Edoxaban Versus Warfarin in Patients With Atrial Fibrillation and History of Liver Disease
Key result
Higher-dose edoxaban shows similar stroke risk to warfarin in AF patients with liver disease.
- HR 1.11
- 95% CI 0.54-2.30
- n=21,105
Why the study?
Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulants, creating uncertainty about anticoagulant safety and efficacy in this population.
Key Points
- To evaluate the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of edoxaban compared to warfarin in patients with atrial fibrillation and a history of liver disease.
- Conducted a subgroup analysis of the randomized, double-blind ENGAGE AF-TIMI 48 trial comparing edoxaban to warfarin across 21,105 patients with atrial fibrillation followed for 2.8 years.
- Identified liver disease (n=1,083) via investigator report or >2-fold transaminase elevation at randomization, assessing stroke or systemic embolic events (SSEE), major bleeding, and factor Xa activity.
- Patients with liver disease experienced similar SSEE risk (adjusted hazard ratio [HRadj]: 0.90; 95% CI: 0.67 to 1.22; p=0.50) but higher major bleeding risk (HRadj: 1.38; 95% CI: 1.10 to 1.74; p=0.005) relative to those without liver disease.
- Higher-dose edoxaban versus warfarin showed consistent effects in patients with versus without liver disease for SSEE (HR: 1.11; 95% CI: 0.54 to 2.30 vs HR: 0.86; 95% CI: 0.73 to 1.01; pint=0.47) and major bleeding (HR: 0.91; 95% CI: 0.56 to 1.47 vs HR: 0.80; 95% CI: 0.70 to 0.91; pint=0.63).
Study Design
Type
RCT (n=21,105)
Blinding
Double-blind
Randomization
Randomized
PICO
P
Population
21,105 patients with atrial fibrillation, including 1,083 with a history of liver disease, randomized to edoxaban or warfarin and followed for 2.8 years.
I
Intervention / Comparator
Edoxaban vs Warfarin (Higher-dose)
O
Primary Outcome
Stroke or systemic embolic event (SSEE) in patients with liver disease — HR 1.11 (0.54-2.30)
Main Result
Hazard Ratio: 1.11 (95% CI 0.54–2.3)
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“In the setting of high risk of bleeding in patients with liver disease, edoxaban should be preferred over warfarin for the prevention of stroke and bleeding in patients with AF and history of liver disease.”
Implication
Edoxaban maintains consistent relative efficacy and safety versus warfarin in AF with liver disease history; extends RCT evidence to this previously excluded population.
Abstract
BACKGROUND Patients with liver disease have increased risk of thrombosis and bleeding but are typically excluded from trials of direct oral anticoagulant agents. OBJECTIVES This study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), clinical efficacy and safety of edoxaban versus warfarin in patients with atrial fibrillation (AF) and history of liver disease. METHODS ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48) was a randomized, double-blind trial 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 stratified by history of liver disease. PK/PD assessments of edoxaban included endogenous and extrinsic factor Xa activity and edoxaban concentration. 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 [HRadj]: 0.90; 95% confidence interval [CI]: 0.67 to 1.22; p = 0.50), but major bleeding was more common in patients with liver disease (HRadj: 1.38; 95% CI: 1.10 to 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 to 1.01) in patients without and 1.11 (95% CI: 0.54 to 2.30) with liver disease (p for interaction [pint] = 0.47), major bleeding 0.80 (95% CI: 0.70 to 0.91) in patients without and 0.91 (95% CI: 0.56 to 1.47) with liver disease (pint = 0.63). There were no significant differences in hepatic adverse events between the 2 treatment groups. CONCLUSIONS Among patients with AF receiving oral anticoagulation, bleeding, but not thromboembolic events, was increased in patients with liver disease. A history of liver disease did not alter the relative efficacy and safety of edoxaban compared with warfarin. Hepatic adverse events were similar between edoxaban and warfarin.
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Cite This Study
Qamar et al. (2019) conducted an RCT in Atrial Fibrillation with history of liver disease (n=21,105). Edoxaban vs. Warfarin was evaluated on Stroke or systemic embolic event (SSEE) in patients with liver disease (HR 1.11, 95% CI 0.54-2.30). Higher-dose edoxaban resulted in similar rates of stroke or systemic embolic events compared to warfarin in atrial fibrillation patients with a history of liver disease (HR 1.11; 95% CI 0.54-2.30).