An evaluation of gene–gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol

Background: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. Objectives: We aimed to provide a definite answer regarding the question whether there exists a gene–gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. Patients/Methods: The EU‐PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over‐anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model – for the outcome measure maintenance dose – or to the Cox regression models – for the outcome measures time to severe over‐anticoagulation and time to achieve stability. Results: No significant interactions – all P‐values above 0.23 for phenprocoumon and 0.30 for acenocoumarol – were observed for all outcome measures. Conclusions: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over‐anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.