DOACs associated with lower risk of liver injury hospitalisation compared to warfarin

Prospective study of oral anticoagulants and risk of liver injury in patients with atrial fibrillation

Literature - Alonso A, MacLehose RF, Chen LY et al. - Heart. 2017 Jan 5, doi:10.1136/heartjnl-2016-310586


Although the efficacy of direct oral anticoagulants (DOACs) have been widely studied [1-3], still concerns exist about adverse effects and safety, particularly for less frequent outcomes. For example, an earlier direct thrombin inhibitor (ximelagatran) had been withdrawn from the market after reports of hepatotoxicity emerged. Moreover, recently isolated cases of liver injury associated with the use of dabigatran and rivaroxaban have been published [4,5].

This study investigated the risk of hospitalisation with liver injury after initiation of oral anticoagulantia in 113 717 patients with atrial fibrillation (AF) using data from the large ‘Truven Health MarketScan Commercial Claims and Encounter Database’ and the ‘Medicare Supplemental and Coordination of Benefits Database’ in the USA. Furthermore, predictors of liver injury hospitalisation were studied and a liver injury risk calculator had been developed to help flag patients at higher risk of the complication. 50% of patients were on warfarin, 27% on rivaroxaban, 15% on dabigatran and 8% on apixaban.

Main results

  • 960 hospitalisations with liver injury were reported during a median follow-up of 12 months. This equalizes to 7.3 events per 1000 person-years (95% CI 6.8-7.8).
  • Cumulative risk of liver injury was highest in warfarin patients and lowest in dabigatran patients; corrected for age and sex this was 55%, 26% and 44% lower in dabigatran, rivaroxaban and apixaban patients compared to warfarin, respectively, which was similar although weaker when correcting for more factors.
  • These associations were similar among all subgroups, although apixaban was associated with reduced risk of liver disease hospitalisation in men but not in women, compared to warfarin (P interaction = 0.03).
  • Compared to dabigatran, rivaroxaban users had an increased risk of liver injury (HR 1.56, 95% CI: 1.22-1.99).
  • Variables associated with the risk of liver injury hospitalisation (predictors) were liver disease, gallbladder disease, excessive alcohol consumption, kidney disease, cancer, anaemia, heart failure and type of oral anticoagulant.
  • An excel-based calculator that provides the 1-year risk estimates of liver injury hospitalisation for each oral anticoagulant is available in the online supplement.


Although literature describes isolated case reports of hepatotoxicity linked to DOACs, the risk of liver injury hospitalisation among patients starting DOACs was lower than those starting warfarin. Among DOACs, risk was highest for rivaroxaban users compared with dabigatran and apixaban users. Moreover, several patient characteristics were predictive for liver injury hospitalisation which were used in an excel-based calculator that can help clinicians deciding between anticoagulants.


1. Romanelli RJ, Nolting L, Dolginsky M, et al. Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2016;9:126–34.

2. Larsen TB, Skjøth F, Nielsen PB, et al. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ 2016;353:i3189.

3. Bengtson LGS, Lutsey PL, Chen LY, et al. Comparative effectiveness of dabigatran and rivaroxaban versus warfarin for the treatment of non-valvular atrial fibrillation. J Cardiol 2016; doi:10.1016/j.jjcc.2016.08.010

4. Rochwerg B, Xenodemetropoulos T, Crowther M, et al. Dabigatran-induced acute hepatitis. Clin Appl Thromb Hemost 2012;18:549–50.

5. Liakoni E, Rätz Bravo AE, Terracciano L, et al. Symptomatic hepatocellular liver injury with hyperbilirubinemia in two patients treated with rivaroxaban. JAMA Intern Med 2014;174:1683–6.

Find this publication online at Heart

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