How to begin treatment in chronic heart failure? Results of CIBIS III
Department of Cardiology, Lund University, University Hospital, S-205 02 Malmö, Sweden
* Corresponding author. Tel: +46 40 33 10 00; fax: +46 40 33 62 09. E-mail address: ronnie.willenheimer{at}med.lu.se
Aims To compare the effect of initial monotherapy with either bisoprolol or enalapril, followed by their combination, on mortality and hospitalization in patients with mild-to-moderate CHF.
Methods and results One thousand and ten patients with mild-to-moderate CHF and left ventricular ejection fraction 
35%, without ACE-inhibitor, beta-blocker, or angiotensin-receptor-blocker therapy were randomized to open-label monotherapy with either bisoprolol (target dose 10 mg od, n=505) or enalapril (target dose 10 mg bid, n=505) for 6 months, followed by their combination for 6–24 months. The combined primary endpoint was all-cause mortality or hospitalization; bisoprolol-first was considered non-inferior to enalapril-first if the upper limit of the 95% CI for the absolute between-group difference was below +5%, corresponding to HR 1.17. In the intention-to-treat population, the primary endpoint occurred in 178 patients allocated bisoprolol-first vs. 186 allocated enalapril-first: absolute difference, –1.6%; 95% CI, –7.6 to +4.4%; HR, 0.94; 95% CI, 0.77–1.16. Thus, non-inferiority was demonstrated in the intention-to-treat population. In the per-protocol population, the primary endpoint occurred in 163 patients in the bisoprolol-first group vs. 165 in the enalapril-first group: absolute difference, –0.7%; 95% CI, –6.6 to +5.1%; HR, 0.97; 95% CI, 0.78–1.21. With bisoprolol-first, 65 patients died vs. 73 with enalapril-first (HR, 0.88; 95% CI, 0.63–1.22; between-group difference P=0.44), and 151 vs. 157 patients were hospitalized (HR, 0.95; 95% CI, 0.76–1.19; between-group difference P=0.66). Post hoc analysis of data from the first year indicated that a bisoprolol-first strategy reduced mortality by 31%, compared with an enalapril-first strategy (HR, 0.69; 95% CI, 0.46–1.02; between-group difference P=0.065).
Conclusion Initiating treatment with bisoprolol is as effective and well-tolerated as initiating treatment with enalapril. Post hoc analysis suggests that starting treatment with bisoprolol may reduce the risk of death, especially in the first year of treatment.
Key Words: Congestive heart failure • Therapy • Beta-blocker • Angiotensin-converting enzyme inhibitor • Sequence of drug initiation