best: beta-blocker evaluation survival trial purpose to determine whether the β-blocker bucindolol...
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BEST: Beta-blocker Evaluation Survival Trial
Purpose
To determine whether the β-blocker bucindolol reduces morbidity and mortality in patients with advanced heart failure
ReferenceThe BEST Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659–67.
BEST: Beta-blocker Evaluation Survival Trial- TRIAL DESIGN -
DesignMulticenter, randomized, double-blind, placebo-controlled
Patients2708 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 endpointPrimary endpoint: all-cause mortality. Mean 24 months follow up
TreatmentPlacebo 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)
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
BEST: Beta-blocker Evaluation Survival Trial- RESULTS continued-
Months after randomization
Probability ofsurvival
0
0.0
6 12 18 24 3630 42
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.
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.
BEST: Beta-blocker Evaluation Survival Trial- RESULTS continued-
0.50 1
Hazard ratios for death in subgroups
1.5 2
Hazard ratio and 95% CI
Bucindololbetter
Placebobetter
No. ofpatients
Annual mortalitywith 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.
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