ENGAGE AF-TIMI 48

Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation (2013)

Condition

Prevention of stroke and systemic embolism in patients with AF

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Objective

To determine if two once-daily regimens (60 mg high-dose strategy and 30 mg low-dose strategy) of edoxaban were non-inferior to warfarin with respect to the composite primary efficacy endpoint of stroke (ischemic or hemorrhagic) and systemic embolic events in patients with non-valvular atrial fibrillation

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Trial design

Randomized, double-blind, double-dummy phase III non-inferiority study; median duration of treatment exposure 907 days, mean duration of follow-up 1022 days (2.8 years)
Active treatment: edoxaban 60 mg (n=7035) or 30 mg (n=7034) p.o. once daily. The dose was halved if any of the following characteristics were present: estimated creatinine clearance of 30–50 ml/min, body weight of ≤60 kg, concomitant use of potent P-glycoprotein inhibitors
Control treatment: warfarin (INR 2.0–3.0; n=7036) once daily

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Endpoints

Primary efficacy endpoint: stroke (ischemic or hemorrhagic) or systemic embolic event during treatment
Primary safety endpoint: major bleeding during treatment
Secondary composite endpoints:

  • stroke, systemic embolic event, or death from cardiovascular causes (including bleeding)
  • major adverse cardiac event (myocardial infarction, stroke, systemic embolic event, or death due to cardiovascular causes or bleeding)
  • stroke, systemic embolic event, or death from any cause

Other composite endpoints (net clinical outcome):

  • stroke, systemic embolic event, major bleeding, or death
  • disabling stroke, life-threatening bleeding, or death
  • stroke, systemic embolic event, life-threatening bleeding, or death

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Trial participants

21,105 patients ≥21 years (mean age 72 years) with AF within the prior 12 months and with moderate to-high-risk atrial fibrillation (CHADS2 risk score ≥2)

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Results

Efficacy outcome: During the treatment period, the primary endpoint (stroke or systemic embolic event) occurred in 232 patients in the warfarin group (representing a rate of 1.50% per year), as compared with 182 patients in the high-dose edoxaban group (1.18% per year; hazard ratio vs. warfarin, 0.79; p<0.001 for non-inferiority) and 253 patients in the low-dose edoxaban group (1.61% per year; hazard ratio vs. warfarin, 1.07; p=0.005 for non-inferiority). In the intention-to-treat analysis (data from the overall study period), there was a trend favoring high-dose edoxaban versus warfarin (1.57% vs. 1.80%; hazard ratio 0.87; p=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (2.04% vs. 1,80%; hazard ratio 1.13; p=0.10). The annualized rate of hemorrhagic stroke was 0.47% in the warfarin group, as compared with 0.26% with high-dose edoxaban (p<0.001) and 0.16% with low-dose edoxaban (p<0.001). The rate of ischemic stroke was 1.25% with warfarin as compared with 1.25% with high-dose edoxaban (p=0.97) and 1.77% with low-dose edoxaban (p<0.001)
Safety outcome: The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio 0.80; p<0.001) and 1.61% with low-dose edoxaban (hazard ratio 0.47; p<0.001)
Composite outcomes: The rates of all three prespecified secondary composite outcomes were significantly lower with high-dose edoxaban than with warfarin; there were no significant differences between low-dose edoxaban and warfarin in the rates of those outcomes. The annualized rate of the primary net clinical outcome (composite of stroke, systemic embolic event, major bleeding, or death from any cause) was significantly lower with both edoxaban regimens than with warfarin: 8.11% with warfarin, as compared with 7.26% with high-dose edoxaban (hazard ratio 0.89; p=0.003) and 6.79% with low dose-edoxaban (hazard ratio 0.83; p<0.001)

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Summary

Efficacy outcome: Both once-daily regimens of edoxaban were non-inferior to warfarin with respect to the prevention of stroke or systemic embolism; the high-dose edoxaban regimen tended to be more effective than warfarin
Safety outcome: As compared with warfarin, edoxaban was associated with consistently lower, dose-related rates of major bleeding, intracranial bleeding, and life-threatening bleeding. The single exception was gastrointestinal bleeding, which occurred more frequently with high-dose edoxaban but less frequently with low-dose edoxaban than it did with warfarin
Composite outcomes: The rates of net clinical outcomes (composites of cardiovascular events, death from any cause, or bleeding) were significantly lower with both edoxaban regimens than with warfarin

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Reference

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; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-2104

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Corresponding author

Dr. Robert P. Giugliano, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, TIMI Study Group, 350 Longwood Ave., 1st. Flr., Boston, MA 02115, rgiugliano@partners.org

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