Alignment of CanMEDS-based Undergraduate and Postgraduate Pharmacy Curricula in The Netherlands.

In this article the design of three master programs (MSc in Pharmacy) and two postgraduate specialization programs for community or hospital pharmacist is described. After a preceding BSc in Pharmacy, these programs cover the full pharmacy education capacity for pharmacists in primary and secondary health care in the Netherlands. All programs use the CanMEDS framework, adapted to pharmacy education and specialization, which facilitates the horizontal integration of pharmacists' professional development with other health care professions in the country. Moreover, it is illustrated that crossing the boundary from formal (university) education to experiential (workplace) education is eased by a gradual change in time spent in these two educational environments and by the use of comparable monitoring, feedback, and authentic assessment instruments. A reflection on the curricula, based on the principles of the Integrative Pedagogy Model and the Self-determination Theory, suggests that the alignment of these educational programs facilitates the development of professional expertise and professional identity of Dutch pharmacists.

Implementation of Competency-Based Pharmacy Education (CBPE).

Implementation of competency-based pharmacy education (CBPE) is a time-consuming, complicated process, which requires agreement on the tasks of a pharmacist, commitment, institutional stability, and a goal-directed developmental perspective of all stakeholders involved. In this article the main steps in the development of a fully-developed competency-based pharmacy curriculum (bachelor, master) are described and tips are given for a successful implementation. After the choice for entering into CBPE is made and a competency framework is adopted (step 1), intended learning outcomes are defined (step 2), followed by analyzing the required developmental trajectory (step 3) and the selection of appropriate assessment methods (step 4). Designing the teaching-learning environment involves the selection of learning activities, student experiences, and instructional methods (step 5). Finally, an iterative process of evaluation and adjustment of individual courses, and the curriculum as a whole, is entered (step 6). Successful implementation of CBPE requires a system of effective quality management and continuous professional development as a teacher. In this article suggestions for the organization of CBPE and references to more detailed literature are given, hoping to facilitate the implementation of CBPE.

Risk of myocardial infarction in patients with atrial fibrillation using vitamin K antagonists, aspirin or direct acting oral anticoagulants.

AIM: Direct-acting oral anticoagulants (DOACs) have become available for the prevention of stroke in patients with atrial fibrillation (AF). Conflicting results have been published on the risk of acute myocardial infarction (AMI) with the use of DOACs in comparison with vitamin K antagonists (VKAs). The objective of the present study was to evaluate the risk of AMI in patients with AF who are exposed to either VKAs, DOACs or low-dose (< 325 mg) aspirin. METHODS: We conducted a population-based cohort study using data from the Clinical Practice Research Datalink (2008-2014). The study population (n = 30 146) consisted of all patients ≥18 years with a diagnosis of AF who were new users of VKAs, DOACs (rivaroxaban and dabigatran) or aspirin. Cox proportional hazards models were used to estimate the hazard ratio (HR) of AMI for users of DOACs or aspirin vs. VKA. Adjustments were made for age, gender, lifestyle, risk factors, comorbidity and other drugs. RESULTS: The risk of AMI was doubled when we compared current use of DOACs with current use of VKAs [adjusted HR 2.11; 95% confidence interval (CI) 1.08, 4.12] and for current users of aspirin vs. current VKA users (adjusted HR 1.91; 95% CI 1.45, 2.51). CONCLUSIONS: There is a twofold increase in the risk of AMI for users of DOACs, in comparison with VKAs, in AF therapy. In addition, the results suggested that in patients with AF, the incidence of AMI is higher during aspirin monotherapy than during the use of VKAs.

Evaluation of the effect of genetic variations in GATA-4 on the phenprocoumon and acenocoumarol maintenance dose.

AIM: To investigate whether the phenprocoumon and acenocoumarol maintenance doses are influenced by genetic variations in GATA-4, a transcription factor of CYP2C9. PATIENTS & METHODS: The influence of seven GATA-4 SNPs on the coumarin maintenance dose was investigated by performing an analysis of variance trend analysis, stratified for CYP2C9 genotypes. Results of the best-explaining SNP were validated in the Rotterdam Study cohort. RESULTS: The largest dose differences were found for rs3735814 in patients using acenocoumarol and having the common allele for CYP2C9. The mean dosages decreased from 2.92 mg/day for the patients having the GATA-4 common alleles to 2.65 mg/day for the patients carrying one GATA-4 variant allele and to 2.37 mg/day for patients carrying two GATA-4 variant alleles (p = 0.004). Results could not be replicated in the validation cohort. For phenprocoumon, no significant effects were observed. CONCLUSION: Genetic variation in GATA-4 does not seem relevant for clinical implementation.

Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose.

BACKGROUND: Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether acenocoumarol and phenprocoumon maintenance doses are influenced by statin use. METHODS: The Pre-EU-PACT database was used, which contains information on 471 acenocoumarol and 624 phenprocoumon users. The influence of individual statins on the acenocoumarol and phenprocoumon maintenance dose was investigated by comparing unadjusted and adjusted mean differences of the maintenance dose between statin and non-statin users. RESULTS: Lower adjusted acenocoumarol dose requirements were observed for patients using atorvastatin, simvastatin, pravastatin, and rosuvastatin. These patients had a reduction in adjusted mean acenocoumarol maintenance dose of 0.11, 0.29, 0.38, and 0.69 mg/day, respectively, compared with a mean adjusted dose of 2.60 mg/day for the patients not using a statin. There was no significant effect of statin use on unadjusted and adjusted phenprocoumon maintenance dose (p=0.23 and p=0.35, respectively). CONCLUSIONS: Mean acenocoumarol maintenance dosages were decreased when acenocoumarol is co-administered with the different statins. Statin use does not affect phenprocoumon maintenance doses significantly.

Validation of the acenocoumarol EU-PACT algorithms: similar performance in the Rotterdam Study cohort as in the original study.

AIM: To evaluate the performance of the European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) acenocoumarol dose algorithms in an independent data set. The EU-PACT trial investigates the added value of pretreatment genotyping for use of warfarin, phenprocoumon and acenocoumarol. PATIENTS & METHODS: External validation was performed in the Rotterdam Study cohort using information about 707 acenocoumarol users. R(2), which measures the strength of correlation between the predicted and observed acenocoumarol dose, mean absolute error and mean squared error were calculated to evaluate the performance of the original algorithm. RESULTS: Validation resulted in a R(2) of 52.7 and 12.9% compared with an R(2) of 52.6 and 17.8% in the original study for the genotype-guided and nongenotype-guided dose algorithm, respectively. For the genotype-guided dose algorithm, the mean absolute error was 0.48 mg/day and the mean squared error was 0.38 (mg/day)(2). For the nongenotype-guided dose algorithm, the mean absolute error was 0.62 mg/day and the mean squared error was 0.63 (mg/day)(2). CONCLUSION: The EU-PACT acenocoumarol algorithm performs just as accurately in this study as in the original study, which implies applicability in various populations.

[Interaction between clopidogrel and proton pump inhibitors]. / Interactie tussen clopidogrel en protonpompremmers.

The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature. Concomitant use of omeprazole and clopidogrel was found to decrease the exposure (AUC) to clopidogrel's active metabolite by 50% and to sharply increase platelet reactivity, as a result of inhibition by omeprazole of CYP2C19, a cytochrome P450 (CYP) enzyme. Pantoprazole has a much weaker effect on clopidogrel's pharmacokinetics and on platelet reactivity during concomitant use. The influence of the other proton pump inhibitors when used simultaneously with clopidogrel has not yet been investigated in adequately randomized studies. Regulatory agencies state that the combination of clopidogrel and the CYP2C19 inhibitors omeprazole and esomeprazole should be avoided. To date, there is no conclusive evidence of a clinically-relevant interaction between any of the proton pump inhibitors and clopidogrel.

Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data.

AIMS: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE. METHODS AND RESULTS: In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters. CONCLUSION: To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.

Clinical and economic consequences of pharmacogenetic-guided dosing of warfarin.

Patients using warfarin for oral anticoagulant therapy need to be frequently monitored because of warfarin's narrow therapeutic range and the large variation in dose requirements among patients. Patients receiving the wrong dose have an increased risk of bleeding or thromboembolic events. The required dose is influenced by environmental factors, such as gender, age, diet and concomitant medication, as well as genetic factors. Pharmacogenetic testing prior to warfarin initiation might improve dosing accuracy and, therefore, safety and efficacy of warfarin treatment. Meckley et al. studied the clinical consequences and costs of genotyping before warfarin treatment. The results of their study suggest that pharmacogenetic-guided dosing of patients initiating warfarin could improve health (quality-adjusted life-years) but at a high cost per quality-adjusted life-year gained. Owing to the inevitable assumptions that have to be made in all cost-effectiveness models, great uncertainty remains regarding the cost-effectiveness of pharmacogenetic-guided warfarin dosing.

Statin prescribing in the elderly in the Netherlands: a pharmacy database time trend study.

