Mortality Risk With Edoxaban vs. Warfarin in Atrial Fibrillation

Study Questions:

What are potential explanations for mortality benefit associated with edoxaban versus warfarin therapy among patients with atrial fibrillation (AF)?


In a post hoc analysis of the ENGAGE AF-TIMI 48 study, where AF patients were randomized to edoxaban or warfarin therapy for stroke prevention, the cause of death was explored over a median follow-up of 2.8 years. Cause of death was categorized as cardiovascular, malignancy-related, major bleeding-related, or other.


Among 21,105 AF patients, there were 839 total deaths (4.35% per year) in the warfarin arm, 773 (3.99% per year, p = 0.08 vs. warfarin) in the higher-dose edoxaban arm, and 737 (3.8% per year, p = 0.06 vs. warfarin) in the lower-dose edoxaban arm. There were no differences between treatment groups for any of the three most common causes of cardiovascular death (sudden cardiac, heart failure, ischemic stroke), fatal malignancy, or other noncardiovascular death. There were 124 fatal bleeding events (65 with warfarin, 35 with high-dose edoxaban [p = 0.003], 24 with low-dose edoxaban [p < 0.001]). The majority of fatal bleeding cases were intracranial bleeding at a rate of 0.27% per year (warfarin), 0.15% per year (high-dose edoxaban, p = 0.012 vs. warfarin), and 0.07% per year (low-dose edoxaban, p < 0.001 vs. warfarin).


The authors concluded that lower mortality rates in the edoxaban-treated arms of the ENGAGE AF-TIMI 48 study were driven largely by lower rates of major bleeding as compared to warfarin-treated AF patients.


Most analyses of the phase 3 direct oral anticoagulant AF trials have demonstrated a consistent reduction in major bleeding risk among direct oral anticoagulant (DOAC)-treated patients versus warfarin-treated patients. This is particularly true for the intracranial bleeding, which is often fatal. However, only the ENGAGE AF-TIMI 48 study (edoxaban vs. warfarin) and the ARISTOTLE study (apixaban vs. warfarin) were able to demonstrate mortality benefit with DOAC therapy. Both studies also demonstrated lower rates of major and intracranial bleeding with DOAC therapy, which likely explain the mortality benefit. Real-world data to confirm these findings are greatly anticipated.

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