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

Apr 25, 2017
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Actelion
Date Presented:
03/20/2002
Date Published:
04/24/2017
Date Updated:
04/25/2017
Original Posted Date:
04/04/2002
References

Contribution To Literature:

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

Description:

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.

Interpretation:

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.

References:

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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