Rationale and design of Triple AXEL: trial for early anticoagulation in acute ischemic stroke patients with nonvalvular atrial fibrillation

Rationale: Patients with atrial fibrillation (AF) in the acute stage of ischemic stroke or transient ischemic attack (TIA) are at high risk of recurrent stroke, but the optimal anticoagulation strategy remains unclear due to the concern of intracranial bleeding. Novel oral anticoagulants compared to warfarin might be more safe and efficacious in patients suitable for early anticoagulation.

Aims: This trial is to evaluate the feasibility of early anticoagulation with rivaroxaban in acute ischemic stroke or TIA patients with nonvalvular AF.

Design: This is a randomized, open-label, blinded endpoint evaluation trial. Inclusion criteria are (1) nonvalvular AF, (2) presumed cardioembolic stroke or transient ischemic attack (TIA) confirmed by MRI within five-days from onset, and (3) mild to moderate stroke severity. We will randomize 196 patients to either rivaroxaban (10 mg once daily for five-days followed by 15 mg or 20 mg once daily) or dose-adjusted warfarin (coadministration of aspirin 100 mg per day until achieving international normalized ratio of 1·7). The study is registered in ClinicalTrials.gov (NCT02042534).

Study outcomes: The primary endpoint is the composite of recurrent ischemic lesion and intracranial bleeding on MRI at four-weeks. Secondary endpoints are recurrent ischemic lesions, intracranial bleeding, major bleeding, major vascular events, four-week modified Rankin Scale score, and duration of hospitalization after randomization.

Discussion: The results of this proof-of-concept trial will guide go/no-go decision to a large phase 3 confirmatory trial.