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

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, Milton Packer, Avi Caspi, Wolfgang Kiowski, Henry Krum, Craig Pratt, Karl Swedberg, Barry Massie, John McMurrayJohn McMurray, Eugene Connally, Mark Petrie, David DeMets, Susan Anderson, Jody Barnet, Robert Cody, Henry Dargie, Gary Francis, Barry Greenberg, Juerg Reichen, J. Karrasch, H. Krum, J. Horowitz, J. Amerena, A. Sindone, P. MacDonald, I. Jeffrey, I. Button, E. DeAngelis, R. Pacher, R. Davies, F. McAlister, P. Tanser, B. Sussex, G. Baumann, E. Fleck, H. G. Olbrich, K. Werdan, H. Klein, on behalf of the, ENABLE Investigators and Committees, ENABLE Investigators and Committees

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98 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)317-326
Number of pages10
JournalJACC: Heart Failure
Issue number5
StatePublished - May 1 2017

Bibliographical note

Publisher Copyright:
© 2017 American College of Cardiology Foundation


  • bosentan
  • clinical trial
  • endothelin
  • heart failure
  • placebo


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