Association of Edoxaban Pharmacokinetics With Bleeding in Older Patients With Atrial Fibrillation Treated With Low-Dose Edoxaban: A Post Hoc Analysis of a Randomized Controlled Trial

Clinical Snapshot

Key Findings

• P Value: P=0.0408 for trend across quartiles; P=0.0060 for PT >13s vs ≤13s

• Effect Size: 6-fold increase in bleeding risk from lowest to highest quartile

• Primary Outcome: Major bleeding incidence across edoxaban trough concentration quartiles: 0.8%, 1.9%, 3.4%, and 4.7% per year

• Nnt Or Sensitivity: PT >13 seconds associated with 4.7-fold higher bleeding rate (4.61% vs 0.98%/year)

• Confidence Interval: Not reported for bleeding rates

Clinical Application

PT monitoring is readily available and cost-effective; trough level monitoring requires specialized laboratory facilities Edoxaban 15mg not currently PBS-listed in Australia; standard doses (30mg/60mg) are available. Results may inform TGA considerations for lower doses in elderly populations Elderly patients (≥80 years) with atrial fibrillation on low-dose edoxaban, particularly those with multiple comorbidities

Abstract

BACKGROUND: Edoxaban is a direct oral anticoagulant used for stroke prevention in patients with atrial fibrillation (AF) and treatment of venous thromboembolism. We examined the relationship between trough edoxaban concentrations (E-trough) and prothrombin time (PT) and major bleeding in very old Japanese patients with atrial fibrillation and high bleeding risk. METHODS: In this post hoc analysis of the multicenter, randomized, double-blind, placebo-controlled ELDERCARE-AF (Study of DU-176b Aged 80 Years or Older) trial, patients were randomly assigned 1:1 to edoxaban 15 mg or placebo once daily. After 8 weeks of treatment, E-trough was determined and the incidence of major bleeding examined in each quartile. The incidence of major bleeding by PT was also examined. RESULTS: Data were obtained from 427 patients. E-trough (ng/mL) was ≤9.24 in the first quartile (107 patients), >9.24 to ≤13.6 in the second (111 patients), >13.6 to ≤21.6 in the third (103 patients), and >21.6 in the fourth (106 patients). Older age, lower body weight, lower creatinine clearance, and the presence of congestive heart failure were independent predictors of higher E-trough. Higher E-trough was associated with greater incidence of major bleeding (0.8%, 1.9%, 3.4%, and 4.7%/year, respectively, P=0.0408). There was a significant positive correlation between E-trough and PT (r=0.426, P<0.0001). Significantly more major bleeding events occurred in the longer (>13 seconds) versus shorter (≤13 seconds) PT subgroups (4.61% versus 0.98%/year, P=0.0060). CONCLUSIONS: Several factors were associated with higher E-trough and increased risk of major bleeding events. PT >13 seconds may be a useful predictor of the development of major bleeding. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02801669.

References

1. 1.Okumura, K., Akao, M., Fukuzawa, M., Igawa, Y., Hayashi, T., & Yamashita, T. (2026). Association of Edoxaban Pharmacokinetics With Bleeding in Older Patients With Atrial Fibrillation Treated With Low-Dose Edoxaban: A Post Hoc Analysis of a Randomized Controlled Trial. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.125.042950