Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan

J Am Coll Cardiol. 2006 May 16;47(10):2049-56. doi: 10.1016/j.jacc.2006.01.057. Epub 2006 Apr 24.


Objectives: 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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antihypertensive Agents / therapeutic use*
  • Bosentan
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Dyspnea / drug therapy
  • Dyspnea / etiology
  • Endothelin A Receptor Antagonists*
  • Exercise Test
  • Exercise Tolerance
  • Female
  • Health Status Indicators
  • Hemodynamics
  • Humans
  • Hypertension, Pulmonary / complications
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / physiopathology
  • Isoxazoles / therapeutic use*
  • Male
  • Middle Aged
  • Risk Assessment
  • Sulfonamides / therapeutic use
  • Thiophenes / therapeutic use*
  • Treatment Outcome


  • Antihypertensive Agents
  • Endothelin A Receptor Antagonists
  • Isoxazoles
  • Sulfonamides
  • Thiophenes
  • sitaxsentan
  • Bosentan