Estimation of the warfarin dose with a pharmacogenetic refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation

Abstract

Pharmacogenetic (PG) dosing algorithms have been confirmed to predict warfarin therapeutic dose more accurately; however, most of them are based on standard intensity of warfarin anticoagulation, and their utility outside this range is limited. This study was designed to develop and validate a PG refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation. Consented Chinese-Han patients (n=310) under stable warfarin treatment were randomly divided into a derivation (n=207) and a validation cohort (n=103), with 83% and 80% of the patients under low-intensity anticoagulation, respectively. In the derivation cohort, a PG algorithm was constructed on the basis of genotypes (CYP2C9*3 and VKORC1-1639A/G) and clinical data. After integrating additional covariates of international normalised ratio (INR) values (INR on day 4 of therapy and target INR) and genotype of CYP4F2 (rs2108622), a PG refinement algorithm was established and explained 54% of warfarin dose variability. In the validation cohort, warfarin dose prediction was more accurate (p < 0.01) with the PG refinement algorithm than with the PG algorithm and the fixed dose approach (3 mg/day). In the entire cohort, the PG refinement algorithm could accurately identify larger proportions of patients with lower dose requirement (≤2 mg/day) and higher dose requirement (≥4 mg/day) than did the PG algorithm. In conclusion, PG refinement algorithm integrating early INR response and three genotypes (CYP2C9*3, VKORC1-1639A/G, CYP4F2 rs2108622) improves the accuracy of warfarin dose prediction in Chinese patients mainly under low-intensity anticoagulation.