An ACE inhibitor in the hole for cardiovascular prevention

Date: Nov. 12, 1999
Time: 8:21 am

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 before publication in the journal.

The Heart Outcomes Prevention Evaluation (HOPE) study involved high-risk patients - those 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 University 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). The study provides "overwhelming proof" of the benefit of ramipril in these patients, she says. She also unequivocally advocates prevention with ramipril in patients with diabetes.

"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, beta-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 percentage-point terms, 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 it 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."

As part of this study, Lonn and associates also obtained ultrasonographic images of the carotid arteries of many patients. This research, not yet published, showed that ramipril retards the progression of atherosclerosis (the process of plaque formation in the arteries, which leads to heart attacks and stroke), and stabilizes the plaques. Research from other centres has also shown that ACE inhibitors have an effect on fibrinolysis, the dissolving of blood clots. As well, ACE has been found in high amounts in arterial tissue at the sites of cardiovascular insults such as atherosclerotic lesions. Therefore, Lonn explains, "ACE inhibitors may decrease the local inflammatory response to injury."

Lonn praises her colleagues and study staff as well as the study participants for their devotion to the long study. The study was funded by the Medical Research Council of Canada, the Heart and Stroke Foundation of Canada, as well as 3 drug companies.

-- C.J. Brown, CMAJ

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