Edoxaban versus warfarin in patients with atrial fibrillation.

Authors

• Robert P Giugliano
• Christian T Ruff
• Eugene Braunwald
• Sabina A Murphy
• Stephen D Wiviott
• Jonathan L Halperin
• Albert L Waldo
• Michael D Ezekowitz
• Jeffrey I Weitz
• Jindřich Špinar
• Witold Ruzyllo
• Mikhail Ruda
• Yukihiro Koretsune
• Joshua Betcher
• Minggao Shi
• Laura T Grip
• Shirali P Patel
• Indravadan Patel
• James J Hanyok
• Michele Mercuri
• Elliott M Antman

Publication/Presentation Date

11-28-2013

Abstract

BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known.

METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding.

RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P< 0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P< 0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P< 0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32).

CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.).

Volume

369

Issue

22

First Page

2093

Last Page

2104

ISSN

1533-4406

Published In/Presented At

Giugliano, R. P., Ruff, C. T., Braunwald, E., Murphy, S. A., Wiviott, S. D., Halperin, J. L., Waldo, A. L., Ezekowitz, M. D., Weitz, J. I., Špinar, J., Ruzyllo, W., Ruda, M., Koretsune, Y., Betcher, J., Shi, M., Grip, L. T., Patel, S. P., Patel, I., Hanyok, J. J., Mercuri, M., … ENGAGE AF-TIMI 48 Investigators (2013). Edoxaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine, 369(22), 2093–2104. https://doi.org/10.1056/NEJMoa1310907

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

24251359

Department(s)

Administration and Leadership

Document Type

Article