Physicians' Academy for Cardiovascular Education

Factor Xa inhibitor effective and safe in AF patients with liver disease

Edoxaban Versus Warfarin in Patients With Atrial Fibrillation and History of Liver Disease

Literature - Qamar A, Antman EM, Ruff CT et al. - J Am Coll Cardiol 2019;74:179–89,

Introduction and methods

Liver disease is associated with increased risk of atrial fibrillation (AF) [1,2] and AF patients with liver disease require anticoagulation. However, there is an increased risk of bleeding in these patients due to decreased production of coagulation factors, thrombocytopenia, and increased fibrinolysis [3]. Randomized clinical trials examining direct oral anticoagulant agents (DOACs) often exclude patients with liver disease [4-6]. In addition, DOACs are metabolized by the hepatobiliary system and therefore patients with liver disease may have different drug levels, thereby affecting anticoagulation and bleeding risk.

Clearance of the direct oral factor Xa (FXa) inhibitor edoxaban is mediated by the liver (up to 50%) and the kidneys (50%) [7]. In the ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48), the higher-dose edoxaban was noninferior to warfarin in preventing the primary endpoint of stroke or systemic embolic events (SSEE) and was associated with significantly lower rates of major bleeding, intracranial hemorrhage, and CV mortality [8]. Based on these results, edoxaban was approved by the FDA for the prevention of stroke or systemic embolism in AF patients.

There have been small studies on edoxaban and other DOAcs in patients with liver disease [9-12] and based on their results, the FDA recommends use of edoxaban without dose adjustment in patients with mild hepatic impairment and contradicts using it in patients with moderate of severe hepatic impairment.

In this analysis of the ENGAGE AF-TIMI 48 study, pharmacokinetics, pharmacodynamics, efficacy and safety of edoxaban vs. warfarin in AF patients with and without liver disease were examined. ENGAGE AF-TIMI 48 enrolled 21,105 patients ≥21 years with AF and a CHADS2 score ≥2. History of liver disease was determined by the site investigator, or determined by elevated liver enzymes at randomization. Patients were assigned in a 1:1:1 ratio to receive high-dose edoxaban, lower-dose edoxaban or warfarin. Median follow-up was 2.8 years.

Main results

Factor Xa inhibitor effective and safe in AF patients with liver disease


In this analysis of the ENGAGE AF-TIMI 48 study, in AF patients with liver disease risk of thrombotic events was not increased, but risk of bleeding was increased when compared to AF patients without liver disease. Effectiveness and safety of high-dose edoxaban compared to warfarin was similar in patients with liver disease compared to those without. PK and PD profiles of edoxaban were similar in patients with and without liver disease and hepatic adverse events were similar in groups.


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