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PULMONARY HYPERTENSION

Ambrisentan Therapy for Pulmonary Arterial Hypertension

Nazzareno Galié, MD^_*,_*, David Badesch, MD, Ronald Oudiz, MD, Gérald Simonneau, MD, Michael D. McGoon, MD^||, Anne M. Keogh, MD^¶, Adaani E. Frost, MD^#, Diane Zwicke, MD^**, Robert Naeije, MD, Shelley Shapiro, MD, PhD, Horst Olschewski, MD and Lewis J. Rubin, MD^||||

^_* University of Bologna, Bologna, Italy
University of Colorado Health Science Center, Denver, Colorado
Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California
Hôpital Antoine Béclère, Clamart, France
^|| Mayo Clinic College of Medicine, Rochester, Minnesota
^¶ Saint Vincent's Hospital, Darlinghurst, Australia
^# Baylor College of Medicine and the Methodist Hospital, Houston, Texas
^** St. Luke's/Aurora Sinai Medical Centers, University of Wisconsin Medical School–Milwaukee Clinical Campus, Milwaukee, Wisconsin
Erasmus University, Brussels, Belgium
University of Southern California, Keck School of Medicine, Los Angeles, California
University Giessen Lung Center, Giessen, Germany
^|||| University of California-San Diego, San Diego, California

Manuscript received December 3, 2004; revised manuscript received March 24, 2005, accepted April 14, 2005.

^_* Reprint requests and correspondence: Prof. Nazzareno Galié, Institute of Cardiology, University of Bologna, Via Massarenti 9, Bologna, Italy 40138 (Email: n.galie{at}bo.nettuno.it).

OBJECTIVES: The purpose of this study was to examine the efficacy and safety of four doses of ambrisentan, an oral endothelin type A receptor-selective antagonist, in patients with pulmonary arterial hypertension (PAH).

BACKGROUND: Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options. Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH.

METHODS: In this double-blind, dose-ranging study, 64 patients with idiopathic PAH or PAH associated with collagen vascular disease, anorexigen use, or human immunodeficiency virus infection were randomized to receive 1, 2.5, 5, or 10 mg of ambrisentan once daily for 12 weeks followed by 12 weeks of open-label ambrisentan. The primary end point was an improvement from baseline in 6-min walk distance (6MWD); secondary end points included Borg dyspnea index, World Health Organization (WHO) functional class, a subject global assessment, and cardiopulmonary hemodynamics.

RESULTS: At 12 weeks, ambrisentan increased 6MWD (+36.1 m, p < 0.0001) with similar and statistically significant increases for each dose group (range, +33.9 to +38.1 m). Improvements were also observed in Borg dyspnea index, WHO functional class, subject global assessment, mean pulmonary arterial pressure (–5.2 mm Hg, p < 0.0001), and cardiac index (+0.33 l/min/m², p < 0.0008). Adverse events were mild and unrelated to dose, including the incidence of elevated serum aminotransferase concentrations >3 times the upper limit of normal (3.1%).

CONCLUSIONS: Ambrisentan appears to improve exercise capacity, symptoms, and hemodynamics in patients with PAH. The incidence and severity of liver enzyme abnormalities appear to be low.

Abbreviations and Acronyms   6MWD = 6-min walk distance   ERA = endothelin receptor antagonist   ET = endothelin   IPAH = idiopathic pulmonary arterial hypertension   mPAP = mean pulmonary arterial pressure   PAH = pulmonary arterial hypertension   PCWP = pulmonary capillary wedge pressure   PVR = pulmonary vascular resistance   WHO = World Health Organization

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