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Relationship Between Edoxaban Dose, Anti-Factor Xa Activity, and Outcomes in the ENGAGE AF-TIMI 48 Trial

ESC Congress 2014 - Hot Line Report

Atrial Fibrillation



By Christian Ruff, (Boston, United States of America)
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List of Authors
Christian T. Ruff, MD, MPH, Robert P. Giugliano, MD, SM, Eugene Braunwald, MD, David A. Morrow, MD, MPH, Sabina A. Murphy, MPH, Julia F. Kuder, MPH, Naveen Deenadayalu, MPH, Petr Jarolim, MD, PhD, Joshua Betcher, PhD, Minggao Shi, PhD, Karen Brown, PhD, Indu Patel, MD, Michele Mercuri, MD, PhD, Elliott M. Antman, MD


The ENGAGE AF-TIMI 48 trial in 21,105 patients with AF showed that both the high (HD) and low dose (LD) regimens of the factor Xa (FXa) inhibitor edoxaban were as effective as warfarin in preventing stroke or systemic embolism (SEE), while reducing major bleeding and cardiovascular death (CVD). The relationships between edoxaban dose, pharmacokinetics, pharmacodynamics, and clinical outcomes have not been previously reported.
We correlated edoxaban dose, concentration, and anti-FXa activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status.
Patients who met clinical criteria for dose reduction had higher stroke, bleeding, and CVD rates. The dose of edoxaban ranged from 15 - 60 mg, resulting in a 2 to 3-fold gradient of mean drug exposure (16.0 - 48.5 ng/mL) and mean anti-FXa activity (0.35 - 0.85 IU/mL). Dose reduction decreased mean exposure by 29% and 35% and mean anti-FXa activity by 25% and 20% in the HD and LD regimens, respectively. Despite the decrease in anti-FXa activity, dose reduction preserved the relative efficacy of edoxaban compared with warfarin (stroke or SEE: HD p-interaction=0.85, LD p-interaction=0.99) and provided even greater safety (major bleeding: HD p-interaction 0.02, LD p-interaction=0.002).
This first analysis of an oral anticoagulant that combines pharmacokinetic, pharmacodynamics, and clinical outcomes demonstrates that dose reduction lowered HD and LD edoxaban concentrations and anti-FXa levels, yet preserved efficacy with even greater relative reductions in bleeding compared with warfarin. The therapeutic window appears narrower for bleeding than thromboembolism.


By Manesh Patel, (Durham, United States of America)
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Clinical Trial Update Hot Line: Stable CAD and atrial fibrillation

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.