The trusted source for
healthcare information and
Beta-Blockers for Heart Failure
Abstract & Commentary
By Michael H. Crawford, MD, Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco. Dr. Crawford is on the speaker's bureau for Pfizer.
Source: Willenheimer R, et al. Effect on Survival and Hospitalization of Initiating Treatment for Chronic Heart Failure with Bisoprolol Followed By Enalapril, As Compared with the Opposite Sequence: Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation. 2005;112:2426-2435.
Given the impressive results of beta-blockers added to angiotensin-converting-enzyme (ACE) inhibitors in heart failure patients, many have suggested that had beta-blockers been studied first for heart failure, they would have been so impressive that we would start them before ACE inhibitors. Accordingly, the group from the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS III) studied the effect of the order of initiating beta-blockers or ACE inhibitors for initial monotherapy of congestive heart failure (CHF). They randomized 1010 patients age > 65 with mild to moderate CHF and left ventricular ejection fraction < 35% who were not on beta-blockers, ACE inhibitors, or angiotensin-receptor blocking therapy to open-label monotherapy with bisoprolol (10 mg a day) or enalapril (10 mg twice a day) for 6 months, then the combination for 6 to 24 months. The primary end point was time to first event of mortality or hospitalization for any cause. The major exclusion criterion was prior study drug use. Two groups were analyzed, the intention-to-treat sample and the per protocol sample. The latter patients were those who actually completed the study protocol.
Results: In the intention to treat group, the primary end point was reached in 35% of the bisoprolol-first patients and 37% of the enalapril-first patients (noninferiority for bisoprolol first, P = .02). In the per-protocol group, 32% bisoprolol first reached the primary end point vs 33% for enalapril first (noninferiority for bisoprolol first, P = .05). Deaths and hospitalizations analyzed separately were not different between the 2 treatments. During monotherapy, 65% of the bisoprolol group reached the target dose of 10 mg daily vs 82% of the enalapril group. Bisoprolol was not tolerated by 7%, enalapril by 10%. Willenheimer and colleagues concluded that bisoprolol-first treatment for patients with CHF was not noninferior to enalapril-first treatment on a per-protocol analysis.
Many beta-blocker proponents were disappointed by these results, since not only was beta-blocker first not superior to ACE inhibitors first, it was not noninferior in the per protocol analysis, which is generally considered more robust for this purpose than the intention-to- treat approach. Also, there was a trend toward more hospitalizations for worsening heart failure in the beta-blocker-first group. This would argue that it is safer to start beta-blockers after ACE inhibitors are onboard.
Another consideration was that patients are often on lower than recommended doses of one drug when they are on both, or end up on only one because of concerns about blood pressure. Thus, order of administration would be important if one drug was clearly superior. These results suggest that ACE inhibitors first is still the preferred policy. There may be selected individuals in whom starting with a beta-blocker first makes sense, (eg, patients with supraventricular arrhythmias, but there are no specific data on this).