Beta-Blocker Evaluation of Survival Trial - BEST (Beta-Blocker Evaluation of Survival Trial)

Aug 06, 2011
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
National Heart, Lung, and Blood Institute; Department of Veterans Affairs Cooperative Studies Program; and Incara Pharmaceuticals.
Date Published:
01/01/2001
Date Updated:
08/06/2011
Original Posted Date:
08/06/2011
References

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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