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ARBs Show No Advantage over ACE Inhibitors

And, a combination of the two leads to higher rates of adverse effects without substantial benefit.

Angiotensin-converting–enzyme (ACE) inhibitors lower the incidence of adverse cardiovascular events among people with heart failure, vascular disease, or advanced diabetes. A newer class of drugs, angiotensin-receptor blockers (ARBs), works by a mechanism similar to that of ACE inhibitors, but benefits and risks of ARBs are understood less well. A series of manufacturer-supported trials, published in 2008, provided little evidence to show that ARBs represent a significant therapeutic advance over ACE inhibitors, beyond a better short-term side-effect profile.

In one study, nearly 6000 patients with cardiovascular disease or advanced diabetes who were unable to tolerate ACE inhibitors were randomized to receive daily telmisartan (Micardis; 80 mg) or placebo, along with their other therapies. After a median 56 months of follow-up, the telmisartan group had lower mean blood pressure (and more frequent hypotensive symptoms) but only a nonsignificant 8% relative reduction in cardiovascular endpoints compared with patients in the placebo group (JW Cardiol Sep 17 2008). When we compare these results to those of similar studies of ACE inhibitors, ARB monotherapy seems to have less robust cardiovascular benefits.

In another trial, researchers sought evidence that ARBs might help prevent recurrent stroke more effectively than do other antihypertensive drugs. More than 20,000 patients with recent ischemic strokes were randomized to receive aspirin plus dipyridamole or clopidogrel and, in a 2x2 factorial design, also were assigned to receive telmisartan or placebo. Other antihypertensive therapies were used at the discretion of treating physicians. After a mean follow-up of 2.5 years, blood pressure was slightly lower in telmisartan recipients than in placebo recipients, but differences in recurrent stroke incidence did not reach statistical significance (JW Sep 4 2008).

What about using ACE inhibitors and ARBs in combination? In the ONTARGET study, researchers randomized about 25,000 patients with atherosclerotic disease or advanced diabetes to receive daily telmisartan (80 mg), ramipril (10 mg), or both for a median of 56 months. All three groups had similar rates of the primary endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure (JW Apr 17 2008). In a secondary analysis of renal effects in ONTARGET, rates of dialysis or doubling of serum creatinine levels were similar in the telmisartan and ramipril groups but were significantly higher in patients who received both agents (JW Sep 2 2008). In a meta-analysis of four trials in which combination therapy was compared with an ACE inhibitor alone in more than 17,000 patients with symptomatic left-ventricular systolic dysfunction, combination therapy was associated with significantly higher rates of adverse-event–related treatment discontinuation, symptomatic hypotension, and declining renal function (JW Nov 13 2007).

Overall, recent data provide little justification for substituting or adding an ARB when an ACE inhibitor is well tolerated. For patients who can’t tolerate ACE inhibitors, ARBs seem to be a safe, if perhaps somewhat less effective, alternative.

— Bruce Soloway, MD

Published in Journal Watch General Medicine December 29, 2008