1. Carvedilol Or Metoprolol European Trial Presented at European Heart Failure Meeting 2003 COMET Trial

2. Carvedilol (target dose 25 mg twice daily)  A multiple adrenergic inhibitor (n = 1,511) Carvedilol (target dose 25 mg twice daily)  A multiple adrenergic inhibitor (n = 1,511) Metoprolol tartrate (target dose 50 mg twice daily)  A beta-1 blockade agent (n = 1,518) Metoprolol tartrate (target dose 50 mg twice daily)  A beta-1 blockade agent (n = 1,518) Endpoints (mean follow-up 58 months):  Primary – 1) All-cause mortality and 2) All-cause mortality or all-cause hospitalization  Secondary – Composite of all cause mortality or cardiovascular hospitalization; Composite of cardiovascular death, non-fatal acute MI, or heart transplantation; Worsening of heart failure; Cardiovascular death; NYHA class Endpoints (mean follow-up 58 months):  Primary – 1) All-cause mortality and 2) All-cause mortality or all-cause hospitalization  Secondary – Composite of all cause mortality or cardiovascular hospitalization; Composite of cardiovascular death, non-fatal acute MI, or heart transplantation; Worsening of heart failure; Cardiovascular death; NYHA class COMET Trial European Heart Failure Meeting 2003 3,029 patients with Class III-IV heart failure Enrolled at 317 centers in 15 European countries 3,029 patients with Class III-IV heart failure Enrolled at 317 centers in 15 European countries

3. COMET Trial: Primary Endpoint Analysis All-cause mortality European Heart Failure Meeting 2003 HR 0.83 95% CI 0.74-0.93 p=0.0017

4. COMET Trial: Primary Endpoint Analysis All-cause mortality or all-cause hospitalization European Heart Failure Meeting 2003 HR 0.93 95% CI 0.86-1.10 p=0.1222

5. COMET: Dosing Issues Metoprolol-Tartrate (immediate release) Target dose: 2 x 50 mg tartrate ~78 mg Metoprolol Metoprolol-Succinate (CR/XR) Target dose: 1 x 190 mg succinate ~155 mg Metoprolol (achieved mean dose in MERIT-HF ~130 mg) COMET MERIT-HF Metoprolol Tartrate Metoprolol Succinate Slide Provided by: Dr. med. M. Elsner, Medizinische Klinik I, St. Josefs Hospital, Solmsstr. 15, 65189, Wiesbaden, Germany, Tel./Fax: +49-611-177-1205. Dr. Elsner has no conflict of interest to declare.

6. COMET Trial: Summary First randomized morality trial to compare 2 beta-blockers in patients with CHF Treatment with carvedilol was associated with  rate of all-cause mortality (primary endpoint) but was not associated with difference in co-primary endpoint of all-cause mortality or all-cause hospitalization in patients with CHF Trial used immediate-release formulation of metoprolol tartrate not controlled-release formulation of metoprolol succinate used in MERIT HF trial, the main trial showing a benefit of metoprolol compared with placebo in heart failure patients First randomized morality trial to compare 2 beta-blockers in patients with CHF Treatment with carvedilol was associated with  rate of all-cause mortality (primary endpoint) but was not associated with difference in co-primary endpoint of all-cause mortality or all-cause hospitalization in patients with CHF Trial used immediate-release formulation of metoprolol tartrate not controlled-release formulation of metoprolol succinate used in MERIT HF trial, the main trial showing a benefit of metoprolol compared with placebo in heart failure patients