Hepatic safety of ambrisentan alone and in combination with tadalafil: a post-hoc analysis of the AMBITION trial.

Treatment with endothelin receptor antagonists (ERA) can result in adverse hepatic effects in patients with pulmonary arterial hypertension (PAH). We evaluated the hepatic safety of ambrisentan (ABS), an ERA, used as monotherapy, or with tadalafil (TAD), a phosphodiesterase-5 (PDE5) inhibitor as initial combination therapy (ABS + TAD) in the AMBITION trial. This was a retrospective analysis set in academic and private outpatient clinics and research centers. This analysis included 596 patients with PAH who were randomized to ABS or TAD as monotherapy or ABS + TAD as initial combination therapy and received at least one dose of study drug, and who had baseline and follow-up hepatic function data. Treatment options following a clinical failure event included blinded combination therapy (BCT). The proportion of patients with elevations in alanine or aspartate aminotransferases (ALT/AST) > 3 × upper limit of normal (ULN), and those with total bilirubin (TBili) > 2× ULN and ALT or AST > 3 × ULN (referred to as potential Hy's law), were determined before BCT as well as including time on BCT. Elevations in ALT/AST > 3 × ULN during the study were in the range of 3.4-3.7%, with an annualized incidence of 2.1-2.93%. The majority of patients with elevations in ALT/AST had elevations > 3 to ≤ 5 × ULN. Three patients (0.5%) had ALT/AST > 3 × ULN plus TBili > 2 × ULN. All three patients had probable alternative causes (cardiogenic shock, liver metastases, lymphoma) for the elevations. Our analysis of the AMBITION trial demonstrated that ABS and ABS + TAD were not associated with drug-induced liver injury.