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

ReferenceCIBIS-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 -

DesignMulticenter, multinational, randomized, double-blind, placebo-controlled

Patients2647 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 pointMean 1.3 years follow up. Primary endpoint all-cause mortality

TreatmentPlacebo 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

CIBIS-II Investigators and Committees. Lancet 1999; 353 :9 – 13.

P<0.0001

0 200 800600400

1.0

0.8

0.6

Days after inclusion

Survival

Placebo

Bisoprolol

CIBIS II: Cardiac Insufficiency Bisoprolol Study II- RESULTS continued-

P

Primary endpoint All-cause mortality

Secondary endpoints All-cause hospital admission

All cardiovascular deaths

Combined endpoint

Exploratory analyses Sudden death

Hospital admission for worsening heart failure

17

39

12

35

6

18

12

33

9

29

4

12

0.66 (0.54 –0.81)

0.80 (0.71 –0.91)

0.71 (0.56 –0.90)

0.79 (0.69 –0.90)

0.56 (0.39 –0.80)

0.64 (0.53 –0.79)

<0.0001

0.0006

0.0049

0.0004

0.0011

0.0001

Primary and secondary outcomes

CIBIS-II Investigators and Committees. Lancet 1999;353 :9–13.

Placebo(n=1320)

(%)

Bisoprolol(n=1327)

(%)

Hazard ratio(95% CI)

CIBIS II: Cardiac Insufficiency Bisoprolol Study II- RESULTS continued-

0.4 0.6 0.8 1.0

Effect of bisoprolol on subgroups

1.2 1.4 1.6 1.8

Ischemia

Primary dilated cardiomyopathy

Undefined

NYHA III

NYHA IV

Total

75/662

13/160

68/505

116/1106

40/221

121/654

15/157

92/509

173/1096

55/224

Relative risk (and 95% CI)

CIBIS-II Investigators and Committees. Lancet 1999;353 :9 –13.

Baseline etiology/functional class

Bisoprolol(n/total)

Placebo(n/total)

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