ENGAGE AF-TIMI 48

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Guigliano RP, et al. "Edoxaban versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 2013. 369(22):2093-2104.
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Clinical Question

Among patients with nonvalvular atrial fibrillation how does edoxaban, a factor Xa inhibitor, compare with warfarin in preventing stroke or systemic embolism?

Bottom Line

Among patients with nonvalvular atrial fibrillation edoxaban is superior to warfarin in preventing stroke or systemic embolism and is associated with lower rates of bleeding and death from CV events.

Major Points

The seminal SPAF trials in the 1990s established the use of warfarin as a cornerstone for stroke prevention in patients with atrial fibrillation (AF). Warfarin, a vitamin K antagonist, has been the gold standard in stroke prevention for patients with AF for many decades but is associated with numerous adverse effects owing to a narrow therapeutic margin and wide variability in dose response, necessitating frequent coagulation monitoring[1] and INR values within the therapeutic range only about 60% of the time.[2] Given the poor time in therapeutic range (TTR) and difficulty in dosing warfarin, it has been hypothesized that non-vitamin K oral anticoagulants (NOACs) may be a better alternative for preventing stroke and decreasing mortality in patients with AF. Numerous prior NOAC trials including ARISTOTLE, RE-LY, and ROCKET AF have had favorable results.

Published in 2013, the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation - Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial randomized 21,105 patients with moderate-to-high risk AF to receive warfarin, high dose edoxaban (60 mg po qday), or low dose edoxaban (30 mg po qday), respectively. With a median follow-up of 2.8 years both regimens of edoxaban were found to be non-inferior to warfarin with respect to the primary efficacy end point of stroke or systemic embolism (1.50% vs. 1.18% vs. 1.61%). However, in the intention-to-treat analysis there was an unfavorable trend in the low-dose arm of the edoxaban group. Additionally, both once-daily regimens of edoxaban were associated with significantly lower rates of bleeding and death from CV causes.

ENGAGE AF-TIMI 48 adds to the growing body of evidence favoring NOACs in the prevention of stroke in patients with nonvalvular AF. A 2014 meta-analysis of 71,683 participants in the 4 major NOAC vs. warfarin trials (ARISTOTLE, RE-LY, ROCKET AF, ENGAGE AF-TIMI 48) showed NOACs to consistently have a favorable risk-benefit profile with significant reductions in stroke, intracranial hemorrhage, and mortality.[3] For many years, the lack of a rapid and safe reversal agent for NOACs has limited the clinical use of these agents in patients with AF given the concern for an irreversible bleed. The 2015 ANNEXA trial evaluated the factor Xa inhibitor antidote andexanet alfa.

Guidelines

Please note that these guidelines did not include edoxaban. AHA/ACC/HRS AF (April 2014, adapted)[4]

  • In patients with nonvalvular AF with prior stroke, TIA, or CHA2DS2-VASc score ≥2, recommend oral anticoagulation with:
    • Warfarin, goal INR 2-3 (class I, level A)
    • Dabigatran (class I, level B)
    • Rivaroxaban (class I, level B)
    • Apixaban (class I, level B)
  • In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
  • In patients with nonvalvular AF with moderate or severe CKD with CHA2DS2-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
  • In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
  • In patients with a mechanical heart valve, do not use dabigatran (class III, level B)

Design

  • Multicenter, double-blind, double-dummy randomized controlled trial
  • N=21,105
    • High dose edoxaban (n=7,035)
    • Low dose edoxaban (n=7,034)
    • Warfarin (n=7,036)
  • Setting: 1,393 centers in 46 countries
  • Enrollment: 2008-2010
  • Median follow-up: 2.8 years
  • Primary outcome: Stroke or systemic embolism
  • Analysis: Noninferiority and modified intention-to-treat

Population

Inclusion Criteria

  • Patients >21 years with documented AF within 12 months prior to randomization
  • Score of >2 on CHADS2
  • Anticoagulation therapy planned for the duration of the trial

Exclusion Criteria

  • Atrial fibrillation due to a reversible condition
  • CrCl <30 ml/min
  • High risk of bleeding
  • Use of dual antiplatelet therapy
  • Moderate-to-severe mitral stenosis
  • Need for anticoagulation therapy outside of AF
  • ACS
  • Coronary revascularization or stroke in prior 30 days
  • Inability to adhere to study procedures

