CIBIS II: Cardiac Insufficiency Bisoprolol Study II Purpose To determine whether bisoprolol, a β1-selective adrenoreceptor blocker, reduces all-cause mortality in chronic heart failure Reference CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13.

CIBIS II: Cardiac Insufficiency Bisoprolol Study II - TRIAL DESIGN - Multicenter, multinational, randomized, double-blind, placebo-controlled Patients 2647 patients, aged 18–80 years, with left ventricular ejection fraction <35% and NYHA class III or IV heart failure, receiving standard therapy (diuretic plus ACE inhibitor/other vasodilator) Follow up and primary end point Mean 1.3 years follow up. Primary endpoint all-cause mortality Treatment Placebo or bisoprolol 1.25 mg daily, increased stepwise over several weeks as tolerated to target dose 10 mg daily

CIBIS II: Cardiac Insufficiency Bisoprolol Study II - RESULTS - Study halted early because all-cause mortality significantly less in bisoprolol group than placebo group Also significant reduction in: Sudden deaths All cardiovascular deaths All-cause hospitalization, as well as hospitalization due to worsening heart failure Treatment effects independent of severity or cause of heart failure Drug well tolerated as defined by permanent early treatment withdrawals (15% in both groups, P=0.98)

CIBIS II: Cardiac Insufficiency Bisoprolol Study II - RESULTS continued- All-cause mortality Survival 1.0 0.8 0.6 Placebo P<0.0001 Bisoprolol 200 400 600 800 Days after inclusion CIBIS-II Investigators and Committees. Lancet 1999; 353 :9 – 13.

CIBIS II: Cardiac Insufficiency Bisoprolol Study II - RESULTS continued- Primary and secondary outcomes Placebo Bisoprolol Hazard ratio (n=1320) (n=1327) P (95% CI) (%) (%) Primary endpoint All-cause mortality 17 12 0.66 (0.54 – 0.81) <0.0001 Secondary endpoints All-cause hospital admission 39 33 0.80 (0.71 – 0.91) 0.0006 All cardiovascular deaths 12 9 0.71 (0.56 – 0.90) 0.0049 Combined endpoint 35 29 0.79 (0.69 – 0.90) 0.0004 Exploratory analyses Sudden death 6 4 0.56 (0.39 – 0.80) 0.0011 Hospital admission for 18 12 0.64 (0.53 – 0.79) 0.0001 worsening heart failure CIBIS-II Investigators and Committees. Lancet 1999; 353 :9 – 13.

CIBIS II: Cardiac Insufficiency Bisoprolol Study II - RESULTS continued- Effect of bisoprolol on subgroups Baseline etiology/ Bisoprolol Placebo functional class (n/total) (n/total) Ischemia 75/662 121/654 Primary dilated 13/160 15/157 cardiomyopathy Undefined 68/505 92/509 NYHA III 116/1106 173/1096 NYHA IV 40/221 55/224 Total 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 Relative risk (and 95% CI) CIBIS-II Investigators and Committees. Lancet 1999; 353 :9 – 13.

CIBIS II: Cardiac Insufficiency Bisoprolol Study II - SUMMARY - In patients with class III or IV heart failure, bisoprolol in addition to standard therapy reduced: All-cause mortality Sudden death and cardiovascular death All-cause hospitalization and hospitalization due to worsening heart failure