ACE Inhibitors and Renal Function
Abstract & 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.
Synopsis: Reduced renal function may define a subset of patients most likely to benefit from ACE-inhibitor therapy for cardiovascular protection.
Source: Solomon SD, et al. Renal Function and Effectiveness of Angiotensin-Converting Enzyme Inhibitor Therapy in Patients with Chronic Stable Coronary Disease in the Prevention of Events with ACE Inhibition (PEACE) Trial. Circulation. 2006;114:26-31.
The HOPE and EUROPA trials showed reduced cardiovascular events in chronic coronary artery disease (CAD) or other evidence of vascular disease patients with ACE inhibitor therapy (ramipril and perindopril, respectfully). The Prevention of Events with ACE Inhibition (PEACE) trial (trandolapril) did not exhibit this benefit, perhaps because the patients were lower risk. Many more had had revascularization or were on highly effective therapy such as statins. Prior studies with ARBs such as VALIANT showed reduced cardiovascular events in coronary artery disease patients with renal insufficiency. Thus, Soloman and colleagues examined the PEACE database to see if those with reduced renal function showed any benefit. Creatinine was measured in 8280 PEACE patients before randomization. The mean estimated glomerular filtration rate (GFR) was 77; 16% had GFRs < 60. Patients with reduced GFR were older, female, hypertensive, and diabetic. Cardiovascular and all-cause mortality was less in the treatment group vs placebo in this subgroup with chronic renal insufficiency (HR, 0.73, 95% CI, 0.54-1.00, P = .02). Soloman et al concluded that trandolapril reduced mortality in CAD patients with reduced GFR, thus identifying a group most likely to benefit from ACE inhibitor therapy for protection against cardiovascular events.
Commentary
The PEACE trial was somewhat of a disappointment after the positive results of HOPE and EUROPA. This analysis of PEACE suggests that they studied a lower-risk group of patients because many had revascularization and were on aggressive statin and platelet inhibition therapy. Over two-thirds were on lipid-lowering drugs, and about 90% were on aspirin. Also, mean left ventricular ejection fraction (LVEF) was 58%, and most were normotensive. Soloman et al speculate that this is why ACE inhibition did not benefit PEACE patients overall. However, those with reduced renal function seemed to benefit, especially with regard to death. This is remarkable since the overall death rate in PEACE was only 1.6% per year. Other studies have confirmed the relationship between renal function and cardiovascular disease, and the beneficial effect of angiotensin receptor blockers in patients with reduced renal function. These studies were in patients post myocardial infarction or with low LVEF. Thus, what is most surprising about these PEACE results is that the patients were much lower risk. This suggests that the beneficial effect of ACE inhibitors in patients with renal dysfunction is independent of the severity of vascular disease in general. Finally, Soloman et al point out that renal insufficiency in an otherwise low-risk vascular disease patient may be an indication for angiotensin blockade.
There are limitations to the study which temper enthusiasm for the results. The trial was not designed to test the effect of ACE inhibitors in patients with renal dysfunction, so there may be selection biases based upon the main selection criteria. In fact, several important risk factors such as diabetes were more common in the renal insufficiency patients. What effect this had on the results is unknown. Also, few patients in PEACE had significant renal insufficiency; GFR ranged from 27 to 320, with a mean of 77. This reduces the power of this analysis as compared to the trial as a whole. In addition, there were few patients with severe renal insufficiency (GFR < 30). Thus, the benefit of this treatment in such patients cannot be inferred from this study. When to use ACE inhibitors in patients with renal insufficiency is controversial because of the potential for causing further decreases in renal function. At this point, if a patient with known or suspected vascular disease does not meet the traditional criteria for ACE inhibitor use, but mild to moderate renal dysfunction is present, ACE inhibitor should at least be considered.
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