Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension

Background: Pulmonary arterial hypertension (PAH) is a deadly disease with limited treatment options. Objectives: The objectives of this study were to assess the effects of bosentan, an orally active dual endothelin receptor antagonist, on exercise capacity and cardiopulmonary hemodynamics, as well as to assess its safety and tolerability in patients with severe PAH. Methods: In this double-blind, placebo-controlled, multicenter study, 32 patients with PAH (primary or associated with scleroderma) were randomized to receive bosentan for a minimum of 12 weeks (62.5 mg BID for 4 weeks, then 125 mg BID) or placebo. The primary end point was the change in exercise capacity. Secondary end points included changes in cardiopulmonary hemodynamics, Borg dyspnea index, and modified New York Heart Association (NYHA) functional class, as well as withdrawal due to clinical worsening. Results: Patients treated with bosentan improved their 6-minute walking distance. Fifteen bosentan-treated patients (71%) improved their walking distance from baseline to week 12 by >30 m, which is considered a clinically relevant improvement. The difference between treatment groups in the mean (±SEM) change at week 12 was 76 ± 31 m in favor of bosentan (95% CI, 12 to 139; P = 0.021). The improvement was maintained for at least 20 weeks. For cardiac index, the difference was 1.0 ± 0.2 L/min/m² in favor of bosentan (95% CI, 0.6 to 1.4; P < 0.001). Bosentan significantly decreased pulmonary vascular resistance, whereas it was increased with placebo (P ≤ 0.001). Bosentan improved both the Borg dyspnea index and the NYHA functional class. All 3 withdrawals due to clinical worsening were in the placebo group (P = 0.033). The number and nature of adverse events were similar in the 2 groups. Conclusions: In these patients with PAH, bosentan increased exercise capacity and improved hemodynamics. These results, which have been summarized previously in a brief report, include all data up to 28 weeks of treatment and support the potential clinical value of endothelin receptor antagonists in the treatment of patients with PAH.