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The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon

Visser, Loes Ea,b; van Vliet, Martinc; van Schaik, Ron HNc; Kasbergen, A A Harried; De Smet, Peter AGMe,f; Vulto, Arnold Gb; Hofman, Alberta; van Duijn, Cornelia Ma; Stricker, Bruno HCha,g

Pharmacogenetics and Genomics: January 2004 - Volume 14 - Issue 1 - p 27-33
Original Articles

Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarin anticoagulant metabolism. The variant alleles CYP2C9*2 and CYP2C9*3 are associated with an increased response to warfarin. However, an effect on acenocoumarol dose requirements appears to be absent for the CYP2C9*2 allele and the consequences for the metabolism of phenprocoumon have not yet been established. We investigated CYP2C9 polymorphisms in relation to the international normalized ratio (INR) during the first 6 weeks of treatment and its effect on the maintenance dose in a cohort of 1124 patients from the Rotterdam Study who were treated with acenocoumarol or phenprocoumon. There was a statistically significant difference in first INR between patients with variant genotypes and those with the wild-type. Almost all acenocoumarol-treated patients with a variant genotype had a significantly higher mean INR and had a higher risk of an INR ≥ 6.0 during the first 6 weeks of treatment. A clear genotype–dose relationship was found for acenocoumarol-treated patients. For patients on phenprocoumon, no significant differences were found between variant genotypes and the wild-type genotype. Individuals with one or more CYP2C9*2 or CYP2C9*3 allele(s) require a significantly lower dose of acenocoumarol compared to wild-type patients. Phenprocoumon appears to be a clinically useful alternative in patients carrying the CYP2C9*2 and *3 alleles.

aPharmacoepidemiology Unit, Departments of Internal Medicine and Epidemiology and Biostatistics, Erasmus MC, Rotterdam, bHospital Pharmacy, Erasmus MC, Rotterdam, cDepartment of Clinical Chemistry, Erasmus MC, Rotterdam, dStichting Trombosedienst and Artsenlaboratorium Rijnmond, Rotterdam, eScientific Institute of Dutch Pharmacists, The Hague, fDepartment of Clinical Pharmacy, University Medical Centre St Radboud, Nijmegen, the Netherlands and gDrug Safety Unit, Inspectorate for Health Care, The Hague, the Netherlands.

Correspondence and requests for reprints to B.H.Ch. Stricker, Department of Epidemiology and Biostatistics, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, the Netherlands. Tel: +31 10 4087 489; fax: +31 10 4089 382; e-mail:

Received 29 July 2003 Accepted 5 October 2003

© 2004 Lippincott Williams & Wilkins, Inc.