The Heart Outcomes Prevention Evaluation (HOPE) Study: Limitations and Strengths

Domenic A. Sica, MD; Division of Clinical Pharmacology and Hypertension, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA.

In This Article

Trial Design

The Heart Outcomes Prevention Evaluation (HOPE) study[7] was a large, simple, factorial-design, double-blind, placebo-controlled trial that determined the risk of cardiovascular events in over 9500 patients studied in 267 centers in 19 countries. These patients were considered at high risk of future vascular death or morbidity by virtue of age, in that they were required to be older than 55 years of age, or because they had either diabetes or evidence of a prior vascular event or existing vascular disease. Diabetics were required to have either known vascular disease or one other risk factor for cardiovascular disease, such as cigarette smoking, blood pressure (BP) greater than 140/90 mm Hg, or elevated cholesterol (>5.2 mmol/L). Diabetics were included in this study because even without recognizable coronary artery disease they have about the same risk for coronary events as nondiabetic patients with established coronary disease.[8] Subjects also could not have CHF or an ejection fraction known to be below 40%.

Patients already receiving Vitamin E or for whom an ACE inhibitor was indicated, such as those with left ventricular dysfunction, were specifically excluded from the study. The HOPE protocol included a run-in period for tolerance. During this period, all 10,576 initially eligible patients received a 2.5-mg dose of ramipril for 7-10 days; thereafter they received a matching placebo for 10-14 days. This approach was taken to identify those prone to early side effects and/or those who experienced an exclusionary change in serum electrolytes or creatinine. Approximately 10% of the population, or 1035 patients, were excluded for these reasons. The remaining 9541 subjects were randomized to ramipril or placebo, beginning with a titration phase of 2.5 mg/day for 1 week, followed by 5 mg/day for 3 weeks. Thereafter, patients received 10 mg/day until study completion. Follow-up was at 1 month and thereafter every 6 months. All patients received either Vitamin E (400 IU) or matching placebo.[9] A substudy in 244 patients compared a low dose of ramipril (2.5 mg/day) with a full dose (10 mg/day) or placebo. The results of this substudy are yet to be published.