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Combination ACE-inhibitor and Angiotensin-Receptor Blocker Therapy: A Review of Safety Data

Proceed with caution when combining drugs that target the renin-angiotensin system.

Pharmacotherapy that targets neurohormonal activation with ACE inhibitors or angiotensin-receptor blockers (ARBs) has demonstrated effectiveness for heart failure (HF). However, persistently high rates of adverse outcomes despite treatment have generated interest in more intensive therapeutic strategies, including dual renin-angiotensin suppression by combined ACE inhibitors and ARBs. Some study results suggest that such combination therapy reduces the risk for HF hospitalization despite no demonstrable evidence of reduced mortality. However, the safety of this approach is not well characterized.

Investigators identified and analyzed randomized trials comparing combination therapy (an ACE inhibitor plus an ARB) with ACE inhibitor alone in patients with symptomatic LV systolic dysfunction, either accompanying chronic HF or after acute MI. Only trials including at least 500 subjects and with at least 3 months of follow-up were eligible for the analysis. In the four studies meeting these criteria (17,337 patients, total), combination therapy was associated with significantly higher rates of adverse-event-related treatment discontinuation (11.5% vs. 9.0%; relative risk, 1.28), symptomatic hypotension (11.1% vs. 7.5%; RR, 1.48), and worsening renal function (4.1% vs. 2.4%; RR, 1.76) than ACE-inhibitor therapy. Hyperkalemia rates were also higher with combination therapy than with ACE inhibitor alone (1.6% vs. 0.8%; RR, 2.46), but the difference was significant only in patients with chronic HF. The risks for worsening renal function and hyperkalemia with combination therapy were particularly high among patients with chronic systolic HF.

Comment: This study raises substantial concerns about the safety of combination ACE-inhibitor plus angiotensin-receptor blocker therapy in patients with symptomatic LV systolic dysfunction. In practice, combination therapy — if it is used at all — should be reserved for patients who are at relatively low risk for adverse consequences (e.g., those without borderline-high blood pressure or moderately high potassium levels), and such patients should be followed carefully for hypotension, worsening renal function, and hyperkalemia.

— Frederick A. Masoudi, MD, MSPH

Published in Journal Watch Cardiology October 31, 2007

Citation(s):

Phillips CO et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: A quantitative review of data from randomized clinical trials. Arch Intern Med 2007 Oct 8; 167:1930.

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