Study argues ACE inhibitors should not be used in some heart patients

Trial results should change practice immediately, physician says

A new study argues that many heart patients receiving modern conventional therapy do not benefit from angiotensin-converting-enzyme (ACE) inhibitors if the patients have stable coronary heart disease and preserved left ventricular function.

The double-blind, placebo-controlled trial studied 8,290 patients, who were randomly assigned to receive either trandolapril at a dose of 4 mg per day or matching placebo. The patients, who were followed for a median of 4.8 years, had normal or near-normal left ventricular function, as indicated by left ventricular ejection fraction of greater than 40%. The study found no evidence that the addition of an ACE inhibitor provides "further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization."

The results of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial were presented at the Nov. 7 American Heart Association Scientific Sessions in New Orleans and also appeared in the Nov. 11 issue of the New England Journal of Medicine.

"With PEACE, we have shown that a huge number of people don’t benefit from ACE inhibitors, specifically patients who have either normal or mildly depressed pump function — an ejection fraction equal to or greater than 40%," says Michael Domanski, MD, a cardiologist who is the head of the National Heart, Lung, and Blood Institute (NHLBI)’s Clinical Trials Scientific Research Group in Bethesda, MD. NHLBI, part of the National Institutes of Health, funded the study.

"If you have greater than or equal to 40% [ejection fraction], assuming you are treated in other modern ways as indicated [with statins, for example], these drugs don’t benefit you. All they have to offer you are side effects."

PEACE was the last of three large international clinical trials that tested whether ACE inhibitors benefit heart disease patients who do not have heart failure. In the other two trials, HOPE (Heart Outcomes Prevention Evaluation) and EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease), ACE inhibitors reduced morbidity and mortality in patients with stable coronary artery disease (or multiple risk factors) and without heart failure.

Reviewers of the study have tried to offer ideas as to why PEACE had this outcome. Some suggested that the trial involved lower-risk patients, such as those with a relatively low concentration of LDL cholesterol. Possibly more of them were using statins and had undergone previous coronary revascularization. Another suggestion is that not all ACE inhibitors are equally effective.

Domanski dismisses the last possibility. "I think we have taken care of that problem," he says. "Trandolapril has been shown in other studies of the same sort of dosing regimen to be effective in reducing mortality following heart attacks in patients for whom it is indicated. I think that is clearly a concern set aside by the fact that we know trandolapril works in a setting where it would be expected to. It’s a completely hollow argument, frankly."

He thinks that practice should change immediately based on the results of PEACE. "The second someone reads [the article], they should say, Let’s not be treating these people with ACE inhibitors.’ They do have side effects."

Regardless of the mechanisms accounting for the failure of trandolapril to reduce the rate of cardiovascular events, the most important finding in the PEACE trial is that, after the exclusion of high-risk patients with diabetes mellitus, patients with known vascular disease who do not have a history of heart failure or left ventricular systolic dysfunction have a low risk of subsequent cardiovascular events when treated with a statin and other contemporary therapies, writes Bertram Pitt, MD, professor of internal medicine at the University of Michigan School of Medicine in Ann Arbor. His comments appeared in an editorial accompanying the article.

"In view of the low cardiovascular risk in this group of patients, it is doubtful that the use of an ACE inhibitor or an angiotensin-receptor blocking agent — even if effective in reducing the rate of cardiovascular events — would be cost-effective."

Wider application of strategies known to be effective (such as statin therapy, weight reduction, and glucose and blood-pressure control) as well as strategies currently under investigation could minimize the risk of cardiovascular events and possibly reduce the financial burden associated with vascular disease, he adds.

Although Pitt says he will no longer recommend an ACE inhibitor to patients like those included in the PEACE trial, he is not yet ready to eliminate the use of ACE inhibitors to treat all patients who have vascular disease without left ventricular systolic dysfunction. "Ongoing vascular inflammation, the production of reactive oxygen species, and plaque instability need to be re-evaluated in low-risk patients who are receiving contemporary therapy to determine their ability to predict cardiovascular events and thus to allow the selection of those at increased cardiovascular risk for ACE inhibition or other strategies."

There certainly are people who have reduced pump function below 40% ejection fraction — factors that would make sense to treat, Domanski says. The ones who would benefit have worse pump function than the patients studied in PEACE. Other indications for ACE inhibitors include high blood pressure and diabetes.

Some other studies, however, would make it sound that ACE inhibitors should be in the drinking water, he says, when in fact PEACE shows otherwise. The bottom line is that PEACE clearly identified the group of patients who would not benefit from ACE inhibitors, Domanski says. "It is easy to figure out who shouldn’t have them based on this study."