Project Summary / Abstract Purpose: The Rhythm Evaluation for AntiCoagulaTion with Continuous Monitoring of Atrial Fibrillation (REACT AF) clinical trial will compare the efficacy and safety of two treatment strategies for stroke prevention in atrial fibrillation (AF): the current standard of continuous direct oral anticoagulation (DOAC) versus a novel strategy of precision, time-delimited DOAC initiated only in response to a ≥ 1-hour AF episode detected by an AF-sensing smartwatch (AFSW (Apple Watch)). Rationale: Stroke risk is often temporally related to AF onset and duration, but bleeding risk continues as a constant risk of anticoagulation exposure even during long AF-free periods when stroke risk may be low. REACT- AF will evaluate the benefits and risks of withholding anticoagulation during prolonged periods of sinus rhythm as guided by an AFSW. Compared with continuous DOAC, AFSW-guided, time-delimited DOAC treatment may reduce bleeding events while maintaining stroke protection. This has potential to improve important major clinical outcomes and quality of life while reducing health care utilization. Design: REACT-AF is a multicenter prospective, randomized, open label, blinded endpoint (PROBE design) trial comparing the current standard of care of continuous DOAC administration versus time-delimited DOAC treatment guided by an AFSW in patients with a history of paroxysmal or persistent AF and low-to-moderate stroke risk (CHA2DS2-VASc score 1-4). The study will have an initial explanatory phase I followed by an explanatory phase II with pragmatic elements. Primary Aim 1 (Efficacy Objective): To assess whether AFSW-guided, time-delimited DOAC therapy is non- inferior to continuous DOAC therapy for a composite endpoint that includes: (1) Ischemic Stroke; (2) Systemic embolism; (3) All-cause mortality. Hypothesis: Time-delimited DOAC therapy is non-inferior to continuous DOAC therapy for the composite endpoint of ischemic stroke, systemic embolism, and all-cause mortality. Primary Aim 2 (Safety Objective): To assess whether AFSW-guided, time-delimited DOAC therapy significantly reduces major bleeding events compared to continuous DOAC therapy. Hypothesis: Major bleeding events will be significantly lower in participants randomized to AFSW-guided, time- delimited DOAC therapy compared with participants receiving continuous DOAC therapy. Exploratory Aim 1: To compare overall participant satisfaction with anticoagulation management between the two study arms. Exploratory Aim 2: To compare estimates of health-related resource utilization in participants randomized to control versus experimental arms.

Project Narrative Chronic, daily, oral anticoagulation reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage, including fatal hemorrhage, even during long periods of sinus rhythm when the risk of cardioembolic stroke is low. This study will compare the current standard of care of continuous anticoagulation with a novel approach of targeted, time-delimited anticoagulation therapy guided by an AF-sensing smartwatch. If successful, this paradigm shift toward individualized or “precision” stroke prevention could reduce anticoagulant use, hemorrhage risk, healthcare utilization and cost for millions of AF patients worldwide.