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Authors: Ashley Barlow, PharmD; Brook Barlow, PharmD; Kristin Watson, PharmD, BCCP

The use oral anticoagulation (OAC) for stroke prevention in atrial fibrillation (AF) remains low despite the known benefits.1,2 One common concern is the risk of bleeding versus the benefit gained.3   Liver disease can cause coagulopathy, and in turn results in an unpredictable risk of both bleeding and thrombosis. In this post, we will discuss the literature surrounding the use of anticoagulation for AF in those with liver disease will be reviewed. Recommendations for selecting an anticoagulant in this population will be provided. Check out one of ATRIUM Cardiology Collabortive’s prior blogs on determining which patients with AF should be considered for OAC.

Cirrhosis has been identified as an independent risk factor for the development of AF. The incidence of AF has been shown to rise in direct  proportion to the severity of liver disease.4 Despite the known benefits of OAC in patients AF, the use of OAC in patients with cirrhosis is variable and relatively low (8.3-54%) due to the potential for altered coagulopathy. Readers wanting to learner more about coagulopathy in patients with liver disease might consider this reference.The findings of a recent meta-analysis demonstrate that patients with cirrhosis receiving OAC for AF derived a net benefit in stroke prevention (pooled hazard ratio (HR): 0.58; 95% confidence interval (CI): 0.35-0.96) without an increased bleeding risk (pooled HR: 1.45; 95% CI: 0.96–2.17). The severity of liver disease was not reported in all studies included in the analysis.5

The decision on which oral anticoagulant to use for stroke prevention in patients with liver disease is complex. Warfarin can be challenging in this population due to the reduced concentrations of circulating clotting factors as well as concomitant hypoalbuminemia and poor nutritional status that can potentiate its anticoagulant effects. In patients with severe liver disease, the baseline elevation in INR can create a difficult scenario when adjusting warfarin doses and in fact, higher rate of thromboembolic events have been observed in severe cirrhosis due to suboptimal warfarin dosing strategies.6 The use of DOAC therapy in this patient population has been explored.

Pharmacokinetics of DOACs in Liver Disease

Data on use of DOAC in patients with AF
Most landmark trials evaluating the use DOACs in patients with AF excluded those with active liver disease.20–22 Product labeling recommendations for the use of DOACs in patients with liver disease can be found in Table 1. In the ENGAGE-TIMI-AF trial, which compared edoxaban to warfarin in non-valvular AF, 5.1% enrolled had liver disease (investigator-reported liver disease or ≥ 2-fold increase in transaminases above the ULN at randomization) despite this being an exclusion criteria. As expected, patients with liver disease had an increase risk of major bleeding on either therapy compared to those without liver disease (HRadjusted: 1.38; 95% CI: 1.10 to 1.74, p=0.005). However, there was no difference in major bleeding events in patients with liver disease who received edoxaban compared to warfarin (3.81% versus 4.32% (HR: 0.91; 95% CI: 0.56 to 1.47)). The rates of stroke or systemic embolism and bleeding were comparable between the edoxaban and warfarin groups in those with or without liver disease. Factor Xa activity as well as peak and trough drug concentrations of edoxaban did not differ between those with or without liver disease, suggesting the pharmacokinetics and pharmacodynamics of edoxaban is not significantly altered in this population. The severity of liver disease could not be assessed by the investigators.19

Several studies have been published to elicit the risk and benefits of DOACs in patients with active liver disease, though only few have solely focused on patients with AF. The first large retrospective cohort study to provide insight in patients with AF and evaluated the differences in bleeding rates between treatment with a DOAC (n=75) or warfarin (n=158) in patients with chronic liver disease identified by ICD-10 codes. Patients had received dabigatran (47%), rivaroxaban (39%) or apixaban (15%). Most patients in the DOAC group had Child-Pugh class A or B compared to class B or C in the warfarin group. The rate of all-cause bleeding between the DOAC and warfarin group (HR: 0.9; 95% CI: 0.4-1.8) was simliar. The rate of all-cause bleeding was comparable between the different DOACs. Factors associated with a difference in the risk of bleeding included severity of liver disease (HR: 1.2; 95% CI: 1.0-1.3, p = 0.01) and history of a bleed within the past year (HR: 4.0; 95% CI: 1.8-8.7, p < 0.001) . Presence of varices or platelet count < 150K were not predictive of bleeding. The dose of the DOACs, INR ranges for patients on warfarin, and efficacy outcomes for stroke prevention were not reported.23 Subsequent studies have reported similar or fewer bleeding risks with DOACs compared with warfarin for other indications for therapy, though are of insufficient sample size to adequately compare thromboembolic outcomes.24,25

