Sitaxsentan for the Treatment of Pulmonary Arterial Hypertension

A 1-Year, Prospective, Open-Label Observation of Outcome and Survival


      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.


      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.


      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 × 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 × ULN at 1 year and a 30% risk of discontinuation due to adverse events.


      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.

      Key words


      ALT (alanine aminotransferase), AST (aspartate aminotransferase), CI (confidence interval), ET (endothelin), ETRA (endothelin-receptor antagonist), IPAH (idiopathic pulmonary arterial hypertension), PAH (pulmonary arterial hypertension), PAH-CHD (pulmonary arterial hypertension associated with congenital heart defect), PAH-CTD (pulmonary arterial hypertension associated with connective tissue disease), 6MWD (6-min walk distance), STRIDE (Sitaxsentan To Relieve Impaired Exercise), ULN (upper limit of normal range), WHO (World Health Organization)
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        • Farber HW
        • Loscalzo J
        Pulmonary arterial hypertension.
        N Engl J Med. 2004; 351: 1655-1665
        • Humbert M
        • Sitbon O
        • Simonneau G
        Treatment of pulmonary arterial hypertension.
        N Engl J Med. 2004; 351: 1425-1436
        • McLaughlin VV
        • Presberg KW
        • Doyle RL
        • et al.
        Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.
        Chest. 2004; 126: 78S-92S
        • Provencher S
        • Sitbon O
        • Humbert M
        • et al.
        Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension.
        Eur Heart J. 2006; 27: 589-595
        • Motte S
        • McEntee K
        • Naeije R
        Endothelin receptor antagonists.
        Pharmacol Ther. 2006; 110: 386-414
        • Nishida M
        • Eshiro K
        • Okada Y
        • et al.
        Roles of endothelin ETA and ETB receptors in the pathogenesis of monocrotaline-induced pulmonary hypertension.
        J Cardiovasc Pharmacol. 2004; 44: 187-191
        • Barst RJ
        • Langleben D
        • Badesch D
        • et al.
        Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan.
        J Am Coll Cardiol. 2006; 47: 2049-2056
        • Actelion
        Tracleer (bosentan) prescribing information, updated August 2004.
        (Accessed March 5, 2007)
        • Humbert M
        • Segal ES
        • Kiely DG
        • et al.
        Results of European post-marketing surveillance of bosentan in pulmonary hypertension.
        Eur Respir J. 2007; 30: 338-344
        • Barst RJ
        • Langleben D
        • Frost A
        • et al.
        Sitaxsentan therapy for pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2004; 169: 441-447
        • Benza RL
        • Mehta S
        • Keogh A
        • et al.
        Sitaxsentan treatment for patients with pulmonary arterial hypertension discontinuing bosentan.
        J Heart Lung Transplant. 2007; 26: 63-69
        • McLaughlin VV
        • Sitbon O
        • Badesch DB
        • et al.
        Survival with first-line bosentan in patients with primary pulmonary hypertension.
        Eur Respir J. 2005; 25: 244-249
        • Sitbon O
        • McLaughlin VV
        • Badesch DB
        • et al.
        Survival in patients with class III idiopathic pulmonary arterial hypertension treated with first line oral bosentan compared with an historical cohort of patients started on intravenous epoprostenol.
        Thorax. 2005; 60: 1025-1030
        • Denton CP
        • Humbert M
        • Rubin L
        • et al.
        Bosentan therapy for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions.
        Ann Rheum Dis. 2006; 65: 1336-1340
        • Girgis RE
        • Mathai SC
        • Krishnan JA
        • et al.
        Long-term outcome of bosentan treatment in idiopathic pulmonary arterial hypertension and pulmonary arterial hypertension associated with the scleroderma spectrum of diseases.
        J Heart Lung Transplant. 2005; 24: 1626-1631
        • Williams MH
        • Das C
        • Handler CE
        • et al.
        Systemic sclerosis associated pulmonary hypertension: improved survival in the current era.
        Heart. 2006; 92: 926-932
        • Channick RN
        • Sitbon O
        • Barst RJ
        • et al.
        Endothelin receptor antagonists in pulmonary arterial hypertension.
        J Am Coll Cardiol. 2004; 43: 62S-67S
        • Provencher S
        • Jais X
        • Yaici A
        • et al.
        Clinical challenges in pulmonary hypertension: Roger S. Mitchell lecture.
        Chest. 2005; 128: 622S-628S
        • Hoeper MM
        • Markevych I
        • Spiekerkoetter E
        • et al.
        Goal-oriented treatment and combination therapy for pulmonary arterial hypertension.
        Eur Respir J. 2005; 26: 858-863
        • McLaughlin VV
        • Oudiz RJ
        • Frost A
        • et al.
        Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2006; 174: 1257-1263
      1. Simmoneau G, Burgess G, Collings L, et al. Safety and efficacy of combination therapy with sildenafil and epoprostenol in patients with pulmonary arterial hypertension. Proceedings of the American Thoracic Society 2006 International Conference. San Diego, CA, May 19–24, 2006; A58

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      • Correction: Chest 2008; 134:775–782
        CHESTVol. 135Issue 4
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          In the October 2008 issue, in the article by Benza et al, “Sitaxsentan for the Treatment of Pulmonary Arterial Hypertension: A 1-Year, Prospective, Open-Label Observation of Outcome and Survival” (Chest 2008; 134:775–782), CHEST inadvertently omitted the conflicts of interest statements for the authors. CHEST regrets the omission. They are as follows: Dr. Barst has received grants, been a consultant for and/or has participated in speaking activities for Actelion, Encysive, Gilead, Pfizer, Novartis, United Therapeutics, GlazoSmithKline, and INO.
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