Systematic Reviews
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jun 27, 2023; 15(6): 841-849
Published online Jun 27, 2023. doi: 10.4254/wjh.v15.i6.841
Liver injury from direct oral anticoagulants
Deven Juneja, Prashant Nasa, Ravi Jain
Deven Juneja, Institute of Critical Care Medicine, Max Super Specialty Hospital, New Delhi 110017, India
Prashant Nasa, Critical Care Medicine, NMC Specialty Hospital, Dubai 7832, United Arab Emirates
Prashant Nasa, Internal Medicine, College of Medicine and Health Sciences, Al Ain 15551, United Arab Emirates
Ravi Jain, Critical Care Medicine, Mahatma Gandhi Medical College and Hospital, Jaipur 302001, Rajasthan, India
Author contributions: Nasa P conceptualized and designed the article; Juneja D, Nasa P, and Jain R performed acquisition of data, analysis and interpretation of data, and drafted the article; Juneja D and Jain R revised the article; and all authors have read and approve the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Prashant Nasa, MD, Chief Doctor, Critical Care Medicine, NMC Specialty Hospital, Amman Street, Al Nahda 2, Dubai 7832, United Arab Emirates. dr.prashantnasa@gmail.com
Received: January 5, 2023
Peer-review started: January 5, 2023
First decision: January 19, 2023
Revised: January 23, 2023
Accepted: May 15, 2023
Article in press: May 15, 2023
Published online: June 27, 2023
Processing time: 170 Days and 22.6 Hours
Abstract
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.

Keywords: Anticoagulants; Direct-acting oral anticoagulants; Drug induced liver injury; Drug reactions; Hepatotoxicity; Novel oral anticoagulants

Core Tip: Drug-induced liver injury (DILI) can be ascribed to practically any prescribed drug. The side effect profile of relatively newer direct-acting oral anticoagulants (DOACs) is yet to be completely determined. Even though the data from earlier clinical trials suggested no significant liver toxicity, several case reports and series describing DOAC-induced DILI have been recently published. Most of these cases have been reported in elderly patients, not on concomitant hepatotoxic drugs. However, these patients may have good clinical outcomes, with complete recovery of liver function, if an early diagnosis is made and the offending agent is stopped.