Chest 2005: Sitaxsentan more effective than bosentan as PAH therapy

Sitaxsentan, a highly selective endothelin-A (ET-A) receptor antagonist undergoing FDA review as an alternative to bosentan for pulmonary arterial hypertension (PAH) treatment, demonstrated improved efficacy over bosentan in a recent study.

"Sitaxsentan is 6,500 times more selective for the ET-A receptor than bosentan," said David Langleben, MD, Professor of Medicine, McGill University, Montreal, Quebec, Canada during the 71st annual scientific meeting of the American College of Chest Physicians.

Sitaxsentan requires once-daily dosing and ongoing trials have demonstrated it may be especially beneficial for patients with PAH due to connective tissue disease, researchers reported.

Overall, patients taking the 100 mg dose (n=115) had significantly greater time to clinical worsening (P=.0345) than those taking placebo (n=119). Clinical worsening was defined as death, transplantation, epoprostenol use, or atrial septostomy in one trial and as death, transplantation, atrial septostomy, additon of a new chronic PAH treatment, hospitalization for worsening PAH, or a combined deterioration in WHO functional class and $15% decrease from baseline in 6-minute walk distance in the second.

In addition, interim results of a 1-year, phase 3 extension study randomizing 145 patients to 100 mg sitaxsentan once daily or 125 mg bosentan twice daily demonstrated significantly fewer liver function abnormalities in the sitaxsentan group (P=.014).

James Seibold, MD, director, University of Michigan Scleroderma Program, Ann Arbor, Mich, presented results seen in 110 patients with PAH due to connective tissue disease included in placebo-controlled sitaxsentan trials. A total of 63 had systemic sclerosis, 25 had systemic lupus erythematosis, and 22 had other connective tissue diseases. Patients with a total lung capacity of less than 80% or a 6-minute walk distance greater than 450 m at baseline were excluded.

Dr Seibold reported that patients taking the 100-mg dose of sitaxsentan demonstrated a 21-m improvement in 6-minute walk distance after 6 weeks of therapy and the improvement was sustained through 18 weeks (P=.042).

Sitaxsentan also appeared improve New York Heart Association (NYHA) functional class among connective tissue disease patients with PAH. In one long-term extension study, 42 of 178 PAH patients were identified with connective tissue disease and NYHA Class II or III heart failure at baseline. After up to 55 weeks treatment with either 100 or 300 mg sitaxsentan, 65% of patients taking the 100-mg dose and 43% of patients taking the 300 mg dose demonstrated improvement in functional class.

Among those in the 100-mg group, 70% had Class III and 30% had Class II heart failure at baseline. At the end of the study, 40% had Class III, 55% had Class II, and 5% had Class I heart failure.