INTRODUCTION: There is some evidence that the beneficial effects of HMG-CoA reductase inhibitors (statins) in the elderly are at least comparable to the effects in middle-aged people. However, several studies have shown prescription rates of statins to be significantly lower in the elderly than in younger populations. OBJECTIVE: The aim of the present study was to monitor statin prescribing trends in the elderly in the Netherlands over time in terms of prevalence, incidence, type of statin, dose prescribed and adherence to clinical guidelines. METHODS: The database of a community pharmacy in Utrecht, which includes prescription data for approximately 11,000 people, was analysed to investigate trends in statin prescriptions from January 1999 to December 2008. The 1-year prevalence and incidence of statin use stratified by age were determined for each calendar year. Rate ratios (RRs) and 95% confidence intervals were calculated with 1999 as the reference year. Furthermore, the following trends of interest were calculated for each calendar year: the percentage of statin users prescribed simvastatin or atorvastatin, the median dose of simvastatin and atorvastatin prescribed, and the percentage of simvastatin users prescribed a dosage of 40 mg/day (which is recommended by the Dutch multidisciplinary guideline). RESULTS: The 1-year prevalence of statin use in medication users aged >or=50 years increased from 13.9% in 1999 to 22.8% in 2008 (RR 1.6; 95% CI 1.4, 1.9; p < 0.001). Overall, the lowest prevalence (5.1% in 1999 and 15.2% in 2008) and incidence rates (3.2% in 2000 and 4.2% in 2008) were found in patients aged >or=80 years. Before 2006, simvastatin was the most commonly prescribed statin, but the number of users declined as the percentage of patients with new simvastatin prescriptions decreased (from 43.4% in 2000 to 36.5% in 2005) and the percentage of patients treated with new atorvastatin prescriptions increased (from 37.7% in 2000 to 47.3% in 2005). As from 2006, when the Dutch multidisciplinary guideline for Cardiovascular Risk Management was introduced, recommending treatment with a daily simvastatin dose of 40 mg, the number of simvastatin users increased again and most treatment-naive patients were started on simvastatin (62.3% in 2006, increasing to 66.7% in 2008). The median simvastatin dose increased from 10 mg in 1999 to 20 mg in 2001, remaining at the same dose until 2008, and appeared to be related to the patient's age. From 2006, patients aged >or=80 years were the least likely group to receive the recommended dose of 40 mg simvastatin daily (10.0-20.0% of simvastatin users aged >or=80 years compared with 32.5-36.9% of simvastatin users aged 60-69 years). CONCLUSION: Despite the benefits of statin treatment previously reported in older patients, the prevalence and incidence of statin use were lower in elderly patients compared with younger patients. In addition, lower dosages of statins were prescribed. These findings suggest the beneficial effects of statins in the elderly observed in clinical trials may not be achieved in everyday practice.

Pharmacogenetics of oral anticoagulant therapy.

The identification of the genes encoding CYP2C9, the principal metabolizing enzyme of the coumarins, and VKORC1, the molecular target for coumarins, has strongly stimulated the research on pharmacogenetics of vitamin K antagonists, also designated as coumarins. From 1999 to 2004 a number of observational studies firmly established associations between being carrier of the CYP2C9*2 and especially the CYP2C9*3 allele and reduced coumarin dose requirements and increased risks of overanticoagulation and even major bleeding compared to CYP2C9 wild type patients. The identification of the VKORC1 gene in 2004 gave rise to more observational studies, which mostly indicated a larger contribution of variants of these gene to the interindividual variability in dose requirements. However, whereas overanticoagulation in the initial period of therapy appears to be associated with VKORC1 as well as CYP2C9 genotype, the CYP2C9 genotype could be a more important predictor for major bleeding and retarded stabilisation. The recent discovery that only one single nucleotide polymorphism in the VKORC1 gene, the -1639G>A polymorphism, is representative for VKORC1 activity and the recent conclusion from a genome-wide scan that VKORC1 and CYP2C9 are the only genes with relevant effects on coumarin response, seem to be definitive demarcations of the genetic information which could be needed for improvement of the existing coumarin dosing algorithms. The observational studies from the last decade provided valuable insights into the effects of genetic factors on variability in coumarin response. During the forthcoming years randomized clinical trials are needed to evaluate whether this genetic information will improve the benefit-risk ratio of coumarins.

Increased bleeding risk with concurrent use of selective serotonin reuptake inhibitors and coumarins.

