Association Between Edoxaban Dose Adjustment, Drug Levels, and Clinical Outcomes | Journal Scan

Study Questions:

What are the associations between edoxaban dose adjustment, drug trough level, and clinical outcomes?


In a substudy of the ENGAGE AF-TIMI 48 trial comparing edoxaban to warfarin in 21,105 patients with atrial fibrillation at moderate to high risk of stroke, patients underwent a 50% dose reduction based on renal function, weight, and potential drug-drug interactions. A subgroup of patients underwent blood testing 1 month after randomization, including mean edoxaban trough levels and anti-Factor Xa activity testing. Clinical outcomes, including stroke and systemic embolism, as well as safety outcomes, including major hemorrhage and intracranial hemorrhage, were stratified based on dose reduction and drug trough levels.


Patients who required an edoxaban dose reduction experienced a higher rate of stroke, bleeding, and death compared to those without a dose reduction. A four-fold range of edoxaban dosing was associated with a three-fold gradient of trough edoxaban levels with significant group overlap. Increasing edoxaban trough level was associated with an increased risk of major bleeding and a decrease in the risk of stroke or systemic embolism. Across most edoxaban trough levels, the risk of major bleeding exceeded the risk of stroke or systemic embolism. Edoxaban dose reduction was associated with a mean drug exposure reduction of 29% and 35%, as well as a mean anti-Factor Xa activity reduction of 25% and 20% in the higher-dose and lower-dose edoxaban groups, respectively. Despite the lower anti-Factor Xa activity, edoxaban dose reduction maintained clinical efficacy (p-value for interaction >0.85 for both doses) with an improvement in safety (p-value for interaction <0.02 for both doses) when compared to warfarin.


The authors concluded that a dose reduction strategy proved effective for reducing the risk of major bleeding while maintaining the benefit of stroke reduction.


This substudy of the ENGAGE AF-TIMI 48 trial demonstrates the effect of an aggressive dose reduction strategy based on renal function, weight, and potential drug-drug interaction for the prevention of major bleeding with edoxaban. While patients who underwent a dose reduction experienced higher rates of major bleeding, the dose reduction strategy was also associated with decreases in the trough drug levels and anti-Factor Xa activity measures. These findings are important given the concerns raised from the RE-LY trial of dabigatran versus warfarin and the potential impact of drug activity levels without a dose reduction strategy and adverse outcome risk. The study demonstrates that the therapeutic window for major bleeding with edoxaban is narrower than that for ischemic stroke prevention, suggesting that the aggressive dose reduction strategy employed was effective. Clinicians should remember that all direct oral anticoagulants (including edoxaban) undergo renal clearance, and therefore, assessment of renal function is important for safe prescribing practices.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Prevention, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents

Keywords: Anticoagulants, Atrial Fibrillation, Stroke, Risk, Drug Interactions, Embolism, Factor Xa, Hemorrhage, Intracranial Hemorrhages, Treatment Outcome, Warfarin, Benzimidazoles, Pyridines, Thiazoles, beta-Alanine, Primary Prevention

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