Beta-Blocker Evaluation of Survival Trial - BEST (Beta-Blocker Evaluation of Survival Trial)
Description:
The goal of this trial was to compare treatment with bucindolol compared with placebo among patients with advanced heart failure.
Hypothesis:
Bucindolol will be more effective at preventing all-cause mortality.
Study Design
- Blinded
- Parallel
- Placebo Controlled
- Randomized
- Stratified
Patient Populations:
- Patients at least 18 years of age with advanced heart failure (NYHA class III-IV) on optimal medical therapy and left ventricular ejection fraction ≤35%
Number of enrollees: 2,708
Duration of follow-up: Mean 2 years
Mean patient age: 60 years
Percentage female: 21%
Ejection fraction: 23%
NYHA class: III-92%, IV-8%
Exclusions:
- Decompensated heart failure (hypotension, hypoperfusion, or acute pulmonary edema)
- Reversible cause of heart failure, which could include primary valvular disease
- Thyroid disease
- Hypertrophic (obstructive) cardiomyopathy
- Pericardial disease
- Amyloidosis
- Active myocarditis
- Malfunctioning artificial heart valve
- History of myocardial infarction within the previous 6 months or coronary revascularization within the previous 2 months
- Candidate for heart transplantation
- Unstable angina
- Bradycardia (heart rate <50 bpm)
- Currently receiving another investigational drug
- Limited life expectancy (<3 years)
- Significant liver disease or renal disease
- Hematologic, central nervous system, gastrointestinal, immunologic, endocrine, or metabolic disorder
- Alcohol abuse
- Currently taking a calcium channel antagonist, theophylline, tricyclic antidepressant, monoamine oxidase inhibitor, beta-agonist within the last week, beta-blocker within the last month, flecainide, encainide, propafenone, disopyramide, or amiodarone
Primary Endpoints:
- All-cause mortality
Secondary Endpoints:
- Cardiovascular mortality
- Hospitalization for any reason
- Hospitalization for heart failure
- Death or heart transplantation
- Left ventricular ejection fraction at 3 and 12 months
- Myocardial infarction
- Quality of life
- Any change in the need for concomitant therapy
Drug/Procedures Used:
Patients in the United States and Canada with advanced heart failure (New York Heart Association [NYHA] class III and IV) were randomized to bucindolol 3 mg twice daily, titrated to 50 mg twice daily or 100 mg twice daily for patients >75 kg (n = 1,354) versus placebo twice daily (n = 1,354).
Concomitant Medications:
At baseline, in the bucindolol group, 91% were on an angiotensin-converting enzyme inhibitor, 6% on an angiotensin-receptor blocker, 3% on spironolactone, 94% on a diuretic, 93% on digitalis, and 23% on a statin.
Principal Findings:
Overall, 2,708 patients were randomized. In the bucindolol group, the mean age was 60 years, 21% were women, 24% were black, 37% were diabetics, 19% were current smokers, mean body mass index was 28 kg/m2, median duration of heart failure was 36 months, cause of heart failure was ischemic in 59% and idiopathic in 26%, mean blood pressure was 117/71 mm Hg, and mean left ventricular ejection fraction was 23%.
The primary outcome, all-cause mortality, occurred in 30% of the bucindolol group versus 33% of the placebo group (p = 0.13).
Cardiovascular mortality was 25% versus 29% (p = 0.04), any hospitalization was 61% versus 65% (p = 0.08), admission due to heart failure was 35% versus 42% (p < 0.001), heart transplantation was 2% versus 3% (p = 0.12), and death or heart transplantation was 32% versus 35% (p = 0.04), respectively, for bucindolol versus placebo.
Blacks did not appear to benefit from bucindolol (hazard ratio [HR] for death 1.17, p = 0.27), although nonblack patients did benefit (HR 0.82, p = 0.01), respectively, for bucindolol versus placebo.
Interpretation:
Among patients with advanced heart failure (NYHA class III-IV), the use of bucindolol was not beneficial compared with placebo. Bucindolol did not reduce the primary outcome of all-cause mortality, although it did reduce cardiovascular mortality and hospitalizations due to heart failure. The reason for the lack of benefit on all-cause mortality is unknown, although it may be related to the differential effect observed in blacks, who comprised a large proportion of this trial.
As a result of the BEST trial, bucindolol was dropped from further development; however, a pharmacogenetics company is proposing to examine the use of this medication in patients with a certain genotype that is associated with a favorable response to beta-blockade.
References:
Beta-Blocker Evaluation of Survival Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659-67.
Keywords: Follow-Up Studies, Blood Pressure, Propanolamines, Vasodilator Agents, Heart Transplantation, Adrenergic alpha-1 Receptor Antagonists, Body Mass Index, Heart Failure, Stroke Volume, Genotype, Pharmacogenetics, Diabetes Mellitus
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