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