Baseline Characteristics

From the warfarin group

  • Demographics: Age 72 years, female sex 38%
  • Cardiac History: pAF 25%
    • Qualifying risk factor:
      • Age >75: 40%
      • Prior stroke or TIA: 28%
      • HF: 58%
      • DM: 36%
      • HTN: 94%
    • Mean CHADS2 score: 2.8
      • ≤3: 77%
      • 4-6: 23%
  • Dose reduction at randomization: 25%
    • CrCl <50 ml/min: 19%
    • Weight <60kg: 10%
    • Use of verapamil or quinidine: 4%
  • Medication History:
    • Previous use of vitamin K antagonist for >60 days: 59%
    • Aspirin: 30%
    • Thienopyridine: 2%
    • Amiodarone: 12%
    • Digoxin or digitalis preparation: 31%

Interventions

  • Patients were randomly assigned in a 1:1:1 ratio to a group:
    • Warfarin - dose-adjusted to INR of 2-3
    • High-dose edoxaban - 60 mg po qday
    • Low-dose edoxaban - 30 mg po qday
  • Edoxaban doses were reduced by 50% for the following reasons:
    • CrCl of 30-50 ml/min,
    • Body weight of 60kg or less, or
    • Concomitant use of verapamil or quinidine

Outcomes

Incidence presented as warfarin vs. high-dose edoxaban vs. low-dose edoxaban. Comparisons presented as high-dose edoxaban vs. warfarin | low-dose edoxaban vs. warfarin.

Primary Outcomes

Rate to first adjudicated stroke or systemic embolic event
Modified intention-to-treat: 1.50%/yr vs. 1.18%/yr vs. 1.61%/yr (RR 0.79; 95% CI 0.63-0.99; noninferiority P<0.001; superiority P=0.02 || RR 1.07; 95% CI 0.87-1.31; noninferiority P=0.005; superiority P=0.44)
Intention-to-treat: 1.80%/yr vs. 1.57%/yr vs. 2.04%/yr (RR 0.87; 95% CI 0.73-1.04; superiority P=0.08 || RR 1.13; 95% CI 0.96-1.34; superiority P=0.10)

Secondary Outcomes

Stroke, systemic embolic event, or CV mortality
4.43%/yr vs. 3.85%/yr vs. 4.23%/yr (superiority P=0.005 || superiority P=0.32)
MI, stroke, systemic embolic event, CV mortality, or bleeding mortality ("major adverse cardiac event")
4.98%/yr vs. 4.41%/yr vs. 4.90%/yr (superiority P=0.01 || superiority P=0.69)
Stroke, systemic embolic event, or all-cause mortality
5.57%/yr vs. 5.01%/yr vs. 5.23%/yr (superiority P=0.02 || superiority P=0.13)

Adverse Events

Major bleeding
3.43%/yr vs. 2.75%/yr vs. 1.61%/yr (superiority P≤0.001 || superiority P≤0.001)

Additional Outcomes

All-cause mortality
4.35%/yr vs. 4.27%/yr vs. 4.03%/yr (superiority P=0.004 || superiority ≤<0.001)

Criticisms

  • High-dose edoxaban met criteria for superiority over warfarin for the primary endpoint during the treatment period, but not during the prespecified superiority analysis for efficacy performed in the intention-to-treat population over the entire study period, making it unclear whether this regimen is truly more efficacious than warfarin.
  • Treatment interruptions more frequent in the warfarin group than in either edoxaban group, potentially overestimating the treatment effect of edoxaban.
  • Of note, no letters to the editor were published by NEJM.

Funding

  • Study funded by Daichi Sankyo Pharma Development, manufacturers of Savaysa (the name brand of edoxaban)
  • Authors with multiple financial conflicts

Further Reading

  1. Bounameaux H & Camm AJ Edoxaban: an update on the new oral direct factor Xa inhibitor. Drugs 2014. 74:1209-31.
  2. Pokorney SD et al. Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry. Am. Heart J. 2015. 170:141-8, 148.e1.
  3. Ruff CT et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014. 383:955-62.
  4. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.