Genetic and environmental risk factors for oral anticoagulant overdose.
BACKGROUND
Cytochrome P450 2C9 (CYP2C9) allelic variant carriers have been shown to experience hyper-responsiveness to small doses of oral anticoagulants (OAs) (warfarin or acenocoumarol) and a higher bleeding rate.


OBJECTIVE
To determine the relative frequencies of different risk factors for OA overdose including diet, concomitant diseases, drug interactions, recent increment of OA dose and CYP2C9 genetic polymorphism among hospitalised patients.


METHODS
Frequencies of the different risk factors for OA overdose were determined in a prospective case-control study. Seventy-five consecutive patients with an International normalised ratio (INR) greater than 4 were matched with seventy-five control patients with an INR greater than 2 but less than 3.5 with respect to age, prescribed OA and daily dose. Genotyping of CYP2C9*2 and CYP2C9*3 allelic variants was detected by the TaqMan allelic discrimination assay.


RESULTS
Drug interactions and a recent increment of OA dose were the only significant independent risk factors identified in the first analysis with odds ratio 2.13 (95% CI: 1.06-4.28) and 3.38 (95%CI: 1.51-7.57), respectively. A recent increment of OA dose was the only significant independent risk factor identified among the patients treated with coumarin derivatives (acenocoumarol or warfarin), excluding those treated with fluindione; the odds ratio was 4.3 (95% CI: 1.5-12.3). CYP2C9 genetic polymorphism did not significantly predict the increased risk of OA overanticoagulation in this study. However three homozygous CYP2C9*3/CYP2C9*3 genotype patients were found among the cases, whereas no such patients could be identified among controls.


CONCLUSIONS
This is the first observational study investigating the role of CYP2C9 genetic polymorphism together with other environmental OA overdose risk factors. Our results support the view that although the CYP2C9*3/CYP2C9*3 genotype is associated soon after the introduction of OA with dramatic overanticoagulation, OA overdose is mostly related to environmental factors.
Verstuyft
C
C
Department of Pharmacology, Saint-Antoine Paris VI University and Assistance-Publique Hôpitaux de Paris, 184 rue du Faubourg Saint Antoine, 75012, Paris, France. celine.verstuyft@chusa.jussieu.fr
Robert
A
A
Morin
S
S
Loriot
M A
MA
Flahault
A
A
Beaune
P
P
Funck-Brentano
C
C
Jaillon
P
P
Becquemont
L
L
D000284:Administration, Oral; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D062787:Drug Overdose; D005260:Female; D018565:Food-Drug Interactions; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007297:Inpatients; D019934:International Normalized Ratio; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D012307:Risk Factors; D014812:Vitamin K / Q000008:administration & dosage
D000925:Anticoagulants; D014812:Vitamin K; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases