Issue 178 Item 4 ACE Inhibitors Would Prevent 250,000 Cardiovascular Deaths

A landmark clinical trial in secondary cardiovascular prevention has shown that all patients with stable coronary heart disease, regardless of risk level, ought to receive an angiotensin-converting enzyme inhibitor. Placing all Americans with known coronary heart disease on an ACE inhibitor would prevent roughly a quarter of a million cardiovascular deaths, acute MIs, or cardiac arrests over the course of 4 years,

Results of the European Trial on Reduction of Cardiac Events With Perindopril in Stable Coronary Artery Disease (EUROPA) were presented at the annual congress of the European Society of Cardiology.

EUROPA was hailed as persuasive—and certain to lead to substantial change in routine clinical management.

“This is a very robust, elegant study. It’s a very important clinical trial. It’ll change clinical practice,” predicted Dr. Sidney C. Smith, former American Heart Association president and a member of the committee that creates the influential joint AHA/American College of Cardiology guidelines on secondary prevention.

“I can’t speak for the group that writes the guidelines, but I am very impressed with these data. This is the evidence that we need to make the strong statement that all patients with coronary disease should be treated with an ACE inhibitor. The findings for perindopril in EUROPA are so strong one would have to question why this shouldn’t be part of the primary therapy,” added Dr. Smith, professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina at Chapel Hill.

EUROPA was the largest clinical trial ever conducted in patients with stable coronary heart disease. The Servier-sponsored study involved 12,218 patients without congestive heart failure or substantial hypertension in 24 European countries. This relatively low-risk population—many participants were asymptomatic—was randomized to 8 mg/day of perindopril or placebo on top of optimal medical management with antiplatelet therapy, a blocker, and lipid-lowering therapy.

After 4.2 years of follow-up, the combined primary end point of cardiovascular death, MI, or cardiac arrest had occurred in 10% of patients in the placebo arm and 8% of those on perindopril. This translated to a highly significant 20% relative risk reduction. Clinical benefits were seen with ACE inhibitor therapy in all prespecified subgroups, including all age categories and patients with or without diabetes, hypertension, or prior MI.

Perindopril reduced the incidence of congestive heart failure by 39% and the rate of fatal or nonfatal acute MI—a particularly meaningful end point—by 24%, added Dr. Fox, professor of clinical cardiology at Royal Brompton Hospital in London.

To prevent one primary event, 50 patients would need to be treated for 4 years. Extrapolating from EUROPA, placing all Americans with known coronary heart disease on an ACE inhibitor would prevent roughly a quarter of a million cardiovascular deaths, acute MIs, or cardiac arrests over the course of 4 years, he said.

EUROPA’s way was paved by the earlier Heart Outcomes Prevention Evaluation (HOPE), in which ramipril showed significant preventive benefits. But HOPE featured a much higher-risk population. The EUROPA population was far more typical of patients encountered in everyday practice, according to Dr. Smith. For example, 39% of HOPE participants were diabetic, compared with 12% in EUROPA.

Investigators in industry-sponsored studies almost always feel compelled to argue that the observed benefits were due to unique effects of the study drug, and EUROPA was no exception, but Dr. Smith wasn’t buying it.

“I think from the evidence that’s accumulating, going back to SAVE [the Survival and Ventricular Enlargement trial], SOLVD [Studies of Left Ventricular Dysfunction], HOPE, and now EUROPA, it would appear that we’re dealing with a class effect,” said the cardiologist, who wasn’t involved in EUROPA.

He agreed with Dr. Fox that the relatively modest blood pressure reduction seen with perindopril in EUROPA was insufficient to explain the clinical benefits.

ACE inhibitors appear to possess important direct vascular effects that fight atherosclerosis and endothelial dysfunction. Annual Congress of the European Society of Cardiology, Oct, 2003