Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials.

Abstract

OBJECTIVES:

The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure.

BACKGROUND:

Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking.

METHODS:

In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure.

RESULTS:

Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure.

CONCLUSIONS:

Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

• Authors: Milton Packer, John J V McMurray, Henry Krum, Wolfgang Kiowski, Barry M Massie, Avi Caspi, Craig M Pratt, Mark C Petrie, David DeMets, Isaac Kobrin, Sebastien Roux, Karl Swedberg, ENABLE Investigators and Committees
• Journal: JACC. Heart failure (JACC Heart Fail) Vol. 5 Issue 5 Pg. 317-326 (05 2017) ISSN: 2213-1787 [Electronic] United States
• PMID: 28449795 (Publication Type: Journal Article, Review)
• Copyright: Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Endothelin Receptor Antagonists
• Sulfonamides
• Bosentan

Topics

• Aged
• Australia
• Bosentan
• Cause of Death
• Chronic Disease
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Endothelin Receptor Antagonists (administration & dosage, adverse effects)
• Europe
• Female
• Heart Failure (diagnosis, drug therapy, mortality)
• Humans
• Internationality
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Morbidity
• North America
• Prognosis
• Proportional Hazards Models
• Randomized Controlled Trials as Topic
• Risk Assessment
• Severity of Illness Index
• Sulfonamides (administration & dosage, adverse effects)
• Survival Analysis
• Time Factors
• Treatment Outcome