Edoxaban versus Warfarin in Patients with Atrial Fibrillation

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; ENGAGE AF-TIMI 48 Investigators; Christian Hassager

doi:10.1056/NEJMoa1310907

Edoxaban versus Warfarin in Patients with Atrial Fibrillation

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 MercuriElliott M Antman, ENGAGE AF-TIMI 48 Investigators, Christian Hassager

Department of Clinical Medicine

2856 Citations (Scopus)

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.)

Original language	English
Journal	New England Journal of Medicine
Volume	369
Issue number	22
Pages (from-to)	2093-2104
Number of pages	12
ISSN	0028-4793
DOIs	https://doi.org/10.1056/NEJMoa1310907
Publication status	Published - 2013

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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., ... Hassager, C. (2013). Edoxaban versus Warfarin in Patients with Atrial Fibrillation. New England Journal of Medicine, 369(22), 2093-2104. https://doi.org/10.1056/NEJMoa1310907

Giugliano, RP, Ruff, CT, Braunwald, E, Murphy, SA, Wiviott, SD, Halperin, JL, Waldo, AL, Ezekowitz, MD, Weitz, JI, Špinar, J, Ruzyllo, W, Ruda, M, Koretsune, Y, Betcher, J, Shi, M, Grip, LT, Patel, SP, Patel, I, Hanyok, JJ, Mercuri, M, Antman, EM, Investigators, ENGAGEAF-TIMI & Hassager, C 2013, 'Edoxaban versus Warfarin in Patients with Atrial Fibrillation', New England Journal of Medicine, vol. 369, no. 22, pp. 2093-2104. https://doi.org/10.1056/NEJMoa1310907

@article{1c6b6d68f6cb48288b35ca16c769e40a,

title = "Edoxaban versus Warfarin in Patients with Atrial Fibrillation",

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.)",

author = "Giugliano, {Robert P} and Ruff, {Christian T} and Eugene Braunwald and Murphy, {Sabina A} and Wiviott, {Stephen D} and Halperin, {Jonathan L} and Waldo, {Albert L} and Ezekowitz, {Michael D} and Weitz, {Jeffrey I} and Jind{\v r}ich {\v S}pinar and Witold Ruzyllo and Mikhail Ruda and Yukihiro Koretsune and Joshua Betcher and Minggao Shi and Grip, {Laura T} and Patel, {Shirali P} and Indravadan Patel and Hanyok, {James J} and Michele Mercuri and Antman, {Elliott M} and Investigators, {ENGAGE AF-TIMI 48} and Christian Hassager",

note = "From Brigham and Women's Hospital and Harvard Medical School, Boston (R.P.G., C.T.R., E.B., S.A.M., S.D.W., L.T.G., E.M.A.); Mount Sinai Medical Center, New York (J.L.H.); University Hospitals Case Medical Center, Cleveland (A.L.W.); Thomas Jefferson Medical College, Philadelphia (M.D.E.); McMaster University, Hamilton, ON, Canada (J.I.W.); University Hospital, Jihlavska, Brno, Czech Republic (J.S.); Institute of Cardiology, Warsaw, Poland (W.R.); Cardiology Research Center, Moscow (M.R.); National Hospital Organization, Osaka National Hospital, Osaka, Japan (Y.K.); Quintiles, Durham, NC (J.B., S.P.P.); and Daiichi Sankyo Pharma Development, Edison, NJ (M.S., I.P., J.J.H., M.M.).",

year = "2013",

doi = "10.1056/NEJMoa1310907",

language = "English",

volume = "369",

pages = "2093--2104",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "22",

}

TY - JOUR

T1 - Edoxaban versus Warfarin in Patients with Atrial Fibrillation

AU - Giugliano, Robert P

AU - Ruff, Christian T

AU - Braunwald, Eugene

AU - Murphy, Sabina A

AU - Wiviott, Stephen D

AU - Halperin, Jonathan L

AU - Waldo, Albert L

AU - Ezekowitz, Michael D

AU - Weitz, Jeffrey I

AU - Špinar, Jindřich

AU - Ruzyllo, Witold

AU - Ruda, Mikhail

AU - Koretsune, Yukihiro

AU - Betcher, Joshua

AU - Shi, Minggao

AU - Grip, Laura T

AU - Patel, Shirali P

AU - Patel, Indravadan

AU - Hanyok, James J

AU - Mercuri, Michele

AU - Antman, Elliott M

AU - Investigators, ENGAGE AF-TIMI 48

AU - Hassager, Christian

N1 - From Brigham and Women's Hospital and Harvard Medical School, Boston (R.P.G., C.T.R., E.B., S.A.M., S.D.W., L.T.G., E.M.A.); Mount Sinai Medical Center, New York (J.L.H.); University Hospitals Case Medical Center, Cleveland (A.L.W.); Thomas Jefferson Medical College, Philadelphia (M.D.E.); McMaster University, Hamilton, ON, Canada (J.I.W.); University Hospital, Jihlavska, Brno, Czech Republic (J.S.); Institute of Cardiology, Warsaw, Poland (W.R.); Cardiology Research Center, Moscow (M.R.); National Hospital Organization, Osaka National Hospital, Osaka, Japan (Y.K.); Quintiles, Durham, NC (J.B., S.P.P.); and Daiichi Sankyo Pharma Development, Edison, NJ (M.S., I.P., J.J.H., M.M.).

PY - 2013

Y1 - 2013

N2 - 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.)

AB - 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.)

U2 - 10.1056/NEJMoa1310907

DO - 10.1056/NEJMoa1310907

M3 - Journal article

SN - 0028-4793

VL - 369

SP - 2093

EP - 2104

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 22

ER -

Edoxaban versus Warfarin in Patients with Atrial Fibrillation

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