1. BEST: Beta-blocker Evaluation Survival Trial Purpose To determine whether the β-blocker bucindolol reduces morbidity and mortality in patients with advanced heart failure Reference The BEST Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659–67.

2. BEST: Beta-blocker Evaluation Survival Trial - TRIAL DESIGN - Design Multicenter, randomized, double-blind, placebo-controlled Patients 2708 patients with NYHA class III/IV heart failure due to primary or secondary dilated cardiomyopathy, of which 59% were due to ischemic heart disease, with left ventricular ejection fraction <35%; patients with MI in previous 6 months excluded Follow up and primary endpoint Primary endpoint: all-cause mortality. Mean 24 months follow up Treatment Placebo or bucindolol 3 mg twice daily, increased as tolerated over several weeks to 50 mg twice daily (100 mg twice daily for patients >75 kg)

3. BEST: Beta-blocker Evaluation Survival Trial - RESULTS - Trial halted early because mortality not significantly different in bucindolol and placebo groups (30 vs. 33%, P=0.10) Bucindolol group had significantly lower: —death from cardiovascular causes (25 vs. 29%, P=0.04) —hospitalization due to heart failure (35 vs. 42%, P<0.001) In pre-specified subgroups: —significant interaction effect between treatment and race ( 2 =5.06, P=0.02), reflecting benefit in non-Black and lack of benefit in Black patients —non-significant trend towards improved survival in less advanced heart failure (LV ejection fraction <20%, NYHA class III); no survival benefit in more advanced heart failure Bucindolol well tolerated as defined by withdrawal rate from trial: marginally higher with placebo

4. BEST: Beta-blocker Evaluation Survival Trial - RESULTS continued- Months after randomization Probability of survival 0 0.0 6121824363042 1.0 0.8 0.6 0.4 Survival according to treatment group P = 0.01 Placebo Bucindolol The BEST Investigators. N Engl J Med 2001; 344:1659–67.

5. BEST: Beta-blocker Evaluation Survival Trial - RESULTS continued- P * Primary endpoint Death from any cause Secondary endpoints Death Cardiovascular causes Noncardiovascular causes Unknown causes Hospitalization Any admission Admission due to chronic heart failure 0.90 (0.78–1.02) 0.86 (0.74–0.99) 1.19 (0.79–1.78) 0.97 (0.50–1.86) 0.92 (0.84–1.01) 0.78 (0.69–0.88) * P values are unadjusted 0.10 0.04 0.41 0.92 0.08 <0.001 Primary and secondary outcomes Placebo (n=1354) No. (%) Bucindolol (n=1354) No. (%) 411 (30) 342 (25) 51 (4) 18 (1) 829 (61) 476 (35) 449 (33) 389 (29) 42 (3) 18 (1) 875 (65) 569 (42) Hazard ratio (95% CI) The BEST Investigators. N Engl J Med 2001; 344:1659–67.

6. BEST: Beta-blocker Evaluation Survival Trial - RESULTS continued- 0.501 Hazard ratios for death in subgroups 1.52 Hazard ratio and 95% CI Bucindolol better Placebo better No. of patients Annual mortality with placebo (%) Sex Coronary artery disease Race LV ejection fraction NYHA class 2115 593 1587 1121 627 2081 1025 1683 2482 226 17 14 20 13 16 17 22 14 16 28 Male Female Yes No Black Non-Black <20% >20% III IV The BEST Investigators. N Engl J Med 2001; 344:1659–67.

7. BEST: Beta-blocker Evaluation Survival Trial - SUMMARY - In patients with advanced heart failure and left ejection fraction <35%, bucindolol: Conferred no overall survival benefit Reduced hospitalization due to heart failure and death from cardiovascular causes Conferred no survival benefit in Black patients or patients with more advanced heart failure, but the trend in non-Black patients and those with less severe heart failure was favorable