VKORC1 en CYP2C9 genotype beinvloeden acenocoumarol antistolling: Interactie tussen genotypes en overantistolling

Objective: To assess the association between CYP2C9 and VKORC1 genotypes and severe overanticoagulation, time to achieve stable therapeutic INRs and stable dose requirements of acenocoumarol therapy. Design: Retrospective observational study on a prospective patient cohort. Methods: Patient DNA was analyzed for the VKORC1 C1173T polymorphism. Collected data were age, acenocoumarol indication, therapeutic INR range, INR results, acenocoumarol dosages, comorbidities (infections), comedication and CYP2C9 genotype (*2, *3 mutations). Endpoints were severe overanticoagulation (INR >6.0), time to achieve stability, mean daily dosage and INR on day 4. Results: Only patients with a combination of CYP2C9 and VKORC1 polymorphisms had an increased risk of severe overanticoagulation compared to one or both genes wild-type individuals [hazard ratio, 3.8 (95% confidence interval 1.6-9.1)]. The time to achieve stability was prolonged in CYP2C9*3 allele carriers [mean difference 13.7 days (CI95 1.9-25.6)]. The mean daily dosage variability of stabilized patients was explained by the VKORC1 and CYP2C9 genotype for respectively 21.4% and 4.9%. A supratherapeutic INR on day 4 was only associated with the VKORC1 TT genotype [OR 5.1 (CI95 2.0-12.8) compared to CC and CT]. Conclusions: Patients with variant alleles in both genes had an increased risk of severe overanticoagulation. To establish the genotypic contribution to acenocoumarol response, knowledge of both CYP2C9 and VKORC1 genotype is imperative.