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BRIEF REPORT
From the Hemostasis and Thrombosis Research Unit,
School of Medicine, University of Navarra, Pamplona,
Spain; the Haematology Service, University Clinic of
Navarra, Pamplona, Spain; and the Department of
Haematology, University Hospital of Salamanca, Spain.
The 2C9*3 and 2C9*2 polymorphisms of cytochrome P-450 CYP2C9 are
associated with hypersensitivity to warfarin and bleeding. The effect
of these polymorphisms on sensitivity to acenocoumarol is unknown.
Three groups of patients, with low, medium, or high acenocoumarol-dose
requirements, were studied. Age influenced the acenocoumarol
sensitivity. Bearing the 2C9*3 allele was associated with the need for
a lower acenocoumarol dose (odds ratio [OR], 6.02; 95% confidence
interval [CI], 1.50-24.18); 80% of carriers of the 2C9*3 allele
required a low dose. The 2C9*2 allele was associated with a lower
acenocoumarol-dose requirement (OR, 2.70; 95% CI, 1.11-6.58) because
of a reduced risk of the need for a high acenocoumarol dose (4.8% of
the patients in the high-dose group carried the 2C9*2 allele versus
34.1% and 30.2%, respectively, in the medium-dose and low-dose
groups). Therefore, carriers of 2C9*3 may need a low initial loading
dose of acenocoumarol. Because acenocoumarol sensitivity with the 2C9*2
variant does not seem to be clinically relevant, the drug could be an
alternative to warfarin in 2C9*2 carriers.
(Blood. 2002;99:4237-4239) Oral anticoagulant therapy with coumarin
derivatives is used broadly to prevent recurrent arterial and venous
thrombosis. The response to coumarin derivatives depends on several
factors, such as sex, age, diet, interacting drugs, and probably other unknown individual and ethnic factors.1,2 Warfarin is the main coumarin derivative used in the United Kingdom and United States.
The biotransformation and subsequent elimination of warfarin are due
mainly to oxidation by cytochrome P-450 CYP2C9. Recently, 2 variant
alleles of this cytochrome that reduce in vitro enzymatic activity have
been identified: 2C9*2 (Arg144Cys) and 2C9*3
(Ile359Leu).3,4 These variant alleles have been strongly
associated with increased sensitivity to warfarin and, less clearly,
with the risk of bleeding during anticoagulant
treatment.5-7
Acenocoumarol is a coumarin derivative used widely for oral
anticoagulant therapy in many European and Latin American countries. Mannucci8 has suggested that acenocoumarol be used instead of warfarin in patients carrying the hyperresponsive alleles 2C9*2 and
2C9*3. Acenocoumarol, like warfarin, is administrated as a racemate
mixture of (R)- and (S)-acenocoumarol. Cytochrome P-450 CYP2C9 is
involved in the oxidation of both enantiomers, whereas cytochrome P-450
CYP2C19 acts on (R)-acenocoumarol only.9 Because the
(S)-enantiomer is more active than the (R)-enantiomer, allelic variations of cytochrome P-450 CYP2C9 could play an important role
in sensitivity to acenocoumarol. In this context, the 2C9*3 allele has been linked to raised plasma levels of
(S)-acenocoumarol in a small group of patients with low acenocoumarol
requirements.10
Because of the broad clinical use of acenocoumarol in many
countries and the possible use of acenocoumarol as an alternative to
warfarin in patients bearing the 2C9*2 and 2C9*3 variants, we studied
the role of these polymorphisms in modulating the acenocoumarol requirement in patients receiving anticoagulation treatment.
Patients
Genotyping
Statistical analysis Dose was treated as an ordinal variable (low, medium, and high). Values for age and dose, when analyzed as a continuous variable, were expressed as means ± SD. A multivariate ordered logistic regression model was used to assess the effect of allelic variants and age (independent variables) on the acenocoumarol requirement. Thus, the relation between the ordinal variable dose (low, medium, or high) and allelic variants and age could be established, with controlling for sex and use of other drugs.11 The adequacy of the model was assessed by using the Pearson goodness-of-fit test. Subjects heterozygous and homozygous for the allelic variants were included in the same category because of the low prevalence of homozygous subjects. One-way analysis of variance was used to compare age between groups. Differences in the acenocoumarol requirement between patients who were carriers and noncarriers of the 2C9*3 allele in the low-dose group were assessed with the Student t test. Statistical analyses were done with SPSS software (version 10.0; SPSS, Chicago, IL).
