Hepatic findings in long-term clinical trials of ximelagatran

Objective: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (> 35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran. Patients and methods: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]). Results: An elevated alanine aminotransferase (ALT) level of > 3 x the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1-6 months after initiation of therapy and data were available to confirm recovery of the ALT level to < 2 x ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of > 3 x ULN and total bilirubin level of > 2 x ULN (within I month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran. Conclusion: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.