Author + information
- Received January 13, 2017
- Revision received February 16, 2017
- Accepted February 19, 2017
- Published online April 24, 2017.
- Milton Packer, MDa,∗ (, )
- John J.V. McMurray, MDb,
- Henry Krum, MD, PhDc,
- Wolfgang Kiowski, MDd,
- Barry M. Massie, MDe,
- Avi Caspi, MDf,
- Craig M. Pratt, MDg,
- Mark C. Petrie, MDb,
- David DeMets, PhDh,
- Isaac Kobrin, MDi,
- Sebastien Roux, MDj,
- Karl Swedberg, MDk,l,
- ENABLE Investigators and Committees
- aBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- bInstitute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- cMonash University, Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
- dUniversity Hospital, Zurich, Switzerland
- eUniversity of California at San Francisco, San Francisco, California
- fKaplan Hospital, Rehovot, Israel
- gHouston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
- hUniversity of Wisconsin, Madison, Wisconsin
- iKobrin Associates GmbH, Basel, Switzerland
- jActelion, Allschwil, Switzerland
- kDepartment of Molecular and Clinical Medicine, University of Goteborg, Goteborg, Sweden
- lNational Heart and Lung Institute, Imperial College, London, United Kingdom
- ↵∗Address for correspondence:
Dr. Milton Packer, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall Street, Dallas, Texas 75226.
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.
This study was funded by Actelion. Dr. DeMets provides consulting services to and receives honoraria for serving on data monitoring committees for industry-sponsored clinical trials. Dr. Roux is an employee of Actelion. Dr. Swedberg provides consulting services to Amgen, AstraZeneca, Novartis, and Servier. Each author had a consulting and/or research and/or employment relationship with the sponsor at the time that the trials were ongoing. Except for S. Roux (an employee of Actelion), none of these relationships have been active for at least the past 5 years.
Drs. Krum and Kiowski are deceased.
- Received January 13, 2017.
- Revision received February 16, 2017.
- Accepted February 19, 2017.
- 2017 American College of Cardiology Foundation