[Significance of cytochrome P450 2C9 genotype for the bleeding complications in patients treated with acenocoumarol].
BACKGROUND
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 comorbidity, age, other drugs used, diet, and pharmacogenetic factors. One of the latters is the polymorphism of the cytochrome P450 CYP2C9 enzyme.


OBJECTIVE
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 patients 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 anamnesis 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.
Márk
László
L
Békés Megyei Képviselotestület Pándy Kálmán Kórháza, Gyula, II. Belgyógyászat-Kardiológia.
Márki-Zay
János
J
Fodor
Lajos
L
Kondacs
András
A
Paragh
György
G
Katona
András
A
D000074:Acenocoumarol / Q000008:administration & dosage / Q000009:adverse effects*; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006470:Hemorrhage / Q000139:chemically induced* / Q000517:prevention & control; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic
D000925:Anticoagulants; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D000074:Acenocoumarol