Stephen P. Glasser, MD, is professor of preventive medicine and epidemiology, University of Alabama at Birmingham, and Associate Editor-in-Chief of Cardiology Review.

Pharmacologic inhibition of the renin-angiotensin aldosterone system (RAAS) has become a widely accepted ap­proach to lowering blood pressure (BP). Angiotensin-converting enzyme (ACE) in­hibitors and angiotensin receptor blockers (ARBs) are two classes of RAAS inhibitors. During the past 5 years or so, and predominantly with the ACE inhibitors, clinical trials have been reported that demonstrate that not only do these drugs lower BP, but they also prevent cardiovascular (CV) events; and this reduction in CV events is likely beyond their BP-lowering effects.^1-3

The clinical trial that had perhaps the greatest impact on the prescribing of ACE inhibitors in patients without elevated BP was the Heart Outcomes Prevention Evaluation (HOPE) trial, which utilized ramipril (Altace) as the ACE inhibitor.¹ More recently, perindopril (Aceon) has been studied with regard to its effect on CV and stroke events beyond its important BP-lowering effects. In the Pro­tection Against Recurrent Stroke Study (PROGRESS), perindopril was associated with a 9/4 mm Hg reduction in BP and a 28% and 26% reduction in stroke and CV events, respectively.²

Most recently, the Efficacy of Perindopril in Reduction of Cardiovascular Events (EUROPA) was reported.³ The results of this trial resulted in a statement in perindopril’s package insert saying that it is indicated in patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or nonfatal myocardial infarction (MI).⁴ This is then ad­d­ed to its antihypertensive indication. Per­indopril also remains one of the only ACE inhibitors in which the package insert discusses its role in favorably affecting arterial compliance, in which it is stated that “an increase in the compliance of large arteries was ob­served, suggesting a direct effect on arterial smooth muscle, consistent with the results of animal studies.”

The HOPE study evaluated the benefits of ACE inhibition in patients aged 55 years or older at high risk for CV complications, characterized by a high prevalence of diabetes, hypertension, stroke, and peripheral vascular disease. EUROPA evaluated patients with stable coronary artery disease over age 18 and importantly without evidence of heart failure. Patients were randomly assigned to 8 mg perindopril or placebo, added to a background of contemporary usual-care therapy (which was quite extensive and in­cluded platelet inhibitors, lipid-lowering therapy, beta blocking agents, calcium channel antagonists, nitrates, and diuretics). The primary end point was a composite of CV death, nonfatal MI, and cardiac arrest with successful resuscitation. Over 12,000 pa­tients were randomized and 6,107 in the perindopril arm and 6,108 in the placebo group completed the study. Remarkably, in this event-driven study that followed patients for 5 years, only three patients were lost to follow-up. A relative risk reduction of 20% was observed in the primary end point, and the number needed to treat to prevent a primary event was 50 patients treated for 4 years to prevent one primary end point event. Some other interesting findings in­cluded favorable effects on all secondary end points analyzed and for all age groups (including those below the age of 55) and with hypertension or not. In­terestingly, in this diseased population on usual-care medical therapy, the annual placebo event rate was 2.4%, which amortizes to about 24% in 10 years, while in HOPE the annual placebo event rate was 4.4% or 44% at 10 years. Thus, both studies enrolled patients with a Framingham Risk Score that placed them in the high-risk category, but clearly the HOPE population was at almost twice the risk.

The EUROPA results clearly imply that ACE inhibitors should be considered for patients with stable coronary artery disease, and they should be added to baseline usual-care therapy. To date, only ramipril and perindopril have the Food and Drug Admin­is­tration approved indication for coronary artery disease protection, and the argument continues as to whether it is a class effect. Because there are differences among the ACE inhibitors, particularly regarding their tissue penetration and trough-to-peak ratios, one should exercise caution if they prescribe a different ACE inhibitor for this indication.

References
1. Sleight P, Yusuf S, Pogue J, et al. Heart Outcomes Prevention Evaluation (HOPE) Study. Blood-pressure reduction and cardiovascular risk in the HOPE study. Lancet. 2001;358(9299):2130-2131.

2. PROGRESS Collaborative Group. Ran­domised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with a previous stroke or transient ischemic attack. Lancet. 2001;358(9287): 1033-1041.

3. Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease investigators. Efficacy of perindopril in reduction of cardiovascular events among people with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: 782-788.

4. Perindopril (Aceon package insert). Marietta, Ga: Solvay Pharmaceuticals; March 2003.