A citokróm P450 2C9 genotípus jelentosége acenocoumarollal kezelt betegek vérzéses szövodmé nyeire

Translated title of the contribution: The importance of the cytochrome P450 2C9 genotyping on the bleeding complications of patients taking acenocoumarol

László Márk, János Márki-Zay, L. Fodor, A. Kondacs, G. Paragh, András Katona

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Introduction: For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the co-morbiditation, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme. Aim: The influence of CYP2C9 polymorphism on the effectiveness of the - in Hungary for oral anticoagulation exclusively used - acenocoumarol therapy and on the occurrence of bleeding complications was investigated. Methods: Genotyping of 421 patiens including 183 men and 238 women, (mean age 66.2 ± 11.8 years) who took acenocoumarol (Syncumar®) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed. Results: The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p <0.001) lower than in patients with the wild type allele (2.12 ± 0.96 mg/day and 2.90 ± 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p <0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnese was significantly (p <0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3. Conclusions: The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.

Original languageHungarian
Pages (from-to)739-743
Number of pages5
JournalOrvosi Hetilap
Volume146
Issue number16
Publication statusPublished - 2005

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Acenocoumarol
Cytochrome P-450 Enzyme System
Hemorrhage
Alleles
International Normalized Ratio
Therapeutics
Hungary
Pharmacogenetics
Primary Prevention
Secondary Prevention
Pharmaceutical Preparations
Anticoagulants
Cytochrome P-450 CYP2C9
Genotype
Diet

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A citokróm P450 2C9 genotípus jelentosége acenocoumarollal kezelt betegek vérzéses szövodmé nyeire. / Márk, László; Márki-Zay, János; Fodor, L.; Kondacs, A.; Paragh, G.; Katona, András.

In: Orvosi Hetilap, Vol. 146, No. 16, 2005, p. 739-743.

Research output: Contribution to journalArticle

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title = "A citokr{\'o}m P450 2C9 genot{\'i}pus jelentos{\'e}ge acenocoumarollal kezelt betegek v{\'e}rz{\'e}ses sz{\"o}vodm{\'e} nyeire",
abstract = "Introduction: For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the co-morbiditation, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme. Aim: The influence of CYP2C9 polymorphism on the effectiveness of the - in Hungary for oral anticoagulation exclusively used - acenocoumarol therapy and on the occurrence of bleeding complications was investigated. Methods: Genotyping of 421 patiens including 183 men and 238 women, (mean age 66.2 ± 11.8 years) who took acenocoumarol (Syncumar{\circledR}) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed. Results: The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p <0.001) lower than in patients with the wild type allele (2.12 ± 0.96 mg/day and 2.90 ± 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p <0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnese was significantly (p <0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3. Conclusions: The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.",
keywords = "Acenocoumarol, Bleeding complications, Cytochrome P 450 2C9, Oral anticoagulants, Pharmacogenetics",
author = "L{\'a}szl{\'o} M{\'a}rk and J{\'a}nos M{\'a}rki-Zay and L. Fodor and A. Kondacs and G. Paragh and Andr{\'a}s Katona",
year = "2005",
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TY - JOUR

T1 - A citokróm P450 2C9 genotípus jelentosége acenocoumarollal kezelt betegek vérzéses szövodmé nyeire

AU - Márk, László

AU - Márki-Zay, János

AU - Fodor, L.

AU - Kondacs, A.

AU - Paragh, G.

AU - Katona, András

PY - 2005

Y1 - 2005

N2 - Introduction: For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the co-morbiditation, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme. Aim: The influence of CYP2C9 polymorphism on the effectiveness of the - in Hungary for oral anticoagulation exclusively used - acenocoumarol therapy and on the occurrence of bleeding complications was investigated. Methods: Genotyping of 421 patiens including 183 men and 238 women, (mean age 66.2 ± 11.8 years) who took acenocoumarol (Syncumar®) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed. Results: The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p <0.001) lower than in patients with the wild type allele (2.12 ± 0.96 mg/day and 2.90 ± 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p <0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnese was significantly (p <0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3. Conclusions: The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.

AB - Introduction: For the primary and secondary prevention of thromboembolic events are used the oral anticoagulants, the drugs having a low therapeutic index and frequent bleeding complication rate. Establishing the proper therapeutic dose of these drugs for different patients is complicated by a variety of conditions, such as the co-morbiditation, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme. Aim: The influence of CYP2C9 polymorphism on the effectiveness of the - in Hungary for oral anticoagulation exclusively used - acenocoumarol therapy and on the occurrence of bleeding complications was investigated. Methods: Genotyping of 421 patiens including 183 men and 238 women, (mean age 66.2 ± 11.8 years) who took acenocoumarol (Syncumar®) for at least 6 months was performed. Based on anamnestic and laboratory data, the correlation between the genotype and the acenocoumarol dose and bleeding complications were retrospectively analysed. Results: The frequency-distribution for the CYP2C9*1, *2, and *3 alleles were found to be: 0.814, 0.110, and 0.076, respectively. In the 145 patients bearing the alleles with reduced activity (CYP2C9*2 and/or *3), the optimised dose of the acenocoumarol was significantly (p <0.001) lower than in patients with the wild type allele (2.12 ± 0.96 mg/day and 2.90 ± 1.45 mg/day, respectively). Although the occurrence of minor bleeding complications in the former group was significantly (p <0.005) higher [OR = 1.99 (CI: 1.20-3.33)], there was no difference in major bleeding complications. In patients taking an acenocoumarol dose lower than 2 mg/day, the occurrence of an INR value higher than 6 in the anamnese was significantly (p <0.05) more frequent. Evaluating separately the variant alleles we have concluded, that in the presence of allele *2 a lower acenocoumarol dose was required than in wild-type subjects, and even lower in the presence of allele *3. Conclusions: The frequency-distribution of the CYP2C9 alleles was as reported by others. In patients bearing alleles with reduced enzymatic activity, the occurrence of minor bleeding complications and the INR values higher than 6 were significantly more frequent. In patients with a lower acenocoumarol demand at the introduction of this therapy, a caution is required. In order to test the hypothesis that before the initiation of acenocoumarol therapy the determination of CYP2C9 polymorphism is cost-effective and could improve the optimization of anticoagulation and reduce the risk of bleeding complications a large prospective randomised trial is required.

KW - Acenocoumarol

KW - Bleeding complications

KW - Cytochrome P 450 2C9

KW - Oral anticoagulants

KW - Pharmacogenetics

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M3 - Article

VL - 146

SP - 739

EP - 743

JO - Orvosi Hetilap

JF - Orvosi Hetilap

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