Ambrisentan, an endothelin-receptor antagonist is now approved by FDA for the treatment of PAH
Plasma endothelin-1 (ET-1) concentrations may be increased as much as 10-fold in patients with pulmonary arterial hypertension (PAH), correlating with increased mean right atrial pressure and disease severity. Ambrisentan is an ET-receptor antagonist that is selective for the ET type A (ETA) receptor; the primary actions of ETA are vasoconstriction and cell proliferation. Ambrisentan was approved on June 15, 2007, for the treatment of PAH (World Health Organization [WHO] Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.
Efficacy. The efficacy of ambrisentan was evaluated in two 12-week, randomized, double-blind, placebo-controlled, multicenter studies (ARIES-1 and ARIES-2) in 393 patients with PAH (WHO Group 1). In ARIES-1, patients were treated with once-daily doses of ambrisentan 5 or 10 mg or placebo; in ARIES-2, patients were treated with once-daily doses of ambrisentan 2.5 or 5 mg or placebo. In both studies, ambrisentan or placebo was added to a patient's current therapy, which could include anticoagulants, diuretics, calcium-channel blockers, and digoxin, but not epoprostenol, treprostinil, iloprost, bosentan, or sildenafil. The primary end point was 6-minute walking distance (6MWD). Clinical worsening, WHO functional class, dyspnea, and Short-Form 36 (SF-36) results were also evaluated. The majority of patients had idiopathic PAH (64%); the remaining patients had PAH associated with connective tissue disease (32%), HIV infection (3%), or anorexigen use (1%). At baseline, the majority of patients had WHO functional class III symptoms (55%); 38% had WHO class II symptoms, 5% had WHO class IV symptoms, and 2% had WHO class I symptoms. The mean age of enrolled patients was 50 years. After 12 weeks in the ARIES-1 study, patients treated with ambrisentan 5 or 10 mg demonstrated a statistically significant improvement in 6MWD compared with patients treated with placebo (P=.008 and P<.001, respectively); after 12 weeks in the ARIES-2 study, patients treated with ambrisentan 2.5 or 5 mg also demonstrated a significant improvement in 6MWD compared with patients who received placebo (P=.022 and P<.001, respectively). In both studies, an increase in 6MWD was observed after 4 weeks of ambrisentan treatment, and a dose-response was observed after 12 weeks of treatment. In both ARIES-1 and ARIES-2, patients treated with ambrisentan also experienced a significant delay in the time to clinical worsening compared with patients who received placebo.
Safety. Treatment with ET-receptor antagonists has been associated with dose-dependent hepatic injury, manifested primarily by serum aminotransferase (ALT and AST) elevations but sometimes accompanied by abnormal liver function (bilirubin elevations). Serum aminotransferase levels must be measured before treatment initiation and at least monthly during treatment. Ambrisentan may cause fetal harm if administered to a pregnant woman; this agent is therefore contraindicated in women who are or who may become pregnant. Patients treated with ET-receptor antagonists have experienced decreases in hemoglobin concentration and hematocrit. As such, hemoglobin must be measured before treatment initiation, at 1 month after treatment initiation, and periodically thereafter. Peripheral edema has been reported in patients treated with ET-receptor antagonists. The most common adverse events reported in patients treated with ambrisentan include peripheral edema, nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, constipation, dyspnea, and headache.