Clinical Trial
Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study

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Abstract

Background

Endothelin receptor antagonism produces favorable short-term hemodynamic effects in heart failure, but the clinical effects of longer term therapy have not been evaluated.

Methods and results

Three hundred and seventy patients with symptoms of heart failure at rest or on minimal exertion and a left ventricular ejection fraction <35% were randomly assigned (double-blind) to placebo (n = 126) or the endothelin receptor antagonist bosentan, titrated slowly (n = 121) or rapidly (n = 123) to a target dose of 500 mg twice daily. Treatment with the study drug was to be maintained for 26 weeks, whereas background medications for heart failure were kept constant. Safety concerns led to early termination of the trial when only 174 patients had had an opportunity to complete 26 weeks of therapy. Bosentan exerted no apparent benefit when all randomized patients were analyzed (P = .709). However, in the first 174 patients who were recruited at least 26 weeks before study termination and who could therefore be followed for the planned duration of the trial, patients in the bosentan groups were more likely to be improved (26% versus 19%) and were less likely to be worse (28% versus 43%), P = .045. When compared with placebo-treated patients, bosentan-treated patients had a increased risk of heart failure during the first month of treatment but a decreased risk of heart failure during the fourth, fifth, and sixth months of therapy. The major noncardiac adverse effects of bosentan included an increase in hepatic transaminases (in 15.6% of patients) and a decrease in hemoglobin (of about 1 g/L).

Conclusion

Although bosentan exerted no favorable effects in the overall study, our findings suggest that the clinical responses to endothelin antagonism with bosentan in patients with severe chronic heart failure may be dependent on the duration of treatment.

Section snippets

Methods

All patients had dyspnea or fatigue at rest or on minimal exertion (New York Heart Association class IIIB-IV) for at least 2 months and a left ventricular ejection fraction within 6 months that was <0.35 despite treatment with diuretics and a converting-enzyme inhibitor (unless intolerant). Patients were also required either to have been hospitalized for heart failure within 12 months or to be unable to walk more than 375 meters during a 6-minute corridor walk test. Treatment with digoxin,

Results

Enrollment into the study began on March 31, 1997, and 370 patients were randomized at 130 centers over 6 to 7 months. During this time, analysis of blinded data revealed a high incidence of liver function abnormalities, and this observation led to a decision by the Steering Committee and the sponsor to reduce the target dose of bosentan (to 125 mg twice daily) in subsequent trials with the drug. When informed of this decision, the Data and Safety Monitoring Board recommended orderly closure of

Discussion

Treatment with bosentan was not associated with any benefit when all randomized patients were included in the analysis, but when the duration of follow-up was considered (as specified in the original protocol), the results of the present study suggest that the clinical responses to endothelin antagonism with bosentan may be dependent on the duration of treatment. Short-term administration of the drug was associated with an increased risk of worsening heart failure, which appeared to be most

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    All decisions regarding this manuscript were made by a guest editor.

    Supported by a grant from Hoffmann-LaRoche Ltd., Basel, Switzerland.

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