title: The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon.
abstract: Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarin anticoagulant metabolism. The variant alleles CYP2C9*2 and CYP2C9*3 are associated with an increased response to warfarin. However, an effect on acenocoumarol dose requirements appears to be absent for the CYP2C9*2 allele and the consequences for the metabolism of phenprocoumon have not yet been established. We investigated CYP2C9 polymorphisms in relation to the international normalized ratio (INR) during the first 6 weeks of treatment and its effect on the maintenance dose in a cohort of 1124 patients from the Rotterdam Study who were treated with acenocoumarol or phenprocoumon. There was a statistically significant difference in first INR between patients with variant genotypes and those with the wild-type. Almost all acenocoumarol-treated patients with a variant genotype had a significantly higher mean INR and had a higher risk of an INR > or = 6.0 during the first 6 weeks of treatment. A clear genotype-dose relationship was found for acenocoumarol-treated patients. For patients on phenprocoumon, no significant differences were found between variant genotypes and the wild-type genotype. Individuals with one or more CYP2C9*2 or CYP2C9*3 allele(s) require a significantly lower dose of acenocoumarol compared to wild-type patients. Phenprocoumon appears to be a clinically useful alternative in patients carrying the CYP2C9*2 and *3 alleles.
authors.affiliation: Pharmacoepidemiology Unit, Department of Internal Medicine, Easmus MC, Rotterdam, The Netherlands.
authors.forename: Loes E
authors.initials: LE
authors.lastname: Visser
authors.forename: Martin
authors.initials: M
authors.lastname: van Vliet
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.forename: A A Harrie
authors.initials: AA
authors.lastname: Kasbergen
authors.forename: Peter A G M
authors.initials: PA
authors.lastname: De Smet
authors.forename: Arnold G
authors.initials: AG
authors.lastname: Vulto
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.forename: Bruno H Ch
authors.initials: BH
authors.lastname: Stricker
mesh_terms: D000074:Acenocoumarol / Q000008:administration & dosage*; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D017931:DNA Primers; D005260:Female; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010644:Phenprocoumon / Q000008:administration & dosage*; D018570:Risk Assessment
chemical_list: D000925:Anticoagulants; D017931:DNA Primers; D007527:Isoenzymes; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000074:Acenocoumarol; D010644:Phenprocoumon