CLINICAL RESEARCH: PULMONARY HYPERTENSION
Long-Term Ambrisentan Therapy for the Treatment of Pulmonary Arterial Hypertension
Ronald J. Oudiz, MD*,*,
Nazzareno Galiè, MD ,
Horst Olschewski, 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,
Brooke C. Harrison, PhD,
Darrin Despain, MS,
Christopher Dufton, PhD,
Lewis J. Rubin, MD|||| for the ARIES Study Group
* LA Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California
Cardiology Institute, University of Bologna, Bologna, Italy
Medical University-Graz, Graz, Austria
University of Texas Southwestern Medical Center, Dallas, Texas
|| Baylor College of Medicine, Houston, Texas
¶ University of Giessen Lung Center, Giessen, Germany
# University of Colorado, Denver, Colorado
** Mayo Clinic, Rochester, Minnesota
University of Michigan, Ann Arbor, Michigan
University of Wisconsin, Madison, Wisconsin
Gilead Sciences, Inc., Boulder, Colorado
|||| UCSD, La Jolla, California
Manuscript received March 12, 2009;
revised manuscript received July 8, 2009,
accepted July 21, 2009.
* Reprint requests and correspondence: Dr. Ronald J. Oudiz, Harbor-UCLA Medical Center, Department of Medicine, Division of Cardiology, LA Biomedical Research Institute at Harbor-UCLA, 1124 West Carson Street #405, Torrance, California 90502-2006 (Email: roudiz{at}labiomed.org).
Objectives: This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH).
Background: Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH.
Methods: In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data.
Results: After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3x the upper limit of normal was  2% per year; most of these events were mild and did not lead to discontinuation of drug.
Conclusions: Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786)
Key Words: ambrisentan • exercise capacity • endothelin • hypertension • pulmonary • long-term survival
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Abbreviations and Acronyms
| | 6MWD = 6-min walk distance | | ALT = alanine aminotransferase | | AST = aspartate aminotransferase | | ERA = endothelin receptor antagonist | | ET = endothelin | | ETA
= endothelin receptor type A | | ETB
= endothelin receptor type B | | PAH = pulmonary arterial hypertension | | ULN = upper limit of normal | | WHO = World Health Organization |
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J. Am. Coll. Cardiol. 2009 54: A32.
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