Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study

Background Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and s afety 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 pu lmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5 mg taken twice daily for 4 weeks then 125 mg tw ice daily) or placebo for a minimum of 12 weeks. The primary endpoint was c hange in exercise capacity. Secondary endpoints included changes in cardiop ulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and with drawal due to clinical worsening. Analysis was by intention to treat. Findings 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 t hose on placebo (difference 76 m [95% Cl 12-139], p = 0.021). The improveme nt was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1 ) m(-2) (95% Cl 0.6-1.4, p < 0.0001) greater in patients given bosentan tha n in those given placebo. Pulmonary vascular resistance decreased by 223 dy n s cm(-5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (d ifference -415 [-608 to -221], p = 0.0002). Patients given bosentan had a r educed 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 grou ps. Interpretation Bosentan increases exercise capacity and improves haemodynam ics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.