Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarin-treated patients: A systematic review and meta-analysis

Background: The main challenge forwarfarin anticoagulation is the risk for hemorrhagic complications. Although certain pharmacogenetic factors may explain the individual variabilities about the therapeutic warfarin dose requirement, the genetic factors to warfarin hemorrhagic complications due to over-anticoagulation are largely unknown. To interpret the potential role ofwarfarin-related genotypes on over-anticoagulation and hemorrhagic complications, we conducted a meta-analysis based on 22 published studies. Methods: A comprehensive search was applied to the reports on over-anticoagulation and hemorrhagic complications published prior to December 31, 2012 in PubMed and EMBASE. References were identified by strict inclusion and exclusion criteria, with additional information obtained by consulting with the authors of primary studies. The roles of genotypes in CYP2C9 and VKORC1 on over-anticoagulation (INR N4) and hemorrhagic complications were analyzed by Revman 5.0.2 software. Results: A total of 6272 patients in 22 reports were included in the meta- analysis, including studies of 18 from Caucasians (3 from both Caucasian and African-American), 3 from Asians, and 1 from Brazilians. Compared to CYP2C9 wild genotype (CYP2C9*1), both CYP2C9*2 (rs 1799853, c. 430 C > T, p. Arg144Cys) and *3 (rs 1057910, c. 1075 A > C, p. Ile359Leu) confer significantly higher risk for warfarin overanticoagulation and hemorrhagic complications. After stratification by CYP2C9 allele status, significantly higher risk for hemorrhagic complications was found only in carriers of at least 1 copy of CYP2C9*3 [For total hemorrhages: *1/*3 HR: 2.05 (1.36-3.10), p < 0.001; *3/*3 HR: 4.87 (1.38-17.14), p = 0.01; For major hemorrhages: *1/*3 HR: 2.43 (1.17-5.06), p = 0.02; *3/*3 HR: 4.81 (0.95-24.22), p = 0.06]. Furthermore, similar susceptibility of total hemorrhage by CYP2C9 genotypes was observed in Caucasians and Asians. After stratification by the occurrence time, both CYP2C9*2 and *3 are risk factors for overanticoagulation within 30 days of warfarin treatment [*2 HR: 1.64 (1.11-2.43), p = 0.01; *3 HR: 2.48 (1.56-3.96), p < 0.001], and only CYP2C9*3 showed higher risk for over-anticoagulation after 30 days [HR: 1.86 (1.08-3.20), P = 0.03]. For VKORC1 c. -1639 G > A (rs 9923231) genotypes, GA and AA contributed significantly higher risk for over-anticoagulation within 30 days [HR: 2.14 (1.75-2.62), p < 0.001], but not for over-anticoagulation after 30 days [HR: 0.78 (0.46-1.33), p = 0.36]. No significant association was found between VKORC1 genotypes and hemorrhagic complications. Conclusions: Both CYP2C9 and VKORC1 genotypes are associated with an increased risk for warfarin over-anticoagulation, with VKORC1 c. -1639 G > A more sensitive early in the course of anticoagulation. CYP2C9*3 is the main genetic risk factor for warfarin hemorrhagic complications. (C) 2013 Elsevier Ireland Ltd. All rights reserved.