Genotypes associated with reduced activity of VKORC1 and CYP2C9 and their modification of acenocoumarol anticoagulation during the initial treatment period.
The objective of this study was to investigate the influence of genotypes associated with reduced activity of vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) on anticoagulation with acenocoumarol during the first 6 weeks of treatment. In 1,525 patients from the Rotterdam Study who were started on anticoagulation therapy with acenocoumarol, the presence of VKORC1 1173C>T and CYP2C9*2 and *3 allele variants was determined. The first international normalized ratio (INR) after initial standard dose, risk of overanticoagulation, and mean dosage at the end of the initiation period were compared between genotypes. The initial standard dosage significantly increased the risk of severe overanticoagulation by 85% for each additional VKORC1 T-allele present. At the end of the initiation period, each VKORC1 T-allele present was shown to decrease the required acenocoumarol dosage by 5.1 mg/week, while each CYP2C9 variant allele present reduced the required dosage by 1.8 mg/week. Our conclusion was that an initial standard dosing regimen with acenocoumarol increases the risk of severe overanticoagulation in patients with variant alleles of the VKORC1 and CYP2C9 genes.
Teichert
M
M
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
van Schaik
R H N
RH
Hofman
A
A
Uitterlinden
A G
AG
de Smet
P A G M
PA
Stricker
B H C H
BH
Visser
L E
LE
D000074:Acenocoumarol / Q000494:pharmacology* / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics; D011446:Prospective Studies; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; D000074:Acenocoumarol