CIBIS IICardiac Insufficiency Bisoprolol Study

CIBIS IICardiac Insufficiency Bisoprolol Study

• Double-blind, placebo-controlled, randomised trial

• 2,647 patients included (NYHA III + IV)

• Bisoprolol administered on top of standard therapy(diuretic + ACE inhibitor)

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CIBIS II – Cardiac Insufficiency Bisoprolol Study Objectives

CIBIS II – Cardiac Insufficiency Bisoprolol Study Objectives

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• Primary objective– All-cause mortality

• Secondary objectives– Cardiovascular mortality

– Hospital admissions

– Cardiovascular mortality orcardiovascular hospital admissions

– Permanent treatment withdrawal

CIBIS II – Cardiac Insufficiency Bisoprolol Study Main inclusion criteria

CIBIS II – Cardiac Insufficiency Bisoprolol Study Main inclusion criteria

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–13• Ambulatory patients with stable CHF of all

aetiologies

• NYHA functional class III or IV

• Stable on ACE inhibitor and diuretic

• Aged 18 – 80 years

• Left ventricular ejection fraction 35%

CIBIS II – Cardiac Insufficiency Bisoprolol Study Design

CIBIS II – Cardiac Insufficiency Bisoprolol Study Design

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7.50

10.00

5.00

3.75

2.50

1.25

W1 W2 W3 W4 W5 W6 W7 W8 W9 W10W11W12W13W14W15W16 Week

Bisoprolol dose (mg)

No run-in period Dose increased according to tolerability

CIBIS II – Cardiac Insufficiency Bisoprolol Study Characteristics (I)

CIBIS II – Cardiac Insufficiency Bisoprolol Study Characteristics (I)

Placebo Bisoprolol(n=1320) (n=1327)

Demographic dataMean (range) age (years) 61 (22–80) 61 (26–80)Sex (M/F) 1062 (80%) 1070 (81%)

258 (20%) 257 (19%)

NYHA classIII 1096 (83%) 1106 (83%)IV 224 (17%) 221 (17%)

Heart failure Documented ischaemic heart disease 654 (50%) 662 (50%)Primary dilated cardiomyopathy 157 (12%) 160 (12%)Others* 509 (40%) 505 (38%)Mean (SD) left-ventricular ejection fraction 27.6 (5.5%)27.5 (6.0%)

*Coronary angiography unavailable or no history of myocardial infarction

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CIBIS II – Cardiac Insufficiency Bisoprolol StudyCharacteristics (II)

CIBIS II – Cardiac Insufficiency Bisoprolol StudyCharacteristics (II)

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Placebo Bisoprolol(n=1320) (n=1327)

Concomitant medication

Diuretic 1310 (99%) 1305 (98%)ACE inhibitor 1274 (96%) 1273 (96%)

Dihydropyridine-type calcium antagonist 23 (2%) 23 (2%)Nitrate 762 (58%) 773 (58%)Digoxin 670 (51%) 697 (53%)Amiodarone 206 (16%) 185 (14%)Anticoagulant 413 (31%) 399 (30%)Antiplatelet agent 558 (42%) 537 (40%)

CIBIS II – Cardiac Insufficiency Bisoprolol StudySurvival

CIBIS II – Cardiac Insufficiency Bisoprolol StudySurvival

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34% reduction in all-cause mortality with bisoprolol

1.0

0.8

0.6

0

0 200 400 600 800Time after inclusion (days)

Su

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Bisoprolol: 156 deaths (n = 1327)

Placebo: 228 deaths (n = 1320)

log rank test, p < 0.0001

CIBIS II – Cardiac Insufficiency Bisoprolol StudyAnalysis of time to death

CIBIS II – Cardiac Insufficiency Bisoprolol StudyAnalysis of time to death

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Patients

Unknown causeof death

Non-cardio-vascular deaths

Other cardio-vascular deaths

Myocardialinfarction

Pumpfailure

Suddendeath

0.45(0.27 – 0.74)

0.75(0.37 – 1.50)

1.17(0.67 – 2.03)

0.85(0.31 – 2.34)

836%

p=0.0011

484%

363%

0.56(0.39 – 0.80)

0.74(0.48 – 1.14)

Hazard ratio:(95% CI)

p=0.17

p=0.75

p=0.58

p=0.41

p=0.0012

Bisoprolol (n = 1327)

Placebo (n = 1320)

0

20

40

60

80

100

474%

71%

81%

282% 23

2%

141%

181%

232%

494%

CIBIS II – Cardiac Insufficiency Bisoprolol StudySecondary endpoints

CIBIS II – Cardiac Insufficiency Bisoprolol StudySecondary endpoints

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(log rank(n = 1320) (n = 1327) (95% Cl) test)

All-cause hospital admissions 513 (39%) 440 (33%) 0.80 (0.71–0.91) 0.0006

All cardiovascular deaths 161 (12%) 119 (9%) 0.71 (0.56–0.90) 0.0049

Combined endpoint 463 (35%) 388 (29%) 0.79 (0.69–0.90) 0.0004

Permanent treatment 192 (15%) 194 (15%) 1.00 (0.82–1.22) 0.98withdrawals

CIBIS II – Cardiac Insufficiency Bisoprolol StudyMortality by baseline findings

CIBIS II – Cardiac Insufficiency Bisoprolol StudyMortality by baseline findings

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–13Ischaemia 75/662

Primary DCM 13/160

Undefined 68/505

NYHA III 116/1106

NYHA IV 40/221

121/654

Bisoprololn/total

Placebon/total

15/157

92/509

173/1096

55/224

Total

0.4Relative risk: 0.6 0.8 1.0 1.2 1.4 1.6 1.8

Mortality did not differ significantly between groupswhatever the aetiology or severity of heart failure

CIBIS II – Cardiac Insufficiency Bisoprolol StudyMain results at a glance

CIBIS II – Cardiac Insufficiency Bisoprolol StudyMain results at a glance

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reduction in

• All-cause mortality (independent of aetiology) by 34% (p<0.0001)

• Sudden death by 44% (p<0.0011)

• All-cause hospital admissions by 20% (p<0.0006)

• Hospital admissions due to worsening heart failure by36%

(p<0.0001)

CIBIS II – Cardiac Insufficiency Bisoprolol StudyConclusions

CIBIS II – Cardiac Insufficiency Bisoprolol StudyConclusions

• CIBIS II successfully demonstrated that ß1-selective bisoprolol – given in addition to standard therapy –reduces significantly all-cause mortality andall-cause hospitalisation in CHF patients.

• Bisoprolol is the first ß-blocker which has provenits efficacy in a single large-scale CHF studywith all-cause mortality as primary objective.

• Bisoprolol was as well tolerated as placebowith a permanent treatment withdrawal rate of 15% in both groups.