Sitaxsentan Treatment for Patients With Pulmonary Arterial Hypertension Discontinuing Bosentan Raymond L. Benza, MD, a Sanjay Mehta, MD, b Anne Keogh, MD, c E. Clinton Lawrence, MD, d Ronald J. Oudiz, MD, e and Robyn J. Barst, MD f Background: Bosentan, an oral ET A /ET B receptor antagonist, is approved for the treatment of pulmonary arterial hypertension (PAH). However, some patients discontinue bosentan because of hepatotoxicity or inadequate efficacy. Sitaxsentan, an oral, ET A -selective endothelin antagonist currently under investigation, may be an alternative treatment option. In this study we evaluate the safety and efficacy of sitaxsentan in patients discontinuing bosentan. Methods: Forty-eight patients with idiopathic PAH or PAH associated with connective-tissue disease or congenital heart disease were randomized (double-blind) to a single daily dose of either 50 mg or 100 mg sitaxsentan. Thirty-five of the 48 patients discontinued bosentan because of inadequate efficacy, as judged by the investigator, and 13 discontinued bosentan for safety concerns. Study end-points included change in 6-minute walk distance (6MWD), change in World Health Organiza- tion (WHO) functional class, time to clinical worsening, and change in Borg dyspnea score (Borg) from baseline to Week 12. Results: With 100 mg sitaxsentan, 5 of 15 patients (33%) who discontinued bosentan because inadequate efficacy improved, demonstrating a 15% increase in 6MWD, vs 2 of 20 patients (10%) treated with 50 mg sitaxsentan. Fifteen percent and 20% of these patients had a 15% decrease in 6MWD in the 50- and 100-mg groups, respectively. Similar results were seen for the Borg and WHO functional class. Of the 12 patients discontinuing bosentan because of hepatotoxicity, 1 developed elevated liver enzymes at 13 weeks of sitaxsentan therapy. Overall, sitaxsentan was well tolerated. Conclusions: Sitaxsentan may represent a safe and efficacious alternative endothelin receptor antagonist for patients discontinuing bosentan. J Heart Lung Transplant 2007;26:63–9. Copyright © 2007 by the International Society for Heart and Lung Transplantation. Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance, resulting in right-heart failure and death. 1 Endothelial dysfunction contributes to the development of PAH through an imbalance between vasodilator/anti- proliferative mediators, such as prostacyclin, and vaso- constrictor/proliferative mediators, such as endothe- lin-1 (ET-1). 2–8 Secreted by vascular endothelial cells, ET-1 plays a key role in the functional changes observed in PAH, including vascular remodeling in small pulmonary arter- ies. 9,10 The pulmonary circulation is a major site for both the production and clearance of ET-1. 11 ET-1 is overexpressed in PAH patients, providing a rationale for targeting ET-1 receptors with endothelin receptor an- tagonists (ETRAs). 12–15 Previous PAH clinical trials with ETRAs demonstrated improvements in exercise capac- ity, WHO functional class and hemodynamic parame- ters. 16 –21 The actions of ET-1 are mediated by two receptors: ET A and ET B . 9,22 Activation of ET A and ET B receptors located on vascular smooth muscle cells leads to vaso- constriction, cell proliferation and hypertrophy. 23–28 In contrast, activation of ET B receptors located predomi- nantly on endothelial cells increases nitric oxide and prostacyclin, with attendant vasodilator and anti-prolif- erative effects. 29 In addition, binding to endothelial ET B receptors represents the primary clearance mechanism for ET-1, particularly in pulmonary and renal vascular beds. 30 –32 Bosentan, the only ETRA approved for treatment of PAH, blocks both ET A and ET B receptors. Bosentan From the a Division of Cardiology, University of Alabama at Birming- ham, Birmingham, Alabama; b Centre for Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada; c University of New South Wales, Darlinghurst, Sydney, Australia; d Emory Univer- sity School of Medicine, Atlanta, Georgia; e Los Angeles Biomedical Research Institute at Harbor–UCLA Medical Center, Torrance, Califor- nia; and f Columbia University College of Physicians and Surgeons, New York, New York. Supported by Encysive Pharmaceuticals, Houston, Texas. Reprint requests: Raymond L. Benza, MD, Division of Cardiology, University of Alabama at Birmingham, THT328A, 1530 Third Avenue South, Birmingham, AL 35294-0006. Tel: 205-934-3438. Fax: 205-975- 9320. E-mail: rbenza@uab.edu Copyright © 2007 by the International Society for Heart and Lung Transplantation. 1053-2498/07/$–see front matter. doi:10.1016/ j.healun.2006.10.019 63 PULMONARY HYPERTENSION