ArticlesEffects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials*
Introduction
By the mid 1990s, evidence about the effects of blood-pressure-lowering regimens based mainly on diuretics and β-blockers was available from a series of randomised controlled trials involving a total of more than 47 000 hypertensive patients.1, 2, 3, 4, 5 Systematic overviews (or meta-analyses) of these trials showed that reductions in blood pressure of about 10–12 mm Hg systolic and 5–6 mm Hg diastolic conferred relative reductions in stroke risk of 38% and in risk of coronary heart disease of 16% within just a few years of beginning treatment.2, 3 The sizes of these effects were broadly consistent with those predicted from observational studies of the long-term associations of blood pressure with risk of stroke and coronary heart disease.6, 7, 8 Additionally, the sizes of these effects were similar in various major subgroups of trials and patients, and seemed to be largely independent of differences in disease event rates among patients assigned control. The few studies that directly compared the effects of diuretics and β-blockers detected no clear differences in risk of stroke or coronary heart disease.9, 10, 11, 12 Similarly, the few studies that had directly compared newer agents such as angiotensin-converting-enzyme (ACE) inhibitors and calcium antagonists with diuretics or β-blockers also failed to detect any clear differences.13, 14, 15, 16 However, these studies were individually and collectively too small to detect any plausibly modest differences (eg, 10–15% differences in relative risk) in the cause-specific effects of the regimens compared.
In addition to this evidence from patients with high blood pressure, other relevant evidence was available at that time from trials of several of the same agents in other groups of patients. Overviews of randomised controlled trials of β-blockers among patients with coronary disease had shown reductions of about a fifth in the risk of reinfarction or death.17 Overviews of trials of ACE inhibitors among patients with heart failure or left-ventricular dysfunction showed reductions of between a quarter and a fifth in the risks of death, myocardial infarction, or hospital admission for heart failure,18, 19 but few data were available about the effects of these agents among patients with preserved left-ventricular function. An overview of trials of ACE inhibitors among patients with acute myocardial infarction also showed relative reductions of about 7% in the risk of death.20 Overviews of trials of calcium antagonists among patients with coronary heart disease21, 22 had provided some evidence suggestive of increased mortality with dihydropyridine agents (mainly short-acting nifedipine) and reduced mortality with non-dihydropyridine agents (diltiazem and verapamil), but the available data were too few to provide reliable evidence about any such separate effects or, indeed, any overall effect of calcium antagonists.23
Over the past 5 years, a new series of trials has been completed, and several other trials started in efforts to further elucidate the effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs on mortality and major cardiovascular morbidity in several populations of patients including those with hypertension, diabetes mellitus, coronary heart disease, or renal disease. Before the results of any of these new trials were known, some studies were recognised as being too small individually to detect moderate, though potentially important, cause-specific effects of treatments or differences between treatment effects. Therefore, in July, 1995, the principal investigators from all of the large-scale trials that were in progress or in advanced stages of planning met and agreed to collaborate in a programme of prospectively planned overviews in which treatment effects and treatment differences would be estimated from the combined results of individual studies.24 Separate overviews were planned for trials that compared active treatment regimens with placebo, those that compared more intensive with less intensive blood-pressure-lowering strategies, and trials that assessed treatment regimens based on different drug classes. Estimates of treatment effects and treatment differences from these overviews should be subject to less random error than those from any one constituent trial, since they would be based on larger numbers of cause-specific outcomes.25 Additionally, by prospectively defining the studies to be included, the hypotheses to be addressed, and the outcomes to be studied, the estimates from these overviews might be less subject to bias than those from other overviews in which the studies, hypotheses, and outcomes are selected retrospectively with full knowledge of the individual study results.25 This report provides results from the first prospectively planned cycle of analyses by this collaborative group under the aegis of the WHO-International Society of Hypertension Liaison Committee.
Section snippets
Trial eligibility
The criteria for selection of trials for inclusion in these overviews were prespecified in the protocol for this project.24 Trials were eligible for inclusion if they met one of the following criteria: (1) randomisation of patients between a blood-pressure-lowering drug and placebo or other inactive control (irrespective of whether the intent of study treatment was to lower blood pressure and irrespective of whether patients were selected on the basis of high blood pressure); (2) randomisation
Characteristics of trials and patients included
Outcome data were available from 15 studies28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 that collectively included 74 696 individuals (table 1). The mean age of all participants was 62 years and 53% were male. Six studies provided outcome data from comparisons of an active agent with a placebo (five of which were among patients with cardiovascular disease or diabetes mellitus); three provided outcome data from comparisons of blood-pressure-lowering regimens of different
Discussion
The results of the first cycle of analyses from this programme of prospectively designed overviews show that benefits of blood-pressure-lowering drugs are not limited to regimens based on diuretics or β-blockers. The overview of placebo-controlled trials of ACE inhibitors shows that, with only a modest reduction in blood pressure, these agents decreased the risks of stroke, coronary heart disease, and major cardiovascular events by 20–30% among high-risk patients selected on the basis of a
References (46)
- et al.
Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context
Lancet
(1990) - et al.
Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias
Lancet
(1990) - et al.
Beta-blockade during and after myocardial infarction: an overview of the randomized trials
Prog Cardiovasc Dis
(1985) - et al.
Update of effects of calcium antagonists in myocardial infarction or angina in light of the Second Danish Verapamil Trial (DAVIT-II) and other recent studies
Am J Cardiol
(1991) - et al.
Long-term ACE inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients
Lancet
(2000) - et al.
Effect of angiotensin converting enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial
Lancet
(1999) - et al.
Morbidity and mortality in patients randomised 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)
Lancet
(2000) - et al.
Randomised trial of effects of calcium antagonists compared with diuretics and ß-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study
Lancet
(2000) - et al.
Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study
Lancet
(1999) - et al.
Randomised, placebocontrolled trial of the angiotensin converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive vascular disease
J Am Coll Cardiol
(2000)
Angiotensin converting enzyme inhibition as antiatherosclerotic therapy: no answer yet
Am J Cardiol
Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension
Lancet
Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial
Lancet
Trials stopped early: too good to be true?
Lancet
The effects of antihypertensive treatment on vascular disease: reappraisal of the evidence in 1994
J Vase Med Biol
Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease
Br Med Bull
Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men: a meta-analysis of individual patient data from randomised controlled trials
Ann Intern Med
Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis
JAMA
Cholesterol, diastolic blood pressure, and stroke: 13,000 strokes in 450,000 people in 45 prospective cohorts
Lancet
Blood pressure, cholesterol, and stroke in eastern Asia
Lancet
MRC trial of treatment of mild hypertension: principal results
BMJ
Medical Research Council trial of treatment of hypertension in older adults: principal results
BMJ
Beta-blockers versus diuretics in hypertensive men: main results from the HAPPHY trial
J Hypertens
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