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J Am Coll Cardiol, 2006; 47:2049-2056, doi:10.1016/j.jacc.2006.01.057 (Published online 20 April 2006).
© 2006 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: PULMONARY HYPERTENSION

Treatment of Pulmonary Arterial Hypertension With the Selective Endothelin-A Receptor Antagonist Sitaxsentan

Robyn J. Barst, MD*,1,*, David Langleben, MD{dagger},1, David Badesch, MD{ddagger},1, Adaani Frost, MD§,1, E. Clinton Lawrence, MD||,1, Shelley Shapiro, MD,1, Robert Naeije, MD#,1, Nazzareno Galie, MD**,1 on behalf of the STRIDE-2 Study Group

* Department of Pediatrics, Columbia University Medical Center, New York, New York
{dagger} Jewish General Hospital, Montreal, Quebec, Canada
{ddagger} University of Colorado, Denver, Colorado
§ Baylor College of Medicine, Houston, Texas
|| McKelvey Lung Transplantation Center, Emory University, Atlanta, Georgia
University of Southern California, Los Angeles, California
# Erasmus University, Brussels, Belgium
** Institute of Cardiology, University of Bologna, Bologna, Italy.

Manuscript received September 20, 2005; revised manuscript received December 23, 2005, accepted January 9, 2006.

* Reprint requests and correspondence: Dr. Robyn J. Barst, Columbia University College of Physicians and Surgeons, 3959 Broadway, BHN 2-255, New York, New York 10032. (Email: rjb3{at}columbia.edu).

OBJECTIVES: We sought to determine the optimal dose of the selective endothelin A (ETA) receptor antagonist sitaxsentan for the treatment of pulmonary arterial hypertension (PAH); for observation only, an open-label (OL) bosentan arm was included.

BACKGROUND: Endothelin is a mediator of PAH. In a preliminary PAH study, the selective ETA receptor antagonist sitaxsentan improved six-min walk (6MW) distance, World Health Organization (WHO) functional class (FC), and hemodynamics.

METHODS: In this double-blind, placebo-controlled 18-week study, 247 PAH patients (idiopathic, or associated with connective tissue disease or congenital heart disease) were randomized; 245 patients were treated: placebo (n = 62), sitaxsentan 50 mg (n = 62) or 100 mg (n = 61), or OL (6MW tests, Borg dyspnea scores, and WHO FC assessments third-party blind) bosentan (n = 60). The primary end point was change in 6MW distance from baseline to week 18. Secondary end points included change in WHO FC, time to clinical worsening, and change in Borg dyspnea score.

RESULTS: At week 18, patients treated with sitaxsentan 100 mg had an increased 6MW distance compared with the placebo group (31.4 m, p = 0.03), and an improved WHO FC (p = 0.04). The placebo-subtracted treatment effect for sitaxsentan 50 mg was 24.2 m (p = 0.07) and for OL bosentan, 29.5 m (p = 0.05). The incidence of elevated hepatic transaminases (>3x the upper limit of normal) was 6% for placebo, 5% for sitaxsentan 50 mg, 3% for sitaxsentan 100 mg, and 11% for bosentan.

CONCLUSIONS: Treatment with the selective ETA receptor antagonist sitaxsentan, orally once daily at a dose of 100 mg, improves exercise capacity and WHO FC in PAH patients, with a low incidence of hepatic toxicity.

Abbreviations and Acronyms
  ALT = alanine aminotransferase
  ANCOVA = analysis of covariance
  AST = aspartate aminotransferase
  DSMB = Data Safety Monitoring Board
  ET = endothelin
  FC = functional class
  INR = international normalized ratio
  ITT = intent-to-treat
  OL = open label
  PAH = pulmonary arterial hypertension
  6MW = six-min walk
  STRIDE = Sitaxsentan To Relieve ImpaireD Exercise study
  ULN = upper limit of normal
  WHO = World Health Organization




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