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

Abstract

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 (INR 3.5 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.

Maintenance of Warfarin Anticoagulation for Patients Undergoing Vitreoretinal Surgery

“…This risk is increased by multiple mechanisms, including interference with platelet function through inhibition of cyclooxygenase 1. 28 The use of cyclooxygenase 2-selective nonsteroidal anti-inflammatory drugs may lead to fewer complications, as these agents do not interfere with platelet function. No patients in our series receiving cyclooxygenase 2 therapy developed new postoperative hemorrhagic complications.…”

Adherence to Guidelines for Avoiding Drug Interactions Associated with Warfarin - A Nationwide Swedish Register Study

“…In addition, they damage the gastrointestinal mucosa [8], and increase the sensitivity to warfarin treatment [9], factors all of which contribute to a substantially increased risk of severe bleeding [5], [10], [11]. The interaction between warfarin and NSAIDs is one of the most prevalent clinically relevant drug-drug interactions, and in a large US prescription study 24% of warfarin-treated patients received an NSAID during a two-year follow-up [12], [13].…”

Risk Factors of Drug Interaction between Warfarin and Nonsteroidal Anti-Inflammatory Drugs in Practical Setting

“…In addition to their antiplatelet function, NSAIDs can affect the pharmacologic action of warfarin through their direct interaction. High protein binding and the cytochrome P450 (CYP)-dependent clearance mechanisms of NSAIDs can affect the serum levels of warfarin (4-6). Accordingly, there have been many case reports describing bleeding complications after NSAIDs were administered along with warfarin (7-13).…”