Cytochrome P450 2C9 polymorphism and acenocoumarol therapy.
BACKGROUND
Oral anticoagulants, in Hungary acenocoumarol being the one exclusively used, have a low therapeutic index and a high bleeding complication rate. The cytochrome P450 2C9 enzyme plays an important role in their metabolism.


OBJECTIVE
To investigate the influence of CYP2C9 polymorphism on the occurrence of bleeding complications related to acenocoumarol therapy.


METHODS
Genotyping of 421 patients (183 men and 238 women, mean age 66.2+/-11.8 years), who had been taking acenocoumarol for at least 6 months, was performed. Based on patient history and laboratory data, the correlations between genotype and acenocoumarol dose and bleeding complications were retrospectively analysed.


RESULTS
In 145 patients bearing alleles with reduced activity (CYP2C9*2 and/or *3), the optimal dose of acenocoumarol was significantly (p<0.001) lower than in patients with the wild type allele (2.12+/-0.96 mg/day and 2.90+/-1.46 mg/day, respectively). In comparison with wild type allele patients, the mean daily acenocoumarol dose was lower in the CYP2C9*2 group, and the lowest in *3 bearers. Although the occurrence of minor bleeding complications in patients with the variant allele was significantly (p <0.005) higher (OR=1.99 [CI: 1.20-3.33]) than in other patients, there was no difference in major bleeding complications.


CONCLUSIONS
Patients bearing CYP2C9 alleles with reduced enzymatic activity have a lower acenocoumarol requirement. In patients with CYP2C9*2 and *3 alleles the frequency of minor bleeding complications and the occurrence of high INR values were significantly higher, but there was no difference in the rate of major bleedings.
Mark
Laszlo
L
2nd Department of Internal Medicine--Cardiology, Pandy Kalman Bekes County Hospital, Semmelweis u. 1., P.O. Box 46., H-5700 Gyula, Hungary. mark@pandy.hu
Marki-Zay
Janos
J
Fodor
Lajos
L
Hajdara
Ildiko
I
Paragh
Gyorgy
G
Katona
Andras
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* / Q000201:enzymology / Q000235:genetics / 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