Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype

Karen N. van Dijk; Arian W. Plat; Alieke A. C. van Dijk; Margriet Piersma-Wichers; Anne M. B. de Vries-Bots; Jennita Slomp; Lolkje T.W. de Jong-van den Berg; Jacobus R. B. J. Brouwers

doi:10.1160/TH03-05-0325

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(01): 95-101
DOI: 10.1160/TH03-05-0325

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Potential interaction between acenocoumarol and diclofenac, naproxen and ibuprofen and role of CYP2C9 genotype

Authors

Karen N. van Dijk

¹Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands

²Department of Clinical Pharmacy, Medical Centre Leeuwarden, The Netherlands
Arian W. Plat

¹Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
Alieke A. C. van Dijk

¹Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
Margriet Piersma-Wichers

³Groningen Thrombosis Service, Groningen, The Netherlands
Anne M. B. de Vries-Bots

⁴Pharmacy ‘t Hooge Zand, Hoogezand, The Netherlands
Jennita Slomp

⁵Department of Clinical Chemistry, Stichting Klinisch Chemisch Laboratorium, Leeuwarden, The Netherlands
Lolkje T.W. de Jong-van den Berg

¹Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands
Jacobus R. B. J. Brouwers

¹Department of Social Pharmacy, Pharmacoepidemiology and Pharmacotherapy, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands

²Department of Clinical Pharmacy, Medical Centre Leeuwarden, The Netherlands

Abstract

Summary

NSAIDs are reported to increase the risk of bleeding in coumarin users. The mechanism underlying this risk is inhibition of platelet aggregation, however a pharmacokinetic mechanism resulting in an increased International Normalised Ratio (INR) was proposed in some case reports in warfarin treated patients. In this retrospective cohort study the influence of diclofenac, naproxen and ibuprofen on the INR of outpatients stabilised on acenocoumarol therapy was investigated. We also determined the role of cytochrome P450 2C9 (CYP2C9) polymorphism on coumarin dosage and INR in NSAID users. The study was carried out at the Groningen Outpatient Thrombosis Service. A retrospective cohort study among patients who received both acenocoumarol and one of the NSAIDs under study was performed. Patients whose INR rose above the upper level of the therapeutic range (INR above 3.5 or 4.0) after an NSAID under study was added to the acenocoumarol therapy, were compared with patients who did not show such an elevation. A two-sample t-test (average acenocoumarol dosage, age), and chi-square tests (sex, therapeutic range, type of NSAID) were used to test for differences. Genotyping was carried out by analysing blood samples for the relevant CYP2C9 alleles. The study population consisted of 112 patients on stable acenocoumarol therapy, of which 52 (46%) showed an elevation of the INR above the desired therapeutic level (INR3.5 and 4.0 respectively) after the start of an NSAID under study. In 12 patients, the INR increased above 6. The INR of the other 60 patients (54%) remained constant after the start of one of the NSAIDs under study. There were no statistically significant differences between patients with increased INR and patients without increased INR with regard to age, sex, therapeutic range and average acenocoumarol dosage. Eighty patients, of whom 36 showed an increased INR as a result of a potential acenocoumarol-NSAID drug interaction, were included in the genotyping study. No association between CYP2C9 genotype and an increased INR as a result of the drug-drug interaction was found. In nearly half of a cohort of elderly patients, the INR increased beyond the therapeutic range (INR 3.5 or 4.0) as a result of a potential pharmacokinetic drug-drug interaction between acenocoumarol and diclofenac, naproxen and ibuprofen. The average increase in INR was between 1 and 4. Polymorphism of CYP2C9 does not seem to be a relevant risk factor for the NSAID-acenocoumarol interaction.

Keywords

Acenocoumarol - NSAIDs - drug-interaction - CYP2C9

Full Text

References

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