Incremental Value of Genotype Bins over the HAS-BLED Score for the Prediction of Bleeding Risk in Warfarin-Treated Patients with Atrial Fibrillation

Abstract

Background. This study aimed to analyse the role of the HAS-BLED score with the addition of genotype bins for bleeding risk prediction in warfarin-treated patients with atrial fibrillation (AF). Methods and Results. Consecutive patients with AF on initial warfarin treatment were recruited. For each patient, CYP2C9 ${}^{\ast }$ 3 and VKORC1-1639 A/G genotyping was performed to create 3 genotype functional bins. The predictive values of the HAS-BLED score with or without the addition of genotype bins were compared. According to the carrier status of the genotype bins, the numbers of normal, sensitive, and highly sensitive responders among 526 patients were 64 (12.17%), 422 (80.23%), and 40 (7.60%), respectively. A highly sensitive response was independently associated with clinically relevant bleeding (HR: 3.85, 95% CI: 1.88–7.91, $P=0.001$ ) and major bleeding (HR:3.75, 95% CI: 1.17–11.97, $P=0.03$ ). With the addition of genotype bins, the performance of the HAS-BLED score for bleeding risk prediction was significantly improved (c-statistic from 0.60 to 0.64 for clinically relevant bleeding and from 0.64 to 0.70 for major bleeding, $P<0.01$ ). Using the integrated discriminatory, net reclassification improvement, and decision curve analysis, the HAS-BLED score plus genotype bins could perform better in predicting any clinically relevant bleeding than the HAS-BLED score alone. Conclusions. Genotypes have an incremental predictive value when combined with the HAS-BLED score for the prediction of clinically relevant bleeding in warfarin-treated patients with AF.