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Background: The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain., Methods: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS 2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA 2 DS 2 -VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores., Results: Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA 2 DS 2 -VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA 2 DS 2 -VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin., Conclusions: The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA 2 DS 2 -VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants., Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.