What were the outcomes of the CIBIS‑II (Cardiac Insufficiency Bisoprolol Study II) trial evaluating bisoprolol versus placebo in patients with chronic systolic heart failure (left ventricular ejection fraction ≤35%)?

CIBIS-II Trial Results

The CIBIS-II trial demonstrated that bisoprolol 10 mg daily significantly reduced all-cause mortality by 34% (relative risk reduction 0.66) in patients with NYHA class III-IV heart failure and LVEF ≤35%, with the trial stopped early due to overwhelming mortality benefit. 1

Primary Mortality Outcomes

The trial enrolled 2,647 symptomatic patients with chronic heart failure (NYHA class III or IV) and left ventricular ejection fraction ≤35% who were already receiving standard therapy with diuretics and ACE inhibitors. Patients were randomized to bisoprolol 1.25 mg daily (n=1,327) or placebo (n=1,320), with progressive titration to a maximum of 10 mg per day over a mean follow-up of 1.3 years. 2

Key mortality findings:

• All-cause mortality: 11.8% (156 deaths) with bisoprolol vs. 17.3% (228 deaths) with placebo (hazard ratio 0.66,95% CI 0.54-0.81, P<0.001) 1
• Sudden cardiac death: 3.6% (48 deaths) with bisoprolol vs. 6.3% (83 deaths) with placebo (relative risk reduction 0.56,95% CI 0.39-0.80, P=0.001) 1
• Number needed to treat: 23 patients treated with bisoprolol for 1 year would prevent 1 death 1

Secondary Outcomes

Hospitalization benefits:

• All-cause hospital admissions were reduced with bisoprolol (hazard ratio 0.80,95% CI 0.71-0.91, P<0.001) 1
• Treatment effects were independent of the severity or cause of heart failure 1

Clinical Significance and Context

CIBIS-II's unique design features:

• Unlike other beta-blocker trials, CIBIS-II did not have a run-in period, making it more representative of real-world clinical practice 1
• The trial had greater statistical power than its predecessor CIBIS-I, which had shown improvements in functional class and reduced readmissions but failed to reach statistical significance for mortality (P=0.22) 1

Important caveat: The trial results should not be extrapolated to patients with severe class IV symptoms and recent instability, as safety and efficacy have not been established in these patients. 2 The trial specifically enrolled stable patients already receiving standard medical treatment.

Comparison with other beta-blockers: When compared in stratified analyses with similar patient populations from MERIT-HF and COPERNICUS, bisoprolol showed comparable efficacy and tolerability to metoprolol CR/XL and carvedilol, with annual mortality reductions of 34-42% across trials. 3