Fifteen of 108 patients carried the 2C9*3 allele, with 14 being
heterozygous and one homozygous; one patient could not be analyzed.
Twenty-nine of 108 patients carried the CYP2C9*2 allele, with 26 being
heterozygous and 3 homozygous; one patient could not be analyzed (Table
1). Three patients in the low-dose group and one in the medium-dose group were double heterozygous. No double-heterozygous patients were found in the high-dose group. The
mean age in the low-, medium-, and high-dose groups was significantly different (74.3 ± 7.7 years, 65.7 ± 10.5 years, and
58.3 ± 11.0 years, respectively; P < .001).
We analyzed the effect of 2C9*3 and 2C9*2 variants, age, sex, and
interacting drugs by using a multivariate ordered logistic regression
model. Neither sex nor drugs affected the acenocoumarol requirement. This finding could have been due to the low number of patients taking other drugs: only 14 patients were taking
metabolism-decreasing drugs (8 in the low-dose, 3 in the medium-dose,
and 3 in the high-dose group) and only 2 were taking
metabolism-increasing drugs (one in the low-dose and one in the
high-dose group). Because there were no significant
interactions among the analyzed variables (data not shown), the final
model was formed by using 2C9*3 and 2C9*2 variants and age (Table
2).
Age was an important factor modulating the sensitivity to acenocoumarol. For every year of age, there was a 12% increase in the risk of needing a lower acenocoumarol dose (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.07-1.17). Carrying the 2C9*3 allele was an important independent factor modulating the sensitivity of patients to the anticoagulant effect of acenocoumarol. Patients with this allele were at a higher risk of needing a lower dose of acenocoumarol than patients without this variant (adjusted OR, 6.02; 95% CI, 1.50-24.18). This effect was due mainly to the remarkable number of carriers of the 2C9*3 allele among the patients in the low-dose group. Eighty percent of patients carrying at least one 2C9*3 allele had a very low acenocoumarol requirement (< 7 mg/week); moreover, the mean weekly dose of acenocoumarol required by patients in the low-dose group with at least one 2C9*3 allele was lower than that of patients in the same group without this allelic variant (5.04 ± 1.26 mg versus 6.15 ± 0.94 mg; P = .04). Together, these results suggest a remarkable effect of the 2C9*3 allele on sensitivity to acenocoumarol, possibly one even greater than the previously observed effect on warfarin metabolism.5,6 This finding could be relevant applied to clinical practice: because it has been suggested that hyperresponsiveness to warfarin is linked to a high risk of bleeding at the beginning of treatment, patients bearing the 2C9*3 allele that are to be treated with acenocoumarol should start treatment with a reduced initial loading dose to avoid overanticoagulation and subsequent bleeding risk. The 2C9*2 variant also played an independent and significant role on patients' sensitivity to acenocoumarol. Carrying at least one 2C9*2 allele also increased the risk of requiring a lower dose of acenocoumarol (OR, 2.70; 95% CI, 1.11-6.58). Interestingly, this effect was due mainly to the remarkably reduced risk of needing an acenocoumarol dose higher than 28 mg/week when this variant was present: only 4.8% of patients in the high-dose group carried the 2C9*2 allele, whereas it was present in 34.1% of patients in the medium-dose group and 30.2% in the low-dose group. Nevertheless, the effect of the 2C9*2 allele on the acenocoumarol requirement was much smaller than the effect exerted by the 2C9*3 allele. In the clinical setting, because the 2C9*2 allele has been described as a major factor conditioning warfarin sensitivity, it may be advisable for patients bearing the 2C9*2 allele to start anticoagulant treatment with acenocoumarol instead of warfarin to avoid overanticoagulation risk and subsequent bleeding.5-7 In conclusion, we demonstrated that the 2C9*3 allele importantly and independently modulates sensitivity to acenocoumarol, a finding indicating that a reduced initial loading dose of acenocoumarol should be used in carriers of this allele. The weak effect on acenocoumarol sensitivity exerted by the 2C9*2 allele makes this drug a potential alternative to warfarin in patients carrying this variant.
Submitted November 21, 2001; accepted January 25, 2002.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Eduardo Rocha, Haematology Service, University Clinic of Navarra, Avenida Pío XII 36, 31008 Pamplona, Spain; e-mail: erocha{at}unav.es.
1.
James AH, Britt RP, Raskino CL, Thompson SG.
Factors affecting the maintenance dose of warfarin.
J Clin Pathol.
1992;45:704-706
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Leung AY, Chow HC, Kwong YL, et al.
Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients.
Blood.
2001;98:2584-2587 3. Rettie AE, Wienkers LC, Gonzalez FJ, Trager WF, Korzekwa KR. Impaired (S)-warfarin metabolism catalysed by the R144C allelic variant of CYP2C9. Pharmacogenetics. 1994;4:39-42[Medline] [Order article via Infotrieve]. 4. Haining RL, Hunter AP, Veronese ME, Trager WF, Rettie AE. Protein allelic variants of human cytochrome P450 2C9: baculovirus-mediated expression, purification, structural characterization, substrate stereoselectivity, and prochiral selectivity of the wild-type and I359L mutant forms. Arch Biochem Biophys. 1996;333:447-458[CrossRef][Medline] [Order article via Infotrieve]. 5. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999;353:717-719[CrossRef][Medline] [Order article via Infotrieve].
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Taube J, Halsall D, Baglin T.
Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment.
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2000;96:1816-1819 7. Margaglione M, Colaizzo D, D'Andrea G, et al. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost. 2000;84:775-778[Medline] [Order article via Infotrieve]. 8. Mannucci PM. Genetic control of anticoagulation. Lancet. 1999;353:688-689[CrossRef][Medline] [Order article via Infotrieve].
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Thijssen HH, Flinois JP, Beaune PH.
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2000;28:1284-1290 10. Thijssen HH, Verkooijen IW, Frank HL. The possession of the CYP2C9*3 allele is associated with low dose requirement of acenocoumarol. Pharmacogenetics. 2000;10:757-760[CrossRef][Medline] [Order article via Infotrieve].
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© 2002 by The American Society of Hematology.
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  S. J. Gardiner and E. J. Begg Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590. [Abstract] [Full Text] [PDF]
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 I. Iida, A. Miyata, M. Arai, M. Hirota, M. Akimoto, S. Higuchi, K. Kobayashi, and K. Chiba CATALYTIC ROLES OF CYP2C9 AND ITS VARIANTS (CYP2C9*2 AND CYP2C9*3) IN LORNOXICAM 5'-HYDROXYLATION Drug Metab. Dispos., January 1, 2004; 32(1): 7 - 9. [Abstract] [Full Text] [PDF]
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J. Zarza, J. Hermida, R. Montes, I. Alberca, M. L. Lopez, and E. Rocha Leu208Val and Ile181Leu variants of cytochrome P450 CYP2C9 are not related to the acenocoumarol dose requirement in a Spanish population Blood, June 28, 2002; 100(2): 734 - 735. [Full Text] [PDF]
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| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
7 mg/week), a group of 45 consecutive patients with medium dose requirements (> 7 mg and < 28 mg/week), and a group of 21 consecutive patients with high dose
requirements (
28 mg/week). Age, sex, weekly dose required, and
intake of drugs affecting acenocoumarol metabolism were recorded. Two
patients with liver disease and 2 with thyroid disease were excluded
from the study. The percentages of patients in the low-, medium-, and
high-dose acenocoumarol groups in the whole population of patients
receiving anticoagulation treatment were 11%, 83.5%, and 5.5%,
respectively. All subjects gave informed consent to participation in
the study.