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 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

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

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

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

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