Effects of CYP2C9 and VKORC1 on INR variations and dose requirements during initial phase of anticoagulant therapy.
BACKGROUND
Anticoagulants of the coumarin type are effective drugs for the treatment and prevention of thromboembolic diseases. However, they have a narrow therapeutic range and show inter- and intra-individual variability in dose requirement, largely conditioned by both environmental and genetic factors.


METHODS
This prospective study investigated, during the initial phase of acenocoumarol therapy, the effect of CYP2C9 variant alleles and VKORC1 haplotypes, single and in combination, in 220 Italians.


RESULTS
CYP2C9*3 was associated with a 25% dose reduction and an increased risk of over-anticoagulation (International Normalized Ratio [INR] > 6) on day 4. Two copies of the VKORC1*2 haplotype were associated with a 45% dose reduction and an increased risk of over-anticoagulation. Homozygosity for VKORC1*3 and VKORC1*4 was associated with an increased dose requirement and a reduced risk of over-anticoagulation. The VKORC1*3 or *4 plus CYP2C9*1 genotype combination was associated with the highest dose requirement and the lowest INR on day 4; VKORC1*2 plus CYP2C9*3 was associated with the lowest dose requirement, the highest INR and an increased risk of over-anticoagulation. Even though they spent approximately 50% of the time within the target therapeutic range, VKORC1*3 or *4 plus CYP2C9*1 carriers spent a large percentage of the remaining time below and carriers of VKORC1*2 plus CYP2C9*3 above the target range.


CONCLUSIONS
The determination of VKORC1*3 and VKORC1*4 haplotypes may be an important addition to CYP2C9 and VKORC1*2 genotyping to identify patients at risk of being outside the target range during initial anticoagulation with acenocoumarol.
Spreafico
Marta
M
A Bianchi Bonomi Hemophilia and Thrombosis Center, University of Milan and Department of Medicine and Medical Specialties, IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation, Via Pace 9, 20122 Milan, Italy. marta.spreafico@unimi.it
Lodigiani
Corrado
C
van Leeuwen
Y
Y
Pizzotti
Denise
D
Rota
Lidia L
LL
Rosendaal
Fr
F
Mannucci
Pier M
PM
Peyvandi
Flora
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000925:Anticoagulants / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000235:genetics*; D006239:Haplotypes / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019934:International Normalized Ratio / Q000379:methods; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / 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