ACE Inhibitors for Patients with Normal Left Ventricular Function

Abstracts & Commentary

By Michael H. Crawford, MD, Professor of Medicine, and Chief of Clinical Cardiology, at the University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.

Sources: Dagenais GR, et al. Angiotensin-Converting-Enzyme Inhibitors in Stable Vascular Disease without Left Ventricular Systolic Dysfunction or Heart Failure: A Combined Analysis of Three Trials. Lancet. 2006;368:581-588; Remuzzi G, Ruggenenti P. Overview of Randomised Trials of ACE Inhibitors. Lancet. 2006;368:555-556.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce mortality and myocardial infarction (MI) in patients with heart failure due to reduced left ventricular (LV) systolic function. Three recent trials have evaluated ACE inhibitors in patients with vascular disease, but normal LV systolic function: HOPE, EUROPA, and PEACE. Although targeted at similar patients, using a similar design, there were differences between the studies. Thus, Dagenais and colleagues explored the consistency of the outcomes between these studies and their variation due to other ancillary therapy or levels of risk. All 3 trials included > 8000 patients each, and followed them for about 5 years. The results were compared to the results of a similar analysis of 5 large ACE inhibitor trials in patients with LV dysfunction or heart failure. The combined results of HOPE, EUROPA, and PEACE showed that ACE inhibitors reduce many end points vs placebo: all-cause mortality from 8.9 to 7.8%; cardiovascular mortality from 5.2 to 4.3%; MI from 6.4 to 5.3%; stroke from 2.8 to 2.2%; and heart failure from 2.7 to 2.1%; all P < .001. Coronary artery bypass surgery was also reduced from 6.9 to 6.0%; P < .01, but not percutaneous interventions (7.6 to 7.4%; P = ns). The composite end point of mortality, MI or stroke was reduced from 12.8 to 10.7% (OR, 0.82; CI, 0.76-0.88, P < .0001). These results were similar, but not exactly the same as those of the 5 large heart failure trials of ACE inhibitors. Dagenais et al concluded that ACE inhibitors reduce major adverse cardiac events in patients with atherosclerotic vascular disease but no known LV dysfunction and, thus, ACE inhibitor therapy should be considered in all vascular disease patients.

Commentary

The thrust of this analysis is for us to ignore the differences in results between the 3 trials of ACE inhibition in chronic vascular disease patients without known LV dysfunction, and embrace this therapy for a broader range of patients. The 3 trials combined include almost 30,000 patients and, per this analysis, show an 18% reduction in major adverse coronary and cerebral events, with a number needed

to treat to prevent one event of 48 patients. Current ACC/AHA guidelines for unstable angina/non-ST elevation MI patients and chronic stable angina patients recommend ACE inhibitors prophylactically only for LV ejection fraction (ejection fraction) < .40 and diabetes, and therapeutically for systolic heart failure and hypertension. Should we be using ACE inhibitors for all vascular disease patients regardless of LV function? The editorial that accompanied this article thought not, due to several deficiencies in this study.

The major problem with this study is that it was not a meta-analysis. Individual data were not available from the 3 trials, so summary data were used, which may obscure individual trends. Also, the patient populations in these studies were different. In HOPE, 80% had coronary artery disease (CAD), whereas it was 100% in the other 2 studies. Eight percent of HOPE patients had LV EF < .40, whereas it was < 1% in the other 2. Antiplatelet therapy was given to 76% in HOPE and > 90% in the other 2. Beta-blocker use was 40% in HOPE and > 60% in the other 2. The use of lipid-lowering therapy increased from 29% in HOPE to 57% in EUROPA, to 70% in PEACE. The individual study results got progressively less impressive as the risk level of the patients decreased and the drug therapy intensified. In HOPE, significant gains were seen in all major cardiac events, except heart failure. EUROPA was significant for all end points, except total mortality and stroke. PEACE, which had the lowest risk patients on the most medications, was only significant for less heart failure in the ACE inhibitor group. Thus, one could argue that in lower-risk CAD patients on aggressive medical therapy, the addition of ACE inhibitor is not valuable. At this time, I would stick to the ACC/AHA guidelines until more persuasive data come along, and only use ACE inhibitors prophylactically for CAD patients with LV systolic dysfunction or diabetics.