Elsevier

The Lancet

Volume 356, Issue 9246, 9 December 2000, Pages 1949-1954
The Lancet

Articles
Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials

https://doi.org/10.1016/S0140-6736(00)03306-7Get rights and content

Summary

Background

Several observational studies and individual randomised trials in hypertension have suggested that, compared with other drugs, calcium antagonists may be associated with a higher risk of coronary events, despite similar blood-pressure control. The aim of this meta-analysis was to compare the effects of calcium antagonists and other antihypertensive drugs on major cardiovascular events.

Methods

We undertook a meta-analysis of trials in hypertension that assessed cardiovascular events and included at least 100 patients, who were randomly assigned intermediate-acting or long-acting calcium antagonists or other antihypertensive drugs and who were followed up for at least 2 years.

Findings

The nine eligible trials included 27 743 participants. Calcium antagonists and other drugs achieved similar control of both systolic and diastolic blood pressure. Compared with patients assigned diuretics, β-blockers, angiotensin-converting-enzyme inhibitors, or clonidine (n=15 044), those assigned calcium antagonists (n=12 699) had a significantly higher risk of acute myocardial infarction (odds ratio 1·26 [95% Cl 1·11–1·43], p=0·0003), congestive heart failure (1·25 [1·07–1·46], p=0·005), and major cardiovascular events (1·10 [1·02–1·18], p=0·018). The treatment differences were within the play of chance for the outcomes of stroke (0·90 [0·80–1·02], p=0·10) and all-cause mortality (1·03 [0·94–1·13], p=0·54).

Interpretation

In randomised controlled trials, the large available database suggests that calcium antagonists are inferior to other types of antihypertensive drugs as first-line agents in reducing the risks of several major complications of hypertension. On the basis of these data, the longer-acting calcium antagonists cannot be recommended as first-line therapy for hypertension.

Introduction

Placebo-controlled trials have established that the lowering of raised blood pressure with diuretics and β-blockers as first-line agents reduces the risk of major cardiovascular complications of hypertension.1 Observational studies have suggested that short-acting calcium antagonists are inferior to diuretics and β-blockers in decreasing the risks of these complications.2, 3 Findings of two large trials have suggested that what may be important is the type of drug used to lower high blood pressure.4, 5 The investigators of the Heart Outcomes Prevention Evaluation (HOPE) trial concluded that most of the benefit of ramipril is mediated through non-blood-pressure-lowering mechanisms.4 In ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial), doxazosin was inferior to chlorthalidone for several cardiovascular outcomes.5 Moreover, several controlled trials of long-acting calcium antagonists, compared with other therapies, have shown similar blood-pressure-lowering potential but trends towards high event rates.6, 7

There are no data from individual trials to allow ranking of the currently available groups of antihypertensive drugs by their preventive effects. For millions of people receiving drug therapy for hypertension, the issue of drug selection is highly relevant. The most reliable information will come from controlled clinical trials of sufficient scope and duration, because the documentation of moderate treatment differences requires a very large number of events. As MacMahon and Neil pointed out lately, about 1000 events are needed for moderate treatment-group differences of 10–15% to be detectable.8 They also drew attention to the need for a meta-analysis.

The findings of observational studies2, 3 and the emerging evidence that the type of blood-pressure-lowering drug is important4, 5 emphasise the need to find out how the long-acting calcium antagonists as a group compare with other antihypertensive agents. The main objective of this meta-analysis was to find out whether the intermediate-acting and long-acting calcium antagonists used as first-line therapy are superior, equal, or inferior to other treatments in reducing the frequency of cardiovascular complications.

Section snippets

Methods

The criteria for studies to be included in the meta-analysis were: a randomised controlled trial published in a peer-reviewed journal; inclusion of patients with hypertension; comparison of a calcium antagonist with another antihypertensive drug; assessment of cardiovascular events; follow-up of 2 years or longer; and sample size of 100 or more. Studies were identified through PubMed searches of the MEDLINE database with the MeSH headings “calcium-channel blockers”, “hypertension”, and

Results

In the nine eligible trials the total number of participants was 27 743; 12 699 were assigned a calcium antagonist and 15 044 another antihypertensive drug (table 1). The follow-up duration ranged from 2 to 7 years with an estimated total follow-up experience of about 120 000 person-years. Two trials took place in the USA, six in Europe and Israel, and one in Japan. ABCD, INSIGHT, MIDAS, and NICS-EH were double-blinded, and VHAS was masked for only 6 months; the other four trials used an

Discussion

In comparative analyses of intermediate-acting or long-acting calcium antagonists versus other antihypertensive therapies, the combined results of the nine trials that met our inclusion criteria showed that calcium antagonists were associated with a significantly higher risk of major complications of hypertension, including acute myocardial infarction, congestive heart failure and combined major cardiovascular events. No significant differences were found for the outcomes of stroke and

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