Cardiac Insufficiency Bisoprolol Study (CIBIS III) Trial

1. 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

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 ACE-inhibitor enalapril (first 6 mos) 10mg B.I.D. n=505 Monotherapy with beta-blocker bisoprolol (first 6 mos) 10mg O.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 = 0.046 for non-inferiority • The per-protocol primary endpoint of death or rehospitalization did not differ by treatment group (HR 0.97, 95% CL 0.78-1.21), 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 0.77-1.16, 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. 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