Scientific
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BACKGROUND AND PURPOSE: A multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication. METHODS: Case-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated. RESULTS: 49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02-1.15) and use of traditional NSAIDs (1.16, 1.12-1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19-1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS. CONCLUSIONS: Risk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13-46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.

BACKGROUND: The objective of this study was to identify patients with diabetes in a comprehensive primary care electronic medical records database using a number of different case definitions (clinical, pharmacy, laboratory definitions and a combination thereof) and understand the differences in patient populations being captured by each definition. METHODS: Data for this population-based retrospective cohort study was obtained from The Health Information Network (THIN). THIN is a longitudinal, primary care medical records database of over 9 million patients in UK. Primary outcome was a diagnosis of diabetes, defined by the presence of a diabetes read code, or an abnormal laboratory result, or a prescription for an Oral Anti-diabetic drug or insulin. A 2-year washout period was applied prior to the index of diabetes to avoid inclusion of prevalent cases for each case definition. RESULTS: This study demonstrated that different case definitions of diabetes identify different sub-populations of patients. When the cohorts were observed based on any measure of central tendency, each of the cohorts were reasonably comparable to each other. However, the distribution of each of the cohorts when grouped by age categories and sex, reveal differences. For example, using pharmacy case definition results in a bimodal distribution among women, one between 1-19 year and 35-39 age categories, and then again between 60-64 and 85 years-however, the histogram becomes more normally distributed when metformin was removed from the case definition. CONCLUSION: Our results suggest that clinical, pharmacy, laboratory case definitions identify different sub-populations and using multiple case definitions is likely required to optimally identify the entire diabetes population within THIN. Our study also suggests that age and sex of patients may affect the indexing of diabetes in THIN and is critical to better understand these variations.

OBJECTIVE: Electronic healthcare databases (EHDs) are useful tools for drug development and safety evaluation but their heterogeneity of structure, validity and access across Europe complicates the conduct of multidatabase studies. In this paper, we provide insight into available EHDs to support regulatory decisions on medicines. METHODS: EHDs were identified from publicly available information from the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance resources database, textbooks and web-based searches. Databases were selected using criteria related to accessibility, longitudinal dimension, recording of exposure and outcomes, and generalisability. Extracted information was verified with the database owners. RESULTS: A total of 34 EHDs were selected after applying key criteria relevant for regulatory purposes. The most represented regions were Northern, Central and Western Europe. The most frequent types of data source were electronic medical records (44.1%) and record linkage systems (29.4%). The median number of patients registered in the 34 data sources was 5 million (range 0.07-15 million) while the median time covered by a database was 18.5 years. Paediatric patients were included in 32 databases (94%). Completeness of information on drug exposure was variable. Published validation studies were found for only 17 databases (50%). Some level of access exists for 25 databases (73.5%), and 23 databases (67.6%) can be linked through a personal identification number to other databases with parent-child linkage possible in 7 (21%) databases. Eight databases (23.5%) were already transformed or were in the process of being transformed into a common data model that could facilitate multidatabase studies. CONCLUSION: A Few European databases meet minimal regulatory requirements and are readily available to be used in a regulatory context. Accessibility and validity information of the included information needs to be improved. This study confirmed the fragmentation, heterogeneity and lack of transparency existing in many European EHDs.

PURPOSE: The purpose of the study is to evaluate the effectiveness of risk minimization measures-labeling changes and communication to health care professionals-recommended by the European Medicines Agency for use of cilostazol for the treatment of intermittent claudication in Europe. METHODS: Observational study of cilostazol in The Health Improvement Network (United Kingdom), EpiChron Cohort (Spain), SIDIAP (Spain), Swedish National Databases, and GePaRD (Germany). Among new users of cilostazol, we compared the prevalence of conditions targeted by the risk minimization measures in the periods before (2002-2012) and after (2014) implementation. Conditions evaluated were prevalence of smoking, cardiovascular conditions, concurrent use of ≥2 antiplatelet agents, concurrent use of potent CYP3A4/CYP2C19 inhibitors and high-dose cilostazol, early monitoring of all users, and continuous monitoring of users at high cardiovascular risk. RESULTS: We included 22 593 and 1821 new users of cilostazol before and after implementation of risk minimization measures, respectively. After implementation, the frequency of several conditions related to the labeling changes improved in all the study populations: prevalence of use decreased between 13% (EpiChron) and 57% (SIDIAP), frequency of cardiovascular contraindications decreased between 8% (GePaRD) and 84% (EpiChron), and concurrent use of high-dose cilostazol and potent CYP3A4/CYP2C19 inhibitors decreased between 6% (Sweden) and 100% (EpiChron). The frequency of other conditions improved in most study populations, except smoking, which decreased only in EpiChron (48% reduction). CONCLUSIONS: This study indicates that the risk minimization measures implemented by the EMA for the use of cilostazol have been effective in all European countries studied, except for smoking cessation before initiating cilostazol, which remains an area of improvement.

PURPOSE: Endogenous human gonadal steroids and especially female sex hormones modulate the risk of developing epileptic seizures. In most circumstances, estrogens increase excitability, while progesterone bears substantial anticonvulsive properties. We questioned whether exogenous gonadal steroids used as hormonal contraception are associated with risk of seizures. METHODS: In a dynamic cohort ascertained within The Health Improvement Network database, we identified 2201 female patients aged 20-44 years with seizures during follow-up. In a nested case-control analysis, we matched these cases to 10,143 controls. Using logistic regression, we calculated the risk of seizure associated with use of contraceptives and adjusted for potential confounders. We performed same analyses among women with no prior hormonal contraception use ("new user" analyses) and in patients with a history of epilepsy. RESULTS: Unadjusted data suggested a lower risk for seizures in patients taking exogenous gonadal steroids irrespective of type of contraception used. After adjustment for potential confounders, neither use of combined oral contraceptives nor progestin-only oral contraceptives was associated with the risk for seizures overall. Analyses of "new users" of oral contraceptives produced similar risk estimates. CONCLUSIONS: We found no evidence supporting an effect of oral exogenous gonadal steroids used for hormonal contraception on the risk of seizures in the general female population.