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Objective To quantify benzodiazepine use non-compliant with guidelines in patients with psychiatric and non-psychiatric chronic diseases and assess the risk of non-recommended use associated with these diseases. Method A cohort study was conducted in the French health insurance databases, including 254,488 new benzodiazepine users between 2007 and 2014. Psychiatric, cardiovascular, cancer, diabetes and inflammatory diseases were identified. Patients were followed for 2 years. Non-recommended use was defined as excessive treatment duration, use of long half-life drugs in older patients and concomitant use of several benzodiazepines. Cox models identified the factors associated with non-recommended use. Results Non-recommended use was frequent, ranging from 44.9% to 68.1%. It was independently associated with each chronic disease, with a slight increase in patients with chronic inflammatory disease (HR = 1.07; 95%CI 1.03–1.13) or diabetes (HR = 1.09; 1.06–1.12), a higher risk in those with chronic cardiovascular disease (HR = 1.34; 1.31–1.37) or cancer (HR = 1.30; 1.25–1.35) and the highest risk in those with psychiatric disease (HR = 2.04; 2.00–2.09). Conclusion Patients with chronic disease have a high risk of benzodiazepine use leading to a higher exposure than recommended. Prescribers should be aware of the need to comply with the recommendations, especially in these patients who are the most frail and vulnerable to adverse events.

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.

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.

Aims To investigate the association between the use of anxiolytic/hypnotic drugs and suicidal thoughts and/or behavior (STB) in students. Methods 12,112 participants who completed the baseline questionnaire in the i-Share cohort between April 2013 and March 2017 were included. STB were defined at inclusion as suicidal thoughts over the previous year and/or a lifetime suicide attempt. The use of prescribed anxiolytic/hypnotic drugs over the previous 3 months was measured at baseline and follow-up time points (in 2,919 students). Psychiatric disorders were assessed through validated scales. Multivariate logistic regression models were run using disease risk score. Results At inclusion, 25.2% of students had STB and 10.3% used anxiolytics/hypnotics. STB at baseline were associated with a more frequent use of anxiolytics/hypnotics in the previous 3 months, after adjustment for covariates including anxiety, depression, sleep, impulsivity, and substance use. The use of anxiolytics/hypnotics at baseline was not associated with the occurrence, persistence or remission of STB one year later. STB at baseline were associated with a new anxiolytic/hypnotic treatment one year later. Conclusions Anxiolytic/hypnotic drug use was associated with STB in students independently of many risk factors of suicide and most psychiatric disorders that require such treatment, which raises drug safety concerns.

Summary Aim of the study To provide a tool for drug misuse or potential misuse monitoring by using a healthcare insurance database. Methods A cross-sectional study repeated quarterly from 2007 to 2014 was conducted using data from a 1/97th random sample of the French national healthcare reimbursement system. For each drug studied, ad hoc indicators were designed to assess drug misuse, defined as prescriptions that did not comply with the label stipulated in the summary of product characteristics, in terms of the drug (e.g., interactions) or the patient (age, medical history). We focused on specifically identified situations of drug misuse involving non-steroidal anti-inflammatory drugs (NSAIDs), antiemetics in patients with Parkinson's disease and antipsychotics in pediatrics; we also focused on direct anticoagulants, asthma and oral antidiabetic drugs but results for these latter are only shown in supplementary materials. Results At-risk prescribing of NSAIDs in patients treated by diuretics or renin-angiotensin system inhibitors always remained higher than 14% over the study (maximum: 19%; 2014 quarter 4: 15.4%). Off-label prescribing of contraindicated anti-dopaminergic antiemetics with dopaminergic antiparkinson drugs was marginal (maximum: 2.2%; 2014 quarter 4: 0.5%) but represented at least 5.5% of antiemetic prescriptions. Despite the rise in antipsychotic prescriptions in pediatrics, no dramatic increase in misuse related to age was observed during the study period (2007 quarter 1: 16.1%; 2014 quarter 4: 11.1%). The highest degree of misuse was observed for aripiprazole and for second-generation antipsychotics other than risperidone and aripiprazole. Conclusion This study provides a simple tool to monitor drug misuse or potential misuse using information from a health insurance database. The results highlight the need for the Regulator to rethink risk management information campaigns and to modify the official information on products.

Some concerns have emerged about the evidence of benefits on survival outcomes or quality of life of new anticancer drugs. In parallel, the decreased cancer mortality leads to an increased number of patients exposed to cancer treatment-related consequences. In this context, pharmacoepidemiology is crucial to assess anticancer drug use, effectiveness and safety in real life conditions. We aimed to describe strengths, limitations and considerations associated with the use of the French national health insurance database (système national des données de santé [SNDS]) to conduct pharmacoepidemiological studies in oncology. The SNDS represents a powerful tool in pharmacoepidemiology owing to its extensive coverage, accurate description and quantification of drug exposure and individual data on patients. The main limitations of this database ensue from the administrative nature resulting in technical difficulties in its management and gaps in availability of data. Another limitation is the lack of accurate identification of diseases, comorbidities or outcomes and potential confounding with notably the lack of data regarding cancer stage, prognosis or risk factors. Finally, the accurate identification of the nature of chemotherapy received by patients is sometimes complex. To minimize these limitations, several approaches and statistical methods could be used as highlighted by national or international initiatives. First, the SNDS may be linked with cancer registry or clinical data. Then, several data sources could be combined using meta-analytical methods. The development of methodological tools and the use of standardized methods are crucial to enhance the quality of studies that can impact clinical practice and guide public decision. Pharmacoepidemiological approaches and pharmacovigilance represent an important cornerstone in oncology for signal detection or long-term follow up of cancer patients. In this context, validated methods to identify cancer patients and to describe chemotherapy regimens within these data should be promoted and remain too scarce despite international guidelines. Moreover, limits and strength of each data sources should be systematically discussed according to the research question. Optimized and framed use of claims database represents a future challenge in onco-pharmacoepidemiology.

