Randomized, Double-Blind Comparison of Half-Dose Versus Full-Dose Edoxaban in 14,014 Patients With Atrial Fibrillation

Abstract

Background: In the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48) trial, the lower dose edoxaban regimen (LDER) and the higher dose edoxaban regimen (HDER) were noninferior to well-managed warfarin for stroke prevention in atrial fibrillation.

Objectives: The objective of the present analysis of the ENGAGE AF TIMI-48 trial was to comprehensively compare the net clinical outcome (NCO) of LDER (30 mg once daily, dose reduced to 15 mg in selective patients) versus HDER (60 mg once daily, dose reduced to 30 mg in selective patients).

Methods: This study performed a pre-specified analysis of the ENGAGE AF-TIMI 48 trial, comparing patients on LDER versus HDER.

Results: The pre-defined primary NCO (stroke/systemic embolism [SEE], major bleeding, death) was less frequent with LDER (7.26% vs. 8.01%; hazard ratio: 0.90; 95% confidence interval: 0.84 to 0.98; p = 0.014). The secondary (disabling stroke, life-threatening bleeding, or all-cause mortality) and tertiary pre-defined NCOs (stroke, SEE, life-threatening bleeding, or all-cause mortality) were similar between the 2 dosing regimens. Patients randomized to LDER versus HDER had a significantly higher risk of stroke/SEE (2.04% vs. 1.56%; hazard ratio: 1.31; 95% confidence interval: 1.12 to 1.52; p < 0.001). Conversely, major bleeding, intracranial hemorrhage, major gastrointestinal bleeding, and life-threatening bleeding occurred significantly less frequently with LDER compared with those of HDER. These findings were supported by multiple pharmacokinetic findings.

Conclusions: In the ENGAGE AF-TIMI 48 trial, the primary NCO was reduced with LDER versus HDER, whereas the secondary and tertiary NCOs were similar between the 2 dosing regimens. These results may aid physicians in evidence-based individualization of edoxaban dosing. However, the approved HDER remains the standard therapy among the available edoxaban dosing regimens for stroke prevention in atrial fibrillation. (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48 [ENGAGE AF-TIMI 48]; NCT00781391).

Keywords: DOAC; anticoagulation; atrial fibrillation; edoxaban.

Conflict of interest statement

Funding Support And Author Disclosures The ENGAGE AF-TIMI 48 trial was supported by Daiichi-Sankyo Pharma Development. Dr. Steffel has received consultant and/or speaker fees from Abbott, Amgen, AstraZeneca, Bayer, Berlin-Chemie, Biosense Webster, Biotronik, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Daiichi-Sankyo, Medscape, Medtronic, Merck/Merck Sharp & Dohme, Novartis, Roche Diagnostics, Pfizer, Portola, Saja, Servier, and WebMD; has ownership in CorXL; and has received grant support, through his institution, from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Daiichi-Sankyo, and Medtronic. Dr. Ruff has received consulting fees from Bayer, Daiichi-Sankyo, Portola, and Boehringer Ingelheim; and has received grant support, through his institution, from Daiichi-Sankyo, Anthos Therapeutics, AstraZeneca, Eisai, and Intarcia. Dr. Braunwald has received consulting fees from Amgen, Boehringer Ingelheim/Lilly, Cardurion, MyoKardia, NovoNordisk, and Verve; and has received grant support, through his institution, from AstraZeneca, Daiichi-Sankyo, Merck & Co., and Novartis. Dr. Park has received grant support, through his institution, from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, The Medicines Company, and Zora Biosciences. Ms. Murphy has received grant support, through her institution, from Daiichi-Sankyo. Dr. Connolly has received research grants and consultation fees from Bayer, Bristol Myers Squibb, Pfizer, Portola, Daiichi-Sankyo, and Boehringer Ingelheim. Dr. Antman has received grant support, through his institution, from Daiichi-Sankyo. Dr. Giugliano has received consulting fees from Bristol Myers Squibb, Janssen, Daiichi-Sankyo, Merck, Pfizer, Portola, SAJA Pharmaceuticals, and Servier; and has received grant support, through his institution, from Anthos Therapeutics, AstraZeneca, Daiichi-Sankyo, Merck, Johnson & Johnson, Pfizer, and Sanofi. Dr. Yin was previously employed by Daiichi-Sankyo and has reported that she has no other relationships relevant to the contents of this paper to disclose.

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