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Pharmacogenetics of acenocoumarol in patients with extreme dose requirements
V Pérez-Andreu1, V Roldán, M F López-Fernández
1University of Murcia, Centro de Hemodonación, Murcia, Spain.
Summary Background:
There is currently intense debate as to whether pharmacogenetic algorithms for estimating the initial dose of coumarins provide a more accurate dose than the fixed-dose approach. Recently, it has been suggested that the greatest benefit of pharmacogenetic algorithms is observed in patients with extreme dose requirements.
Objectives:
To identify clinical and genetic factors that better characterize patients who need extreme acenocoumarol doses for steady anticoagulation state.
Patients/Methods:
We reviewed 9538 patients with a steady acenocoumarol dose from three Spanish hospitals, selecting 83 who took
Results:
Comparison between p5 and p95 revealed five parameters with significant differences: body surface area (BSA) (P = 0.006), age, VKORC1, CYP2C9 and CYP4F2 genotypes (all P < 0.001). First VKORC1, and second, CYP2C9 SNPs played a strong effect by determining extreme doses, particularly in p95. Only one out of 203 p95 had the VKORC1 A-1639A genotype, but this subject was CYP2C9*1/*1. In contrast, nine out of 83 p5 carried the VKORC1 G-1639G genotype, although six of them were CYP2C9*3 homozygotes and another two were heterozygotes. Surprisingly, CYP4F2 V433M SNP displayed prevalences that suggest that its influence might only be evident when patients are treated with high doses.
Conclusion:
Two clinical data, age and BSA, and three SNPs in the VKORC1, CYP2C9 and CYP4F2 genes strongly predict outlier patients treated with acenocoumarol.
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