ACE Inhibitors May Aid Patients With Atherosclerosis

By Kate Johnson

Angiotensin-converting enzyme inhibitors are beneficial in patients who have atherosclerosis alone, without heart failure or left ventricular systolic dysfunction, according to a review of the three largest trials of this therapy.

"The use of ACE inhibitors should be considered in all patients with vascular disease as long as they can tolerate these agents," wrote Dr. Gilles R. Dagenais of Laval University's Heart and Lung Institute in Quebec City, and his colleagues.

Their review of Heart Outcomes Prevention Evaluation (HOPE), the European trial on reduction of cardiac events with perindopril among patients with stable coronary artery disease (EUROPA), and the Prevention of Events With Angiotensin-Converting-Enzyme Inhibition trial (PEACE) assessed total mortality and fatal and nonfatal cardiovascular events in almost 30,000 patients over a mean follow-up of 4.5 years (Lancet 2006;368:581-8).

The three trials included a total of 14,913 stable patients with atherosclerosis but no history of heart failure or left ventricular systolic dysfunction (LVSD) who were allocated to receive an ACE inhibitor; 14,892 patients received placebo.

Compared with placebo, ACE inhibitors were linked to a reduction in all cause mortality (odds ratio 0.86), cardiovascular death (OR 0.82), nonfatal myocardial infarction (OR 0.82), rate of coronary artery bypass graft during follow-up (OR 0.87), and stroke (OR 0.77). (See box.)

ACE inhibitors were not linked to a significant reduction in the rate of percutaneous coronary intervention compared with placebo (7.4% vs. 7.6%; OR 0.97).

A composite outcome measuring cardiovascular mortality, nonfatal MI, and stroke showed a "clear benefit" of ACE inhibitors over placebo (OR 0.82), noted the authors. "This finding implies that for every 1,000 patients treated over 4.5 years, 21 patients will not have any serious vascular events," they wrote.

The results of the three trials were then compared with results of five other trials that evaluated the effects of ACE inhibitors in patients with heart failure or LVSD. These five trials were the Studies of Left Ventricular Dysfunction (SOLVD-T and SOLVD-P), the Survival and Ventricular Enlargement (SAVE) study, the Acute Infarction Ramipril Efficacy (AIRE) study, and the Trandolapril Cardiac Evaluation (TRACE) study.

The benefits of ACE inhibitors in patients with heart failure or LVSD were similar to the benefits seen in patients without these conditions, with two exceptions: ACE inhibitor use was not linked to a reduction in stroke risk in patients with heart failure or LVSD but it was associated with a reduction in the risk of percutaneous coronary intervention (OR 0.7).

"By comparison with patients in the HOPE, EUROPA, and PEACE studies, the patients in the five older trials were at a much higher risk and, thus, saw a greater benefit," the investigators wrote.

They also noted that for every 1,000 patients treated for about 3 years, approximately 50 would be protected from a fatal event, a nonfatal MI, or a stroke.

Referring to both the first and second group of studies, the authors noted that "both estimates of benefit are substantial and in view of the broad populations that could benefit, the public health and clinical benefits are important."

But an editorial that accompanied the article challenged the authors' conclusions on the benefits of the drug (Lancet 2006;368:555-6).

"A closer examination of the data, however, shows that ACE inhibitors were beneficial in HOPE and EUROPA, but they were not better than placebo in the PEACE trial," wrote Dr. Giuseppe Remuzzi and Dr. Piero Ruggenenti of the Mario Negri Institute for Pharmacological Research and Unit of Nephrology and Dialysis, Ospedali Riuniti, Bergamo, Italy.

They noted that compared with patients in the HOPE and EUROPA trials, patients in the PEACE trial "had lower arterial blood pressure and serum LDL-cholesterol levels at study entry and on follow-up, and more were already on statins and antiplatelet agents."

In contrast to the researchers' conclusion, the editorialists argued that "what the data actually show is that ACE inhibitors are of value for high-risk patients with diabetes mellitus and for those whose serum lipid concentrations are not controlled (or with other risk factors), but do not offer added benefit to low-risk patients already on aspirin, ß-blockers, and statins."