By Walter Alexander
SAN FRANCISCO—The new endothelin-receptor agonist, ambrisentan (Letairis), which received FDA approval after a priority review, may be a safe and effective long-term option for patients with pulmonary artery hypertension (PAH) who have not responded to treatment with the older drugs in that class, experts reported at the American Thoracic Society annual meeting.
The other 2 endothelin-receptor antagonists, bosentan (Tracleer) and sitaxsentan (not approved in this country), have been associated with significant liver abnormalities (as shown by liver function tests), which does not appear to be as significant with ambrisentan, according to Ronald J. Oudiz, MD, of the University of California, Los Angeles, School of Medicine, who presented long-term results from ARIES-E, a trial based on 2 earlier clinical trials called ARIES-1 and ARIES-2.
This randomized, double-blind, placebo-controlled trial included 316 patients with PAH and investigated the long-term safety and efficacy of once-daily ambrisentan (2.5-10.0 mg). At 48 weeks, 92.8% of the patients randomized to ambrisentan monotherapy were still using it.
In the ambrisentan-treated patients, 6-minute walk distance increased by approximately 40 m from baseline, an improvement that persisted through week 48. Other functional tests also improved consistently.
Levels of B-type natriuretic peptide, which correlate significantly with mean pulmonary arterial pressure and pulmonary vascular resistance, had decreased by 37% by week 24. One-year survival was 95% for all patients. In contrast, the National Institutes of Health?predicted survival for this population is 72%. Most deaths in thistrial were the result of worsening right heart failure.
Michael D. McGoon, MD, of the Mayo Clinic, Rochester, Minn, reported the long-term results from a second, smaller, dose-ranging study of ambrisentan (2.5, 5.0, or 10.0 mg/d) in
36 patients with PAH who had to stop taking bosentan and/or sitaxsentan because of serum aminotransferase abnormalities. With ambrisentan, only 1 of 31 evaluable patients required a temporary dose reduction because alanine aminotransferase increased by 3.2 times the upper limit of normal at week 12. However, none of the patients had to discontinue therapy because of liver function test abnormalities. In this study, ambrisentan improved all of the efficacy parameters evaluated in the ARIES studies. Based on these results, Dr McGoon concluded that "patients who have failed bosentan and/or sitaxsentan because of [liver function] abnormalities can be successfully treated with ambrisentan."
Despite these results, Gilead, the drug's manufacturer, cautions that elevated liver enzymes have been reported with ambrisentan, and that seriousliver injury has occurred with related drugs in the same class. Ambrisentan should therefore be discontinued if liver aminotransferase levels are >5 times the upper limit of normal, or if the patient has signs or symptoms of liver dysfunction. Ambrisentan is contraindicated during pregnancy.