1. Cardiac Insufficiency Bisoprolol Study (CIBIS III) Trial
Presented at
The European Society of Cardiology
Hot Line Session 2005
Presented by Dr. Ronnie Willenheimer

2. 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 bisoprolol (first 6 mos)
10mg O.D.
n=505
Monotherapy with ACE-inhibitor enalapril (first 6 mos)
10mg B.I.D.
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.
Presented at ESC 2005

3. CIBIS III Trial: Per-Protocol (PP) Primary Endpoint
PP Analysis of death or rehospitalization (%)
p = for non-inferiority
The per-protocol primary endpoint of death or rehospitalization did not differ by treatment group (HR 0.97, 95% CL ), and
In the per-protocol group , non-inferiority criteria, trended to be significant, but significance was not met
Baseline characteristics were similar between the two treatment groups:
Ischemic heart disease
present in 62% of patients
Mean LVEF of 28.8% NYHA
heart failure classification was
evenly divided by class II and III
Adverse even rate was similar
between two treatment groups
Presented at ESC 2005

4. CIBIS III Trial: Intent-to-Treat (ITT)
ITT Analysis of death or rehospitalization
In the intent-to-treat group, non-inferiority criteria was met (HR 0.94, 95% CL , p=0.019)
There was no difference in the individual components of death (n=65 vs n=73, HR 0.88) or hospitalization (n=151 vs n=157, HR 0.97) among the intent-to-treat group
At the end of the monotherapy phase, there was no difference in the primary endpoint (HR 1.02, p=0.90)
p=0.86
n=157
n=151
p=0.44
n=73
n=65
Presented at ESC 2005

5. Worsening CHF requiring hospitalization or occuring in-hospital
CIBIS III Trial
Worsening CHF requiring hospitalization or occuring in-hospital
p = 0.23
Worsening CHF requiring hospitalization or occurring in-hospital was non-significantly higher in the bisoprolol group (HR 1.25)
Study drug discontinuation during the monotherapy arm occurred in 6.9% of the bisoprolol-first strategy and 9.7% of the enalapril-first strategy
n=63
n=51
Presented at ESC 2005

6. 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.
Presented at ESC 2005