title: Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study.
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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.forename: John
authors.initials: J
authors.lastname: McMurray
authors.forename: Barry M
authors.initials: BM
authors.lastname: Massie
authors.forename: Abraham
authors.initials: A
authors.lastname: Caspi
authors.forename: Vincent
authors.initials: V
authors.lastname: Charlon
authors.forename: Alain
authors.initials: A
authors.lastname: Cohen-Solal
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kiowski
authors.forename: William
authors.initials: W
authors.lastname: Kostuk
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Barry
authors.initials: B
authors.lastname: Levine
authors.forename: Paolo
authors.initials: P
authors.lastname: Rizzon
authors.forename: Jordi
authors.initials: J
authors.lastname: Soler
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.forename: Susan
authors.initials: S
authors.lastname: Anderson
authors.forename: David L
authors.initials: DL
authors.lastname: Demets
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000077300:Bosentan; D004311:Double-Blind Method; D004906:Erythrocyte Count; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000401:mortality / Q000503:physiopathology; D006454:Hemoglobins / Q000032:analysis; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D017211:Treatment Failure
chemical_list: D000959:Antihypertensive Agents; D006454:Hemoglobins; D013449:Sulfonamides; D000077300:Bosentan