Elsevier

The Lancet

Volume 385, Issue 9984, 6–12 June 2015, Pages 2288-2295
The Lancet

Articles
Association between edoxaban dose, concentration, anti-Factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial

https://doi.org/10.1016/S0140-6736(14)61943-7Get rights and content

Summary

Background

New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events.

Methods

We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1:1:1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2·0–3·0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30–50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov, number NCT00781391.

Findings

Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16·0–48·5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0·35–0·85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48·5 ng/mL [SD 45·8] to 34·6 ng/mL [30·9]) and 35% (from 24·5 ng/mL [22·7] to 16·0 ng/mL [14·5]) and mean anti-FXa activity by 25% (from 0·85 IU/mL [0·76] to 0·64 IU/mL [0·54]) and 20% (from 0·44 IU/mL [0·37] to 0·35 IU/mL [0·28]) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose pinteraction=0·85, lower dose pinteraction=0·99) and provided even greater safety (major bleeding: higher dose pinteraction 0·02, lower dose pinteraction=0·002).

Interpretation

These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism.

Funding

Daiichi-Sankyo Pharma Development.

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.

Section snippets

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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