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.

Research output: Contribution to journalArticle


Background - In patients with chronic heart failure (CHF), a beta-blocker is generally added to a regimen containing an angiotensin-converting-enzyme ( ACE) inhibitor. It is unknown whether beta-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, beta-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.


  • Ronnie Willenheimer
  • Dirk J van Veldhuisen
  • Bernard Silke
  • Erland Erdmann
  • Ferenc Follath
  • Henry Krum
  • Piotr Ponikowski
  • Allan Skene
  • Louis van de Ven
  • Patricia Verkenne
  • Philippe Lechat
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cardiac and Cardiovascular Systems


  • adrenergic beta-antagonists, drugs, angiotensin-converting enzyme inhibitors, heart failure
Original languageEnglish
Pages (from-to)2426-2435
Issue number16
Publication statusPublished - 2005
Publication categoryResearch