Objectives This study sought to determine the influence of warfarin dose associated pharmacogenetic factors on hemorrhagic complications in Chinese patients treated with warfarin.
Methods Consecutively recruited Han-Chinese patients, who need more than 1-year warfarin treatment, were followed from the initiation of their warfarin anticoagulation for at least 3 months. Warfarin dose associated pharmacogenetic polymorphisms, CYP2C9*3 A/C at (rs1057910), VKORC1-1639 G/A at (rs9923231), and CYP4F2 1347 C/T at (rs2108622), were genotyped by resequencing. The association between genotypes and warfarin hemorrhagic complications was evaluated using Cox proportional hazard regression with adjustment for demographic and clinical factors.
Results Among 312 eligible patients obtaining stable warfarin anticoagulation in 3 months, 11 major and 69 minor haemorrhages occurred over 147 person-years. Most of the major haemorrhages (81.82%) occurred after the first stabilisation of warfarin treatment. The CYP2C9*3 genotype conferred an increased risk of all (hazard ratio (HR) 3.07; 95% confidence interval (CI): 1.57- 6.01) and minor haemorrhage (HR 3.28; 95% CI: 1.62- 6.65), but not major haemorrhage (HR 0.44; 95% CI: 0.04- 4.72). CYP2C9*3 also conferred an increased risk of over-anticoagulation with international normalisation ratio (INR) ≥ 4 (HR 2.92; 95% CI: 1.08- 7.85). VKORC1-1639G/A, and CYP4F2 rs2108622 did not confer significant increase in the risk for haemorrhage or over-anticoagulation. Kaplan-Meier curves showed time to all haemorrhage events was significantly shorter for patients with CYP2C9*3 genotype than wild-type genotype (p = 0.001), but not for patients with VKORC1-1639G/A and CYP4F2 rs2108622 genotype (p = 0.3 and 0.2).
Conclusions CYP2C9*3 might be the main pharmacogenetic contributor for the hemorrhagic complications in Chinese patients under warfarin anticoagulation.