Edoxaban versus warfarin in patients with atrial fibrillation

ENGAGE AF-TIMI 48 Investigators

Research output: Contribution to journalArticle

2148 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 languageEnglish
Pages (from-to)2093-2104
Number of pages12
JournalNew England Journal of Medicine
Volume369
Issue number22
DOIs
Publication statusPublished - 01-01-2013

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Warfarin
Atrial Fibrillation
Confidence Intervals
Embolism
Cause of Death
Stroke
Hemorrhage
edoxaban
Safety
Intention to Treat Analysis
Mortality
Therapeutics

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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ENGAGE AF-TIMI 48 Investigators. / Edoxaban versus warfarin in patients with atrial fibrillation. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 22. pp. 2093-2104.
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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 = "{ENGAGE AF-TIMI 48 Investigators} and 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 Jindřich Špinar 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 Luca Peruzzotti-Jametti and Yaroslav Malynovsky and Morin, {S. E.} and Hoffman, {E. B.} and N. Deenadayalu and H. Lanz and V. Curt and A. Duggal and J. Dav{\'e} and D. Morgan and Y. Choi and M. Shi and J. Jin and J. Xie and W. Crerand and J. Kappelhof and W. Maxwell and M. Skinner and G. Selicato and C. Otto and C. Reissner and K. Smith and J. Ostroske and A. Ron and S. Connolly and J. Camm and E. Paolasso and P. Aylward and H. Heidbuchel",
year = "2013",
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Edoxaban versus warfarin in patients with atrial fibrillation. / ENGAGE AF-TIMI 48 Investigators.

In: New England Journal of Medicine, Vol. 369, No. 22, 01.01.2013, p. 2093-2104.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Edoxaban versus warfarin in patients with atrial fibrillation

AU - ENGAGE AF-TIMI 48 Investigators

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 - Peruzzotti-Jametti, Luca

AU - Malynovsky, Yaroslav

AU - Morin, S. E.

AU - Hoffman, E. B.

AU - Deenadayalu, N.

AU - Lanz, H.

AU - Curt, V.

AU - Duggal, A.

AU - Davé, J.

AU - Morgan, D.

AU - Choi, Y.

AU - Shi, M.

AU - Jin, J.

AU - Xie, J.

AU - Crerand, W.

AU - Kappelhof, J.

AU - Maxwell, W.

AU - Skinner, M.

AU - Selicato, G.

AU - Otto, C.

AU - Reissner, C.

AU - Smith, K.

AU - Ostroske, J.

AU - Ron, A.

AU - Connolly, S.

AU - Camm, J.

AU - Paolasso, E.

AU - Aylward, P.

AU - Heidbuchel, H.

PY - 2013/1/1

Y1 - 2013/1/1

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.)

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U2 - 10.1056/NEJMoa1310907

DO - 10.1056/NEJMoa1310907

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

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