title: Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.
abstract: BACKGROUND
  Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension.
  
  
  METHODS
  In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat.
  
  
  RESULTS
  In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups.
  
  
  CONCLUSIONS
  Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA, USA. rchannick@ucsd.edu
authors.forename: R N
authors.initials: RN
authors.lastname: Channick
authors.forename: G
authors.initials: G
authors.lastname: Simonneau
authors.forename: O
authors.initials: O
authors.lastname: Sitbon
authors.forename: I M
authors.initials: IM
authors.lastname: Robbins
authors.forename: A
authors.initials: A
authors.lastname: Frost
authors.forename: V F
authors.initials: VF
authors.lastname: Tapson
authors.forename: D B
authors.initials: DB
authors.lastname: Badesch
authors.forename: S
authors.initials: S
authors.lastname: Roux
authors.forename: M
authors.initials: M
authors.lastname: Rainisio
authors.forename: F
authors.initials: F
authors.lastname: Bodin
authors.forename: L J
authors.initials: LJ
authors.lastname: Rubin
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists; D015444:Exercise; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000150:complications; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan