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

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

• Of 21,105 patients enrolled in ENGAGE AF-TIMI 48, 1,083 (5.1%) had a history of liver disease.
• There was no difference between patients with liver disease compared to patients without liver disease for the risk of SSEE, ischemic SSEE or hemorrhagic stroke. Nor were all-cause death, CV death and myocardial infarction different between groups.
• Risk of ISTH major bleeding was higher in patients with liver disease than in those without (adjHR: 1.38, 95%CI: 1.10-1.74, P=0.006), as well major or clinically relevant nonmajor bleeding. Intracranial hemorrhage and fatal bleeding were not different between the groups.
• There were no significant differences in PK and PD assessment of edoxaban in patients with liver disease compared to those without.
• Annualized rate of SSEE was similar with high-dose edoxaban vs. warfarin in patients without liver disease (HR: 0.86; 95%CI: 0.73-1.01) compared to patient with liver disease (HR: 1.11, 95%CI:0.54-2.30) (P-interaction=0.47). There were also no interactions for the individual components ischemic stroke, hemorrhagic stroke, systemic embolic event or all-cause death.
• Annualized rate of ISTH major bleeding was similar with high-dose edoxaban vs. warfarin in patients without liver disease (HR: 0.80, 95%CI:0.70-0.91) compared to those with liver disease (HR: 0.91, 95%CI:0.56-1.47) (P-interaction=0.63). No significant interaction were seen for fatal bleeding and clinically relevant nonmajor bleeding or major bleeding by presence of liver disease.
• Primary net clinical outcome, a composite of SSEE, major bleeding or death by any cause for high-dose edoxaban vs. warfarin was not different between patients without liver disease (HR: 0.86) or with liver disease (HR: 1.07) (P-interaction=0.26).
• There were no significant differences in rates of severe, moderate, mild or minimal liver injury between low-dose edoxaban, high-dose edoxaban and warfarin groups.

Conclusion

References

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