RESUMO
A few trials so far have evaluated the effectiveness of algorithms designed to calculate doses in oral anticoagulant therapy, with negative or contradictory results. We compared a genotype-guided algorithm vs physician management for the initiation of acenocoumarol. In a two-arm, prospective, randomised study with patients with atrial fibrillation who started therapy, the first dose was administered to all patients according to the physician's criteria. At 72 hours, the corresponding dose was calculated based on INR in the standard care group (SC, N=92), whereas genetic data (VKORC1, CYP2C9 and CYP4F2) were also considered for the genotype-guided dosing (pharmacogenetic) group (PGx, N=87) by using an algorithm previously validated in 2,683 patients. The primary outcomes were: patients with steady dose, the time needed to reach the same and the percentage of therapeutic INRs. After 90 days, 25% of the SC and 39% of the PGx patients reached the steady dose (p=0.038). Kaplan-Meier analysis showed that PGx group needed fewer days to reach therapeutic INR (p=0.033). Additionally, PGx had a higher percentage of therapeutic INRs than SC patients (50% and 45%, respectively) (p=0.046). After six months the proportion of steadily anticoagulated patients remained significantly higher in PGx (p=0.010). In conclusion, genotype-guided dosing was associated with a higher percentage of patients with steady dose than routine practice when starting oral anticoagulation with acenocoumarol.
Assuntos
Acenocumarol/administração & dosagem , Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Sistema Enzimático do Citocromo P-450/genética , Cálculos da Dosagem de Medicamento , Farmacogenética/métodos , Medicina de Precisão/métodos , Vitamina K Epóxido Redutases/genética , Acenocumarol/efeitos adversos , Acenocumarol/farmacocinética , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Distribuição de Qui-Quadrado , Citocromo P-450 CYP2C9/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Família 4 do Citocromo P450 , Monitoramento de Medicamentos/métodos , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Espanha , Vitamina K Epóxido Redutases/metabolismoRESUMO
AIM: To analyze VKORC1, CYP2C9 and CYP4F2 polymorphisms in relation to the main outcomes in the first stages of acenocoumarol therapy. PATIENTS & METHODS: Nine hundred and forty one patients who had started therapy and in whom time to stable dosage, time to over-anticoagulation and adverse events occurred during 3 first months were retrospectively analyzed. RESULTS: VKORC1 AA patients needed fewer days to reach stable dosage (p = 0.017). International normalized ratio [INR] at 72 h, and VKORC1 and CYP2C9 genotypes conditioned INR values >2.5 (p < 0.001, p = 0.002 and p < 0.001, respectively), whereas CYP4F2 T carriers had a low risk of the same outcome (p = 0.009). In regards to combined genotypes, CYP4F2 had a significant effect on over-anticoagulation at the beginning of therapy except for the VKORC1 AA and CYP2C9*3 combination. CONCLUSION: In addition to VKORC1 and CYP2C9, CYP4F2 gene has a slight but significant role in reaching INR >2.5 during the first weeks of acenocoumarol therapy.
Assuntos
Acenocumarol/administração & dosagem , Transtornos da Coagulação Sanguínea/tratamento farmacológico , Citocromo P-450 CYP2C9/genética , Sistema Enzimático do Citocromo P-450/genética , Vitamina K Epóxido Redutases/genética , Acenocumarol/efeitos adversos , Adulto , Idoso , Biomarcadores Farmacológicos , Transtornos da Coagulação Sanguínea/genética , Família 4 do Citocromo P450 , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Resultado do TratamentoRESUMO
Acenocoumarol is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries. In counterpart of warfarin, there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation. The aim of this study was to develop an algorithm of prediction for acenocoumarol.The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2,683 patients. The best regression model to predict stable dosage in the Primary Cohort included clinical factors (age and body mass index, BSA) and genetic variants (VKORC1, CYP2C9* and CYP4F2 polymorphisms) and explained up to 50% of stable dose. In the validation study the clinical algorithm yielded an adjusted R²=0.15 (estimation´s standard error=4.5) and the genetic approach improved the dose forecast up to 30% (estimation´s standard error=4.6). Again, the best model combined clinical and genetic factors (R² = 0.48; estimation´s standard error=4) which provided the best results of doses estimates within 20% of the real dose in patients taking lower (≤ 7 mg/week) or higher (≥ 25 mg/week) acenocoumarol doses. In conclusion, we developed a prediction algorithm using clinical data and three polymorphisms in VKORC1, CYP2C9* and CYP4F2 genes that provided a steady acenocoumarol dose for about 50% of patients in the Validation Cohort. Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses, those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication.