Milton Packer1, John J V McMurray2, Henry Krum3, Wolfgang Kiowski4, Barry M Massie5, Avi Caspi6, Craig M Pratt7, Mark C Petrie2, David DeMets8, Isaac Kobrin9, Sebastien Roux10, Karl Swedberg11. 1. Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas. Electronic address: milton.packer1526@baylorhealth.edu. 2. Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom. 3. Monash University, Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia. 4. University Hospital, Zurich, Switzerland. 5. University of California at San Francisco, San Francisco, California. 6. Kaplan Hospital, Rehovot, Israel. 7. Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas. 8. University of Wisconsin, Madison, Wisconsin. 9. Kobrin Associates GmbH, Basel, Switzerland. 10. Actelion, Allschwil, Switzerland. 11. Department of Molecular and Clinical Medicine, University of Goteborg, Goteborg, Sweden; National Heart and Lung Institute, Imperial College, London, United Kingdom.
Abstract
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 receiveplacebo 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.
RCT Entities:
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.
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