions are made by the authors on the basis of their own personal experience and expertise. Additionally, in some instances, summarizing comments have been retained for influential studies that have been published within recent years. Finally, the content of The Year in Hypertension is likely to evolve and alter as the relevance of different therapeutic areas changes with time. It is our intention to modify and adapt our chapters continuously in the light of these changes. Nevertheless, our primary aim is the presentation of up-to-date information in a readily accessible format. Henry Elliott, John Connell and Gordon McInnes
Part I Clinical trials and guidelines
1 Recent trial results
Introduction In epidemiological studies, there is a close relationship between blood pressure (BP; systolic and diastolic) and risk of stroke, coronary heart disease (CHD) and other cardiovascular events |1|. The higher the BP, the greater is the risk. This relationship is consistent in different populations, in younger and older subjects, in men and women, and is independent of other cardiovascular risk factors. The relationship is continuous across the range of BP, indicating that there is no lower threshold or safe level of BP. The slope of the relationship between BP and stroke is about 50% steeper than that between BP and CHD. However, many more coronary events are experienced in Western populations, although strokes are the predominant events in individuals from South-East Asia. Over the past four decades, numerous studies have examined the influence of drug treatment of hypertension on risk of cardiovascular events |2|. The usual aim was to achieve diastolic BP less than 90 mmHg. The average reduction in diastolic BP of 5–6 mmHg in these trials conferred a reduction of about 38% in stroke incidence, a 16% reduction in CHD events, a 21% reduction in all vascular events and a 12% reduction in all cause mortality, all highly significant. Effects on fatal and non-fatal events were similar. The proportional reductions were the same in high—and low-risk individuals, in the young and the elderly, and in mild, moderate and severe hypertension. At least equivalent benefits are associated with treatment of systolic hypertension |3–7|. Benefits are likely to be greater with larger reductions of BP. Epidemiological data indicate no lower threshold for risk and observational findings suggest that patients with the lowest on-treatment BP have the best prognosis |8|. The Hypertension Optimal Treatment (HOT) Study |9| confirmed that rigorous control of BP is associated with a reduced risk of cardiovascular events. Attainment of low BP was achievable in a high proportion of patients |10,11| without unacceptable side-effects |11|, and was associated with an improved quality of life |12|. Concordance with therapy was high in all groups |13|. Failure to achieve target BP, therefore, cannot be attributed to side-effects or patient non-compliance. Epidemiological data suggest that a difference in usual BP of the magnitude seen in the trials would result in a reduction in stroke incidence of 35–40% and of 20–25% for CHD events. Thus, treatment attains all that can be expected in stroke prevention but there appears to be a shortfall in protection against CHD events. As most of the trials used diuretics or beta-blockers, with potentially adverse metabolic effects, it has been suggested that newer agents might achieve greater cardiovascular protection for an equivalent reduction in BP. Early findings were inconclusive. The overall findings of the Captopril Prevention Project (CAPPP) |14| indicate that antihypertensive therapy based on an angiotensin-converting enzyme (ACE)
RECENT TRIAL RESULTS
3
inhibitor is no better than therapy based on diuretics and beta-blockers in the prevention of cardiovascular events and may be less effective in prevention of stroke although ACE inhibitors may confer an advantage in patients with diabetes mellitus. In the Swedish Trial of Old Patients with Hypertension-2 (STOP-2) study |15|, diuretics and beta-blockers and newer antihypertensive drugs (ACE inhibitors and calcium channel blockers) where equally useful in the management of elderly patients with hypertension. The hypothesis that some classes of drugs would have advantages was not substantiated. However, both trials had major shortcomings. In CAPPP |14|, the use of captopril once daily in half the patients randomized to this form of therapy was illogical in view of the short duration of action of this drug. The observed BP