Elsevier

The Lancet

Volume 358, Issue 9290, 20 October 2001, Pages 1305-1315
The Lancet

Articles
Cardiovascular protection and blood pressure reduction: a meta-analysis

https://doi.org/10.1016/S0140-6736(01)06411-XGet rights and content

Summary

Background

Whether antihypertensive drugs offer cardiovascular protection beyond blood pressure lowering has not been established. We aimed to investigate whether pharmacological properties of antihypertensive drugs or reduction of systolic pressure accounted for cardiovascular outcome in hypertensive or high-risk patients.

Methods

In a meta-analysis we extracted summary statistics from published reports, and calculated pooled odds ratios for experimental versus reference treatment. We correlated across-trials odd ratios for differences in systolic pressure between groups.

Findings

We analysed nine randomised trials comparing treatments in 62 605 hypertensive patients. Compared with old drugs (diuretics and β-blockers), calcium-channel blockers and angiotensin converting-enzyme inhibitors offered similar overall cardiovascular protection, but calcium-channel blockers provided more reduction in the risk of stroke (13·5%, 95% CI 1·3–24·2, p=0·03) and less reduction in the risk of myocardial infarction (19·2%, 3·5–37·3, p=0·01). Heterogeneity was significant between trials because of high risk of cardiovascular events on doxazosin in one trial, and high risk of stroke on captopril in another; but systolic pressure differed between groups in these two trials by 2–3 mm Hg. Similar systolic differences occurred in a trial of diltiazem versus old drugs, and in three trials of converting-enzyme inhibitor against placebo in high-risk patients. Meta-regression across 27 trials (136 124 patients) showed that odds ratios could be explained by achieved differences in systolic pressure.

Interpretation

Our findings emphasise that blood pressure control is important. All antihypertensive drugs have similar long-term efficacy and safety. Calcium-channel blockers might be especially effective in stroke prevention. We did not find that converting-enzyme inhibitors or α-blockers affect cardiovascular prognosis beyond their antihypertensive effects.

Introduction

Lifetime risk of hypertension is about 20%. Several trials have been done to find the best possible protection against the cardiovascular complications of this widespread condition. Various drugs were tested to see whether their mode of action or ancillary properties could offer benefit beyond their effect of lowering blood pressure.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 In normotensive and hypertensive high-risk patients in the HOPE study,7 the angiotensin-converting enzyme (ACE) inhibitor ramipril significantly reduced rates of death, stroke, and myocardial infarction compared with placebo. In hypertensive patients enrolled in ALLHAT,10 fewer cardiovascular events happened during treatment with chlorthalidone than with the α-blocker doxazosin. However, in both studies,7, 10 systolic pressure was 2–3 mm Hg lower in the group with the best outcome, which could have been sufficient to explain the results.17, 18, 19 Two quantitative overviews20, 21 reached opposite conclusions with respect to cardiovascular protection of calcium-channel blockers compared with diuretics or β-blockers. However, neither of these overviews20, 21 specifically assessed blood pressure differences between randomised groups in relation to heterogeneity among trials, or included α-blockers in the group of newer drugs.

We investigated whether pharmacological properties of antihypertensive drugs or blood pressure reduction explained cardiovascular outcome. We focused on systolic pressure because, in middle-aged and older patients, systolic pressure is a better predictor of cardiovascular risk than diastolic pressure,22 and systolic pressure can be measured more reliably than diastolic pressure.23 First, we assessed whether differences in achieved systolic pressure between randomised groups led to heterogeneity among outcome trials of old versus new classes of antihypertensive drugs. Second, we used metaregression to measure to what extent blood pressure reduction accounts for results of outcome trials.

Section snippets

Trials

We searched for outcome trials that tested drugs to lower blood pressure in normotensive or hypertensive patients who did not have overt heart failure at enrolment. Other inclusion criteria were a randomised controlled design, publication in a peer-reviewed journal, inclusion of patients with hypertension, assessment of blood pressure and cardiovascular events, follow-up of 2 years or longer, and sample size of 100 or more. Outcome trials of drugs to lower blood pressure were identified from

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