PURPOSE: In short term studies, Sitaxsentan, a selective endothelin-A receptor antagonist, has been shown to improve exercise capacity, functional class and pulmonary hemodynamic parameters in pulmonary arterial hypertension (PAH) patients. In this study, we aimed to determine the efficacy and safety of long-term Sitaxsentan monotherapy in PAH patients after 1 year of therapy.
METHODS: Design: Multicenter, open-label cohort, subgroup analysis.Setting: Six Canadian Pulmonary Hypertension Centers.Patients and Interventions: 49 patients (mean age 54 years, range 21-78) with WHO functional class I,II,III,IV (2,16,29,2) PAH (idiopathic, n=26; associated with congenital heart disease, n=9; or connective tissue disease, n=14) were treated with open-label Sitaxsentan in clinical trials and followed up to 1year. 16 of the 49 patients has previously discontinued bosentan therapy because of limited efficacy or hepatotoxicity. Long-term efficacy was assessed at 1 year by 6-min walk test (6MWT), WHO functional class, and time to clinical worsening.
RESULTS: After one year of monotherapy with Sitaxsentan, 6MWT improved by 21m(range -83 to +176m) from 364m at baseline. WHO functional class improved by 1 class in 15 subjects and declined by 1 class in 3 subjects. 29 subjects experienced 52 adverse events (edema 26%, headache 14%, and 10% nasal/sinus congestion), including 9 subjects with elevated AST/ALT, 4 of whom required discontinuation. 14 of 49 subjects discontinued after a mean 80 weeks sitaxsentan therapy for liver toxicity (n=4), death (n =2) due to pneumonia/sepsis or sudden death, worsening PAH (n=6), and subject decision (n=2). 35 subjects continue on Sitaxsentan monotherapy at 96 weeks (range 52-156).
CONCLUSION: Long-term sitaxsentan treatment over 1 year is associated with significant clinical and functional capacity benefit in PAH patients, and is generally well tolerated.
CLINICAL IMPLICATIONS: Long-term efficacy and safety data on Sitaxsentan monotherapy in PAH patients support previous short-term data. Sitaxsentan is an important therapeutic option in the growing armamentarium for the treatment of PAH patients.
DISCLOSURE: Abdullah Al-Harbi, No Product/Research Disclosure Information; University grant monies N/A; Grant monies (from sources other than industry) N/A; Grant monies (from industry related sources) Many authors (JTG, DH, DL, RDL, SP, SM) have received clinical research support from Actelion, Encysive, Glaxo-Smith-Kline, Gilead/Myogen, Lilly, Pfizer, and/or United Therapeutics; Shareholder N/A; Employee N/A; Fiduciary position (of any organization, association, society, etc, other than ACCP N/A; Consultant fee, speaker bureau, advisory committee, etc. Many authors (JTG, DH, DL, RDL, SP, SM) have served as either Consultants or members of Speakers’ Bureaus (Actelion, Encysive, Glaxo-Smith-Kline, Lilly, Pfizer, and/or United Therapeutics; Other N/A