PURPOSE: Ambrisentan is a high affinity, propanoic acid-class, ETA-selective endothelin receptor antagonist (ERA) with once-daily oral doses. Ambrisentan doses of 2.5 and 5 mg once-daily improved 6-minute walk distance (6MWD) and delayed clinical worsening in a placebo-controlled PAH study (ARIES-2), with no incidence of serum aminotransferases >3xULN. ARIES-1 evaluated ambrisentan doses of 5 and 10 mg once-daily, compared to placebo.
METHODS: All patients (n = 202) were randomized to one of three treatment groups for 12 weeks. The primary endpoint was a placebo-adjusted change from baseline in 6MWD at week 12. Secondary endpoints included time to clinical worsening, WHO functional class, the SF-36; health survey, and Borg dyspnea index.
RESULTS: Sixty-three percent of patients had idiopathic PAH and 37% had PAH associated with connective tissue disease, anorexigen use, or HIV infection. WHO class I (3%), II (32%), III (58%), and IV (7%) patients were enrolled, with a mean baseline 6MWD of 341 ± 76 meters (m). The placebo-adjusted change from baseline in 6WMD was +51.4 m (95% CI: +26.6 to +76.2; p = 0.0001) for the 10 mg group and +30.6 m (95% CI: +2.9 to +58.3; p = 0.0084) for the 5 mg group. Improvements in WHO functional class and Borg dyspnea index were also observed. Six subjects in the placebo group developed clinical worsening, compared to 3 subjects in each of the ambrisentan groups (p >0.05). No patients receiving ambrisentan developed serum aminotransferase concentrations >3xULN, compared to 2 subjects in the placebo group. No clinically relevant change in warfarin-type anticoagulant therapy was observed.
CONCLUSION: During the 12-week study, ambrisentan improved exercise capacity and symptoms in patients with PAH. Ambrisentan was well tolerated and was not associated with any clinically relevant serum aminotransferase abnormalities.
CLINICAL IMPLICATIONS: Two placebo-controlled ambrisentan studies have demonstrated robust efficacy for a range of doses, with no clinically relevant liver function test abnormalities or adverse drug interactions with warfarin. Therefore, ambrisentan may provide an improved risk-to-benefit ratio for ERA therapy in patients with PAH.
DISCLOSURE: Ronald Oudiz, Consultant fee, speaker bureau, advisory committee, etc. Myogen Inc.; Product/procedure/technique that is considered research and is NOT yet approved for any purpose, ambrisentan.