Timing of DOAC Initiation After Atrial Fibrillation-Related Acute Ischemic Stroke: A Unified Protocol Harmonizing Clinical Safety and Imaging-Based Precision in the Post-CATALYST Era

Atrial fibrillation-related ischemic strokes carry a high risk of early recurrence. Historically, anticoagulation was delayed by conservative 1-3-6-12 day rules necessitated by the hemorrhagic risks of Vitamin K Antagonists. The 2025 CATALYST individual participant data meta-analysis and recent trials (ELAN, OPTIMAS, TIMING) have now established the safety of ultra-early direct oral anticoagulant initiation within four days. Yet clinicians still face the challenge of reconciling clinical severity with radiological findings, and critical distinctions between trial-level evidence and pooled meta-analytic inferences require explicit navigation. This narrative review synthesizes landmark evidence into a practical framework that bridges high-level safety data and imaging-based precision. We present a unified seven-step clinical protocol for direct oral anticoagulant initiation that distinguishes evidence sources, prioritizing more conservative estimates when findings diverge. The protocol utilizes CATALYST safety criteria for screening while adopting ELAN's radiological infarct size tiers to dictate precise timing within a 0-4 day Safe Zone - interpreted as a target range, not a maximum threshold. Key innovations include tiered hemorrhagic transformation management, validating early initiation in petechial infarction (HI1/HI2) while mandating delay for parenchymal hematomas (Days 6-7 for PH1; ≥4 weeks for PH2); integrated safety failsafe’s, including the Conservative Discordance rule to mitigate inter-reader variability and a categorical prohibition of antiplatelet bridging; and dynamic post-initiation monitoring emphasizing renal re-evaluation and an anticoagulant-only transition at discharge. Synthesis confirms that direct oral anticoagulants offer superior safety over Vitamin K Antagonists, though a hierarchy of bleeding risk among agents informs drug selection without altering the timing window. The post-CATALYST era marks a definitive shift toward a streamlined, direct oral anticoagulant-first approach, though important uncertainties remain for patients with severe stroke, extremely large infarcts, extensive hemorrhagic transformation, pre-existing disability, or multiple exclusion risks-populations where evidence is insufficient and shared decision-making is essential. This unified seven-step protocol provides an actionable framework for the multidisciplinary stroke team, replacing outdated Vitamin K Antagonist-era rules and hazardous antiplatelet bridging with individualized, imaging-directed care.