Development and validation of the DOAC Score: a novel bleeding risk prediction tool for patients with atrial fibrillation

Abstract

Abstract Background Clinicians and patients must balance the ischemic benefits and bleeding risks when deciding to anticoagulate patients with atrial fibrillation (AF). Current clinical decision tools for assessing bleeding risk have limited performance and were developed for individuals anticoagulated with warfarin. Purpose This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with AF taking direct-acting oral anticoagulants (DOACs). Methods Among individuals taking dabigatran 150mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial, a risk score was developed to determine the probability for bleeding, based on covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. We then refined the model in the GARFIELD-AF registry, with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACS, the risk prediction model was validated in the COMBINE-AF pooled clinical trial cohort and the RAMQ administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared to the HAS-BLED score. Results Of the 5684 patients in RE-LY, 386 experienced a major bleeding event, within a median follow-up of 1.74-years. The prediction model was well-calibrated (goodness-of-fit P = 0.57) and had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping. The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, non-steroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI: 38.9%-59.3%, P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C Statistic: 0.73 vs 0.60, P for difference <0.001) and among 12,296 individuals in GARFIELD-AF (C statistic: 0.71 vs 0.66, P for Difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25,586 individuals in COMBINE-AF (C statistic: 0.67 vs 0.63, P for Difference <0.001) and 11,945 individuals in RAMQ (C statistic: 0.65 vs 0.58, P for Difference <0.001). Conclusion In individuals with AF on DOAC therapy, the DOAC Score can help stratify patients based on expected bleeding risk.