CLINICAL QUESTION: Does therapy with an angiotensin-converting-enzyme (ACE) inhibitor reduce the rate of cardiovascular events in high-risk patients with no known left ventricular (LV) dysfunction or heart failure?
BACKGROUND: The renin-angiotensin-aldosterone system is an important contributor to the pathogenesis of cardiovascular disease. ACE inhibitors improve outcomes in patients with LV dysfunction (with or without heart failure). This study assessed whether therapy with an ACE inhibitor, ramipril, reduced the rate of cardiovascular events in high-risk patients with no known LV dysfunction or heart failure.
POPULATION STUDIED: From December 1993 through June 1995, the Heart Outcomes Prevention Evaluation (HOPE) investigators recruited patients from 277 centers in Canada, the United States, Argentina, Brazil, Mexico, and 14 western European countries. The final study population included 9297 patients at high risk for a cardiovascular event. All patients were aged 55 years or older and had either evidence of vascular disease or diabetes mellitus plus one other cardiovascular risk factor. Exclusion criteria included known history of heart failure or low LV ejection fraction (<40%), use of an ACE inhibitor or vitamin E, uncontrolled hypertension, overt nephropathy, and myocardial infarction or stroke in the 4 weeks before the study began.
STUDY DESIGN AND VALIDITY: The study was part of a double-blinded 2-by-2 factorial randomized trial evaluating both ramipril and vitamin E. This paper reports the placebo-controlled study of ramipril 10 mg per day compared with placebo. Allocation of patients to ramipril or placebo was adequately concealed. Treatments were compared using the log-rank test, and subgroup analyses were conducted using tests for interactions in the Cox regression model. Treatment was scheduled to last 5 years, but an independent monitoring board recommended termination of the study after 4 years because of clear evidence of a beneficial effect of ramipril.
OUTCOMES MEASURED: The primary study outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. Secondary outcomes were death from any cause, the need for revascularization, hospitalization for unstable angina or heart failure, diabetes-related complications, and each of the primary outcomes reported individually.
RESULTS: Compared with controls, treatment with ramipril reduced the combined rate of myocardial infarction, stroke, or death from cardiovascular causes (relative risk reduction [RRR]=21%, absolute risk reduction [ARR]=3.8%, number needed to treat [NNT]=27). It also reduced the rates of the secondary outcomes, including death from any cause (RRR=15%, ARR=1.9%, NNT=54), revascularization procedures (RRR=13%, ARR=2.3%, NNT=43), cardiac arrest (RRR=38%, ARR=0.5%, NNT=200), heart failure (RRR=22%, ARR=2.5%, NNT=40), and complications related to diabetes (RRR=16%, ARR=1.2%, NNT=83). All these reductions in risk were statistically significant. Reduction in blood pressure was not felt to be a major factor in the improved outcomes; the majority of patients did not have underlying hypertension and the treatment group’s mean reduction in blood pressure was minimal (3/2 mm Hg).
ACE inhibitors are already considered a first-line treatment for patients with LV dysfunction or diabetic microalbuminuria (with or without hypertension). This well-designed study provides solid evidence that ramipril therapy reduces the likelihood of a cardiovascular event in a broader range of high-risk patients, potentially expanding the role of ACE inhibitors in the treatment of cardiovascular disease. However, it would be premature to supplant well-established therapies (eg, β-blockers following myocardial infarction) with ACE inhibitors until comparative studies and studies with other ACE inhibitors are completed. Meanwhile, physicians continue to underuse and underdose ACE inhibitors in patients with known LV dysfunction; significant educational efforts are needed to modify practice patterns in this area before attempting to expand the role of ACE inhibitors to additional indications.1