Early Apixaban Use Following Stroke in Patients With Atrial Fibrillation: Results of the AREST Trial.

BACKGROUND AND PURPOSE: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals. METHODS: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS (<1.5 cm), and day 7 to 9 for medium-sized AIS (≥1.5 cm, excluding full cortical territory), to warfarin, in a 1:1 ratio at 1 week post-TIA, or 2 weeks post-AIS. RESULTS: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P=0.78), death (4.9% versus 8.5%, P=0.68), fatal strokes (2.4% versus 8.5%, P=0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P=0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm. CONCLUSIONS: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials. Registration: URL: https://www.clinicaltrials.gov/; Unique identifier: NCT02283294.

Complex Re-Entrant Arrhythmias Involving the His-Purkinje System: A Structured Approach to Diagnosis and Management.

OBJECTIVES: This study sought to characterize the presentations, electrophysiological features and diagnostic maneuvers for a series of unique arrhythmias involving the HPS. BACKGROUND: By virtue of its unique anatomy and ion channel composition, the His-Purkinje system (HPS) is prone to a variety of arrhythmic perturbations. METHODS: The authors present a collaborative multicenter case series of 6 patients with HPS-related arrhythmias. All patients underwent electrophysiological studies using standard multipolar catheters. RESULTS: In 3 patients, both typical and reverse bundle branch re-entry were seen, with 1 patient demonstrating "figure of 8" re-entry likely involving the septal fascicle. One patient presented with systolic dysfunction associated with a high premature ventricular complex burden, with the mechanism being bundle-to-bundle re-entrant beats masquerading as dual response to a single sinus impulse. Two patients were diagnosed with interfascicular re-entry. Diagnosis was aided by careful assessment of HV interval in sinus rhythm and ventricular tachycardia, multipolar catheters to assess the activation sequence of the His-right bundle branch, and fascicles and entrainment of different components of the HPS. Cure of the arrhythmia was achieved by ablation of the right bundle branch block in 3 patients, the left septal fascicle in 2 patients, and the left posterior fascicle in 1 patient. CONCLUSIONS: Proper diagnosis of re-entrant arrhythmias involving the HPS may prove challenging. We emphasize a structured approach for diagnosis and effective therapy.

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.

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.