Sitaxsentan for treatment of pulmonary hypertension

OBJECTIVE: To review the literature pertinent to the efficacy and safety of sitaxsentan, a selective endothelin (ET)-A receptor antagonist under evaluation for the treatment of pulmonary arterial hypertension (PAH). DATA SOURCES: Articles were identified through searches of the MEDLINE (1966-November 2006) and International Pharmaceutical Abstracts (1970-November 2006) databases, using the key words endothelin antagonist, pulmonary arterial hypertension, pulmonary hypertension, sitaxsentan, and TBC11251. Searches were limited to articles published in English. STUDY SELECTION AND DATA EXTRACTION: Due to the limited number of articles on sitaxsentan, all studies captured in the search results were evaluated. DATA SYNTHESIS: Four studies of sitaxsentan in humans with PAH have been published to date. An uncontrolled open-label study and a randomized placebo-controlled study (STRIDE-1; Sitaxsentan to Relieve Impaired Exercise-1) showed sitaxsentan to improve exercise tolerance in patients with PAH, as evidenced by significant increases in the distance walked in 6 minutes. Significant hepatotoxicity developed in patients receiving sitaxsentan 300 mg. The benefits of sitaxsentan with respect to exercise tolerance and hemodynamics were sustained in a one year extension of the placebo-controlled study. The results of a multicenter, randomized, placebo-controlled trial of 2 doses of sitaxsentan with an open-label bosentan arm (STRIDE-2) suggested that only the 100 mg dose provided superior benefit in exercise tolerance and improvement in functional class. Treatment-related effects were similar for all groups. CONCLUSIONS: Sitaxsentan appears to be superior to placebo in improving exercise tolerance in patients with PAH but may produce therapeutic outcomes similar to those of bosentan, a comparator agent. The optimal dose of sitaxsentan appears to be 100 mg once daily. Information about the use of sitaxsentan in a greater number of patients with PAH for longer periods is necessary to further define its place in the treatment of PAH.