A large international study has found that ramipril, an angiotensin-converting-enzyme (ACE) inhibiting drug, cuts the risk of cardiovascular-related death, heart attack, stroke, angioplasty/bypass surgery, admission to hospital, and complications of diabetes in patients with risk factors for cardiovascular disease. The 5-year study, involving 267 centres in 20 countries, was run out of McMaster University in Hamilton, Ont. The results were reported by Dr. Salim Yusuf, a professor of medicine at McMaster and the principal investigator, on behalf of all of the study investigators, and have been released on the Web site of the New England Journal of Medicine (www.nejm.org) before publication in the journal.
The Heart Outcomes Prevention Evaluation (HOPE) study involved high-risk patients - those aged 55 years and older with evidence of vascular disease or diabetes plus one other risk factor, such as high blood pressure, high "bad" cholesterol levels, low "good" cholesterol levels, or smoking. Patients with heart failure or a low ejection fraction were not included.
"Our study was predominantly a secondary prevention study," explains Dr. Eva Lonn, an associate professor of medicine at McMaster who served on the International Steering Committee, worked with the coordinating centre for the trial and was the site principal study investigator at the Hamilton Health Sciences Corporation. She says that most of the patients enrolled had already had one cardiovascular event (such as a heart attack). She says the study provides "over-whelming proof" of the benefit of ramipril in these patients and she unequivocally advocates the use of ramipril in patients with diabetes as a preventive measure.
"Patients with diabetes and one other risk factor are at extremely high risk. The benefits of ramipril in this subpopulation are very, very strong." In fact, in people with diabetes the drug prevented not only cardiovascular problems but also complications of diabetes such as kidney disease.
In all patient groups, benefits were observed whether or not patients were already taking drugs for cardiovascular-disease prevention, such as ASA, β-blockers, lipid-lowering drugs or drugs to lower blood pressure. Ramipril seems to add to the benefit from these other drugs.
ACE inhibitors such as ramipril have traditionally been used for treatment of high blood pressure and heart failure, but this study shows that they could play a much larger clinical role in cardiovascular disease prevention.
The reduction in risk varied according to the outcome and the group of patients examined. For example, the rate of cardiovascular-related death was 6.1% in the patients taking ramipril and 8.1% in those taking a placebo. Ramipril reduced the rate of heart attack from 12.2% to 9.9%, and the rate of stroke from 4.9% to 3.4%. While the rate reduction appears moderate in terms of percentage, it is statistically significant. And when all of the outcomes are considered together, the benefit becomes more apparent. Dr. Lonn calculates that only 6 patients need to be treated with ramipril to prevent 1 adverse event: death, heart attack, stroke or hospital admission for cardiovascular events.
A key question is why ramipril is effective. Lonn says there are many ideas and theories, but the answer is not entirely clear. "Its benefit in lowering blood pressure we know, but the magnitude of the benefit [in this study] is over and above what would be expected from lowering blood pressure."
The entire study - everything from sending out enrolment and consent forms, arranging investigators' meetings and entering information into a database - was done on a "lean" budget by a small staff, says Lonn. "It relied on the dedication of the patients, the nurses and the investigators. It's a very big effort."