Key result
Carrying 3 CYP2C9 and VKORC1 variants linked to ~4.3-fold higher major bleeding risk on warfarin.
Why the study?
Warfarin therapy is limited by bleeding risk due to narrow therapeutic index and response variability potentially linked to CYP2C9 and VKORC1 gene polymorphisms.
Cohort (n=194)
Hazard Ratio: 4.34 (95% CI 1.95–9.65)
p-value: p=<0.001
May warrant closer monitoring in warfarin patients with 3 variant alleles; leaves open prospective validation before genotype-guided practice changes.
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.
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Tomek et al. (2013) conducted a cohort in Arterial and venous thromboembolism (n=194). Carriage of 3 variant alleles of CYP2C9 and VKORC1 genes vs. Fewer variant alleles was evaluated on Major bleeding events (HR 4.34, 95% CI 1.95-9.65, p=<0.001). Carrying 3 variant alleles of the CYP2C9 and VKORC1 genes was associated with a significantly higher risk of major bleeding events during warfarin therapy (HR 4.34; 95% CI 1.95-9.65; P<0.001).
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