Editor's Notes:
1. Commentary based on Giugliano RP, Ruff CT, Braunwald E, et al for the ENGAGE AF-TIMI 48 Investgators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
2. Edoxaban is not yet FDA-approved.

Background

Strokes occurring in the context of atrial fibrillation (AF) are associated with a 30-day mortality of 24%.¹ The effectiveness of stroke preventive therapy is challenged by the competing risk of anticoagulant-related hemorrhage and patient's ability to remain on treatment long-term. Edoxaban, an oral direct factor Xa inhibitor, was compared to warfarin in the The Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.²

Methods

This was a randomized, double-blind, double-dummy, noninf-eriority trial that enrolled patients with CHADS₂ score ≥2 into 3 treatment arms: edoxaban 60 mg per day (high dose strategy), edoxaban 30 mg per day (low dose strategy), or warfarin (INR target 2.0 to 3.0). The edoxaban dose was reduced by 50% at randomization (or during the trial) if any one of the following was present: estimated creatinine clearance 30-50 mL/min, weight 60 kg or less, or presence of a strong P-glycoprotein inhibitor (verapamil, quinidine, dronedarone). The primary efficacy endpoint was stroke/systemic embolic event (SEE). The primary safety endpoint was major hemorrhage according to the International Society on Thrombosis and Haemostasis criteria.

Results

The mean age of the 21,105 patients enrolled was 72, and the mean CHADS₂ score was 2.8. At randomization, 25% of patients had their edoxaban dose reduced (additional 7% during follow-up). Edoxaban was found to be noninferior to warfarin for the prevention of stroke/SEE: Hazard Ratio (HR) 0.87 (0.73-1.04) for high-dose edoxaban and HR 1.13 (0.96-1.34) for the low dose. Both doses were associated with marked reductions in hemorrhagic stroke: HR 0.54 (0.38-0.77) for the high dose, and HR 0.33 (0.22-0.55) for the low dose. For ischemic stroke, high-dose edoxaban was noninferior to warfarin: HR 1.00 (0.83-1.19), but low-dose edoxaban was associated with a higher rate as compared with warfarin, HR 1.41 (1.19-1.67). Major bleeds were significantly reduced in both edoxaban arms compared to warfarin: HR 0.80 (0.71-0.91) for the high dose, HR 0.47 (0.41-0.55) low dose. Gastrointestinal (GI) bleeds were increased with high-dose edoxaban, HR 1.23 (1.02-1.50). Both doses were associated with similar reductions in cardiovascular mortality, HR 0.86 (0.77-0.97).

Conclusion

Both dose strategies of edoxaban, 60 mg and 30 mg, were non-inferior to warfarin for prevention of stroke/SEE in AF. Both doses were associated with decreased risk of fatal bleeds, major bleeds, hemorrhagic stroke, and cardiovascular mortality. There was a 23% increased risk of GI bleeding with the 60 mg dose and a 41% increased risk of ischemic stroke with the lower dose strategy.

Commentary/Perspective

ENGAGE AF-TIMI 48 was the largest trial to date, achieved the highest time in the therapeutic range, mean 68%, instituted an end of trial protocol that minimized transition risk, and reported the lowest lost to follow up (n=1). The protocol-driven 50% reduction in dose contributed to the significant reduction in major bleeds, but likely resulted in loss of efficacy for the 30 mg dose. Edoxaban was consistent with the other non-vitamin K oral antagonists (NOACs) in its reduced risk of fatal and intracranial hemorrhage.^3-5 As with the higher dose of dabigatran and rivaroxaban, GI bleeding was increased with the higher dose of edoxaban. Edoxaban is a once daily therapy proven to be noninferior to warfarin for prevention of stroke in AF. Similar to the other NOACs, edoxaban is a P-glycoprotein substrate and dependent to some degree on renal clearance (~35%). Of the oral factor Xa inhibitors, it is least dependent (<4%) on CYP3A4 metabolism. Based on the results of the ENGAGE AF-TIMI 48 trial, edoxaban 60 mg daily is efficacious for the prevention of stroke. The 30 mg dose appears to be indicated for those patients who are taking a potent P-gp inhibitor, have moderate renal impairment, or weigh 60 kg or less.

References

1. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019-1026.
2. Giugliano RP, Ruff CT, Braunwald E, et al for the ENGAGE AF-TIMI 48 Investgators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104.
3. Patel MR, Mahaffey KW, Garg J, et al, and the ROCKET AF Steering Committee for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91.
4. Granger CB, Alexander JH, McMurray JJV, et al, for the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-92.
5. Connolly SJ, Ezekowitz MD, Yusuf S, et al, and the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-51.

Keywords: Anticoagulants, Creatinine, Factor Xa, Heparin, Pulmonary Embolism, Venous Thromboembolism, Warfarin

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