Background: There is growing interest in combining angiotensin-converting enzyme (ACE) inhibitors with angiotensin-II receptor blockers (ARBs) to treat heart failure, even though this is not part of current therapeutic guidelines. This combination therapy appears to reduce the number of hospitalizations for heart failure, although mortality is not reduced. A major concern with combination therapy is the potential for increased risk of adverse effects, especially life-threatening hyperkalemia.

The Study: A meta-analysis of randomized controlled trials was conducted using Medline and other databases by searching for studies that had used standard therapy for heart failure or acute cardiac events, compared with combination ACE inhibitor/ARB therapy. Eligible studies analyzed at least 500 patients, had a minimum follow-up period of three months, and reported the frequency and type of adverse events—particularly those requiring discontinuing medications, worsening renal function (i.e., elevations in serum creatinine greater than 0.5 mg per dL [40 μmol per L]), hyperkalemia, cough, angioedema, and symptomatic hypotension. Adverse events were evaluated separately for patients with left ventricular dysfunction arising from an acute cardiac event and those with chronic heart failure to take into account potential differences between these populations.

Results: Four studies (VALIANT, CHARM-added, ValHeFT, and RESOLVD) containing 17,337 patients were reviewed, with a mean follow-up period of 25 months. Patients fell into two distinct study populations: those with chronic stable heart failure (n = 7,543) and those with an acute cardiac event complicated by left ventricular dysfunction (n = 9,794). Compared with patients receiving ACE inhibitors, patients treated with combination therapy were significantly more likely to develop symptomatic hypotension or have worsening renal function and to stop their medications because of adverse effects (see accompanying table). Combination therapy contributed to significantly more hyperkalemia in patients with chronic heart failure compared with their conventionally treated counterparts, but no such increase occurred in those with ventricular dysfunction from acute cardiac events.

Conclusion: Combination ACE inhibitor/ARB therapy in patients with symptomatic left ventricular dysfunction is associated with significant increases in the risk of medication discontinuation, symptomatic hypotension, and renal dysfunction when compared with conventional therapy (i.e., using ACE inhibitors alone). Patients with chronic heart failure were also more likely to develop hyperkalemia when using this combination. Appropriate caution should be taken when considering using these agents together.

editor's note: The bottom line is that this combination therapy may lead to fewer hospitalizations in patients with left ventricular heart failure than those treated with ACE inhibitors alone, but at a significantly increased risk of adverse events. Two separate meta-analyses have reported that combination therapy led to about 25 percent fewer hospitalizations for symptomatic heart failure compared with ACE inhibitor monotherapy, but mortality was unaffected.^1,2 This discussion is reminiscent of the earlier debates over digoxin, a medication that also improved morbidity, but not mortality; its use came with its own significant risk of problems, yet it became a widely accepted therapeutic option for patients with heart failure.

Undoubtedly, there will be ongoing arguments about whether combination ACE inhibitor/ARB therapy should become a mainstream treatment. For the present, it's important to remember that ACE inhibitor mono-therapy is the recommended treatment for patients with left ventricular dysfunction. This study provides much needed insight into the risks of combination therapy, which we can use in conjunction with our informed patients' wishes in deciding if the benefits outweigh the risks in a particular situation.—k.t.m.