Elsevier

The Lancet

Volume 357, Issue 9266, 5 May 2001, Pages 1385-1390
The Lancet

Fast track —Articles
Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial

https://doi.org/10.1016/S0140-6736(00)04560-8Get rights and content

Summary

Background

The beneficial effects of β-blockers on longterm outcome after acute myocardial infarction were shown before the introduction of thrombolysis and angiotensin-converting-enzyme (ACE) inhibitors. Generally, the patients recruited to these trials were at low risk: few had heart failure, and none had measurements of left-ventricular function taken. We investigated the long-term efficacy of carvedilol on morbidity and mortality in patients with leftventricular dysfunction after acute myocardial infarction treated according to current evidence-based practice.

Methods In a multicentre, randomised, placebo-controlled trial, 1959 patients with a proven acute myocardial infarction and a left-ventricular ejection fraction of ≤40% were randomly assigned 6·25 mg carvedilol (n=975) or placebo (n=984). Study medication was progressively increased to a maximum of 25 mg twice daily during the next 4–6 weeks, and patients were followed up until the requisite number of primary endpoints had occurred. The primary endpoint was all-cause mortality or hospital admission for cardiovascular problems. Analysis was by intention to treat.

Findings

Although there was no difference between the carvedilol and placebo groups in the number of patients with the primary endpoint (340 [35%] vs 367 [37%], hazard ratio 0·92 [95% CI 0·80–1·07]), all-cause mortality alone was lower in the carvedilol group than in the placebo group (116 [12%] vs 151 [15%], 0·77 [0·60–0·98], p=0·03). Cardiovascular mortality, non-fatal myocardial infarctions, and all-cause mortality or non-fatal myocardial infarction were also lower on carvedilol than on placebo.

Interpretation

In patients treated long-term after an acute myocardial infarction complicated by left-ventricular systolic dysfunction, carvedilol reduced the frequency of all-cause and cardiovascular mortality, and recurrent, non-fatal myocardial infarctions. These beneficial effects are additional to those of evidence-based treatments for acute myocardial infarction including ACE inhibitors.

Introduction

The efficacy of β-blockers in reducing major coronary events and improving short-term and long-term outcome has established their beneficial role in the management of acute myocardial infarction.1, 2, 3 However, the randomised trials whose results showed these effects were done before thrombolysis or primary angioplasty were used for reperfusion, and before the introduction of angiotensin-converting-enzyme (ACE) inhibitors. β-blockers have now been shown to reduce mortality and morbidity substantially, and improve left-ventricular function in patients with chronic heart failure when given together with ACE inhibitors.4, 5, 6, 7

Since coronary heart disease is a major cause of heart failure, attention has focused once more on the use of β-blockers in patients with acute myocardial infarction. Although there have been many randomised, placebo-controlled trials of β blockade in acute myocardial infarction, none has studied patients with confirmed left-ventricular systolic dysfunction who might also have had clinical evidence of heart failure during the index hospital admission. Post-hoc subgroup analyses of previous trials, however, have suggested a similar mortality benefit in patients with heart failure.8, 9, 10 Conversely, several trials of ACE inhibitors have conclusively shown substantial improvement in mortality and morbidity in this group of patients.11, 12, 13

Registries from Europe and the USA indicate that the use of β-blockers in eligible patients post myocardial infarction is substantially lower than would be expected from the convincingly positive results of the older trials.14, 15 One explanation for this finding could be the absence of contemporary data from trials in the post thrombolytic era, specifically in patients who have substantial left-ventricular dysfunction, who might also have heart failure, and in whom ACE inhibitors will have been prescribed. We designed the Carvedilol Post- Infarct Survival Control in LV Dysfunction (CAPRICORN) study to test the hypothesis that the addition of carvedilol to standard modern management of acute myocardial infarction in patients with leftventricular dysfunction with or without heart failure would improve outcome in terms of mortality and morbidity.

Section snippets

Patients

The CAPRICORN study, whose design and protocol have been published elsewhere,16 was a multicentre, double-blind, randomised controlled trial of carvedilol versus placebo involving 17 countries and 163 centres worldwide. Eligible patients were aged 18 years or older with a stable, definite myocardial infarction occurring 3–21 days before randomisation. Other inclusion criteria were: left-ventricular ejection fraction of 40% or less by two-dimensional echocardiography or by radionuclide or

Results

We recruited 1959 patients, of whom 975 were assigned carvedilol and 984 placebo, and who were followed up for a mean of 1·3 years (figure 1). The trial continued to its planned conclusion when 633 primary endpoints had been validated. In total, 707 such events were judged by the endpoints committee to have occurred.

Baseline characteristics, which were similar between the two groups, are shown in Table 1. The mean left-ventricular ejection fraction was 32·8%, and intravenous diuretics and

Discussion

The results of this study show substantial benefit from carvedilol with respect to major coronary events. The 23% relative reduction in mortality is identical to that reported in a meta-analysis of 22 long-term, randomised, controlled trials of β-blockers in acute myocardial infarction.3 However, in CAPRICORN, the all-cause mortality rate on placebo was 15% compared with 12% on carvedilol after an average followup of 1·3 years, whereas in the previous trials, the average mortality was 10% on

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