Introduction

We have referred briefly on this site to the recently published results of the Heart Outcomes Prevention Evaluation (HOPE) Study. This study, conducted at 267 centers in 19 countries in North and South America and Europe, compared the angiotensin-converting-enzyme (ACE) inhibitor, ramipril, with placebo for effectiveness in reducing cardiovascular events in at-risk patients. The trial included 9,541 individuals 55 years or older who had a history of coronary artery disease, peripheral vascular disease, or stroke, or who had diabetes with one additional coronary risk factor. The study was stopped after 4.5 years because of a consistent benefit of ramipril compared with placebo. Overall, ramipril cut the risk of cardiovascular deaths, myocardial infarction and stroke by 22% in patients at risk of such events.¹ An additional finding was a reduction of >30% in the risk of new-onset diabetes in the ramipril cohort.

Almost 40% of the participants in the HOPE study had diabetes at baseline. The authors of the study summarized here have analyzed the study results in these diabetics with respect to their cardiovascular (HOPE) and microvascular outcomes microalbuminuria, cardiovascular and renal outcomes (MICRO-HOPE study).

Method

Eligible participants had to be 55 or over, and have a history of cardiovascular disease or diabetes plus at least one cardiovascular risk factor (cholesterol >5.2 mmol/L, HDL-cholesterol < 0.9 mmol/L, hypertension, microalbuminuria, or smoking). They were excluded if they had overt proteinuria, nephropathy, hyperkalemia, congestive failure or recent/uncontrolled cardiovascular disease.

The participants were randomized using a 2-by-2 factorial design to 10 mg ramipril or placebo once a day, and 400 IU vitamin E or placebo daily. The combined primary endpoint was myocardial infarction, stroke, or cardiovascular death. Secondary endpoints were total mortality, congestive failure, unstable angina, cardiovascular revascularization, or overt nephropathy.²

The subjects for analysis were 1,808 diabetics - 98% were type 2 who were given ramipril and 1,769 (97% type 2) given placebo. Their mean age was 65.4 years, 37% were women, and 56% had a history of hypertension.

Results

At the end of the study, 65% of the ramipril and 66% of the placebo patients were still taking study medication. Reasons for stopping medication were the same in both groups, except for cough (a known side effect of ACE inhibitors), which was more common in the ramipril patients (7% vs. 2%).

The risk of the combined primary outcome was lowered by ramipril by 25% (95% CI, 12-36); myocardial infarction was lowered by 22%, stroke by 33%, and cardiovascular death by 37% (all statistically significant). The reduction on the primary outcome risk was 16% after 1 year (not significant) and 26% (95% CI, 6-41) after 2 years.

Blood pressure was lowered slightly in the participants on ramipril compared with those on placebo at the end of the study mean systolic levels were 1.92 mmHg lower on ramipril, and 0.55 mmHg higher on placebo. The beneficial action of ramipril on the combined primary endpoint persisted after adjustment for blood pressure changes the risk was reduced by 25% (95% CI, 12-36).

Overt nephropathy developed during the study in 6.5% of ramipril participants and in 8.4% of those on placebo. This represented a risk reduction by ramipril of 24% (95%CI, 3-40).

Comment

This analysis showed that an ACE inhibitor, ramipril, was able to lower the risk of major cardiovascular events over 4½ years by 25% - 30% in older people with diabetes. Another way of expressing this: 15 high-risk diabetics would have to be treated with ramipril for 4½ years to prevent one individual having a major cardiovascular event or diabetic complication.

The benefits observed were independent of blood pressure changes, and ramipril had no effect on glycemic control. The authors of the study suggest that ACE inhibitors have a protective effect on the arterial wall, by lowering local angiotensin-II concentrations and possibly by increasing bradykinin concentrations.

The effects on microvascular outcomes are consistent with those from other, smaller studies previously reported.³ There is little doubt that the use of ACE inhibitors in high-risk diabetics has obvious advantages other than just lowering elevated blood pressures. Now we need studies of these drugs (and the angiotensin-II receptor antagonists) in otherwise-healthy type 2 diabetics.