Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials

doi:10.1016/S0140-6736(06)69201-5

The Lancet

Volume 368, Issue 9535, 12–18 August 2006, Pages 581-588

https://doi.org/10.1016/S0140-6736(06)69201-5 Get rights and content

Summary

Background

Angiotensin-converting-enzyme (ACE) inhibitors reduce cardiovascular mortality and morbidity in patients with heart failure or left ventricular systolic dysfunction (LVSD). Three large trials have assessed the effect of ACE inhibitors in stable patients without these conditions but with atherosclerosis. We undertook a systematic review of the Heart Outcomes Prevention Evaluation (HOPE), the European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA), and the Prevention of Events with ACE inhibition (PEACE) studies to determine the consistency with which ACE inhibitors reduce total mortality and fatal and non-fatal cardiovascular events.

Methods

We computed cardiovascular outcomes and total mortality in the 29 805 patients of these three trials, randomly assigned an ACE inhibitor or placebo and followed up for a mean of about 4·5 years. The results were also analysed within the context of five large trials of ACE inhibitors in patients with heart failure or LVSD.

Findings

When the findings of the HOPE, EUROPA, and PEACE trials were combined, ACE inhibitors significantly reduced all-cause mortality (7·8 vs 8·9%, p=0·0004), cardiovascular mortality (4·3 vs 5·2%, p=0·0002), non-fatal myocardial infarction (5·3 vs 6·4%, p=0·0001), all stroke (2·2 vs 2·8%, p=0·0004), heart failure (2·1 vs 2·7%, p=0·0007), coronary-artery bypass surgery (6·0 vs 6·9%, p=0·0036) but not percutaneous coronary intervention (7·4 vs 7·6%, p=0·481). The composite outcomes of cardiovascular mortality, non-fatal myocardial infarction, or stroke occurred in 1599 (10·7%) of the patients allocated ACE inhibitor and in 1910 (12·8%) of those allocated placebo (odds ratio, 0·82; 95% CIs 0·76–0·88; p<0·0001). Except for stroke and revascularisation, these results were similar to those of the five trials in patients with heart failure or LVSD.

Interpretation

ACE inhibitors reduce serious vascular events in patients with atherosclerosis without known evidence of LVSD or heart failure. Results showing these benefits in intermediate-risk patients complement existing evidence of similar benefit in higher-risk patients with LVSD or heart failure. Therefore, use of ACE inhibitors should be considered in all patients with atherosclerosis.

Introduction

Angiotensin-converting-enzyme (ACE) inhibitors reduce mortality, hospital admissions for heart failure, and myocardial infarction in patients with left heart failure or low ejection fraction.¹ Since these benefits are seen in patients with normal blood pressure (mean systolic blood pressure around 120 mm Hg), it has been postulated that these benefits are independent of blood-pressure lowering.

Subsequently, three large clinical trials assessed the impact of ACE inhibitors in populations with vascular disease but no heart failure or left ventricular systolic dysfunction: the Heart Outcomes Prevention Evaluation (HOPE),² the European trial on Reduction Of cardiac events with Perindopril among patients with stable coronary Artery disease (EUROPA),³ and the Prevention of Events with Angiotensin-Converting-Enzyme inhibition trial (PEACE).⁴ All three ACE inhibitors used in these trials (ramipril, perindopril, and trandolapril, respectively) share several pharmacological characteristics and have been shown to reduce cardiovascular events in patients with heart failure and recent myocardial infarction5, 6 or stroke.⁷ In the HOPE and EUROPA studies, ramipril and perindopril reduced cardiovascular events, but trandolapril in the PEACE study did not significantly improve cardiac outcomes. Although patients in these trials shared some characteristics and the trials had substantial similarities in design, the primary outcomes, ancillary treatments, and inherent risks of patients in the control groups differed.

We investigated the consistency of the effects of ACE inhibitors on the same outcomes from each trial, and explored whether the benefits varied by ancillary treatments or between patients with varying levels of risk. We did similar analyses of data from the five large long-term trials in patients with heart failure or left ventricular systolic dysfunction (LVSD).5, 6, 8, 9, 10

Section snippets

Data collection

The HOPE, EUROPA, and PEACE studies were selected because they are the three main large trials of ACE inhibitors in patients with atherosclerosis, but without heart failure or LVSD. All three trials included more than 8000 stable patients, and followed them up for about 4·5 years. We thus undertook a systematic review of these trials (which includes more than 95% of all events in trials of this population) and analysed the results of various outcomes in the context of five large trials of ACE

Results

The HOPE, EUROPA, and PEACE studies selected stable patients without known history of heart failure or LVSD. Table 1 shows the main inclusion and exclusion criteria, outcomes, recruitment periods, and follow-up of the three trials. The HOPE investigators deliberately enrolled high-risk patients aged 55 years or older with previous cardiovascular disease (coronary heart disease [80%], previous stroke, or peripheral-artery disease) or diabetes plus another risk factor (hypertension, smoking,

Discussion

This overview of large trials with a total of 29 805 patients without known LVSD or heart failure shows clear benefits for use of ACE inhibitors for a range of outcomes. Overall, there was an 18% and highly significant reduction in odds ratio for the combined outcomes of cardiovascular mortality, non-fatal myocardial infarction, or stroke, with narrow confidence limits. This finding implies that for every 1000 patients treated over 4·5 years, 21 patients will not have any of these serious

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ArticlesAngiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Data collection

Results

Discussion

Lancet

Lancet

Prog Cardiovasc Dis

Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

N Engl J Med

Efficacy of perindopril in reduction of cardiovascular events in stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study)

Lancet

Angiotensin-converting-enzyme inhibition in stable coronary artery disease

N Engl J Med

Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure

Lancet

Randomised trial of a perindopril-based blood pressure-lowering regimen among 6105 individuals with previous stroke or transient ischemic attack

Lancet

Articles
Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials