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Sitaxsentan for the Treatment of Pulmonary Arterial Hypertension: A One Year, Prospective, Open Label, Observation of Outcome and Survival

^a University of Alabama at Birmingham, Birmingham, AL ^b Columbia University College of Physicians and Surgeons, New York, NY ^c Cardiology Institute, University of Bologna, Bologna, Italy ^d Baylor College of Medicine, Houston, TX, United States ^e Johns Hopkins University, School of Medicine, Baltimore, MD ^f Department of Medicine, Medical University of South Carolina, Charleston, SC ^g Department of Medicine, Medical University of South Carolina, Charleston, SC ^h President, Royal College of Physicians of London, London, England ⁱ University of Colorado Health Sciences Center, Denver, CO ^j University of California, San Diego Medical Center, La Jolla, CA ^k University of Washington, Seattle, WA ^l Erasmus University Brussels, Brussels, Belgium

rbenza{at}uab.edu

Abstract

BackgroundDespite advances in the management of pulmonary arterial hypertension, mortality remains excessive. In light of this, long term efficacy evaluations are needed to guide therapeutic management. The purpose of the current study is to present one year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study.

MethodsThe present study was a prospective, international, multicenter, randomized, open-label extension of the Sitaxsentan To Relieve ImpaireD Exercise-2 trial. All cause mortality, time to discontinuation (all causes) from monotherapy, time to discontinuation due to adverse events, time to elevations in and time to discontinuation due to elevated hepatic transaminases, and time to first clinical worsening event were evaluated. Patients initially receiving sitaxsentan 50 mg were excluded from the main analysis. The distributions of time-to-event variables are estimated using Kaplan-Meier methods and treatment effects are evaluated using the Cox proportional hazards model.

ResultsPatients treated with sitaxsentan 100 mg had 96% overall survival and 34% risk of experiencing a clinical worsening event by 1 year. In addition, there was a 6% risk of developing elevated AST and/or ALT > 3 x ULN at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan experienced 88% overall survival and 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk of developing elevated AST and/or ALT > 3 x ULN at 1 year and a 30% risk of discontinuation due to adverse events.

ConclusionsAt one year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk of experiencing clinical worsening events provide support for durability of efficacy.

Key Words: Pulmonary Arterial Hypertension • endothelin antagonists • bosentan • sitaxsentan