PURPOSE: Ambrisentan is an oral, ETA-selective endothelin receptor antagonist (ERA) that is approved for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO class II or III symptoms. Ambrisentan improved 6-minute walk distance in two 12-week placebo-controlled studies (ARIES-1 and ARIES-2) with no events of alanine transaminase (ALT) and/or aspartate transaminase (AST) >3xULN (LFT abnormalities). ARIES-3 is an ongoing long-term study evaluating efficacy and safety of ambrisentan in a broad population of patients with PAH and pulmonary hypertension (PH) due to other etiologies.
METHODS: Patients received 5mg ambrisentan once-daily for 24 weeks. After the initial 24-week treatment period, investigators were allowed to adjust ambrisentan dose as clinically indicated (available doses: 2.5, 5, and 10mg). Patients had serum aminotransferase concentrations <3xULN at study entry and were monitored with laboratory tests every 4 weeks.
RESULTS: Twenty-six (12%) of the 226 patients enrolled in ARIES-3 had previously discontinued bosentan (n=23), sitaxsentan (n=2), or both (n=1) due to LFT abnormalities. This subpopulation was comprised of patients with PAH (73%) or PH associated with lung diseases (12%) or chronic thromboembolic disease (15%), primarily with WHO class II (27%) or III (58%) symptoms at baseline. Median duration of exposure prior to discontinuation of previous ERA treatment was approximately 6 months. As of April 2008, all 26 of these patients were still receiving ambrisentan (median exposure=13 months) with only 1 patient having experienced LFT abnormalities during this time period (2nd month of treatment: ALT=4.1xULN, AST=3.5xULN). The patient continued receiving ambrisentan with no change in dose and serum aminotransferase concentrations returned to baseline levels within 1 month. This patient was subsequently up-titrated to 10mg ambrisentan and has reported no additional LFT abnormalities (current exposure=14 months).
CONCLUSION: Long-term ambrisentan therapy was well tolerated in patients who previously could not tolerate bosentan and/or sitaxsentan due to LFT abnormalities.
CLINICAL IMPLICATIONS: Ambrisentan is a potential treatment for patients with PAH who have failed other ERA therapies due to LFT abnormalities.
DISCLOSURE: Jeremy Feldman, Consultant fee, speaker bureau, advisory committee, etc. Dr. Feldman has received speaker fees from Gilead and United Therapeutics. He has served on advisory boeards for Gilead, Encysive, Actelion and United Therapeutics.; No Product/Research Disclosure Information