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

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.