Physicians' Academy for Cardiovascular Education

Greater absolute reduction in safety events in the elderly with NOAC than with warfarin

Kato S et al., J Am Heart Assoc. 2016

Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF–TIMI 48 Trial

Kato ET, Giugliano RP, Ruff CT, et al.
J Am Heart Assoc. 2016;5:e003432


The prevalence of atrial fibrillation (AF) and the associated risk of embolic stroke is much higher in the elderly [1,2]. However, the use of oral anticoagulant therapy with vitamin K antagonists for the prevention of ischaemic events is limited in this age group, due to the increased bleeding risk, the multiple drug and food interactions, and the need of frequent INR monitoring [3-5].
Although the non-vitamin K oral anticoagulants (NOACs) are generally as effective as warfarin with lower major bleeding rates [6], NOACs dabigatran and rivaroxaban have a reduced safety margin with respect to bleeding in the elderly [7,8]. The therapeutic window for the direct factor Xa inhibitor edoxaban is narrower for major bleeding than for thromboembolism, since the risk of major bleeding increased more steeply with increasing edoxaban concentration than the risk of stroke or systemic embolic event (SEE) decreased [9].
In this pre-specified analysis of the ENGAGE AF-TIMI 48 study (n=21105), the efficacy and safety of edoxaban compared with warfarin was assessed stratified by age (median age: 72, IQR: 64-78, 40,2% >75 years)  [9].

Main results

  • Elderly patients were more likely to meet criteria for an edoxaban dose reduction at baseline (criteria: female gender, creatinine clearance ≤ 50 mL/min, body weight ≤ 60 kg): 41.2% in the elderly (≥75 years of age) as compared with 18.2% in patients aged 65-74 years and 10.4% in patients aged <65 years (P<0.001).
  • There was no significant effect modification by age group of the relative treatment effect of the high-dose edoxaban regimen (60 mg once daily) compared with warfarin for the primary and key secondary efficacy, safety, and net clinical outcome analyses (Pinteraction>0.05 for each comparison).
  • Event rates with warfarin increased across age groups, with stroke or SSE in 1.1%, 1.8%, and 2.3% respectively, and major bleeding in 1.8%, 3.3%, and 4.8% (Ptrend<0.001 for both).
  • When age was analysed as a continuous variable in the warfarin group, major bleeding showed a steeper slope than stroke or SSE across the range of age.
  • In the elderly (≥75 years), the rates of stroke/SSE were similar with edoxaban and warfarin (HR: 0.83; 95% CI: 0.66–1.04), while major bleeding was significantly reduced with edoxaban (HR: 0.83; 95% CI: 0.70–0.99) as compared with warfarin.
  • Exploratory analyses in very elderly groups (3591 patients aged >80 and 899 patients aged >85 years) showed that patients >80 had even higher event rates compared to patients >75 years. Efficacy and safety of edoxaban and warfarin were similar in those >80 or >85 years when compared with those younger than the respective age cut-offs.


In a pre-specified analysis from the ENGAGE AF-TIMI 48 trial, age had a greater influence on major bleeding than on thromboembolic risk in AF patients. Relative reduction of major bleeding with edoxaban treatment was similar across age groups, but considering the higher rates of bleeding in the elderly, edoxaban resulted in a greater absolute reduction in safety events compared with warfarin than in younger patients.
Find this article online at J Am Heart Assoc


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