Very old AF patients in Japan benefit from very low-dose DOAC
Effect of 15-mg Edoxaban on Clinical Outcomes in 3 Age Strata in Older Patients With Atrial Fibrillation – A Prespecified Subanalysis of the ELDERCARE–AF Randomized Clinical Trial
Introduction and methods
To prevent cardioembolic stroke in patients with AF, clinical guidelines recommend using direct oral anticoagulants (DOACs ), even in the elderly [1,2]. In the ELDER-CARE-AF (Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients) trial, very low-dose edoxaban (15 mg) reduced the incidence of stroke or systemic embolism compared to placebo in older Japanese patients (≥80 years) with AF, without a significant difference in bleeding between the two arms. However, the effectiveness and safety of DOACs in extremely old AF patients (≥90 years) with a high bleeding risk still need to be elucidated.
Aim of the study
The study aim was to assess the effects of very low-dose edoxaban (15 mg) across three age strata (80–84 years, 85–89 years, and ≥90 years) of AF patients who took part in the ELDERCARE-AF trial.
This was a prespecified subanalysis of the ELDERCARE-AF trial. In this multicenter, double-blind, placebo-controlled, phase 3 RCT conducted in Japan from August 2016 to December 2019, 984 AF patients who were not considered candidates for a standard OAC regimen were randomized (1:1 ratio) to edoxaban 15 mg once daily or placebo .
Inclusion criteria were: aged ≥80 years; history of AF documented within 1 year of consent; CHADS2 score ≥2 points; and ineligibility for standard-dose OACs due to increased bleeding risk (f.e., creatinine clearance <30 mL/min, or history of bleeding from a critical area/organ or gastrointestinal bleeding). Exclusion criteria were moderate-severe mitral stenosis and/or mechanical heart valves, among others.
The primary efficacy endpoint was the composite outcome of stroke and systemic embolism. The primary safety endpoint was major bleeding according to the International Society on Thrombosis and Hemostasis criteria.
- In the placebo group, the estimated event rate(SE ) of stroke or systemic embolism increased with age: 3.9% (1.2%) per patient-year in the group aged 80–84 years (n=181), 7.3% (1.7%) per patient-year in the 85–89 year age group (n=184), and 10.1% (2.5%) per patient-year in the ≥90 year age group (n=127).
- Edoxaban treatment decreased the event rates of stroke or systemic embolism compared with placebo, with no interaction with age. The hazard ratio (HR) was 0.41 (95% CI: 0.13–1.31; P=0.13) in the 80–84 year age group (n=173), 0.42 (95% CI: 0.17–0.99; P=0.05) in the 85–89 year age group (n=190), and 0.23 (95% CI: 0.08–0.68; P=0.008) in the ≥90 year age group (n=129) (interaction P=0.65).
- In both the placebo and edoxaban groups, the incidence of all-cause death increased with age, but there were no differences between the two treatment groups in all age subgroups.
- In the placebo group, the event rates of major bleeding were 0.4% per patient-year in the 80–84 year age group, 3.0% per patient-year in the 85–89 year age group, and 2.1% per patient-year in the ≥90 year age group.
- In the edoxaban group, the event rates of major bleeding were 2.2%, 2.2%, and 6.5% per patient-year, respectively. There was no interaction with age (HR for 80–84 years: 5.27; 95% CI: 0.61–45.36; P=0.13; HR for 85–89 years: 0.74; 95% CI: 0.24–2.33; P=0.61; HR for ≥90 years: 3.02; 95% CI: 0.82–11.21; P=0.10; interaction P=0.15).
- The incidence of gastrointestinal bleeding—a major bleeding event—only reached statistical significance in the oldest stratum (placebo vs. edoxaban: 0.7% vs. 5.9% per patient-year; HR: 8.37; 95% CI: 1.04–67.07; P=0.05).
- Although the incidence of major or clinically relevant nonmajor bleeding was numerically higher in the edoxaban than in the placebo group, there were no statistically significant differences between the two groups in the age subgroups and there was no interaction with age.
- There was no fatal bleeding in the edoxaban group.
In Japanese AF patients aged ≥80 years who were not eligible for standard OAC therapy, edoxaban 15 mg was superior to placebo in preventing stroke or systemic embolism in all tree age strata. The numbers of major bleeding and major or clinically relevant nonmajor bleeding events were not significantly, albeit numerically, higher with edoxaban. The authors warn that care should be taken when applying these results to other ethnic populations.