Elsevier

The Lancet

Volume 362, Issue 9386, 6 September 2003, Pages 782-788
The Lancet

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

https://doi.org/10.1016/S0140-6736(03)14286-9Get rights and content

Summary

Background

Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events. We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure.

Methods

We recruited patients from October, 1997, to June, 2000. 13 655 patients were registered with previous myocardial infarction (64%), angiographic evidence of coronary artery disease (61%), coronary revascularisation (55%), or a positive stress test only (5%). After a run-in period of 4 weeks, in which all patients received perindopril, 12 218 patients were randomly assigned perindopril 8 mg once daily (n=6110), or matching placebo (n=6108). The mean follow-up was 4·2 years, and the primary endpoint was cardiovascular death, myocardial infarction, or cardiac arrest. Analysis was by intention to treat.

Findings

Mean age of patients was 60 years (SD 9), 85% were male, 92% were taking platelet inhibitors, 62% β blockers, and 58% lipid-lowering therapy. 603 (10%) placebo and 488 (8%) perindopril patients experienced the primary endpoint, which yields a 20% relative risk reduction (95% Cl 9–29, p=0·0003) with perindopril. These benefits were consistent in all predefined subgroups and secondary endpoints. Perindopril was well tolerated.

Interpretation

Among patients with stable coronary heart disease without apparent heart failure, perindopril can significantly improve outcome. About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event. Treatment with perindopril, on top of other preventive medications, should be considered in all patients with coronary heart disease.

Published online Sept 1, 2003 http://image.thelancet.com/extras/03art7384web.pdf

Introduction

Cardiovascular disease remains the leading cause of death in most regions of the world, mostly in the form of coronary heart disease.1 Over the past few decades, preventive and therapeutic measures have substantially improved the prognosis of these patients.2, 3 Nevertheless, the risk of cardiovascular complications remains high and progression can be halted only in a few patients, despite treatment with aspirin, statins, and β blockers.4 More effective secondary preventive strategies are needed, and angiotensin-converting-enzyme (ACE) inhibitors could fill an important gap. ACE inhibitors effectively reduce mortality and morbidity among patients with heart failure, left-ventricular dysfunction, after myocardial infarction, with hypertension, and among other high-risk patients.5, 6, 7, 8, 9, 10, 11 In particular, previous ACE-inhibitor studies have suggested a reduction in the rate of myocardial infarction and the need for revascularisation in patients with heart failure and left-ventricular dysfunction.12, 13 The Heart Outcomes Prevention Evaluation (HOPE) study11 confirmed the benefits of ACE inhibition in patients aged 55 years or older at high risk of cardiovascular complications, characterised by a high prevalence of diabetes, hypertension, stroke, and obstructive peripheral vascular disease. In addition to lowering blood pressure, ACE inhibitors possess direct cardiovascular protective effects through angiotensin II reduction and increased bradykinin availability.14 Consequently, ACE inhibition may result in antiatherosclerotic effects, reduced neointimal formation, and improved endothelial function, plaque stabilisation, and fibrinolysis.15, 16, 17 In animal models, ACE inhibitors reverse atherosclerosis.18 This multifactorial antiatherosclerotic profile of ACE inhibition suggests that its application might be extended to all patients with established coronary heart disease and should not be restricted to patients with impaired left-ventricular function, heart failure, or a high risk of atherosclerotic events.11, 12, 13

Therefore, in the EUropean trial on Reduction Of cardiac events with Perindopril in patients with stable coronary. Artery disease (EUROPA) study, we aimed to assess the ability of the ACE inhibitor perindopril to reduce cardiovascular death, myocardial infarction, and cardiac arrest in a broad population of patients with stable coronary heart disease and without heart failure or substantial hypertension. We used perindopril, a long-acting ACE inhibitor, because, in addition to its blood-pressure-lowering properties, it has documented anti-ischaemic and antiatherogenic effects, as well as an effect on cardiovascular remodelling.19, 20, 21, 22, 23

Section snippets

Patients and methods

We did a randomised, double-blind, placebo-controlled, multicentre study. The design of the trial has been described previously.24

Results

13 655 patients were registered; 8775 (64%) had a history of myocardial infarction, 8302 (61%) of angiography with substantial stenoses, 7550 (55%) of previous revascularisation, and 1670 (12%) of diabetes mellitus. 603 (5%) men were registered with only an abnormal stress test. After the run-in period, 12 218 patients were randomised: 10 439 (85%) men and 1779 (15%) women (figure 1). Reasons for registered patients not proceeding to randomisation were: hypotension (290), raised potassium or

Discussion

We show a substantial benefit with perindopril in a broad population of patients with stable coronary artery disease and no evidence of heart failure or notable hypertension. Cardiovascular death, myocardial infarction, cardiac arrest, acute coronary syndromes, and development of heart failure were all reduced. Our findings confirm the reduction in myocardial infarction with ACE inhibitors originally noted in earlier studies of patients with heart failure or left-ventricular dysfunction.12, 13

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