Early Administration of Edoxaban After Acute Ischemic Stroke in Patients With Non-valvular Atrial Fibrillation: A Pilot Randomized Trial.

Without anticoagulation, the risk of early recurrence in the first 14 days after atrial fibrillation (AF)-related ischemic stroke is approximately 0.5%–1.3% per day. Anticoagulation is an essential strategy for preventing recurrent stroke in patients with AF-related stroke. However, it increases the incidence of intracranial hemorrhage (ICH) in the early stages of stroke. For the timing of anticoagulation, the “1–3–6–12 days rule” has been used: administration of anticoagulant at day 1 for transient ischemic attack (TIA), day 3 for mild stroke (National Institutes of Health Stroke Scale [NIHSS] <8), day 6 for moderate stroke (NIHSS 8–16), and day 12 for severe stroke (NIHSS >16). However, this rule was established when vitamin K-dependent anticoagulation was used. Non-vitamin K-dependent oral anticoagulants (NOACs) have a similar efficacy and are associated with a lower bleeding risk; they may be administered earlier than warfarin in patients with acute ischemic stroke (AIS). However, no randomized controlled trials have focused on the timing of NOAC administration in patients with AF-related AIS. The purpose of this study was to examine the feasibility and possible efficacy of NOAC administration at timepoints earlier than the conventional rules. Considering that early recurrent infarcts identified using diffusion-weighted imaging (DWI) and ICH identified using gradient-echo imaging (GRE) are common in patients with AF-related AIS, we used these imaging endpoints in this pilot study. This was a multicenter, randomized, open-label, blinded endpoint trial. Patients with AIS identified by DWI were included if they (1) were ≥20 years old, (2) had cardioembolic infarction (due to AF) identified before randomization, (3) had mild to moderately severe stroke (TIA and severe strokes were excluded), and (4) could be administered edoxaban within 48 hours of symptom onset. The exclusion criteria are summarized in Supplementary Table 1. Patients were randomized to either the conventional edoxaban treatment group (C-group) or the early edoxaban treatment group (E-group). In the C-group, a standard dose of edoxaban was administered to patients on day 3 for mild stroke and on day 6 for moderate stroke after symptom onset. Before administration of edoxaban, the use of anticoagulants was prohibited. In the E-group, a half-dose of edoxaban was administered from onset until day 3 (for mild stroke) or day 6 (for moderate stroke), and a standard dose of edoxaban was then administered as in the C-group. Baseline magnetic resonance imaging (MRI) was performed 24–48 hours after symptom onset, and follow-up MRI was performed between days 10 and 14. MRI images, including DWI, GRE, fluid-attenuated inversion recovery, and magnetic resonance angiography, were collected at the Asan Medical Center Central Image Laboratory and read by neuroradiologists blinded to treatment allocation. Thrombolysis or endovascular therapy was permitted if appropriate. Edoxaban was administered 24 hours later to patients who received thrombolysis therapy. This trial was performed in accordance with the Good Clinical Practice guidelines and approved by the Institutional Review Boards of all participating centers. Written informed consent was obtained from all patients (clinicaltrials.gov–NCT03433235). The primary outcome was the occurrence of new symptomatic Letter to the Editor Journal of Stroke 2023;25(2):311-314 https://doi.org/10.5853/jos.2023.00325