In the 3.5-year period from June 15, 2007, to December 14, 2010, 10,927 patients were exposed to marketed ambrisentan in the United States with a total exposure representing 9,893 patient-years (Figure 1). The mean time on ambrisentan was 330.5 days, with 62% of patients on ambrisentan for longer than 3 months and 50% longer than 6 months. The LEAP database included 314 (2.87%) post-marketing spontaneous reports of possible hepatic injury, of which 156 (1.43%) were medically confirmed. A total of 77 medically confirmed cases did not meet the criteria of clinically significant hepatic events (all of these cases reported small or unspecified elevations in liver function tests) with 79 (0.72%) remaining as clinically significant hepatic events. Six of the 79 clinically significant hepatic events had both elevated aspartate and alanine aminotransferase >3× ULN and serum total bilirubin >2× ULN and were considered as potential Hy's Law cases (Hy's Law is defined as >3× ULN for serum alanine or aspartate aminotransferase and serum total bilirubin >2× ULN), with no other reason to explain the combined increase and is considered a marker of possible drug-induced liver injury (3). In 5 of the 6 reports, probable alternative causes of the hepatic events were reported, with the sixth case having intermittent enzyme elevations for 2 years and a poorly documented medical history. Possible alternative causes or contributory factors for the hepatic events were also present in 55 of the 73 remaining medically confirmed clinically significant cases, and in 38 of these, ambrisentan was successfully restarted.