Sitaxsentan for the treatment of pulmonary arterial hypertension: a 1-year, prospective, open-label observation of outcome and survival.
BACKGROUND
Despite advances in the management of pulmonary arterial hypertension (PAH), the mortality rate remains excessive. Long-term efficacy evaluations are needed to guide therapeutic management. The purpose of this study is to present 1-year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study.


METHODS
The 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 at 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.


RESULTS
Patients treated with sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening event by 1 year. In addition, there was a 6% risk of elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels > 3 x upper limit of normal range (ULN) at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan had 88% overall survival and a 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk for elevated AST and/or ALT levels > 3 x ULN at 1 year and a 30% risk of discontinuation due to adverse events.


CONCLUSIONS
At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy.
Benza
Raymond L
RL
University of Alabama at Birmingham, Birmingham, AL. Electronic address: rbenza@wpahs.org.
Barst
Robyn J
RJ
Columbia University College of Physicians and Surgeons, New York, NY.
Galie
Nazzareno
N
Cardiology Institute, University of Bologna, Bologna, Italy.
Frost
Adaani
A
Baylor College of Medicine, Houston, TX.
Girgis
Reda E
RE
Johns Hopkins University, School of Medicine, Baltimore, MD.
Highland
Kristin B
KB
Department of Medicine, Medical University of South Carolina, Charleston, SC.
Strange
Charlie
C
Department of Medicine, Medical University of South Carolina, Charleston, SC.
Black
Carol M
CM
Royal College of Physicians of London, London, UK.
Badesch
David B
DB
University of Colorado Health Sciences Center, Denver, CO.
Rubin
Lewis
L
University of California, San Diego Medical Center, La Jolla, CA.
Fleming
Thomas R
TR
University of Washington, Seattle, WA.
Naeije
Robert
R
Erasmus University Brussels, Brussels, Belgium.
D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015996:Survival Rate; D013876:Thiophenes / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D065128:Endothelin Receptor Antagonists; D007555:Isoxazoles; D013876:Thiophenes; C106276:sitaxsentan