Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension.
OBJECTIVE
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 approximately 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).
Oudiz
Ronald J
RJ
LA Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA. roudiz@labiomed.org
Galiè
Nazzareno
N
Olschewski
Horst
H
Torres
Fernando
F
Frost
Adaani
A
Ghofrani
Hossein A
HA
Badesch
David B
DB
McGoon
Michael D
MD
McLaughlin
Vallerie V
VV
Roecker
Ellen B
EB
Harrison
Brooke C
BC
Despain
Darrin
D
Dufton
Christopher
C
Rubin
Lewis J
LJ
D000284:Administration, Oral; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000008:administration & dosage*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011724:Pyridazines / Q000008:administration & dosage*; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D016896:Treatment Outcome
D010666:Phenylpropionates; D011724:Pyridazines; C467894:ambrisentan