Clinical Relevance of Concomitant Large Artery Steno-occlusion and Risk of Recurrent Stroke in Atrial Fibrillation

Abstract Background Recurrent ischemic stroke remains a major concern in patients with nonvalvular atrial fibrillation (NVAF) despite anticoagulation. However, not all NVAF-related strokes are purely cardioembolic—concomitant large artery steno-occlusion (cLASO) is frequently observed and may represent an independent contributor to stroke recurrence. Current guidelines address these cases but focusing almost exclusively on the cardioembolic source. This approach contrasts sharply with the management of acute coronary syndrome in patients with NVAF, where identifying and targeting the ’culprit lesion’ is standard practice. We evaluated whether the presence and clinical relevance of cLASO predict stroke recurrence in NVAF-related acute ischemic stroke (AIS). Methods This prospective multicenter cohort study enrolled 2,035 patients with NVAF-related AIS at 14 stroke centers in South Korea between October 2017 and April 2020. Patients underwent brain magnetic resonance imaging and angiography. cLASO, defined as any degree of stenosis or occlusion in major cerebral arteries, was categorized by anatomical severity (mild, moderate-to-severe, or occlusion) and clinical relevance. Clinically relevant cLASO was defined as a steno-occlusive lesion topographically concordant with the infarction, thereby sufficiently explaining the index stroke regardless of concurrent cardioembolic source; otherwise, lesions were classified as bystander. The primary outcome was recurrent ischemic stroke within 3 years, analyzed using competing risk analysis. Results Among 2,035 patients (mean age, 74.9 years; 54.8% male), 1,308 (64.3%) had cLASO, and 583 (28.6%) had clinically relevant cLASO. The 3-year cumulative incidence of recurrent ischemic stroke was 7.0%, with over 40% of recurrences occurring within the first month. Recurrence risk increased significantly with cLASO presence (4.5% vs. 8.1%), severity (mild, 5.7%; moderate-to-severe, 9.7%; occlusion, 9.1%) and clinical relevance (bystander, 3.8%; relevant, 13.9%) (all P’s < 0.05). In multivariable analysis, clinical relevance—rather than severity—was independently associated with recurrence (aHR, 4.10; 95% CI, 2.57-6.54). Conclusions Clinically relevant cLASO identifies a mechanistically distinct, high-risk phenotype that warrants a paradigm shift from a uniform cardioembolic model toward a ’lesion-specific approach. The early clustering of recurrence suggests an urgent window for intervention. This well-characterized phenotype may represent a potential target population for future trials evaluating intensified antithrombotic strategies that address both cardioembolic and atherothrombotic pathways. Clinical Perspective What is New? Two-thirds of patients with AF-related stroke harbor concomitant large artery steno-occlusion (cLASO), yet current guidelines provide no recommendations for this common dual-mechanism scenario This prospective multicenter study introduces a novel classification distinguishing clinically relevant cLASO from bystander atherosclerosis; only clinical relevance—not anatomic severity—independently predicted stroke recurrence, conferring a fourfold increased risk. Over 40% of recurrences occurred within the first month, with relevant cLASO conferring a 6.0% early recurrence risk—substantially exceeding reported annual major hemorrhage risks in landmark anticoagulant trials. What Are the Clinical Implications? AF-related stroke is mechanistically heterogeneous; assuming all cases are cardioembolic may lead to suboptimal risk stratification and missed opportunities for targeted prevention. Routine vascular imaging should assess not merely stenosis severity, but topographic concordance with the infarct pattern—a straightforward approach using standard DWI and MRA that can be applied in diverse healthcare settings. The early clustering of recurrence in patients with relevant cLASO highlights a critical unmet need and identifies a well-characterized target population for future trials evaluating intensified antithrombotic strategies.