Development and Validation of the GLORIA-AF Stroke Weighted Risk Score for Patients with Atrial Fibrillation

BACKGROUND AND AIMS: Accurate stroke-risk stratification is central to anticoagulation decision-making in patients with atrial fibrillation (AF), but conventional scores may not fully capture risk heterogeneity. We aimed to develop and externally validate an interpretable weighted score using a time-to-event framework. METHODS: GLORIA-AF Phase II/III data were used to evaluate 17 baseline predictors using LASSO-penalized Cox regression with stability selection; coefficients were converted into integer weights. Performance was assessed using discrimination, calibration, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and decision-curve analysis. External validation was performed in EORP-AF and APHRS-AF registries. RESULTS: Among 20,517 patients included in the derivation cohort (mean [SD] age, 69.9 [10.3] years; 9,196 women [44.8%]), 487 (2.4%) had stroke, and 17,397 (84.8%) were receiving anticoagulation at baseline. Ten selected predictors formed a 0-23-point score. The derived score achieved a C-index of 0.661 (95% CI, 0.636-0.685), higher than CHA2DS2-VA (0.626; P < 0.001), CHA2DS2-VASc (0.615; P < 0.001), and the unweighted score (P = 0.016), with no significant difference from the full Cox or machine learning models. In external validation (8,309 patients; 147 strokes), the C-index was 0.652 (95% CI, 0.614-0.690) versus 0.616 for CHA2DS2-VA (95%CI, 0.598-0.634; P < 0.001). IDI/NRI, calibration, and decision-curve analyses supported improved risk differentiation, close calibration, and generally greater net benefit than CHA2DS2-VA. The score retained higher discrimination than CHA2DS2-VA among patients without baseline anticoagulation (P < 0.001). CONCLUSION: The GLORIA-AF Stroke Weighted Risk Score provides risk refinement beyond CHA2DS2-VA while retaining discrimination consistent with more complex models. External validation supports its transportability and potential adjunctive role in guideline-directed thromboembolic risk assessment.