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

Abstract

Background: Elderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF-TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age.

Methods and results: Twenty-one thousand one-hundred and five patients enrolled in the ENGAGE AF-TIMI 48 trial were stratified into 3 prespecified age groups: <65 (n=5497), 65 to 74 (n=7134), and ≥75 (n=8474) years. Older patients were more likely to be female, with lower body weight and reduced creatinine clearance, leading to higher rates of edoxaban dose reduction (10%, 18%, and 41% for the 3 age groups, P<0.001). Stroke or systemic embolic event (1.1%, 1.8%, and 2.3%) and major bleeding (1.8%, 3.3%, and 4.8%) rates with warfarin increased across age groups (Ptrend<0.001 for both). There were no interactions between age group and randomized treatment in the primary efficacy and safety outcomes. In the elderly (≥75 years), the rates of stroke/systemic embolic event were similar with edoxaban versus warfarin (hazard ratio 0.83 [0.66-1.04]), while major bleeding was significantly reduced with edoxaban (hazard ratio 0.83 [0.70-0.99]). The absolute risk difference in major bleeding (-82 events/10 000 pt-yrs) and in intracranial hemorrhage (-73 events/10 000 pt-yrs) both favored edoxaban over warfarin in older patients.

Conclusions: Age has a greater influence on major bleeding than thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with edoxaban provides an even greater absolute reduction in safety events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients.

Clinical trial registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00781391.

Keywords: antithrombotic; bleeding; death; elderly; stroke.

Figure 1

Influence of age on outcomes (warfarin group only). Multivariable model included all baseline characteristics with univariate P<0.05 (body mass index, sex, creatinine, hypertension, dyslipidemia, diabetes, smoking, prior stroke or transient ischemic attack, heart failure, type of atrial fibrillation, race, region, increased risk of falling, risk of neuropsychiatric disease, coronary artery disease, history of hepatic disease, history of nonintracranial hemorrhage, alcohol intake, and medication predisposing to bleeding). HR indicates hazard ratio.

Figure 2

Calculated probabilities by continuous age. The outcomes were analyzed by age as a continuous variable for stroke or SEE (blue line) and major bleeding (red line). The dotted lines represent the 95% CI. SEE indicates systemic embolic event.

Figure 3

Efficacy and safety outcomes comparing the higher‐dose edoxaban regimen vs warfarin by age. Intracranial hemorrhage (ICH) and major bleeding events include primary ischemic strokes with hemorrhagic conversion. GI indicates gastrointestinal; HR indicates hazard ratio; SEE, systemic embolic event.

Figure 4

Absolute risk differences in net clinical outcomes with the higher‐dose edoxaban regimen as compared to warfarin. Primary Net Clinical Outcome: stroke, systemic embolic events, major bleeding, or death from any cause. Secondary Net Clinical Outcome: disabling stroke, life‐threatening bleeding, or death from any cause. Tertiary Net Clinical Outcome: stroke, systemic embolic events, life‐threatening bleeding, or death from any cause. Higher‐dose edoxaban regimen compared to warfarin; primary net clinical outcome; age <65 years; HR 0.99 (0.82–1.18), 65 to 74 years; 0.87 (0.76–1.00), and ≥75 years; 0.88 (0.79–0.97); P _interaction=0.48, secondary net clinical outcome age <65 years; HR 1.11 (0.89–1.37), 65 to 74 years; 0.81 (0.69–0.96), and ≥75 years; 0.86 (0.76–0.97); P _interaction=0.07, tertiary net clinical outcomes; age <65 years; HR 1.1 (0.85–1.28), 65 to 74 years; 0.83 (0.71–0.97), and ≥75 years; 0.85 (0.76–0.97); P _interaction=0.16. *P<0.05 for comparison vs warfarin. HDER indicates higher‐dose edoxaban regimen; HR, hazard ratio; Pt‐yr, patient years; yr, years.