CIBIS III Trial

Cardiac Insufficiency Bisoprolol Study (CIBIS III)

Trial

Presented at
The European Society of Cardiology
Hot Line Session 2005
Presented by Dr. Ronnie Willenheimer
 CIBIS III Trial
1010 patients > 65 years with mild to moderate CHF (NYHA class II or III) and LV ejection
fraction < 35% in 3 months prior to randomization, clinically stable CHF for 7 days
Randomized
32% female, mean age 72 years, mean follow-up 1.22 years
13% received aldosterone-receptor blocker and 84% diuretic

Monotherapy with beta-blocker Monotherapy with ACE-inhibitor

bisoprolol (first 6 mos) enalapril (first 6 mos)
10mg O.D. 10mg B.I.D.
n=505 n=505

Combination beta-blocker and

ACE-inhibitor therapy (6-24 mos)

 Primary Endpoint: Time-to-the-first-event of combined all-cause mortality and all-cause

hospitalization throughout study.
 Secondary Endpoint: Combined primary endpoint at end of monotherapy phase; individual
components of primary endpoint at study end and at end of monotherapy phase.

www. Clinical trial results.org Presented at ESC 2005

 CIBIS III Trial: Per-Protocol (PP) Primary Endpoint

PP Analysis of death or rehospitalization (%)

p = 0.046 for non-inferiority
• The per-protocol primary endpoint of
death or rehospitalization did not differ
40% by treatment group (HR 0.97, 95% CL
0.78-1.21), and
32.4% 33.1%

30% • In the per-protocol group , non-inferiority

criteria, trended to be significant, but
significance was not met
20%
• Baseline characteristics were similar
between the two treatment groups:
10% •Ischemic heart disease
present in 62% of patients
•Mean LVEF of 28.8% NYHA
0% heart failure classification was
evenly divided by class II and III
Beta-blocker bisoprolol ACE-inhibitor enalapril •Adverse even rate was similar
between two treatment groups

www. Clinical trial results.org Presented at ESC 2005

 CIBIS III Trial: Intent-to-Treat (ITT)

ITT Analysis of death or rehospitalization

p=0.86 • In the intent-to-treat group, non-

200 inferiority criteria was met (HR 0.94,
n=151 n=157 95% CL 0.77-1.16, p=0.019)
150
# of patients

p=0.44 • There was no difference in the

100 individual components of death (n=65
n=73
n=65 vs n=73, HR 0.88) or hospitalization
50 (n=151 vs n=157, HR 0.97) among the
intent-to-treat group
0
Death Hospitalization • At the end of the monotherapy phase,
there was no difference in the primary
Beta-blocker bisoprolol endpoint (HR 1.02, p=0.90)
ACE-inhibitor enalapril

www. Clinical trial results.org Presented at ESC 2005

 CIBIS III Trial

Worsening CHF requiring hospitalization

or occuring in-hospital
p = 0.23
• Worsening CHF requiring
75 hospitalization or occurring in-
n=63 hospital was non-significantly
60 higher in the bisoprolol group
n=51 (HR 1.25)
# of patients

45
• Study drug discontinuation
30 during the monotherapy arm
occurred in 6.9% of the
15 bisoprolol-first strategy and
9.7% of the enalapril-first
0 strategy

Beta-blocker bisoprolol ACE-inhibitor enalapril

www. Clinical trial results.org Presented at ESC 2005

 CIBIS III Trial Summary

• 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 non-inferiority
in the per-protocol population for death or hospitalization
compared with a strategy of initial treatment with the ACE-
inhibitor enalapril.
• Non-inferiority was met in the intent-to-treat population.
• Current guidelines recommend first-line therapy with an
ACE-inhibitor after initial heart failure diagnosis, followed by
addition of beta-blocker.

www. Clinical trial results.org Presented at ESC 2005