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Edoxaban in Patients With Atrial Fibrillation and History of Liver Disease
Study Questions:
What are the pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and a history of liver disease?
Methods:
The investigators conducted an exploratory subgroup analysis of the randomized, double-blind trial, ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis In Myocardial Infarction Study 48) comparing edoxaban with warfarin in patients with AF followed for 2.8 years. History of liver disease was defined as investigator-reported liver disease or >2-fold transaminase elevation at randomization. The primary efficacy and safety endpoints of stroke or systemic embolic event (SSEE) and major bleeding were assessed and stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. All efficacy and net clinical outcome analyses of edoxaban versus warfarin were performed on an intention-to-treat basis using Cox proportional hazard modeling with randomized treatment as a covariate.
Results:
Among 21,105 patients, 1,083 (5.1%) had a history of liver disease; they had a higher prevalence of many comorbidities. The adjusted risks of SSEE were similar (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.67-1.22; p = 0.50), but major bleeding was more common in patients with liver disease (aHR, 1.38; 95% CI, 1.10-1.74; p = 0.005). There were no significant differences in PK/PD assessment of edoxaban in patients with versus without liver disease. The HRs for higher-dose edoxaban versus warfarin for SSEE were 0.86 (95% CI, 0.73-1.01) in patients without and 1.11 (95% CI, 0.54-2.30) with liver disease (p for interaction = 0.47), major bleeding 0.80 (95% CI, 0.70-0.91) in patients without and 0.91 (95% CI, 0.56-1.47) with liver disease (p for interaction = 0.63). There were no significant differences in hepatic adverse events between the two treatment groups.
Conclusions:
The authors concluded that among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease.
Perspective:
This study reports that a history of liver disease was associated with a significantly increased risk of bleeding, with no difference in the risk of stroke compared with patients without liver disease. Furthermore, the PK and PD of edoxaban were not modified by the presence of liver disease; consequently, the relative efficacy and safety of edoxaban compared with warfarin for preventing stroke or systemic embolic events or bleeding was maintained irrespective of liver disease status. In addition, there were no significant differences in the rates of liver injury with either doses of edoxaban as compared with warfarin. While this exploratory subgroup analysis appears to suggest that in the setting of high risk of bleeding in patients with liver disease, edoxaban may be preferred over warfarin for stroke prevention in patients with AF, larger prospective dedicated trials are indicated to evaluate the efficacy and safety of oral anticoagulant agents in this high-risk population.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiovascular Care Team, Dyslipidemia, Prevention, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents
Keywords: Anticoagulants, Arrhythmias, Cardiac, Atrial Fibrillation, Factor Xa, Liver Diseases, Myocardial Infarction, Pharmacokinetics, Secondary Prevention, Stroke, Transaminases, Treatment Outcome, Vascular Diseases, Warfarin
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