1. COMET: Carvedilol Or Metoprolol European Trial Purpose To compare the effects of carvedilol (a β 1 -, β 2 - and α 1 -receptor blocker) and short-acting metoprolol tartrate (a β 1 -receptor blocker) on clinical outcome in patients with chronic heart failure Reference Poole-Wilson PA, Swedberg K, Cleland JGF et al. for the COMET Investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7–13.

2. COMET: Carvedilol Or Metoprolol European Trial - TRIAL DESIGN - Design Multicenter, multinational, randomized, double-blind, parallel group Patients 3029 patients in NYHA class II – IV, previously hospitalized for a cardiovascular reason, who had left ventricular ejection fraction <0.35 and were receiving optimal treatment with diuretics and ACE inhibitors unless not tolerated Follow up and primary endpoint Primary endpoint: all-cause mortality. Mean 4.8 years follow up. Treatment Short-acting metoprolol tartrate titrated to target dose 50 mg twice daily or carvedilol titrated to target dose 25 mg twice daily

3. COMET: Carvedilol Or Metoprolol European Trial - TRIAL DESIGN continued- Age (years) a Male NYHA class II III IV Heart failure cause Ischemic heart disease Hypertension Dilated cardiomyopathy Previous valve surgery Left ventricular ejection fraction a NT-proBNP ( mg/L) b Medications Diuretics ACE inhibitors Angiotensin receptor antagonists Aldosterone antagonists Baseline characteristics (%) 62.3 80 49 47 4 54 18 44 2 Metoprolol tartrate (n=1518) 61.6 79 48 3 51 18 44 3 Carvedilol (n=1511) a Mean b Median 0.26 1185 99 91 7 11 Metoprolol tartrate (n=1518) 0.26 1298 99 92 6 11 Carvedilol (n=1511) Poole-Wilson et al.Lancet 2003;362:7–13.

4. COMET: Carvedilol Or Metoprolol European Trial - RESULTS - All-cause mortality significantly reduced in carvedilol group compared with short-acting metoprolol tartrate (34 vs. 40%, P=0.0017) Cardiovascular mortality significantly reduced (29 vs. 35%, P=0.0004) No significant difference in composite secondary endpoint of all- cause mortality or admission (74 vs. 76%, hazard ratio 0.94, 95% CI 0.86–1.02, P=0.122): Withdrawal rate identical (32%) and incidence of adverse events similar (94 vs. 96%) in both treatment groups

5. COMET: Carvedilol Or Metoprolol European Trial - RESULTS continued - Years after randomization Mortality (%) 0 0 12345 10 20 30 40 All-cause mortality Poole-Wilson et al. Lancet 2003; 362:7–13. Metoprolol tartrate Carvedilol

6. COMET: Carvedilol Or Metoprolol European Trial - RESULTS continued - P All deaths 5 year Kaplan–Meier Months at risk a Yearly mortality rate Cardiovascular deaths 0.002 0.0004 All-cause mortality and cardiovascular death Carvedilol (n=1511) 600 (40%) 41.0% 45.2 (19.5) 10.0 534 (35%) 512 (34%) 35.3% 46.8 (18.9) 8.3 438 (29%) 0.83 (0.74–0.93) 0.80 (0.70–0.90) Metoprolol tartrate (n=1518) Hazard ratio (95% CI) a Mean (SD) Poole-Wilson et al. Lancet 2003; 362:7–13.

7. COMET: Carvedilol Or Metoprolol European Trial - SUMMARY - Compared with short-acting metoprolol tartrate, in patients with chronic heart failure carvedilol reduced: All-cause mortality Cardiovascular death Whether COMET compared regimens that were equivalent in degree and duration of beta-blockade has been debated. a In COMET: Reduction in resting heart rate and BP were significantly greater with carvedilol than metoprolol, suggesting under-dosing with metoprolol Comparing metoprolol groups, mortality rate was higher and reduction in heart rate from baseline was lower than in MERIT-HF COMET did not use the formulation and dose of metoprolol approved by authorities in CHF and used in MERIT-HF (200 mg metoprolol succinate CR/XL) a See McMurray JV, Commentary on COMET, in Key Opinions, www.InCirculation.net 2003.