differences between the groups could not be explained by chance in such a large sample size and is almost certainly related to the use of envelopes for randomization |16|. The excess of stroke in captopril-treated patients is probably the consequence of the trial-long difference in BP; statistical adjustment cannot compensate for such an effect. The STOP-2 study |15| also had potential weaknesses and uncertainties. The newer drugs were used at low doses in a once daily regimen raising the possibility that 24-h control of BP might be less complete in these patients. Additional therapy was with older drugs regardless of the randomized group reducing the distinction between older and newer drugs. This is particularly relevant as about 50% of patients required older drugs and at least one-third of patients discontinued randomized therapy during the course of the trial. The potential advantage of newer agents thus remains uncertain. The last year has seen the publication of several large outcome trials and meta-analyses that have addressed this question. In addition, a further overview has examined the risks associated with systolic BP in older patients with isolated systolic hypertension. Influence of newer antihypertensive agents The International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT)
Morbidity and mortality in patients randomized to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT). M J Brown, C R Palmer, A Castaigne, et al. Lancet 2000; 356:366–72. BACKGROUND. The aim was to compare the effects of the calcium channel blocker nifedipine once daily with the diuretic combination co-amilozide on cardiovascular mortality and morbidity in high-risk patients with hypertension. INTERPRETATION. Nifedipine once daily and co-amilozide were equally effective in preventing overall cardiovascular and cerebrovascular complications.
4
I·CLINICAL TRIALS AND GUIDELINES
Comment INSIGHT was a double-blind randomized trial of morbidity and mortality, in which the comparison was between older and newer classes of antihypertensive drugs in patients at high absolute risk of cardiovascular events. These patients are the main target for treatment in modern guidelines. The primary objective was to compare the efficacy in preventing the major complications from hypertension of nifedipine, a calcium channel blocker, administered in a long-acting gastrointestinal therapeutic system (GITS) formulation and co-amilozide a common and effective combination of the diuretics hydrochlorothiazide and amiloride. The study recruited 2929 men and 3392 women, aged 55–80 years, with BP during placebo run-in ≥150/ 95 mmHg or isolated systolic BP≥160 mmHg, from nine countries (Israel, France, Italy, Spain, the Netherlands, UK, Norway, Sweden and Finland). To be eligible, patients had to have ≥1 other additional major cardiovascular risk factor. Treatment allocation to nifedipine GITS 30 mg daily (n=3157) or coamilozide (hydrochlorothiazide 25 mg/amiloride 5 mg) once daily (n=3164) was performed by minimization rather than randomization to balance additional risk factors. Optimal increases in treatment by dose doubling and/or addition of atenolol or enalapril, and then by other antihypertensive drugs, excluding calcium channel blockers or diuretics, was allowed to achieve target BP ≤140/90 mmHg or a fall ≥20/10 mmHg. The primary outcome variable was a composite of death from any cardiovascular or cerebrovascular cause, together with non-fatal stroke, myocardial infarction (MI) and heart failure. Three secondary variables were: (a) total mortality; (b) death from a vascular cause; and (c) non-fatal vascular events, including transient ischaemic attacks, angina (new or worsening), and renal failure. Mean age of participants was 65 years. BP at randomization was 173/99 mmHg. The proportion of additional risk factors were: total cholesterol >6.43 mmol/l, 52%; smoking >10/day, 28%; diabetes mellitus, 21.6%; family history of premature MI or stroke, 21%; left ventricular hypertrophy 11%; previous MI, CHD and peripheral vascular disease, each 6%; proteinuria, 3%. The main outcomes in INSIGHT are shown in Table 1.1. Primary outcomes occurred in 200 (6.3%) patients in the nifedipine group and in 182 (5.8%) in the co-amilozide group [18.2 vs 16.5 events per 1000 patient-years; relative risk (RR) 1.10 [95% confidence interval (CI) 0.91, 1.34], P=0.35]. Overall mean BP fell from 173/99 mmHg to 138/82 mmHg. There was an 8% excess of withdrawals from the nifedipine group because of peripheral oedema (725 vs 518, P
