NEW YORK, NY—Selective blocking of the endothelin_A receptor appears to be as effective as  blocking both receptor isoforms and may be a safer alternative for treating pulmonary arterial hypertension (PAH) in patients with connective tissue disease (CTD), Reda E. Girgis, MD, and colleagues report in Annals of the Rheumatic Diseases.¹ The selective endothelin_A receptor antagonist sitaxsentan (Thelin®, Encysive Pharmaceuticals) did not meet the primary endpoint of improving peak oxygen uptake on cycle ergometry for patients in the STRIDE (Sitaxsentan to Relieve Impaired Exercise)-1 trial but the drug did enable the subgroup of PAH and CTD patients to add 20 meters to the 6-minute walk distance (6MWD).

This might add a much-needed alternative for this subgroup. "Currently available therapies for PAH have had variable short-term efficacy in the CTD population, with long-term outcomes less than ideal. Despite aggressive treatment, 3-year survival rate in systemic sclerosis and scleroderma-related PAH is ~50%," says Dr. Girgis, at Johns Hopkins University School of Medicine, in Baltimore, Maryland.

Treatment enables PAH patients to walk farther

This posthoc subgroup analysis included 42 patients from the STRIDE-1 trial who had PAH associated with CTD. The researchers pooled data from 33 patients assigned to sitaxsentan 100 mg or 300 mg daily and compared the results with nine placebo-treated patients. In a blinded extension study, 41 patients received either sitaxsentan 100 mg or 300 mg a day and CTD diagnosis included scleroderma, systemic lupus erythematosus, mixed connective tissue disease, or overlap syndrome. Peak oxygen uptake on cycle ergometry was not analyzed separately as a primary outcome in this CTD subgroup. Secondary endpoints included change in 6MWD, New York Heart Association functional class, quality of life as measured by the SF-36 questionnaire, and hemodynamics from baseline to week 12.

Sitaxsentan-treated patients walked an additional 20 meters in the 6MWD after 12 weeks of daily treatment, whereas placebo patients walked 38 fewer meters (P = .0037). The researchers also observed significant improvements in quality of life in sitaxsentan-treated patients. Two patients had elevated hepatic levels during treatment, one of whom (on the 300 mg dose) had to stop treatment. The researchers note that a subsequent 18-week trial "has confirmed a low incidence of transaminase elevation with the 100 mg/day dose, and preliminary day from a 1-year extension of this study support the long-term safety of this dosage in patients with PAH and CTD."

Sitaxsentan is currently undergoing phase III trials in the US. It has been approved for PAH treatment in Canada, Australia, and the European Union.



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