Asunto(s)
Acenocumarol/administración & dosificación , Anticoagulantes/administración & dosificación , Citocromo P-450 CYP3A/genética , Sistema Enzimático del Citocromo P-450/genética , Esquema de Medicación , Fenprocumón/administración & dosificación , Algoritmos , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea/genética , Estudios Transversales , Familia 4 del Citocromo P450 , Genotipo , Humanos , Farmacogenética , Polimorfismo de Nucleótido Simple , Enfermedades Vasculares/genética , Enfermedades Vasculares/prevención & controlRESUMEN
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.
Asunto(s)
Acenocumarol/uso terapéutico , Anticoagulantes/uso terapéutico , Hidrocarburo de Aril Hidroxilasas/genética , Coagulación Sanguínea/efectos de los fármacos , Coagulación Sanguínea/genética , Oxigenasas de Función Mixta/genética , Fenprocumón/uso terapéutico , Acenocumarol/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/efectos adversos , Citocromo P-450 CYP2C9 , Monitoreo de Drogas/métodos , Femenino , Genotipo , Humanos , Relación Normalizada Internacional , Modelos Lineales , Masculino , Persona de Mediana Edad , Países Bajos , Farmacogenética , Fenotipo , Fenprocumón/efectos adversos , Modelos de Riesgos Proporcionales , Vitamina K Epóxido ReductasasRESUMEN
BACKGROUND: The required acenocoumarol dose and the risk of underanticoagulation and overanticoagulation are associated with the CYP2C9 and VKORC1 genotypes. However, the duration of the effects of these genes on anticoagulation is not yet known. OBJECTIVES: In the present study, the effects of these polymorphisms on the risk of underanticoagulation and overanticoagulation over time after the start of acenocoumarol were investigated. PATIENTS/METHODS: In three cohorts, we analyzed the relationship between the CYP2C9 and VKORC1 genotypes and the incidence of subtherapeutic or supratherapeutic International Normalized Ratio (INR) values (< 2 and > 3.5) or severe overanticoagulation (INR > 6) for different time periods after treatment initiation. RESULTS: Patients with polymorphisms in CYP2C9 and VKORC1 had a higher risk of overanticoagulation (up to 74%) and a lower risk of underanticoagulation (down to 45%) in the first month of treatment with acenocoumarol, but this effect diminished after 1-6 months. CONCLUSIONS: Knowledge of the patient's genotype therefore might assist physicians to adjust doses in the first month(s) of therapy.