title: Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions.
abstract: BACKGROUND
  Endothelin-1 is considered to be a central pathogenic factor in connective tissue diseases (CTDs) such as systemic sclerosis (SSc), leading to vasoconstriction, fibrosis, hypertrophy and inflammation. A frequent complication of CTD is pulmonary arterial hypertension (PAH), which has a major effect on functioning and quality of life, and is associated with a particularly poor prognosis.
  
  
  OBJECTIVE
  To present a subgroup analysis that summarises experiences from the pivotal studies and their open-label extensions with the oral dual endothelin-1 receptor antagonist bosentan in patients with PAH and CTD, mostly SSc and lupus erythematosus.
  
  
  METHODS
  66 patients with PAH secondary to CTD, in World Health Organization functional class III or IV, were randomised to two double-blind, placebo-controlled studies and followed up for 12 and 16 weeks, respectively. The primary end point was change in exercise capacity, assessed using the 6-min walk test. In both studies and their extensions, survival was assessed from start of treatment to death or data cut-off and analysed as Kaplan-Meier estimates.
  
  
  RESULTS
  44 patients with PAH secondary to CTD who were treated with bosentan were stable in 6-min walk distance at the end of the study (+19.5 m, 95% confidence interval (CI) -3.2 to 42.2), whereas patients treated with placebo deteriorated (-2.6 m, 95% CI -54.0 to 48.7). 64 patients subsequently received bosentan in an open-label long-term extension study. Mean (standard deviation (SD)) exposure to bosentan was 1.6 (0.9) years, and duration of observation was 1.8 (0.8) years. 8 (16%) patients received epoprostenol as add-on treatment and 7 (14%) after discontinuation of bosentan. Survival in those receiving bosentan was 85.9% after 1 year and 73.4% after 2 years.
  
  
  CONCLUSIONS
  Short-term bosentan treatment in a subgroup of patients with PAH secondary to CTD seems to have a favourable effect compared with placebo. The long-term follow-up of these patients suggests that first-line bosentan, with the subsequent addition of other PAH treatments if required, is safe for long-term treatment and may have a positive effect on outcome.
authors.affiliation: Centre for Rheumatology, Royal Free Hospital, Pond Street, London, NW3 2QG, UK. c.denton@medsch.ucl.ac.uk
authors.forename: C P
authors.initials: CP
authors.lastname: Denton
authors.forename: M
authors.initials: M
authors.lastname: Humbert
authors.forename: L
authors.initials: L
authors.lastname: Rubin
authors.forename: C M
authors.initials: CM
authors.lastname: Black
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000077300:Bosentan; D003240:Connective Tissue Diseases / Q000150:complications*; D065130:Endothelin A Receptor Antagonists; D004812:Epidemiologic Methods; D017079:Exercise Tolerance; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008180:Lupus Erythematosus, Systemic / Q000150:complications; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000150:complications; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan