Overview of the European post-authorisation study register post-authorization studies performed in Europe from September 2010 to December 2018.

BACKGROUND: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register. OBJECTIVES: To analyse and describe PAS in the EU PAS register, with focus on MDS. METHODS: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models. RESULTS: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%). CONCLUSIONS: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency.

Effectiveness of first-line cetuximab in wild-type RAS metastatic colorectal cancer according to tumour BRAF mutation status from the EREBUS cohort.

AIMS: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC). METHODS: EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression. RESULTS: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients. CONCLUSIONS: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment.

Misuse of benzodiazepines: Prevalence and impact in an inpatient population with psychiatric disorders.

AIMS: Use and misuse of benzodiazepine might be very prevalent in patients with acute psychiatric symptoms, whereas they might be associated with specific adverse events in this population. The study investigated their prevalence in these patients. Secondary objectives were to identify risk factors for misuse of benzodiazepines, and its impact. METHODS: A cohort study was based on the hospital's electronic patient records and conducted in patients aged 18 years and over and admitted to a psychiatric hospital. They were followed up for 84 days or until the end of hospitalisation. Four variables of misuse were built: excessive duration of treatment, type of product, excessive dosage and concomitant benzodiazepines. Backward stepwise multivariate logistic regression analysis was used to assess risk factors for each misuse criterion, on the 1 hand, and impact of benzodiazepine misuse, on the other. RESULTS: In total, 511 psychiatric inpatients were included with 89.0% of them exposed to benzodiazepine. Discharge prescription included no benzodiazepine or a dosage lower than the maximum dosage prescribed during hospitalisation for 78.2% of patients exposed to benzodiazepine during their stay. Of benzodiazepine treatments, 31.4% were associated with at least 1 misuse criterion. Excessive dosage was associated with age ≥65 years (OR 11.57; 95% confidence interval 4.92-27.17), substance/alcohol use disorders (3.35; 95% confidence interval 1.70-6.62) and parenthood (0.49; 0.25-0.97). Some criteria of benzodiazepine misuse were associated with a higher frequency of adverse events occurring after treatment initiation. CONCLUSIONS: Misuse of benzodiazepines is very common in inpatients with psychiatric disorders. These findings should alert clinicians to comply with clinical recommendations.

Use of benzodiazepines and z-drugs not compliant with guidelines and associated factors: a population-based study.

Benzodiazepines and z-drugs are primarily indicated for the treatment of sleep disorders and anxiety symptoms. Their frequent long-term use contrasts with the international guidelines that limit treatment duration to a maximum of 4 weeks. The objective of this study was to assess the frequency of their use that was not in accordance with guidelines in the French general population between 2007 and 2012 and associated characteristics. A cohort of 67,550 benzodiazepine new users was set up in an exhaustive database for health-care reimbursements and representative of the French population. Benzodiazepine use not in accordance with guidelines was defined as the concomitant dispensation of several benzodiazepines, the dispensation of treatment over a period longer than recommended, or a new dispensing within the 2 months following the end of a previous treatment of maximum recommended duration, considering that French recommendations distinguish between hypnotic (4 weeks) and anxiolytic benzodiazepines (12 weeks). Benzodiazepine use not in accordance with guidelines was high, in about 30% of new hypnotic users and 20% of new anxiolytic users. Its frequency was stable over the study period. Associated characteristics were similar for new hypnotic or anxiolytic users, i.e.. older age, treatment initiation by a psychiatrist, presence of a chronic disease, hospitalization, or another psychotropic treatment. These findings provide a solid basis for establishing a public health policy to reduce benzodiazepine use not compliant with guidelines. They should be further explored in patients most at risk in the present study, e.g., patients treated by a psychiatrist.

Overall and progression-free survival with cabazitaxel in metastatic castration-resistant prostate cancer in routine clinical practice: the FUJI cohort.

BACKGROUND: Cabazitaxel is a treatment of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel failure. The FUJI cohort aimed to confirm the real-life overall and progression-free survival (OS, PFS) and safety of cabazitaxel. METHODS: Multicentre, non-interventional cohort of French mCRPC patients initiating cabazitaxel between 2013 and 2015, followed 18 months. RESULTS: Four hundred one patients were recruited in 42 centres. At inclusion, median age was 70, main metastatic sites were bones (87%), lymph nodes (42%) and visceral (20%). 18% had cabazitaxel in 2nd-line treatment, 39% in 3rd-line and 43% in 4th-line or beyond. All had prior docetaxel, and 82% prior abiraterone, enzalutamide or both. Median duration of cabazitaxel treatment was 3.4 months. Median OS from cabazitaxel initiation was 11.9 months [95% CI: 10.1-12.9]. In multivariate analyses, grade ≥ 3 adverse events, visceral metastases, polymedication, and >5 bone metastases were associated with a shorter OS. Main grade ≥ 3 adverse events were haematological with 8% febrile neutropenia. CONCLUSION: Real-life survival with cabazitaxel in FUJI was shorter than in TROPIC (pivotal trial, median OS 15.1 months) or PROSELICA (clinical trial 20 vs 25 mg/m2, median OS, respectively, 13.4 and 14.5 months). There was no effect of treatment-line on survival. No unexpected adverse concerns were identified. STUDY REGISTRATION: It was registered with the European Medicines Agency EUPASS registry, available at www.encepp.eu, as EUPAS10391. It has been approved as an ENCEPP SEAL study.

Prescription medicine use by pedestrians and the risk of injurious road traffic crashes: A case-crossover study.

BACKGROUND: While some medicinal drugs have been found to affect driving ability, no study has investigated whether a relationship exists between these medicines and crashes involving pedestrians. The aim of this study was to explore the association between the use of medicinal drugs and the risk of being involved in a road traffic crash as a pedestrian. METHODS AND FINDINGS: Data from 3 French nationwide databases were matched. We used the case-crossover design to control for time-invariant factors by using each case as its own control. To perform multivariable analysis and limit false-positive results, we implemented a bootstrap version of Lasso. To avoid the effect of unmeasured time-varying factors, we varied the length of the washout period from 30 to 119 days before the crash. The matching procedure led to the inclusion of 16,458 pedestrians involved in an injurious road traffic crash from 1 July 2005 to 31 December 2011. We found 48 medicine classes with a positive association with the risk of crash, with median odds ratios ranging from 1.12 to 2.98. Among these, benzodiazepines and benzodiazepine-related drugs, antihistamines, and anti-inflammatory and antirheumatic drugs were among the 10 medicines most consumed by the 16,458 pedestrians. Study limitations included slight overrepresentation of pedestrians injured in more severe crashes, lack of information about self-medication and the use of over-the-counter drugs, and lack of data on amount of walking. CONCLUSIONS: Therapeutic classes already identified as impacting the ability to drive, such as benzodiazepines and antihistamines, are also associated with an increased risk of pedestrians being involved in a road traffic crash. This study on pedestrians highlights the necessity of improving awareness of the effect of these medicines on this category of road user.

Antidepressant use and cognitive decline in community-dwelling elderly people - The Three-City Cohort.

BACKGROUND: Cognitive impairment is very common in late-life depression, principally affecting executive skills and information processing speed. The aim of the study was to examine the effect of antidepressant treatment on cognitive performances over a 10-year period. METHODS: The community-based cohort included 7381 participants aged 65 years and above. Five cognitive domains (verbal fluency, psychomotor speed, executive function, visuospatial skills and global cognition) were assessed up to five times over 10 years of follow-up. Treatment groups included participants under a specific antidepressant class at both baseline and the first follow-up and their follow-up cognitive data were considered until the last consecutive follow-up with a report of antidepressant use of the same class. Linear mixed models were used to compare baseline cognitive performance and cognitive decline over time according to antidepressant treatment. The models were adjusted for multiple confounders including residual depressive symptoms assessed by the Center for Epidemiologic Studies-Depression scale. RESULTS: At baseline, 4.0% of participants were taking antidepressants. Compared to non-users, tricyclic antidepressant users had lower baseline performances in verbal fluency, visual memory and psychomotor speed, and selective serotonin reuptake inhibitor users in verbal fluency and psychomotor speed. For the two other cognitive abilities, executive function and global cognition, no significant differences were found at baseline irrespective of the antidepressant class. Regarding changes over time, no significant differences were observed in comparison with non-users whatever the cognitive domain, except for a slight additional improvement over the follow-up in verbal fluency skills for tricyclic antidepressant users. CONCLUSIONS: In this large elderly general population cohort, we found no evidence for an association between antidepressant use and post-treatment cognitive decline over 10 years of follow-up in various cognitive domains.

National trends in use and costs of oral anticancer drugs in France: An 8-year population-based study.

PURPOSE: During the last decade, many oral anticancer drugs (OAcDs) have been marketed, providing interesting but potentially costly pharmaceutical alternatives to intravenous treatments. This study aims to provide updated information on their use and costs. METHODS: A cross-sectional yearly repeated study was conducted from 2006 to 2014 using the representative sample of the French national health care insurance system claims database (EGB). OAcD use was described for each year, among prevalent (ie, patients with at least 1 OAcD reimbursement) and incident users (ie, patients with no OAcD reimbursement within the prior year) and according to their pharmacological classes (Hormone Therapy [HT], Cytotoxic Therapy [CT], Targeted Therapy [TT], and others). Demographic characteristics were described for both users; comorbidities and direct medical costs were described for incident users only. RESULTS: The yearly prevalence and incidence of OAcD use, mainly represented by HT, remained stable from 2006 to 2014 (1.2%; 0.4%). Compared with users of other OAcD classes, the proportion of TT users substantially increased over the 8-year study period (+9.3%), and TT incident users had more severe comorbidities at treatment initiation. The health expenditures were the most important in TT users with median monthly medical direct costs varying from 2995€ to 4968€ per patient between 2006 and 2014. CONCLUSION: With the development of new OAcDs, the TTs use reaches a wider population of patients but is responsible for increasing health expenditures.

Real-life patterns of use, safety and effectiveness of sunitinib in first-line therapy of metastatic renal cell carcinoma: the SANTORIN cohort study.

PURPOSE: To investigate sunitinib in the real-life first-line treatment of metastatic renal cell carcinoma (mRCC). METHODS: SANTORIN is a French observational multicentre cohort. Patients initiating sunitinib in first-line mRCC therapy were included (January 2008 to April 2010) and followed for 24 months. Data were collected from medical files. The outcomes were 24-month overall survival (OS) and progression-free survival (PFS), response and safety. RESULTS: Three hundred two patients were included: median age, 64.8 years; male, 73.2%; clear cell mRCC, 83.1%; prior nephrectomy, 85.4%; >1 metastatic sites, 64.2%; brain metastases, 6.3%; ECOG-PS ≥ 2, 9.9%. Median duration of first-line therapy with sunitinib was 10.7 months. Initial sunitinib dose was 50 mg/day for 83.4% of patients; dose reduction occurred in 65.2%. Sunitinib was discontinued in 73.2% of the patients: for progression (61.1%), death (31.2%) or adverse events (6.8%). More than half (58.3%) had grade ≥3 adverse events, mainly hypertension (12.6%) and hand-foot syndrome (12.3%). The 24-month OS and PFS rates [95%CI] were 49.5% [43.7;55.0] and 16.4% [12.5;20.9], respectively. Median OS was 23.6 months [20.2;-] and median PFS 8.4 months [7.6;9.9]. Overall best response rate was 31.1%. CONCLUSIONS: Results from this large observational study suggest that effectiveness of sunitinib in first-line mRCC as predicted by clinical trials is maintained in real-life clinical practice. The expected benefit in poor-prognosis patients that were not evaluated in the pivotal clinical trial remains; however, questionable and long-term safety monitoring is still warranted. Copyright © 2017 John Wiley & Sons, Ltd.

Persistence to 5-year hormonal breast cancer therapy: a French national population-based study.

BACKGROUND: Non-persistence to oral hormonal therapy (HT) in breast cancer (BC) is an emerging health issue, and estimations vary according to the population selected and/or the statistical method applied. This study aimed to estimate non-persistence over 5 years to HT in an unselected sample of women with BC using a French national population-based database and accounting for competing risks. METHODS: A retrospective cohort of 600 women initiating a HT between 2006 and 2007 was constituted using a representative sample of the French national healthcare insurance system database. The Cumulative Incidence Function method was used to estimate the probability of first treatment discontinuation of at least 90 days accounting for competing risk of death from any cause over the theoretical 5-year period of treatment. RESULTS: Thirty one percent of patients who initiated a HT were identified as non-persistent at the fifth year of follow-up. Patients who switched to another HT (HR 3.10, 95% CI (2.20; 4.36)) or had metastatic BC (HR 3.07, 95% CI (1.73; 5.46)) were more likely to be non-persistent. Women who initiated aromatase inhibitors as compared with tamoxifen (HR 0.62, 95% CI (0.46; 0.83)), had administrative registration for BC (HR 0.21, 95% CI (0.13; 0.32)), or had received an adjuvant chemotherapy (HR 0.65, 95% CI (0.48; 0.89)) were less likely to discontinue. CONCLUSIONS: The estimate of long-term non-persistence in an unselected sample of women treated in France by oral hormonal therapy is substantial, even accounting for competing risks.

Preventability of adverse effects of analgesics: analysis of spontaneous reports.

OBJECTIVES: The aims of this study were to determine the patterns of analgesic adverse drug reactions (ADRs) and to assess their preventability and contributing factors. METHODS: This is a retrospective, descriptive study conducted on ADRs of analgesics and other drugs indicated as analgesics, spontaneously reported to the Bordeaux pharmacovigilance center from January 2011 to June 2012. RESULTS: The 141 cases selected for the analysis included 16 cases of medication errors (11.3%) and 15 addiction cases (10.6%). In total, 214 ADRs were registered, for which 173 analgesic medicines were suspected. The most frequent ADRs reported were nervous system disorders (26.6%), psychiatric disorders (15.0%), and skin and subcutaneous tissue disorders (12.1%). Tramadol alone or in combination (17.3%), followed by morphine (15%), fentanyl (9.8%), and paracetamol (8.7%) were the most frequently involved analgesics. More than half of the cases (54.6%) were serious and led to hospitalization or prolonged hospitalization. Preventability was determined for 134 cases (95%): 51.5% were considered as preventable, 26.1% not preventable, and 22.4% not assessable. The main contributing factors for the preventable cases included negligence of recommendations for analgesic use and failure to consider patients' risk factors when prescribing. CONCLUSIONS: A significant number of analgesic ADRs could be prevented, and being aware of their contributing factors promotes efficient analgesia with minimum risks to the patients.

Pharmacological prioritisation of signals of disproportionate reporting: proposal of an algorithm and pilot evaluation.

PURPOSE: Data mining in spontaneous reporting databases generates large numbers of signals of disproportionate reporting (SDRs) that need to be prioritised for assessment. The pharmacological relevance of drug-event associations is not considered in SDR prioritisation algorithms. This aimed to propose and test a pharmacological score for SDR prioritisation. METHODS: The Pharmacological Score for SDRs Prioritisation (PS-SP) was developed using a Delphi approach. An expert group agreed that PS-SP should include general criteria concerning SDRs and criteria concerning pharmacological relevance, and that criteria should be weighted for their risk representation. Once defined, the PS-SP was tested for prioritisation of SDRs for extrapyramidal syndrome in the French Pharmacovigilance database; the SDR classification was compared to that obtained using a traditional disproportionality approach. RESULTS: For a given drug, the general criteria retained were the reporting rate of the adverse drug reaction (ADR) and value of the 95% confidence interval (CI) lower boundary of the Reporting Odds Ratio (ROR). Pharmacological criteria consisted of the ADR reporting rate without concomitant at-risk drugs or those indicated for ADR treatment, and the value of the ROR 95% CI lower boundary as estimated in the subset of reports concerning drugs from the same therapeutic and then pharmacological class. Compared with traditional disproportionality, PS-SP prioritised specific drugs within congeners: metoclopramide, indoramin, and trimetazidine appeared as outliers within their classes; conventional antipsychotics had higher prioritisation than atypical antipsychotics. CONCLUSION: The pilot evaluation of PS-SP performed in extrapyramidal syndrome advocates for the use of pharmacological criteria in SDR prioritisation algorithms.

Pilot evaluation of an automated method to decrease false-positive signals induced by co-prescriptions in spontaneous reporting databases.

PURPOSE: To test an automated method to decrease the number of false-positive (FP) signals of disproportionate reportings (SDRs) generated by co-prescription. METHODS: Automated backward stepwise removal of reports concerning the drug associated with the highest ranked SDR for an event was tested for gastric and oesophageal haemorrhages (GOH), central nervous system haemorrhages and cerebrovascular accidents (CNSH), ischaemic coronary artery disorders and muscle pains (MP) using the reporting odds ratio in the French spontaneous reporting research database. After ranking SDRs detected in the complete dataset on the lower limit of the reporting odds ratio 95% confidence interval, reports concerning the drug with the highest ranked SDR were removed. In the dataset thus generated, SDRs were again identified, ranked and reports related to the drug involved in the newly highest ranked SDR removed. The process was repeated until no signal was detected. Initially detected SDRs eliminated using this technique were assessed regarding the summary of products characteristics and the literature to determine their FP nature. RESULTS: Seventeen SDRs were successively eliminated for GOH, 37 for CNSH, 15 for ischaemic coronary artery disorders, and 36 for MP. Four were FP for GOH, 29 for CNSH, 7 for ACI and none were FP for MP. The positive predictive value of the backward stepwise removal procedure in identifying FP SDRs ranged from 0% (MP) to 78.4% (CNSH). CONCLUSIONS: Although further adjustment is needed to improve the method presented herein, our results suggest that numerous FP signals because of co-prescription bias could be eliminated using an automated method.

Information and communication on risks related to medications and proper use of medications for healthcare professionals and the general public: precautionary principle, risk management, communication during and in the absence of crisis situations.

Recent drug crises have highlighted the complexity, benefits and risks of medication communication. The difficulty of this communication is due to the diversity of the sources of information and the target audience, the credibility of spokespersons, the difficulty to communicate on scientific uncertainties and the precautionary principle, which is influenced by variable perceptions and tolerances of the risk. Globally, there is a lack of training in risk management with a tendency of modern society to refuse even the slightest risk. Communication on medications is subject to regulatory or legal requirements, often uses tools and messages that are not adapted to the target audience and is often based on a poor knowledge of communication techniques. In order to improve this situation, the available information must be coordinated by reinforcing the unique medication information website and by coordinating communication between authorities by means of a single spokesperson. A particular effort must be made in the field of training in the proper use and risk of medications for both the general population and patients but also for healthcare professionals, by setting up a unified academic on-line teaching platform for continuing medical education on medications and their proper use.

Use of the French National Health Data System (SNDS) in pharmacoepidemiology: A systematic review in its maturation phase.

AIM OF THE STUDY: The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase. METHODS: We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018. RESULTS: A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%). CONCLUSION: The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials.

Cetuximab infusion reactions: French pharmacovigilance database analysis.

OBJECTIVES: To compare characteristics of patients exhibiting cetuximab infusion reactions or another adverse drug reaction related to cetuximab and to identify factors associated with the severity of cetuximab infusion reactions. METHODS: All cases of adverse drug reaction reported with cetuximab from 1985 to 2010 were extracted from the French Pharmacovigilance database. The severity of infusion reactions was assessed according to the NCI-CTCAE criteria (v4.0). Multiple logistic regression analysis was performed to identify factors associated with the severity of infusion reactions. RESULTS: Among the 602 adverse drug reaction reported with cetuximab during the study period, 374 infusion reactions were identified. Indication is more likely to be head and neck than colorectal cancer among patients experiencing an infusion reaction (p < 0.001). Among the seven deaths related to an infusion reaction, five patients were treated for head and neck cancer. Infusion reactions were more likely to be severe when they occurred during the first administration (OR = 7.40 95% CI [2.21-24.71]), adjusted for age, sex, region of France, quarter of the year, indication, year of occurrence, and premedication. CONCLUSION: Our study found that reports of infusion reactions more often concerned patients treated for head and neck cancer, that in these patients the adverse drug reaction was more often fatal and severe infusion reactions were more likely during the first administration. In daily practice, the close monitoring of patients during the first infusion, especially patients with head and neck cancer, is recommended. Considering the possible immunoglobulin E-mediated mechanism, reliable tests for their detection need to be readily available.

The EU-ADR corpus: annotated drugs, diseases, targets, and their relationships.

Corpora with specific entities and relationships annotated are essential to train and evaluate text-mining systems that are developed to extract specific structured information from a large corpus. In this paper we describe an approach where a named-entity recognition system produces a first annotation and annotators revise this annotation using a web-based interface. The agreement figures achieved show that the inter-annotator agreement is much better than the agreement with the system provided annotations. The corpus has been annotated for drugs, disorders, genes and their inter-relationships. For each of the drug-disorder, drug-target, and target-disorder relations three experts have annotated a set of 100 abstracts. These annotated relationships will be used to train and evaluate text-mining software to capture these relationships in texts.

Engagement in leisure activities and benzodiazepine use in a French community-dwelling elderly population.

OBJECTIVE: The prevalence of benzodiazepine use among community-dwelling older persons varies between 10% and 30%. The aim of this study was to explore the association between leisure activities and the use of benzodiazepine among older persons living at home. METHODS: The study population included 4848 persons aged 65 years and over living in either of two French cities. Information was collected from a questionnaire administered to the respondents by trained psychologists during face-to-face interviews at home and from a self-administered questionnaire. Baseline examination included socio-demographic characteristics, drug use and leisure activities. We classified as benzodiazepine users subjects who reported use of at least one benzodiazepine during the month preceding the interview. The association between the use of benzodiazepine and leisure activities was assessed by logistic regression adjusted on known potential confounders. RESULTS: More than 18% of participants reported use of at least one benzodiazepine. The adjusted odds ratio (OR) of benzodiazepine use associated with no or lower participation versus participation in the following activities were as follows: OR = 1.31 (95% confidence interval (CI): 1.09 to 1.58) for mental activity; OR = 1.50 (CI: 1.12 to 2.03) for physical activity; OR = 1.28 (CI: 1.05 to 1.55) for productive activity and OR = 0.82 (CI: 0.69 to 0.97) for recreational activity. CONCLUSION: Low engagement in stimulating activities and high engagement in sedentary activities were associated with recent benzodiazepine use.

Use of health insurance claim patterns to identify patients using nonsteroidal anti-inflammatory drugs for rheumatoid arthritis.

PURPOSE: To determine healthcare claim patterns associated using nonsteroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis (RA). METHODS: The CADEUS study randomly identified NSAID users within the French health insurance database. One-year claims data were extracted, and NSAID indication was obtained from prescribers. Logistic regression was used in a development sample to identify claim patterns predictive of RA and models applied to a validation sample. Analyses were stratified on the dispensation of immunosuppressive agents or specific antirheumatism treatment, and the area under the receiver operating characteristic curve was used to estimate discriminant power. RESULTS: NSAID indication was provided for 26,259 of the 45,217 patients included in the CADEUS cohort; it was RA for 956 patients. Two models were constructed using the development sample (n = 13,143), stratifying on the dispensation of an immunosuppressive agent or specific antirheumatism treatment. Discriminant power was high for both models (AUC > 0.80) and was not statistically different from that found when applied to the validation sample (n = 13,116). CONCLUSIONS: The models derived from this study may help to identify patients prescribed NSAIDs who are likely to have RA in claims databases without medical data such as treatment indication.

Seizure freedom is not adversely affected by early discontinuation of concomitant anti-epileptic drugs in the EULEV cohort of levetiracetam users.

PURPOSE: Fear of discontinuing concomitant anti-epileptic drugs (AEDs) may lead to potentially unnecessary and perhaps unsafe polypharmacy. The effect of withdrawing concomitant AEDs on epilepsy control was therefore studied in long-term users of levetiracetam. METHODS: The EULEV cohort followed patients initiating levetiracetam in France in 2005 or 2006 for one year. In those maintaining levetiracetam throughout the study period, the association of a reduction in the number of concomitant AEDs during the first six months with seizure-freedom during the last six months of follow-up was investigated using logistic regression. RESULTS: Of the 356 patients continuing levetiracetam for at least 1 year, 140 (39.3%) were seizure-free during the last six months of follow-up. Partial symptomatic or generalised idiopathic epilepsy were associated with greater seizure-freedom than partial cryptogenic disease. Factors associated with seizures were: longer disease duration, initial incapacity, increased number of seizures in the six months preceding levetiracetam initiation, and number of consultations for epilepsy in the six months preceding levetiracetam initiation. There was a trend for the association between the early reduction in the number of concomitant AEDs and seizure-free status later during follow-up, which however did not reach statistical significance in the final propensity score-adjusted multivariate model (OR = 1.8, 95%CI [0.8;4.0]). CONCLUSIONS: Taking into account the various risk factors for seizures, the early reduction of concomitant AEDs was not associated with worse seizure rates during follow-up in real-life users of levetiracetam.