A large registry analysis from Korea provided insight on thromboembolic outcomes with DOACs in patients with AF and demonstrated that, compared to warfarin, DOAC use was associated with a lower risk the composite outcome (ischemic stroke, intracranial hemorrhage, hospitalization for gastrointestinal bleeding and all-cause death, HR: 0.691; CI: 0.577-0.827) in patients with significant active liver disease. Significant active liver disease was defined as the presence of viral hepatitis, AST or ALT > 2 times the ULN, or cirrhosis. The risk of ischemic stroke (HR: 0.445; CI: 0.312-0.636), as well as the risk of intracranial hemorrhage (HR: 0.424; CI: 0.241-0.723), and hospitalization for major bleeding (HR: 0.622; CI: 0.442-0.870) were reduced in patients with significant liver disease who received DOAC therapy. 26

An analysis of Taiwan insurance database also found that treatment with a DOAC was associated with a similar risk of ischemic stroke or thromboembolism compared with warfarin, with lower rates of intracranial hemorrhage, major gastrointestinal bleeding, and any major bleeding in patients with cirrhosis and AF. Rivaroxaban was the most commonly used DOAC (50.9%), followed by dabigatran (37.2%) and apixaban (11.9%).  The risk of intracranial hemorrhage was lower in patients with advanced cirrhosis (defined by complications of liver disease) who received a DOAC versus warfarin. It should be noted that those with advanced liver disease represented 22% of the overall study population.  In addition, whereas previous reports employed full treatment doses or failed to report DOAC dosing strategies, this registry revealed that reduced doses (69% apixaban, 88.8% dabigatran, 95.2% rivaroxaban) were nearly a universal prescribing practice for DOACs despite the low presence of indications for dose adjustments (e.g., drug interactions, renal disease). Reduced dosing did not appear to impact the rate of thromboembolisms; however, this data is insuffient to warrent dose reductions based on the presence liver of disease. Interestingly, rates of intracranial hemorrhage were comparable between both warfarin, dabigatran, and rivaroxaban, but not apixaban. However, conclusions cannot be drawn due to the low frequency of apixaban use.27 Child-Pugh scores were not provided; therefore, one can not determine the severity of the liver disease for those included.  It is unknown whether or not we can extrapolate the outcomes of this study to patients in the United States given that all patients were of Asian descent.

Conclusion
The selection of anticoagulation should be made with each patient, taking into consideration the severity of liver disease, risks and benefits of therapy as well as additional patient factors (e.g., renal disease, concurrent medications, history of bleeding/thrombosis). The dose of a DOAC should not be lowered based on the presence of liver disease. We recommend the following based on the severity of liver disease:

  • Mild liver disease (Child-Pugh class A): A DOAC can be considered an alternative to warfarin in patients with AF
  • Moderate liver disease (Child-Pugh class B): Caution is still be advised before universal adoption of DOAC therapy in this patient population as studies did not consistently define the severity of disease
  • Severe liver disease (Child-Pugh class C): Recommend against the use of DOAC therapy; warfarin should be considered in this population.

 

Check out the ATRIUM Cardiology Oral Anticoagulation Selection app for DOAC dosing recommendations for patients with AF.

Apple App Store: https://apps.apple.com/us/app/atrium-anticoagulation-tool/id146266801

Google Play Store: https://play.google.com/store/apps/details?id=edu.umaryland.rx.atrium

Ashley Barlow, PharmD

At the time of this writing, Ashley Barlow was a postgraduate year 1 (PGY1) pharmacy practice resident at the University of Maryland Medical Center in Baltimore, MD. Drs. Ashley and Brooke Barlow completed their Doctorate of Pharmacy training at the Jefferson College of Pharmacy. Their combined Twitter account is used to share their daily pharmacy pearls and their passion for lifelong learning @theABofPharmaC.

Brooke Barlow, PharmD

At the time of this writing, Brooke Barlow was a postgraduate year 1 (PGY1) pharmacy practice resident at the  University of Kentucky Healthcare in Lexington, Kentucky. Drs. Ashley and Brooke Barlow completed their Doctorate of Pharmacy training at the Jefferson College of Pharmacy. Their combined Twitter account is used to share their daily pharmacy pearls and their passion for lifelong learning @theABofPharmaC.

Kristin Watson, PharmD, BCCP

Dr. Watson is an associate professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in the ambulatory heart failure clinic at the Veterans Affairs Medical Center in Baltimore, MD. Follow her on Twitter @cards_pharm_gal

Reviewed by: Zachary R Noel, Pharm D, BCCP

References:

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Say It Ain’t (Mostly) So? DOAC therapy for Stroke Prevention in Patients with Liver Disease and Atrial Fibrillation

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