TY - JOUR
T1 - The bleeding risk during warfarin therapy is associated with the number of variant alleles of CYP2C9 and VKORC1 genes
AU - Tomek, Aleš
AU - Maťoška, Václav
AU - Kolářová, Tereza
AU - Neumann, Jiří
AU - Šrámek, Martin
AU - Šarbochová, Ivana
AU - Táborský, Luděk
AU - Bojar, Martin
AU - Goetz, Petr
AU - Serebruany, Victor L.
PY - 2013/6
Y1 - 2013/6
N2 - Background: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. Aim: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. Methods: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. Results: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p <0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B <CYP2C9 *1/*1 + VKORC1 A/B <CYP2C9 *1/*2 + VKORC1 B/B. Conclusion: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.
AB - Background: Warfarin is commonly used for the treatment and prevention of arterial and venous thromboembolism but its use is hindered by the risk of bleeding. The main reason for this risk is a narrow therapeutic index and a wide response variability after warfarin treatment. These shortcomings affect clinical outcomes including bleeding complications and may be associated with variant polymorphisms in the CYP2C9 and VKORC1 genes. Aim: It was the aim of this study to assess the impact of the total variant allele count of CYP2C9 and VKORC1 genes on bleeding related to warfarin treatment. Methods: In a retrospective cohort-design study, patients were genotyped for polymorphisms in genes CYP2C9 (*1, *2, *3) and VKORC1 (haplotype A, B). Extensive clinical data were obtained. Adjusted hazard ratios (HR) for the occurrence of major bleeding events (MBE) were counted separately for the induction and maintenance phases of warfarin therapy. Results: Out of the 329 patients in our clinical database, 194 patients were eligible and included in the analysis. MBE occurred in 51 patients (26.3%) during a mean follow-up of 26 months: 6 patients (11.8%) experienced early MBE during warfarin initiation, and 45 MBE occurred during the maintenance phase. The adjusted HR for MBE risk for patients with any CYP2C9 variant allele was 1.962 [95% confidence interval (CI) 1.08-3.56, p = 0.027]; for the VKORC1 AA haplotype, HR was 1.841 (95% CI 0.97-3.48, p = 0.06), while for 3 variant allele carriers of both genes, HR was 4.34 (95% CI 1.95-9.65, p <0.001). Despite the insignificant association of the VKORC1 genotype with bleeding in our study, we have noted a warfarin dose-dependent effect with risk significance ascending: CYP2C9 *1/*1 + VKORC1 B/B <CYP2C9 *1/*1 + VKORC1 A/B <CYP2C9 *1/*2 + VKORC1 B/B. Conclusion: Patients who are carriers of 3 variant alleles of the genes CYP2C9 and VKORC1 exhibited a significantly higher risk of MBE during the initiation and maintenance phases of warfarin therapy. Vigilant and careful management of patients with a higher variant allele count, including switching to newer anticoagulants, could be considered in this high-risk cohort.
KW - Bleeding risk
KW - CYP2C9 gene
KW - Major bleeding event
KW - VKORC1 gene
KW - Warfarin
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U2 - 10.1159/000350407
DO - 10.1159/000350407
M3 - Article
C2 - 23774101
AN - SCOPUS:84878923105
VL - 125
SP - 182
EP - 191
JO - Bollettino della Societa italiana di cardiologia
JF - Bollettino della Societa italiana di cardiologia
SN - 1558-2027
IS - 3
ER -