Late-Breaking Trials from the European Society of Cardiology Congress

Source: Fox KM and EUROPA Investigators. Lancet. 2003;362:782-788.

The European Trial of Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study tested the hypothesis that perindopril in patients with stable coronary artery disease (CAD), but without heart failure or substantial hypertension, will reduce cardiovascular deaths, myocardial infarction (MI), and cardiac arrest. In this randomized, double-blind, placebo-controlled multicenter study, 13,655 patients were entered with previous MI (64%), coronary revascularization (55%), or a positive stress test only (5%). Exclusion criteria included clinical evidence of heart failure, blood pressure < 110 mm Hg systolic or >180/100 mm Hg, or renal insufficiency. The primary end point was a combination of CV death, MI, and resuscitated cardiac arrest. 

All patients underwent a run in a period of 4 weeks on perindopril before randomization and 1437 (11%) were not randomized due to hypotension (2%), elevated potassium, or creatinine (1%) and other intolerances. The remaining 12,218 patients were treated with perindopril 8 mg/d or placebo. The mean follow-up was 4.2 years. The largely male population was also taking platelet inhibitors (92%), beta blockers (62%), and lipid-lowering therapy (58%). The primary end point was reached in 8% of the perindopril patients and 10% of the placebo patients, which is a 20% relative risk reduction (95% CI 9-29%; P = .0003). The results were consistent across all predefined subgroups including age, sex, hypertension, diabetes, and other drug therapy. 

When the primary end point was broken down, cardiovascular mortality alone was not significantly reduced, nor were total mortality or cardiac arrest, but MI was. The average blood pressure reduction on perindopril was 5/2 mm Hg. During the randomized portion of the trial, 23% of patients on perindopril withdrew from treatment vs 21% of placebo patients. More perindopril patients experienced cough and hypotension, but other adverse effects were similar between the 2 groups. Fox and colleagues concluded that treatment with perindopril plus other preventive medications should be considered in all patients with CAD even without apparent heart failure or substantial hypertension.

Comment by Michael H. Crawford, MD

Previous studies have shown that angiotensin converting enzyme inhibitors (ACEI) reduce morbidity and mortality in heart failure, left ventricular dysfunction, post-MI, hypertension, and high risk for vascular disease patients. These results extend the secondary prevention role of ACEI to stable CAD patients. Fox et al chose perindopril because it is a long-acting ACEI with high tissue penetration that has been shown to have anti-ischemic, anti-atherosclerosis, and positive left ventricular remodeling effects. Perindopril has similar properties to ramapril, which was used in the HOPE study. Whether other ACEIs would perform similarly is not known. 

One unknown in the EUROPA study is the patients’ left ventricular function. Although most probably had normal or near normal left ventricular function, some may have had reduced function since 64% had a previous MI. Thus, some of the observed benefit may have been due to patients with reduced left ventricular function. Also, it is hard to know how much of the benefit observed was due to blood pressure lowering since only patients with substantial hypertension were excluded (> 180/100 mm Hg). Finally, although the drug appeared well tolerated, 11% were excluded in the run-in phase on perindopril and another 23% withdrew during the study. So despite the intentions of Fox et al, only two-thirds of the enrolled patients could take perindopril long term. In a less selected general population of CAD patients, this figure is likely to be lower. However, given the growing mass of positive data for secondary prevention with ACEI, it appears that ACEI and perhaps the long-acting, tissue-penetrating ACEIs should be part of the regimen of aspirin, statins, beta blockers, and other risk factor-lowering strategies in all CAD patients.

Dr. Crawford, Professor of Medicine, Associate Chief of Cardiology for Clinical Programs, University of California, San Francisco, is Editor of Clinical Cardiology Alert.