Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study.
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.
Packer
Milton
M
College of Physicians and Surgeons, Columbia University, New York, New York, USA.
McMurray
John
J
Massie
Barry M
BM
Caspi
Abraham
A
Charlon
Vincent
V
Cohen-Solal
Alain
A
Kiowski
Wolfgang
W
Kostuk
William
W
Krum
Henry
H
Levine
Barry
B
Rizzon
Paolo
P
Soler
Jordi
J
Swedberg
Karl
K
Anderson
Susan
S
Demets
David L
DL
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
D000959:Antihypertensive Agents; D006454:Hemoglobins; D013449:Sulfonamides; D000077300:Bosentan