Sitaxsentan Therapy for Pulmonary Arterial Hypertension

TLDR

Sitaxsentan may benefit pulmonary arterial hypertension patients by blocking endothelin‑A vasoconstriction while preserving endothelin‑B vasodilatory and clearance functions. In a 12‑week randomized trial of idiopathic, connective‑tissue‑disease, or congenital‑heart‑disease PAH patients, participants received placebo, sitaxsentan 100 mg, or 300 mg daily, with the primary endpoint being change in peak VO₂ at week 12 and secondary endpoints including 6‑minute walk, NYHA class, VO₂ at anaerobic threshold, VE/CO₂, hemodynamics, quality of life, and time to clinical worsening. The 300‑mg group showed a significant increase in peak VO₂ (+3.1 %, p < 0.01) versus placebo, but other exercise‑testing endpoints were not met; both 100‑mg and 300‑mg doses improved 6‑minute walk (+35 m and +33 m, respectively), functional class, cardiac index, and pulmonary vascular resistance (p < 0.02), while elevated aminotransferases occurred in 3 % of placebo, 0 % of 100‑mg, and 10 % of 300‑mg patients.

Abstract

Sitaxsentan may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictor effects of endothelin-A while maintaining the vasodilator/clearance functions of endothelin-B receptors. Patients with pulmonary arterial hypertension that was idiopathic, related to connective tissue disease or congenital heart disease, were randomized to receive placebo (n = 60), sitaxsentan 100 mg (n = 55), or sitaxsentan 300 mg (n = 63) orally once daily for 12 weeks. The primary endpoint was change in peak VO(2) at Week 12. Secondary endpoints included 6-minute walk, New York Heart Association class, VO(2) at anaerobic threshold, VE per carbon dioxide production at anaerobic threshold, hemodynamics, quality of life, and time to clinical worsening. Although the 300-mg group increased peak VO(2) compared with placebo (+3.1%, p < 0.01), none of the other endpoints derived from cardiopulmonary exercise testing were met. However, both the 100-mg dose and the 300-mg dose, compared with placebo, increased 6-minute walk distance (100 mg: +35 m, p < 0.01; 300 mg: +33 m, p < 0.01); functional class, cardiac index, and pulmonary vascular resistance also improved (p < 0.02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group.