Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin

Abstract

The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time-varying covariates. Forty-four major and 203 minor hemorrhages occurred over 555 person-years among 446 patients (60.6+/-15.6 years, 50% men, 227 African Americans). The variant CYP2C9 genotype conferred an increased risk for major (hazard ratio (HR) 3.0; 95% confidence interval (CI): 1.1-8.0) but not minor (HR 1.3; 95% CI: 0.8-2.1) hemorrhage. The risk of major hemorrhage was 5.3-fold (95% CI: 0.4-64.0) higher before stabilization of therapy, 2.2-fold (95% CI: 0.7-6.5) after stabilization, and 2.4-fold (95% CI: 0.8-7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7-4.4) or minor (HR 0.8; 95% CI: 0.5-1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.

Figure 1

Time to major hemorrhage by CYP2C9 and VKORC1 genotype. Kaplan—Meier curves for time to major hemorrhagic complication analyses plotted for (a) CYP2C9 wild-type vs variant genotype and (b) VKORC1 1173C/T wild-type vs variant genotype. (c) Estimated survival curve from Cox PH model adjusted for VKORC1 1173C/T genotype, age, warfarin dose, gender, body mass index, INR, alcohol intake, vitamin K intake, number of comorbid conditions, and drug interactions (note: y axis starts at 0.98).