Cardiac Insufficiency Bisoprolol Study - CIBIS III


The goal of the trial was to evaluate a strategy of initial treatment with the beta-blocker bisoprolol compared with a strategy of initial treatment with the angiotensin-converting enzyme (ACE) inhibitor enalapril among patients with newly diagnosed mild to moderate heart failure.

Study Design

Study Design:

Patients Enrolled: 1,010
NYHA Class: Class II 49%; class III 50%
Mean Follow Up: Mean 1.22 years
Mean Patient Age: Mean age 72 years
Female: 32
Mean Ejection Fraction: Mean 28.8% at baseline

Patient Populations:

Age ≥65 years, clinically stable mild to moderate congestive heart failure (NYHA class II or III), and LV ejection fraction ≤35% in three months prior to randomization


Treatment with an ACE inhibitor, angiotensin receptor blocker, or beta-blocker for >7 days during the three months prior to randomization, acute coronary syndrome in the prior three months, percutaneous coronary intervention or coronary artery bypass grafting planned or performed within prior three months, stroke within one month or with permanent neurological sequelae within six months, heart rate at rest <60 bpm, systolic blood pressure at rest <100 mg, serum creatinine ≥220 µmol/l, AV block >first degree without a pacemaker, or obstructive lung disease contraindicating bisoprolol

Primary Endpoints:

Time-to-the-first-event of combined all-cause mortality or all-cause hospitalization throughout the study, evaluating noninferiority in the per-protocol population

Secondary Endpoints:

Primary endpoint at the end of the monotherapy phase; individual components of the primary endpoint at study end and at end of the monotherapy phase; and cardiovascular death and cardiovascular hospitalization

Drug/Procedures Used:

Patients were randomized open-label to a strategy of initial treatment of six-month monotherapy with the beta-blocker bisoprolol (target dose 10 mg QD) (n=505) or a strategy of initial treatment of six-month monotherapy with the ACE inhibitor enalapril (target dose 10 mg BID) (n=505). All patients received combination beta-blocker and ACE-inhibitor therapy during the six- to 24-month period. The primary endpoint comparison was noninferiority with an upper bound hazard ratio (HR) of 1.17 in the per protocol population.

Concomitant Medications:

Diuretic 84%, aldosterone-receptor blocker 13%

Principal Findings:

Baseline characteristics were well-matched between groups, with ischemic heart disease in 62% and mean left ventricular (LV) ejection fraction 28.8%. New York Heart Association (NYHA) heart failure classification was evenly divided by class II and class III.

In the per-protocol primary endpoint analysis, death or rehospitalization occurred in 32.4% of the bisoprolol-first strategy and 33.1% of the enalapril-first strategy (HR 0.97, 95% confidence interval [CI] 0.78-1.21, p=0.046 for noninferiority), missing the prespecified criteria for noninferiority of HR 1.17. The noninferiority criteria were met in the intent-to-treat analysis (HR 0.94, 95% CI 0.77-1.16, p=0.019 for noninferiority). By intent-to-treat, there was no difference in the individual components of mortality (n=65 for bisoprolol-first strategy vs. n=73 for the enalapril-first strategy, HR 0.88, p=0.44) or hospitalization (n=151 and n=157, respectively, HR 0.97, p=0.86). At the end of the monotherapy phase, there was also no difference in the primary endpoint (HR 1.02, p=0.90). Worsening congestive heart failure requiring hospitalization or occurring in-hospital was nonsignificantly higher in the bisoprolol group (n=63 vs. n=51, HR 1.25, p=0.23).

Study drug discontinuation during the monotherapy phase occurred in 6.9% of the bisoprolol-first strategy and 9.7% of the enalapril-first strategy. The adverse event rate was similar between the two strategies.


Among patients with newly diagnosed mild to moderate heart failure, a strategy of initial treatment with the beta-blocker bisoprolol did not meet the criteria for noninferiority in the per-protocol population for death or hospitalization compared with a strategy of initial treatment with the ACE inhibitor enalapril. However, the intent-to-treat analysis did demonstrate noninferiority.

Current guidelines recommend first-line therapy with an ACE inhibitor following initial heart failure diagnosis, with subsequent addition of a beta-blocker. Despite the guideline recommendation to follow this order of administration, little randomized data exist to justify the recommendation.

The present trial does not provide clear-cut evidence to justify starting with beta-blocker or ACE inhibitors. While meeting the noninferiority criteria for the primary endpoint in the intent-to-treat analysis, the primary analysis was to be conducted in the per-protocol population given the open-label design of the trial. The overall safety profile of the two strategies was similar.


Presented by Dr. Ronnie Willenheimer at the European Society of Cardiology Hot Line Session, September 2005.

Willenheimer R, van Veldhuisen DJ, Silke B, 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:[Epub ahead of print]

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Myocardial Ischemia, Enalapril, Heart Failure, Bisoprolol, Hospitalization

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