Liver injury from direct oral anticoagulants

BACKGROUND: Drug-induced liver injury (DILI) can be caused by any prescribed drug and is a significant reason for the withdrawal of newly launched drugs. Direct-acting oral anticoagulants (DOACs) are non-vitamin K-based antagonists recently introduced and increasingly used for various clinical conditions. A meta-analysis of 29 randomised controlled trials and 152116 patients reported no increased risk of DILI with DOACs. However, it is challenging to predict the risk factors for DILI in individual patients with exclusion of patients with pre-existing liver disease from these studies. AIM: To determine the risk factors and outcomes of patients who developed DILI secondary to DOACs by systematic review and meta-summary of recent case reports and series. METHODS: A systematic search was conducted on multiple databases including PubMed, Science Direct, Reference Citation Analysis, and Google Scholar. The search terms included “Acute Liver Failure” OR “Acute-On-Chronic Liver Failure” OR “Acute Chemical and Drug Induced Liver Injury” OR “Chronic Chemical and Drug Induced Liver Injury” AND “Factor Xa Inhibitors” OR “Dabigatran” OR “Rivaroxaban” OR “apixaban” OR “betrixaban” OR “edoxaban” OR “Otamixaban”. The results were filtered for literature published in English and on adult patients. Only case reports and case studies reporting cases of DILI secondary to DOACs were included. Data on demographics, comorbidities, medication history, laboratory investigations, imaging, histology, management, and outcomes were extracted. RESULTS: A total of 15 studies (13 case reports and 2 case series) were included in the analysis, comprising 27 patients who developed DILI secondary to DOACs. Rivaroxaban was the most commonly implicated DOAC (n = 20, 74.1%). The mean time to onset of DILI was 40.6 d. The most common symptoms were jaundice (n = 15, 55.6%), malaise (n = 9, 33.3%), and vomiting (n = 9, 33.3%). Laboratory investigations showed elevated liver enzymes and bilirubin levels. Imaging studies and liver biopsies revealed features of acute hepatitis and cholestatic injury. Most patients had a favourable outcome, and only 1 patient (3.7%) died due to liver failure. CONCLUSION: DOACs are increasingly used for various clinical conditions, and DILI secondary to DOACs is a rare but potentially serious complication. Prompt identification and cessation of the offending drug are crucial for the management of DILI. Most patients with DILI secondary to DOACs have a favourable outcome, but a small proportion may progress to liver failure and death. Further research, including post-marketing population-based studies, is needed to better understand the incidence and risk factors for DILI secondary to DOACs.