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.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, EP Basic Science, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant

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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