Cigarette smoking, diabetes mellitus, hypertension and hyperlipidemia have been identified as major risk factors for cardiovascular disease. Experimental and observational studies have shown that activation of the renin-angiotensin-aldosterone system increases the risk of cardiovascular events. Additional data suggest that angiotensin-converting enzyme (ACE) inhibitors block the activation of the renin-angiotensin system and may play a role in impeding the progression of heart failure and atherosclerosis. Further data suggest that treatment with an ACE inhibitor in patients with low ejection fractions may reduce the risk of myocardial infarction. The Heart Outcomes Prevention Evaluation Study was undertaken to determine if the ACE inhibitor ramipril affected cardiovascular mortality in patients who did not have left ventricular dysfunction.

Patients who were at least 55 years of age with a history of coronary artery disease, stroke, peripheral vascular disease, hypertension, elevated total cholesterol levels or diabetes, plus one additional cardiac risk factor, were eligible for the study. Excluded were patients with an ejection fraction of less than 40 percent, uncontrolled hypertension, heart failure or overt nephropathy and those who had a stroke or myocardial infarction within the past four weeks or were already taking an ACE inhibitor or vitamin E. The patients were randomized to receive 2.5 mg of ramipril or placebo for one week, 5 mg of ramipril or placebo for the following three weeks and 10 mg of ramipril or placebo for the remainder of the study. All patients were additionally given 400 IU of vitamin E or placebo daily. Participants were seen for follow-up visits at months 1 and 6, then every six months. At these visits, compliance was assessed, and outcome data were collected. Primary outcomes assessed included myocardial infarction, stroke or death from cardiovascular causes. Secondary outcomes included death from any cause, hospitalization for angina or heart failure, complications related to diabetes or the need for cardiac revascularization. The patients were followed for a mean of five years.

Of the 9,297 patients randomized into the trial, more than one half were 65 years of age or older, and 2,480 were women. Cardiovascular disease was present in 8,160 patients, 4,355 patients had hypertension and 3,578 patients had diabetes. At study entry, the mean blood pressure of patients in both groups was 139/79 mm Hg.

In reviewing the primary outcomes, 653 (14.1 percent) patients in the ramipril group died from cardiovascular causes or had a myocardial infarction or stroke compared with 824 (17.7 percent) patients in the placebo group. Separate evaluation of the three end points revealed that 282 patients in the ramipril group died from cardiovascular causes compared with 375 patients in the placebo arm. Myocardial infarction occurred in 460 patients in the ramipril group compared with 567 patients in the placebo group. Stroke occurred in 157 patients in the ramipril group and 226 patients in the placebo group. Overall, the relative risk of death from the three primary end points was 0.78 (95 percent confidence interval [CI]) in the patients who received the ACE inhibitor. In addition, the risk of death from any cause was 0.84 (95 percent CI) in patients in the ramipril group. In the assessment of secondary end points, 742 of the patients in the ramipril group underwent cardiac bypass surgery compared with 864 in the placebo group. Significant reductions in cardiac arrest, heart failure and worsening angina were noted in the patients in the ramipril group.

The authors conclude that the ACE inhibitor ramipril significantly reduces the risk of death from cardiovascular disease. It also reduces the risk of stroke and myocardial infarction in a large number of patients. The magnitude of benefit observed in this study was at least as great as that seen with other secondary prevention therapies, including the use of aspirin, beta blockers and lipid-lowering agents.