ArticlesAssociation between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial
Introduction
Atrial fibrillation predisposes patients to an increased risk of embolic stroke and is associated with a higher mortality rate than sinus rhythm.1, 2, 3 Although warfarin and other vitamin K antagonists (VKAs) are highly effective in reducing the risk of embolic stroke, their use is limited by several genetic, food, and drug interactions, and a narrow therapeutic index that necessitates frequent monitoring and dose adjustments, resulting in substantial bleeding risk and inconvenience.4, 5, 6, 7 Several new or non-VKA oral anticoagulants (NOACs) that directly inhibit thrombin or activated factor Xa (FXa) in a dose-dependent manner have been identified to be at least as effective as, and safer than, warfarin in preventing stroke and systemic embolic events in patients with atrial fibrillation.8, 9, 10, 11, 12 Their predictable anticoagulant effect has translated into their administration in fixed doses without the need for routine coagulation monitoring, thereby simplifying therapy. However, a pharmacokinetic analysis from the RE-LY trial13 with dabigatran, a thrombin inhibitor, identified that fixed dosing of dabigatran resulted in significant variation in plasma concentrations that depended on patient factors. Older age and renal dysfunction were strongly correlated with higher dabigatran concentrations and the risk of bleeding. These data have suggested that measurement of drug concentration or anticoagulant activity when prescribing NOACs might be necessary.
The ENGAGE AF-TIMI 48 trial compared two once-daily regimens of the FXa inhibitor edoxaban with warfarin in 21,105 patients with AF at moderate-high risk of stroke.11, 14 We previously reported that both edoxaban regimens were non-inferior to warfarin in the prevention of stroke or systemic embolic events and significantly reduced major bleeding, intracranial haemorrhage, and cardiovascular mortality.11 Both doses of edoxaban incorporated a 50% dose reduction in patients with clinical features known to increase drug exposure and the risk of bleeding. We aimed to test whether tailoring of the dose of NOACs on the basis of clinical information alone prevented excess drug levels and optimised the balance between the risk of ischaemic and bleeding events in the ENGAGE AF-TIMI 48 trial.
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Study design and patients
We analysed data from the ENGAGE AF-TIMI 48 randomised, double-blind, double-dummy trial.11, 14 The trial was done in 1393 centres in 46 countries. The trial design and findings have been described previously.11, 14 Eligible patients were aged 21 years or older, with atrial fibrillation documented on an electrical tracing within 12 months, a CHADS2 risk score (stroke risk factor scoring system where 1 point is given for history of congestive heart failure, hypertension, age≥75, diabetes, and 2
Results
Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited to participate in this trial. Trough edoxaban concentration was measured in 6780 of the 14 069 patients randomly assigned to edoxaban (appendix). Trough anti-FXa activity was measured in 2865 of the 3351 patients enrolled in the biomarker substudy who were randomly assigned to edoxaban (appendix). Baseline characteristics of patients with and without measured edoxaban concentration were qualitatively similar, although
Discussion
This is the first analysis of an NOAC that combines drug concentration, anti-FXa activity, efficacy, and bleeding outcomes (panel). In the ENGAGE AF-TIMI 48 trial, two dose regimens of once-daily edoxaban were compared with warfarin for prevention of thromboembolism in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical factors (impaired renal function, low bodyweight, and concomitant use of potent P-glycoprotein inhibitors) that had been
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