Protocol for AREST: Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation—A Randomized Controlled Trial of Early Anticoagulation After Acute Ischemic Stroke in Atrial Fibrillation

Abstract

Background: Optimal timing to initiate anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF) is currently unknown. Compared to other stroke etiologies, AF typically provokes larger infarct volumes and greater concern of hemorrhagic transformation, so seminal randomized trials waited weeks to months to begin anticoagulation after initial stroke. Subsequent data are limited and non-randomized. Guidelines suggest anticoagulation initiation windows between 3 and 14 days post-stroke, with Class IIa recommendations, and level of evidence B in the USA and C in Europe.Aims: This open-label, parallel-group, multi-center, randomized controlled trial AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) is designed to evaluate the safety and efficacy of early anticoagulation, based on stroke size, secondary prevention of ischemic stroke, and risks of subsequent hemorrhagic transformation.Methods: Subjects are randomly assigned in a 1:1 ratio to receive early apixaban at day 0–3 for transient ischemic attack (TIA), 3–5 for small-sized AIS (<1.5 cm), and 7–9 for medium-sized AIS (1.5 cm or greater but less than a full cortical territory), or warfarin at 1 week post-TIA or 2 weeks post-stroke. Large AISs are excluded.Study Outcomes: Primary: recurrent ischemic stroke, TIA, and fatal stroke; secondary: intracranial hemorrhage (ICH); hemorrhagic transformation (HT) of ischemic stroke; cerebral microbleeds (CMBs); neurologic disability [e.g., modified Rankin Scores (mRS), National Institutes of Health Stroke Scale (NIHSS), Stroke Specific Quality of Life scale (SS-QOL)]; and cardiac biomarkers [e.g., AF burden, transthoracic echo (TTE)/transesophageal echo (TEE) abnormalities].Sample Size Estimates: Enrollment goal was 120 for 80% power (two-sided type I error rate of 0.05) to detect an absolute risk reduction of 16.5% postulated to occur with apixaban in the primary composite outcome of fatal stroke/recurrent ischemic stroke/TIA within 180 days. Enrollment was suspended at 91 subjects in 2019 after a focused guideline update recommended direct oral anticoagulants (DOACs) over warfarin in AF, excepting valvular disease (Class I, level of evidence A).Discussion: AREST will offer randomized controlled trial data about timeliness and safety of anticoagulation in AIS patients with AF.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02283294.

Protocol for LASER: A Randomized Evaluation and an Associated Registry of Early Anticoagulation With Edoxaban After Ischemic Stroke in Patients With Atrial Fibrillation

“…While encouraging with respect to the safety of early DOAC initiation, these studies are far from definitive. Several trial protocols have been published and/or registered for the safety and efficacy of early vs. delayed anticoagulation after ischemic stroke in patients with AF (26)(27)(28). Patients in these trials are randomized to DOAC initiation as early as 24 h and up to 5 days after onset, or delayed initiation 6-14 days.…”

Prognostic analysis of atrial fibrillation patients with acute cerebral infarction: a retrospective study of 330 cases over a 10-year period

“…The National Institutes of Health Stroke Scale (NIHSS) was used to evaluate the severity of stroke symptoms at admission, which was divided into two grades: scores of ≤ 10 and > 10 [5]. Based on the maximum diameter of the infarct area involving anterior or posterior circulation on brain MRI or CT, large-, medium-and small-size infarction were > 3.0, 3.0-1.5 and < 1.5 cm, respectively [6,7]. Subtypes of HT were de ned as follows: hemorrhagic infarction (HI)-1 with scattered, heterogeneous petechiae along the margins of the infarct; HI-2 with more con uent but still heterogeneous petechiae within the infarct area; parenchymal hematoma (PH)-1 with a homogeneous hematoma covering < 30% of the infarct area and only mild space-occupying effect; and PH-2 with a dense hematoma > 30% of the lesion volume with signi cant space-occupying effect [8].…”

Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation

“…AREST design details were previously published. 19 The AREST randomization target was 120 patients to provide a detailed assessment of safety of apixaban, and while not powered specifically for efficacy, to have 80% power to detect a potential absolute risk reduction of 16.5% with apixaban compared with warfarin therapy. Eligible subjects included individuals ≥18 years, with a new ischemic stroke or a TIA diagnosed within 48 hours of symptom onset, plus historical or newly diagnosed AF by ECG, telemetry, or other cardiac electronic device, such as insertable loop recorders or wearable patch.…”

“…17,18 Thus, we conducted the investigator-initiated, randomized, open-label AREST study (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation), to examine early DOAC use at prespecified timepoints based on stroke size, versus conventional VKA at 14 days, or 7 days for TIA. 19…”