Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease

Introduction: 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 ETA receptor, in a cohort of patients with PAH and CTD. Short- term clinical and haemodynamic effects and longer- term followup 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.