EXTENDED REPORTS

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

Reda E Girgis¹, Adaani E Frost², Nicholas S Hill³, Evelyn M Horn⁴, David Langleben⁵, Vallerie V McLaughlin⁶, Ronald J Oudiz⁷, Ivan M Robbins⁸, James R Seibold⁶, Shelley Shapiro⁹, Victor F Tapson¹⁰, Robyn J Barst¹¹

¹ Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
² Baylor College of Medicine and the Methodist Hospital, Houston, Texas, USA
³ Tufts New England Medical Center, Boston, Massachusetts, USA
⁴ Department of Medicine, Columbia University College of Physicians and Surgeons, New York, USA
⁵ Sir Mortimer B Davis Jewish General Hospital, Montreal, Canada
⁶ University of Michigan Health System, Ann Arbor, Michigan, USA
⁷ Harbor-UCLA Medical Center, UCLA Geffen School of Medicine, Torrance, California, USA
⁸ Vanderbilt University Medical Center, Nashville, Tennessee, USA
⁹ VA Greater Los Angeles Healthcare System, UCLA Geffen School of Medicine, Los Angeles, California, USA
¹⁰ Duke University Medical Center, Durham, North Carolina, USA
¹¹ Department of Pediatric Cardiology, Columbia University College of Physicians and Surgeons, New York, USA

Robyn J Barst, MD, 3959 Broadway, BHN 2-255, New York, NY 10032 USA; rjb3{at}columbia.edu

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 ET_A receptor, in a cohort of patients with PAH and CTD. Short-term clinical and haemodynamic effects and longer-term follow-up 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.

Abbreviations: 6MWD, 6-minute walk distance; CI, Cardiac Index; CTD, connective tissue disease; ET, endothelin; ET_A, endothelin receptor isoform type A; ET_B, endothelin receptor isoform type B; IPAH, idiopathic pulmonary arterial hypertension; MCTD, mixed connective tissue disease; mPAP, mean pulmonary artery pressure; mRAP, mean right atrial pressure; NO, nitric oxide; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PCWPm, mean pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; SF-36, Short Form 36; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; STRIDE-1, Sitaxsentan to Relieve Impaired Exercise trial; STRIDE-1X, Sitaxsentan to Relieve Impaired Exercise extension trial; ULN, upper limit of the normal range

Keywords: endothelin; exercise capacity; hemodynamics; pulmonary hypertension; scleroderma

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