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

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.

Prescribing indicators for evaluating drug use in nursing homes.

OBJECTIVE: To evaluate drug use in 2 Dutch nursing homes (254 residents) by developing and evaluating prescribing indicators based on pharmacy prescription data. METHODS: We evaluated the prescribing of benzodiazepines, nonsteroidal antiinflammatory drugs (NSAIDs), ulcer-healing drugs, and diuretics. Prescribing indicators were used to identify prescribing that was potentially not in line with recommendations in national and regional prescribing guidelines. We used both descriptive indicators, such as the number and percentage of users, and indicators reflecting potentially suboptimal prescribing, such as use of drugs outside the regional drug formulary, use of >1 drug from the same drug class, and prescription of drug dosages above recommended values. When potentially suboptimal prescribing was found, we verified the findings by means of an interview with 1 of the prescribers. RESULTS: The prescribing indicators we assessed were generally in agreement with national and regional guidelines. However, prescribing of NSAIDs without concomitant prescribing of gastroprotective drugs was found in a relatively high number of patients. After prescriber interview and patient chart review, it was found that some prescribing indicators, such as dosages above recommended values, were not always indicative for suboptimal prescribing. CONCLUSIONS: This pilot study showed that prescribing indicators based solely on pharmacy prescription data can be a useful tool to evaluate drug prescribing. With some of these prescribing indicators, we identified cases of potentially suboptimal prescribing. However, with other indicators such as those based on drug dosages, we could not identify suboptimal prescribing, and clinical information from the prescriber was necessary to get insight into the appropriateness of prescribing.