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Trial of the Beta-Blocker Bucindolol in Patients with Advanced Chronic Heart Failure - Bucindolol in Patients with Advanced Chronic Heart Failure
Description:
A Trial of the Beta-Blocker Bucindolol in Patients with Advanced Chronic Heart Failure.
Hypothesis:
Although beta-adrenergic-receptor antagonists reduce morbidity and mortality in patients with mild-to-moderate chronic heart failure, their effect on survival in patients with more advanced heart failure is unknown.
Study Design
Study Design:
Patients Enrolled: 2708
Patient Populations:
Patients with heart failure designated as New York Heart Association (NYHA) functional class III (in 92% of the patients) or IV (in 8%) and a left ventricular ejection fraction of 35% or lower.
Primary Endpoints:
Death.
Drug/Procedures Used:
A total of 2708 patients with heart failure designated as New York Heart Association (NYHA) functional class III (in 92% of the patients) or IV (in 8%) and a left ventricular ejection fraction of 35% or lower were randomly assigned to double-blind treatment with either bucindolol (1354 patients) or placebo (1354 patients) and followed for the primary end point of death from any cause.
Principal Findings:
The data and safety monitoring board recommended stopping the trial after the seventh interim analysis. At that time, there was no significant difference in mortality between the two groups (unadjusted p=0.16). The results presented here are based on complete follow-up at the time of study termination (average, 2.0 years). There were a total of 449 deaths in the placebo group and 411 deaths in the bucindolol group. The risk of the secondary end point of death from cardiovascular causes was lower in the bucindolol group, as was the risk of heart transplantation or death.
In a demographically diverse group of patients with NYHA class III and IV heart failure, bucindolol resulted in no significant overall survival benefit.
Interpretation:
As a member of the Data and Safety Monitoring Board, I found the ongoing overall neutrality of treatment in this study to be perplexing, since other studies of beta adrenergic blockade were suggesting class effect benefit. While heterogeneity of response, based on ethnic origin, has been offered as one explanation, this is only one of several possibilities. When the study was terminated by the DSMB, no single conclusive explanation could be offered, for the absence of statistically significant bucindolol benefit. We have come to expect clarity in all clinical trials, but the statistical play of chance remains a factor, even in large multicenter trials. The features of this study are well summarized by Dr. Braunwald in the accompanying editorial.
References:
1. Eichhorn E, Domanski M, Krause-Steinrauf H, et al. N Engl J Med 2001;344:1659-67.
Keywords: Heart Failure, Clinical Trials Data Monitoring Committees, Stroke Volume, Propanolamines, Receptors, Adrenergic, beta, Adrenergic Antagonists, Heart Transplantation
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