Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan.
OBJECTIVE
We sought to determine the optimal dose of the selective endothelin A (ET(A)) receptor antagonist sitaxsentan for the treatment of pulmonary arterial hypertension (PAH); for observation only, an open-label (OL) bosentan arm was included.


BACKGROUND
Endothelin is a mediator of PAH. In a preliminary PAH study, the selective ET(A) receptor antagonist sitaxsentan improved six-min walk (6MW) distance, World Health Organization (WHO) functional class (FC), and hemodynamics.


METHODS
In this double-blind, placebo-controlled 18-week study, 247 PAH patients (idiopathic, or associated with connective tissue disease or congenital heart disease) were randomized; 245 patients were treated: placebo (n = 62), sitaxsentan 50 mg (n = 62) or 100 mg (n = 61), or OL (6MW tests, Borg dyspnea scores, and WHO FC assessments third-party blind) bosentan (n = 60). The primary end point was change in 6MW distance from baseline to week 18. Secondary end points included change in WHO FC, time to clinical worsening, and change in Borg dyspnea score.


RESULTS
At week 18, patients treated with sitaxsentan 100 mg had an increased 6MW distance compared with the placebo group (31.4 m, p = 0.03), and an improved WHO FC (p = 0.04). The placebo-subtracted treatment effect for sitaxsentan 50 mg was 24.2 m (p = 0.07) and for OL bosentan, 29.5 m (p = 0.05). The incidence of elevated hepatic transaminases (>3x the upper limit of normal) was 6% for placebo, 5% for sitaxsentan 50 mg, 3% for sitaxsentan 100 mg, and 11% for bosentan.


CONCLUSIONS
Treatment with the selective ET(A) receptor antagonist sitaxsentan, orally once daily at a dose of 100 mg, improves exercise capacity and WHO FC in PAH patients, with a low incidence of hepatic toxicity.
Barst
Robyn J
RJ
Department of Pediatrics, Columbia University Medical Center, New York, New York, USA. rjb3@columbia.edu
Langleben
David
D
Badesch
David
D
Frost
Adaani
A
Lawrence
E Clinton
EC
Shapiro
Shelley
S
Naeije
Robert
R
Galie
Nazzareno
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004417:Dyspnea / Q000188:drug therapy / Q000209:etiology; D065130:Endothelin A Receptor Antagonists; D005080:Exercise Test; D017079:Exercise Tolerance; D005260:Female; D006305:Health Status Indicators; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007555:Isoxazoles / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D013449:Sulfonamides / Q000627:therapeutic use; D013876:Thiophenes / Q000627:therapeutic use*; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D007555:Isoxazoles; D013449:Sulfonamides; D013876:Thiophenes; C106276:sitaxsentan; D000077300:Bosentan