Abstract Body (Do not enter title and authors here): Introduction: Cancer induces a prothrombotic state through multiple mechanisms. Although patients with cancer are at increased risk of thromboembolism, stroke risk stratification tools in atrial fibrillation (AF) patients have historically excluded malignancy and may underestimate overall risk.

Hypothesis: Patients with AF and cancer have increased stroke incidence compared to those without cancer after adjusting for established risk factors.

Methods: We utilized the TriNetX Research Network to access de-identified patient data from 73 healthcare organizations using International Classification of Diseases, Tenth Revision codes. We identified AF patients with and without a diagnosis of any of 21 cancers occurring within one year of AF diagnosis. Cumulative stroke or transient ischemic attack incidence was calculated for the period between Jan.1st, 2015 to Dec. 31st, 2024. Subgroup analyses were performed by CHA₂DS₂-VASc score (0 to 7, excluding prior stroke). A Cox proportional hazards model assessed the independent contribution of cancer relative to individual CHA₂DS₂-VASc variables. We also performed a 10-year Kaplan-Meier survival analysis for ischemic stroke in a propensity-matched cohort of AF patients with and without cancer.

Results: A total of 162,993 AF patients with cancer were compared to 1,753,126 AF patients without cancer. Higher CHA₂DS₂-VASc scores were associated with higher stroke incidence, and the presence of cancer further increased stroke incidence at each score level. In the multivariable Cox model, cancer was independently associated with stroke after accounting for CHA₂DS₂-VASc variables (adjusted hazard ratio [aHR] 1.37; 95% confidence interval [CI], 1.34-1.41; p < 0.0001; Figure 1). After matching for CHA₂DS₂-VASc components, 10-year stroke-free survival was significantly lower in AF patients with cancer (HR 1.72; 95% CI, 1.68–1.76; p < 0.0001; Figure 2).

Conclusion: In this large, real-world cohort, cancer emerged as an independent predictor of ischemic stroke in AF patients, with a magnitude of risk comparable to established CHA₂DS₂-VASc variables. These findings support the incorporation of malignancy into future stroke risk stratification frameworks for AF.