Edoxaban Versus Warfarin for Patients with AF

Dallas—A randomized, double-blind trial that included patients with atrial fibrillation (AF) found that 2, once-daily doses of edoxaban were noninferior to warfarin in preventing strokes or systemic embolic events. Patients who received edoxaban also had a significant reduction in major bleeding, intracranial hemorrhage, hemorrhagic stroke, and cardiovascular death.

The annualized rate of strokes or systemic embolic events was 1.5% in the warfarin group, 1.18% in the high-dose edoxaban (60 mg once daily) group, and 1.61% in the low-dose edoxaban (30 mg once daily) group.

Major bleeding was reduced 20% with high-dose edoxaban and 53% with low-dose edoxaban compared with warfarin, while cardiovascular death was reduced 14% with high-dose edoxaban and 15% with low-dose edoxaban compared with warfarin.

With a median follow up of 2.8 years, this was the longest trial for a novel anticoagulant for AF, according to Robert Giugliano, MD, lead author of the study. Dr. Giugliano presented the results at the AHA Scientific Sessions during a late-breaking abstract session. The findings were also published in New England Journal of Medicine [2013;369(22):2093-2104]. Daiichi Sankyo, manufacturer of edoxaban, sponsored the study.

Dr. Giugliano said that warfarin reduces strokes by 64% compared with placebo in patients with AF, although the medication increases bleeding and has several limitations. He added that 3 novel anticoagulants have been found to be at least as effective as warfarin, and the drugs also reduce hemorrhagic stroke by 51%. The FDA has approved all 3 anticoagulants (apixaban, dabigatran, and rivaroxaban) since 2010.

Edoxaban is a once daily investigational direct oral factor Xa inhibitor with a rapid onset of action. Daiichi Sankyo may file a new drug application with the FDA this year for edoxaban’s approval.

In the ENGAGE AF-TIMI 48 [Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation] trial, the authors enrolled 21,105 patients at 1393 centers in 46 countries who had documented AF within the past 12 months and were at moderate to high risk of stroke based on a CHADS₂ score of 2 or higher. Patients were randomized to receive warfarin, high-dose edoxaban, or low-dose edoxaban. Dr. Giugliano said the edoxaban doses were adjusted based on anticipated clearance.

The groups were well balanced. The median age was 72 years, 38% of patients were females, 25% had paroxysmal AF, 59% had previous experience with vitamin K antagonists, and 25% underwent dose reduction at randomization.

The annualized rate of major bleeding was 3.43% in the warfarin group, 2.75% in the high-dose edoxaban group, and 1.61% in the low-dose edoxaban group. The annualized rate of death from causes was 3.17% in the warfarin group, 2.74% in the high-dose edoxaban group, and 2.71% in the low-dose edoxaban group. Fatal bleeding and intracranial hemorrhage were also reduced if patients received edoxaban.

Compared with warfarin, both doses of edoxaban reduced the combination of stroke, systemic embolic events, death, and major bleeding, as well as the combination of disabling stroke, life-threatening bleeding and death and the combination of stroke, systemic embolic events, life-threatening bleeding, and death.

Edoxaban was also well tolerated. Significantly more patients who received edoxaban completed the trial without interruption compared with those who received warfarin. There was no difference in severe adverse events and liver function abnormalities.