BACKGROUND: Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. Because use of selective serotonin reuptake inhibitors (SSRIs) is also associated with an increased risk of bleeding, we assessed the odds ratio (OR) of abnormal bleeding associated with SSRI use in users of the coumarins acenocoumarol or phenprocoumon and compared this with the OR of bleeding as a result of use of nonsteroidal anti-inflammatory drugs. METHODS: We used data from a Dutch linkage system including pharmacy and linked hospitalization records for approximately 2 million subjects to conduct a case-control study in a cohort of new users of coumarins. Cases were patients who were hospitalized having a primary diagnosis of abnormal major bleeding while taking a coumarin and were matched with up to 4 control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CIs) for the risk of hospitalization because of abnormal bleeding associated with concurrent use of SSRIs or nonsteroidal anti-inflammatory drugs. RESULTS: We identified 1848 case patients with abnormal bleeding. Users of SSRIs were at significantly increased risk of hospitalization because of nongastrointestinal tract bleeding (hereafter referred to as "nongastrointestinal bleeding") (adjusted OR, 1.7; 95% CI, 1.1-2.5) but not because of gastrointestinal tract bleeding (hereafter referred to as "gastrointestinal bleeding") (adjusted OR, 0.8; 95% CI, 0.4-1.5). Users of nonsteroidal anti-inflammatory drugs had a similar increased risk of nongastrointestinal bleeding (adjusted OR, 1.7; 95% CI, 1.3-2.2), whereas the risk of gastrointestinal bleeding was higher (adjusted OR, 4.6; 95% CI, 3.3-6.5). CONCLUSION: In users of coumarins, SSRI usage was associated with increased risk of hospitalization because of nongastrointestinal bleeding but not because of gastrointestinal bleeding.

Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon.

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of the VKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 and VKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect of VKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Effect of oral antiplatelet agents on major bleeding in users of coumarins.

Treatment with vitamin K antagonists (coumarins) is associated with an increased risk of bleeding. In order to elucidate the bleeding risk of users of antiplatelet drugs among users of coumarins, we assessed the odds ratio of major bleeding associated with use of antiplatelet drugs in users of the coumarins acenocoumarol and phenprocoumon. We used data from a Dutch record linkage system, including pharmacy and linked hospitalization records for approximately two million subjects, to conduct a nested case control study in a cohort of new users of coumarins. Cases were patients who were hospitalized with a primary diagnosis of major bleeding while taking coumarin and were matched with up to four control subjects. Conditional logistic regression analysis was used to determine ORs and 95% confidence intervals (CI). We identified 1848 case patients who were matched to 5818 controls. Users of clopidogrel or aspirin showed a significantly increased risk of hospitalization because of major bleeding (OR 2.9, 95% CI 1.2-6.9 and OR 1.6, 95% CI 1.3-1.9, respectively), whereas users of dipyridamole and combinations of antiplatelet drugs showed a strong trend (OR 1.5, 95% CI 1.0-2.3 and OR 1.8, 95 % CI 1.0-3.3, respectively). In all cases, the risks were greater for upper gastrointestinal bleedings than for other bleedings. In conclusion, the use of any antiplatelet drug increases the risk of hospitalization for major bleeding among users of coumarins. Concurrent use of clopidogrel or dipyridamole and coumarins is probably not safer than concurrent use of aspirin and coumarins.

Compliance with national guidelines for the management of drug-drug interactions in Dutch community pharmacies.

BACKGROUND: Pharmacists contribute to the detection and prevention of drug therapy-related problems, including drug-drug interactions. Little is known about compliance with pharmacy practice guidelines for the management of drug-drug interaction alerts. OBJECTIVE: To measure the compliance of community pharmacists with Dutch guidelines for the management of drug-drug interactions and to determine patient- and prescriber-related determinants for noncompliance. METHODS: Sixteen clinically relevant drug-drug interactions were included in the study based on certain described criteria. From June to August 2005, Dutch pharmacists (N = 149) collected alerts occurring in daily patient care for these interactions as well as information related to the patient, the alert itself, the prescriber, and the management of the alert. Noncompliance was measured by comparing the management executed by the pharmacy with the national guidelines. RESULTS: Overall compliance with the guidelines was 69.3% (n = 423), with large differences between the various drug-drug interactions. Male sex (OR 2.25; 95% CI 1.52 to 3.31), oldest age (>75 y; OR 1.97; 95% CI 1.03 to 3.75), and polypharmacy (>7 medications; OR 2.35; 95% CI 1.46 to 3.80) were associated with a higher probability for noncompliance with the guidelines. Prescriber-related variables had no significant influence on guideline compliance. Substitution of one of the involved agents, recommended for most of the drug-drug interactions, was executed in a small minority of cases. The outcome of interaction management, such as substitution, dose reduction, or temporary stop of one of the agents, was frequently inconsistent with the guidelines. Compliance rates were partly influenced by the ultimate decision made by the prescriber. In that way, pharmacies' compliance was not solely assessed. However, in only 22.5% of the cases was the drug-drug interaction presented to the prescriber. CONCLUSIONS: Noncompliance with Dutch guidelines for the management of drug-drug interaction alerts is common in community pharmacies. Further research into underlying reasons for noncompliance is warranted, such as the relation between pharmacist and prescriber in this context.

Coumarin anticoagulants and co-trimoxazole: avoid the combination rather than manage the interaction.

OBJECTIVE: The objective of our study was to examine the management of the interaction between acenocoumarol or phenprocoumon and several antibiotics by anticoagulation clinics and to compare the consequences of this interaction on users of co-trimoxazole with those for users of other antibiotics. METHODS: A follow-up study was conducted at four anticoagulation clinics in The Netherlands. Data on measurements of the International Normalised Ratio (INR), application of a preventive dose reduction (PDR) of the coumarin anticoagulant, fever and time within or outside the therapeutic INR range were collected. RESULTS: The study cohort consisted of 326 subjects. A PDR was given more often to users of co-trimoxazole PDR than to users of other antibiotics. The PDR in co-trimoxazole users resulted in a significantly reduced risk of both moderate overanticoagulation (INR >4.5) and severe overanticoagulation (INR >6.0) compared with no PDR, with odds ratios (ORs) of 0.06 [95% confidence interval (CI): 0.01-0.51] and 0.09 (95% CI: 0.01-0.92), respectively. In co-trimoxazole users without PDR, the risk of overanticoagulation was significantly increased compared with users of other antibiotics. All co-trimoxazole users spent significantly more time under the therapeutic INR range during the first 6 weeks after the course than users of other antibiotics. CONCLUSION: PDR is effective in preventing overanticoagulation in co-trimoxazole users, but results in a significantly prolonged period of underanticoagulation after the course. Avoidance of concomitant use of co-trimoxazole with acenocoumarol or phenprocoumon seems to be a safer approach than management of the interaction between these drugs.

VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation.

OBJECTIVE: Our objective was to assess the effects of VKORC1 and CYP2C9 genotypes on severe overanticoagulation and time to achieve stability and their contributions to dose requirement during the initial phase of acenocoumarol treatment. METHODS: A prospective follow-up study was conducted at 2 anticoagulation clinics in The Netherlands. We assessed the CYP2C9 genotype (CYP2C9*2 and CYP2C9*3 polymorphisms) and the VKORC1 C1173T genotype of the subjects and collected data on international normalized ratio, dose, comedication, and comorbidity. RESULTS: Of the 231 patients in the cohort, 150 (64.9%) had a VKORC1 C1173T polymorphism and 84 (36.4%) had a CYP2C9*2 or CYP2C9*3 allele. Only carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had an increased risk of severe overanticoagulation compared with subjects with no polymorphism or only 1 polymorphism (hazard ratio, 3.83 [95% confidence interval, 1.62-9.05]). The time to achieve stability was associated with the possession of the CYP2C9 genotype, not with the VKORC1 genotype (hazard ratio for CYP2C9*3 allele compared with CYP2C9 wild type, 0.59 [95% confidence interval, 0.40-0.87]). Patients with a VKORC1 polymorphism required significantly lower doses than VKORC1 CC wild-type patients. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (21.4% and 4.9%, respectively). CONCLUSION: Being a carrier of a combination of polymorphisms of VKORC1 and CYP2C9, rather than of one of these polymorphisms, is associated with severe overanticoagulation. The time to achieve stability is mainly associated with the CYP2C9 genotype.

Discrepancies between medication records of anticoagulation clinics and pharmacy records.

PURPOSE: To determine whether there were discrepancies between with coumarin anticoagulants interacting medications recorded in medical files of anticoagulation clinics (AC-records) and computerized records of community pharmacies (pharmacy records). METHODS: A descriptive study was conducted at two Dutch anticoagulation clinics (AC's). Records of with coumarin anticoagulants interacting drugs at the AC's were compared with the pharmacy records. A drug registered in the pharmacy records but not in the AC-records, was recorded as a discrepancy, while a drug registered in AC-records as well as in pharmacy records, was recorded as a match. RESULTS: Of the 117 identified interacting drugs registered in pharmacy records 32 (27%) were not registered in the AC-records. In four out of seven patients of whom the use of a pharmacokinetically interacting drug was not registered in the AC-records, several INR-values exceeded the upper therapeutic range. CONCLUSION: This study demonstrates that a substantial percentage of drugs of which an interaction with coumarin anticoagulants can be expected, is not registered in the medical files of anticoagulation clinics.