Refining Stroke and Bleeding Prediction in Atrial Fibrillation by Adding Consecutive Biomarkers to Clinical Risk Scores

Background and Purpose Current European guidelines for the management of atrial fibrillation suggest using biomarkers to refine the risk stratification process. However, it is unclear whether 2 biomarkers incrementally improve risk prediction beyond 1 biomarker alone. We investigated whether the predictive performance of CHA(2)DS(2)-VASc and HAS-BLED scores could be enhanced by incrementally adding consecutive different biomarkers in real-world atrial fibrillation patients taking vitamin K antagonists therapy. Methods We included 940 atrial fibrillation patients stable on vitamin K antagonists (international normalized ratio, 2.0-3.0) for at least the previous 6 months. At inclusion, VWF (von Willebrand factor), high-sensitivity troponin T, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity IL (interleukin)-6, fibrin monomers, and BTP (-trace protein) concentrations were quantified. During follow-up, all adverse events were recorded, and biomarkers were added to CHA(2)DS(2)-VASc and HAS-BLED scores depending on the C index. Results During 6.5 (4.3-7.9) years, there were 98 ischemic strokes (1.60% per year) and 172 major bleeds (1.60% per year). After the addition of biomarkers, the predictive performance of CHA(2)DS(2)-VASc was not significantly increased, although the model with 3 biomarkers (ie, NT-proBNP+BTP+VWF) showed a low gain in sensitivity (integrated discrimination improvement, 2.70%; P<0.001). The predictive performance of HAS-BLED was enhanced in all biomarker-based models, with the best prediction shown by the model with 3 biomarkers (ie, VWF+NT-proBNP+high-sensitivity IL-6; C index, 0.600 [95% CI, 0.561-0.625] versus 0.639 [95% CI, 0.607-0.669]; P=0.025). This model also confirmed an increased sensitivity (integrated discrimination improvement, 5.20%; P<0.001) and positive reclassification (net reclassification improvement, 19.20%; P=0.020). Conclusions By adding consecutive biomarkers, the predictive ability of CHA(2)DS(2)-VASc for ischemic stroke was not increased, whereas the predictive ability of HAS-BLED for major bleeding was only slightly enhanced. The net benefit and clinical usefulness of the biomarker-based models were marginal in comparison to the original scores based on clinical factors.