title: Selective endothelin A receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease.
abstract: BACKGROUND
  Endothelin receptor antagonism has become an important component in the treatment of pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD). The purpose of this study was to analyse the safety and effectiveness of sitaxsentan, a selective antagonist of the ET(A) receptor, in a cohort of patients with PAH and CTD. Short-term clinical and haemodynamic effects and longer-term follow-up data are presented.
  
  
  METHODS
  A post hoc subgroup analysis was performed on 42 patients who had PAH associated with CTD, out of a group of 178 patients enrolled in a 12-week, double-blind, randomised clinical trial of sitaxsentan versus placebo. Data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily were pooled and compared with nine placebo-treated patients. There were 41 patients entered into the blinded extension study, in which all patients received either 100 mg or 300 mg sitaxsentan once daily.
  
  
  RESULTS
  Patients treated with sitaxsentan had a mean (SD) increase in 6 minute walk distance of 20 (5) m from baseline to week 12 (p = 0.037), whereas the placebo group had a decrease of 38 (84) m, resulting in a placebo-subtracted treatment effect of 58 m (p = 0.027). Parallel improvements in quality of life and haemodynamics were also observed. No patient discontinued their drug during the 12-week trial. In the blinded extension study (median treatment duration 26 weeks), more patients were in functional class I-II than in III-IV (p<0.001) at the end of the study compared with the start of active therapy. Elevation of hepatic transaminase levels occurred in two patients.
  
  
  CONCLUSIONS
  Sitaxsentan appears to be efficacious in patients with PAH associated with CTD.
authors.affiliation: Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
authors.forename: Reda E
authors.initials: RE
authors.lastname: Girgis
authors.forename: Adaani E
authors.initials: AE
authors.lastname: Frost
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.forename: Evelyn M
authors.initials: EM
authors.lastname: Horn
authors.forename: David
authors.initials: D
authors.lastname: Langleben
authors.forename: Vallerie V
authors.initials: VV
authors.lastname: McLaughlin
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Oudiz
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Robbins
authors.forename: James R
authors.initials: JR
authors.lastname: Seibold
authors.forename: Shelley
authors.initials: S
authors.lastname: Shapiro
authors.forename: Victor F
authors.initials: VF
authors.lastname: Tapson
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003240:Connective Tissue Diseases / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D013876:Thiophenes / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects; D016138:Walking
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D007555:Isoxazoles; D013876:Thiophenes; C106276:sitaxsentan