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Efficacy, Safety of Edoxaban by AF Subtype: An Analysis From ENGAGE AF-TIMI 48


Post hoc analysis of the ENGAGE AF-TIMI 48 study looked at safety and efficacy of a novel oral anticoagulant in distinct groups with paroxysmal, persistent, or permanent atrial fibrillation.

The ENGAGE AF-TIMI 48 study1 was a double-blind randomized study of 21,105 patients with atrial fibrillation (AF) who received either one of two once-daily doses of the direct factor Xa inhibitor edoxaban or warfarin and were followed for a median of 2.8 years. The results demonstrated noninferiority of both doses of edoxaban with respect to stroke/systemic embolism with significantly lower rates of death from cardiovascular causes and bleeding. 

Clinical trials, such as ENGAGE AF-TIMI 48, that study AF often pool patients with paroxysmal, persistent, and permanent AF. However, these patient populations and the clinical phenotypes of AF are quite distinct, clinically and pathophysiologically. Whether the efficacy and safety profile of the novel oral anticoagulants (NOACs) in these clinically distinct subtypes of patients is different from results in the pooled population has not been previously reported. 

In a late-breaking clinical trial presented at the Heart Rhythm Society meeting in March 2014 in San Francisco, Giugliano and colleagues from the TIMI Study Group presented a post hoc analysis from ENGAGE AF-TIMI 48.2 Patients were divided into groups by AF subtypes: paroxysmal AF (<7 days), persistent AF (7 days to <1 year), or permanent AF (>1 year or failed cardioversion). Researchers sought to compare the safety and efficacy of edoxaban (both doses) with that of warfarin across the AF subtypes. 

There were more women with paroxysmal AF (45%) compared with persistent (38%) or permanent (35%) AF. In addition, the paroxysmal AF subtype group had fewer patients with CHADS2 scores >3 (20%); more diabetics (38%); and more individuals receiving aspirin (36%) and amiodarone (19%) in a 3-way analysis comparing them with the persistent and permanent AF subtypes. The rates of stroke/systemic embolism (HR = 0.76), ischemic stroke (HR = 0.77), cardiovascular death (HR = 0.65), and all-cause mortality (HR = 0.68) were lower in those with paroxysmal AF compared with those with permanent AF. Although there was no difference in the occurrence of hemorrhagic stroke, intracranial hemorrhage, fatal bleeding, or major bleeding across subtypes, there was an increase in the composite of major bleeding/clinically relevant non-major bleeding (HR = 1.17) and as a result, an increase in all bleeding (HR = 1.19). Edoxaban remained superior to warfarin in terms of efficacy and safety across all AF subtypes. (Note: Edoxaban is not yet approved by the US FDA; a new drug application was submitted in January 2014.)

There is some heterogeneity across AF subtypes, with more clinically relevant non-major bleeding observed in those with paroxysmal AF. The underlying mechanisms remain unclear but according to these results, the efficacy and safety of edoxaban is preserved across all types of AF. This study suggests that edoxaban is a reasonable alternative to warfarin in all subtypes of AF. Furthermore, since edoxaban decreases bleeding compared with warfarin, it may therefore be a more desirable option in those with paroxysmal AF, who are slightly more prone to bleeding. Whether these results can be extrapolated to the other NOACs remains to be seen, and additional such analyses with these agents are needed.


  • Giugliano RP, Ruff CT, Braunwald E, et al for the ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013; 369:2093-2104. 
  • Giugliano RP. Baseline characteristics, outcomes and comparison of edoxaban vs. warfarin by AF subtype in 21,105 patients enrolled in the ENGAGE-AF TIMI 38 trial. Late Breaking Clinical Trial 02-04, presented May 9, 2014, HRS Scientific Session, San Francisco, CA.

For additional information Trial Summary ENGAGE AF-TIMI 48

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