Effects of the Endothelin Receptor Antagonist Bosentan on the Morbidity and Mortality in Patients With Chronic Heart Failure - ENABLE

Contribution To Literature:

The ENABLE trial failed to show that low doses of endothelin antagonists improved survival among patients with chronic heart failure.


The goal of the trial was to evaluate low-dose endothelin antagonism compared to placebo among patients with chronic heart failure.

Study Design

Patients Enrolled: 1,613
Mean Follow-Up: 1.5 years

Randomized, Parallel, Placebo

Drug/Procedures Used:

A total of 1,613 patients with severe chronic heart failure were randomized to receive bosentan 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily thereafter (n = 805) versus placebo (n = 808). These doses represent 10-25% of previously evaluated doses of bosentan. Patients were followed until 600 events occurred, or for 1.5 years.

Principal Findings:

The primary outcome, death or rehospitalization for heart failure, occurred in 38.8% of the bosentan group versus 39.7% of the placebo patients (p = 0.9).

All-cause mortality occurred in 19.9% of the bosentan group versus 21.4% of the placebo group (p = 0.54).

There was no early increase in risk of death associated with bosentan among subgroups analyzed by age, ejection fraction, New York Heart Association class, ischemia, or beta-blocker usage.

Treatment with bosentan also unexpectedly produced fluid retention and resulting changes in body weight and hemoglobin that were evident during the first 2 weeks of therapy at the lower dosage. This effect did not increase with increased dosage of bosentan, but did persist throughout follow-up despite physicians being encouraged to prescribe diuretics. Patients experiencing greater fluid retention also incurred a greater risk of death or cardiovascular events.


Treatment with reduced doses of bosentan among patients with severe congestive heart failure was not associated with a reduction in death or rehospitalization for heart failure. Treatment with bosentan was associated with fluid retention in some patients, which was associated with a higher risk of adverse clinical outcomes.


Presented by Dr. Milton Packer at the American College of Cardiology Annual Scientific Session, March 2002, Atlanta, GA.

Packer M, McMurray JJ, Krum H, et al. 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. JACC Heart Fail 2017;5:317-26.

Keywords: Receptors, Endothelin, Hemoglobins, Endothelins, Diuretics, Heart Failure, Body Weight, Sulfonamides

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