Published Online
on May 27, 2008

A more recent version of this article appeared on June 10, 2008

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Submitted on September 27, 2007
Accepted on March 25, 2008

Ambrisentan for the Treatment of Pulmonary Arterial Hypertension. Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES) Study 1 and 2

Nazzareno Galiè MD^*, Horst Olschewski MD, Ronald J. Oudiz MD, Fernando Torres MD, Adaani Frost MD, Hossein A. Ghofrani MD, David B. Badesch MD, Michael D. McGoon MD, Vallerie V. McLaughlin MD, Ellen B. Roecker PhD, Michael J. Gerber MD, Christopher Dufton PhD, Brian L. Wiens PhD, Lewis J. Rubin MD, for the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group

From the Institute of Cardiology, Università di Bologna, Bologna, Italy (N.G.); Medical University Graz, Graz, Austria (H.O.); Los Angeles Biomedical Research Institute at Harbor–UCLA, Torrance, Calif (R.J.O.); University of Texas Southwestern Medical Center, Dallas (F.T.); Baylor College of Medicine, Houston, Tex (A.F.); University Hospital, Justus-Liebig-University, Giessen, Germany (H.A.G.); University of Colorado Health Sciences Center, Denver (D.B.B.); Mayo Clinic College of Medicine, Rochester, Minn (M.D.M.); University of Michigan Health System, Ann Arbor (V.V.M.); University of California at San Diego, La Jolla (L.J.R.); University of Wisconsin, Madison (E.R.); and Gilead Sciences, Westminster, Colo (M.J.G, C.D., B.L.W.).

^* To whom correspondence should be addressed. E-mail: nazzareno.galie{at}unibo.it.

Background—Ambrisentan is a propanoic acid–based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension.

Methods and Results—Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m.

Conclusions—Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Key words: ambrisentan • drugs • endothelin • hypertension, pulmonary • receptors

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