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

Background

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.

Conclusion

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

References

1. Feigin VL, Forouzanfar MH, Krishnamurthi R, et al; Global Burden of Diseases I, Risk Factors S, the GBDSEG. Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet. 2014;383:245–254.
2. Go AS, Hylek EM, Phillips KA, Chang Y, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA. 2001;285:2370–2375.
3. Perera V, Bajorek BV, Matthews S, et al. The impact of frailty on the utilisation of antithrombotic therapy in older patients with atrial fibrillation. Age Ageing. 2009;38:156–162.
4. Scowcroft AC, Lee S, Mant J. Thromboprophylaxis of elderly patients with AF in the UK: an analysis using the general practice research database (GPRD) 2000–2009. Heart. 2013;99:127–132.
5. Hylek EM, D’Antonio J, Evans-Molina C, et al. Translating the results of randomized trials into clinical practice: the challenge of warfarin candidacy among hospitalized elderly patients with atrial
fibrillation. Stroke. 2006;37:1075–1080.
6. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–962.
7. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RELY) trial. Circulation. 2011;123:2363–2372.
8. Halperin JL, Hankey GJ, Wojdyla DM, et al; Committee RAS Investigators. Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation.2014;130:138–146.
9. Ruff CT, Giugliano RP, Braunwald E, et al. Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, doubleblind ENGAGE AF-TIMI 48 trial. Lancet. 2015;385:2288–2295.