HOPE (Heart Outcomes Prevention Evaluation)

ACE inhibitors had established roles in heart failure and in patients with reduced ejection fraction after myocardial infarction, where their benefit was attributed to reducing afterload and attenuating ventricular remodeling. HOPE asked a different question: whether ACE inhibition could reduce cardiovascular events in high-risk patients who did not have heart failure or depressed LV function, so that the drug would be given for vascular protection. Far more patients would qualify on that basis.

HOPE enrolled 9,297 patients aged 55 or older with established vascular disease or diabetes plus at least one other cardiovascular risk factor who were not known to have heart failure or a low ejection fraction. Patients were randomized to ramipril 10 mg daily or placebo for a mean of five years, in a two-by-two factorial design that also tested vitamin E. The composite primary endpoint of cardiovascular death, myocardial infarction, and stroke occurred in 14.0% of the ramipril group and 17.8% of the placebo group, a relative risk reduction of 22%. Each component of the composite was reduced individually. Death from any cause fell from 12.2% to 10.4%, and heart failure, revascularization and diabetes-related complications were also less frequent. Salim Yusuf of McMaster University was first author of the report.

The mean fall in office blood pressure was modest, about 3 mmHg systolic and 2 mmHg diastolic, and could account for only part of the benefit. That gap prompted theories of direct vascular effects, and the SECURE substudy found slower progression of carotid wall thickening on ramipril 10 mg. But ramipril was given at bedtime while pressure was measured in the daytime, and in a 2001 substudy of 38 patients with peripheral arterial disease, 24-hour ambulatory pressure fell by 10/4 mmHg and nighttime pressure by 17/8 mmHg, suggesting that office readings understated the drug's effect on blood pressure.

The MICRO-HOPE report on the 3,577 patients with diabetes found reductions of 25% in the combined primary outcome, 37% in cardiovascular death, 24% in total mortality and 24% in overt nephropathy. The benefit held after adjustment for small changes in blood pressure, and the investigators described the effect as vasculoprotective and renoprotective.

The same McMaster group, again led by Yusuf, went on to run ONTARGET in patients with vascular disease or high-risk diabetes. That trial randomized 25,620 patients to ramipril, telmisartan or both; over a median of 56 months telmisartan proved equivalent to ramipril, with less angioedema, and the combination added no benefit while causing more renal dysfunction.