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on September 4, 2005

A more recent version of this article appeared on October 18, 2005

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Submitted on August 10, 2005
Revised on August 29, 2005
Accepted on August 29, 2005

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

Ronnie Willenheimer MD, PhD^*, Dirk J. van Veldhuisen MD, PhD, Bernard Silke MD, PhD, Erland Erdmann MD, PhD, Ferenc Follath MD, PhD, Henry Krum MD, PhD, Piotr Ponikowski MD, PhD, Allan Skene PhD, Louis van de Ven MD, PhD, Patricia Verkenne MD, Philippe Lechat MD, PhD, on behalf of the CIBIS III Investigators

From Lund University, Department of Cardiology, University Hospital, Malmö, Sweden (R.W.); Thoraxcenter, Department of Cardiology, University Hospital Groningen, the Netherlands (D.J.v.V.); Department of Pharmacology and Therapeutics, Trinity Centre, St James’ Hospital, Dublin, Ireland (B.S.); Medizinische Klinik III, University of Cologne, Germany (E.E.); Medicine A, University Hospital Zürich, Switzerland (F.F.); Departments of Epidemiology and Preventive Medicine and Medicine, Monash University, Alfred Hospital, Melbourne, Australia (H.K.); Cardiology Department, Clinical Military Hospital, Wroclaw, Poland (P.P.); The Nottingham Clinical Research Limited, Nottingham, UK (A.S.); Merck KGaA, Darmstadt, Germany (L.v.d.V., P.V.); and Service de Pharmacologie, Hopital Pitié-Salpetriere, Paris, France (P.L.).

^* To whom correspondence should be addressed. E-mail: ronnie.willenheimer{at}med.lu.se.

Background--In patients with chronic heart failure (CHF), a -blocker is generally added to a regimen containing an angiotensin-converting-enzyme (ACE) inhibitor. It is unknown whether -blockade as initial therapy may be as useful.

Methods and Results--We randomized 1010 patients with mild to moderate CHF and left ventricular ejection fraction 35%, who were not receiving ACE inhibitor, -blocker, or angiotensin receptor blocker therapy, to open-label monotherapy with either bisoprolol (target dose 10 mg QD; n=505) or enalapril (target dose 10 mg BID; n=505) for 6 months, followed by their combination for 6 to 24 months. The 2 strategies were blindly compared with regard to the combined primary end point of all-cause mortality or hospitalization and with regard to each of these end point components individually. Bisoprolol-first treatment was noninferior to enalapril-first treatment if the upper limit of the 95% confidence interval (CI) for the absolute between-group difference was <5%, corresponding to a hazard ratio (HR) of 1.17. In the intention-to-treat sample, the primary end point occurred in 178 patients allocated to bisoprolol-first treatment versus 186 allocated to enalapril-first treatment (absolute difference -1.6%, 95% CI -7.6 to 4.4%, HR 0.94; 95% CI 0.77 to 1.16). In the per-protocol sample, 163 patients allocated to bisoprolol-first treatment had a primary end point, versus 165 allocated to enalapril-first treatment (absolute difference -0.7%, 95% CI -6.6 to 5.1%, HR 0.97; 95% CI 0.78 to 1.21). With bisoprolol-first treatment, 65 patients died, versus 73 with enalapril-first treatment (HR 0.88; 95% CI 0.63 to 1.22), and 151 versus 157 patients were hospitalized (HR 0.95; 95% CI 0.76 to 1.19).

Conclusion--Although noninferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, our results indicate that it may be as safe and efficacious to initiate treatment for CHF with bisoprolol as with enalapril.

Key words: heart failure • drugs • adrenergic beta-antagonists • angiotensin-converting enzyme inhibitors

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