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.

Background WHO pharmacovigilance indicators have been recommended as a useful tool towards improving pharmacovigilance activities. Nigeria with a myriad of medicines related issues is encouraging the growth of pharmacovigilance at peripheral centres. This study evaluated the status of pharmacovigilance in tertiary hospitals in the South-South zone of Nigeria with a view towards improving the pharmacovigilance system in the zone. Methods A cross-sectional descriptive survey was conducted in six randomly selected tertiary hospitals in the South-South zone of the country. The data was collected using the WHO core pharmacovigilance indicators. The language of assessment was phrased and adapted in this study for use in a tertiary hospital setting. Data is presented quantitatively and qualitatively. Results A total of six hospitals were visited and all institutions had a pharmacovigilance centre, only three could however be described as functional or partially functional. Only one centre had a financial provision for pharmacovigilance activities. Of note was the absence of the national adverse drug reaction reporting form in one of the hospitals. The number of adverse drug reaction reports found in the databases of the centres ranged from none to 26 for the previous year and only one centre had fully committed their reports to the National Pharmacovigilance Centre. There were few documented medicines related admissions ranging from 0.0985/1000 to 1.67/1000 and poor documentation of pharmacovigilance activities characterised all centres. Conclusion This study has shown an urgent need to strengthen the pharmacovigilance systems in the South-South zone of Nigeria. Improvement in medical record documentation as well as increased institutionalization of pharmacovigilance may be the first steps to improve pharmacovigilance activities in the tertiary hospitals. Electronic supplementary material The online version of this article (10.1186/s40360-018-0217-2) contains supplementary material, which is available to authorized users.

Aims The purpose of this study was to determine the effects of cancer occurrence on persistence of oral antidiabetic drugs (OAD) in France. Methods A retrospective cohort including incident OAD users between 2006 and 2011 was set up using a permanent sample of health insurance beneficiaries (Echantillon Generaliste de Beneficiaires, EGB). A Cox model was used to assess the association between cancer occurrence and OAD persistence. Non-persistence was defined as a gap in OAD treatment coverage between the end of a given prescription and a new one greater than or equal to 90 days. Cancer occurrence was studied as a time-dependent variable. Results The study included 13,943 OAD users. Median follow-up was 760 days. After adjustment for age, sex, first OAD used, type of prescriber and polypharmacy, non-persistence risk was higher after a diagnosis of cancer: (HR: 1.93 and IC 95% 1.69; 2.21). Subgroup analyses according to cancer localization found a higher risk of non-persistence for lung cancer (HR: 2.66 and IC 95% 1.68; 4.23) and colorectal cancer (HR: 2.02 and IC 95% 1.40; 2.91). Conclusions Our findings indicate there is an association between cancer diagnosis and OAD non-persistence. Additional studies of this type would be useful to evaluate the association between cancer diagnosis and persistence of treatment of other chronic diseases.

In this population-based elderly cohort, participants using selective serotonin reuptake inhibitor (SSRI) antidepressants have an increased risk of falls and fractures notably when the treatment was continued over 4 years. Among the various SSRI types, citalopram only was at significant risk for falls and fluoxetine for fractures.Increased risk of falls and fractures has been reported in elderly users of SSRIs. However, biases were insufficiently addressed notably temporality between exposure and outcome and confounding by residual depression. Our objective was to examine the associations between SSRIs and fall or fracture incidence focusing on their chronic use and different types of SSRIs.The population-based cohort included participants aged 65 years and above, who had not fallen before inclusion (n = 6599) or were free of recent fracture (n = 6823) and were followed up twice over 4 years. New fall and fracture events were self-reported and defined as at least two falls and one fracture, respectively, during the previous 2 years. SSRI users were compared with those taking no antidepressants. Hazard ratios (HRs) were estimated using Cox models with delayed entry and adjusted for many confounders including residual depressive symptoms.Incidence of falls was 19.3 % over 4 years and that of fractures 9.5 %. After multi-adjustment, SSRI intake was significantly associated with a higher risk of falls (HR, 95 % CI = 1.58, 1.23-2.03) and fractures (HR, 95 % CI = 1.61, 1.16-2.24). The risks were significantly increased by 80 % in those continuing the treatment over 4 years. Citalopram intake only was at significant risk for falls and fluoxetine for fractures.In this large community-dwelling elderly sample, SSRI users were at higher risk of falls and fractures. This association was not due to reverse causality or residual depressive symptoms. Different SSRI drugs may have specific adverse effects on falls and fractures.

OBJECTIVE: Data from electronic healthcare records (EHR) can be used to monitor drug safety, but in order to compare and pool data from different EHR databases, the extraction of potential adverse events must be harmonized. In this paper, we describe the procedure used for harmonizing the extraction from eight European EHR databases of five events of interest deemed to be important in pharmacovigilance: acute myocardial infarction (AMI); acute renal failure (ARF); anaphylactic shock (AS); bullous eruption (BE); and rhabdomyolysis (RHABD). DESIGN: The participating databases comprise general practitioners' medical records and claims for hospitalization and other healthcare services. Clinical information is collected using four different disease terminologies and free text in two different languages. The Unified Medical Language System was used to identify concepts and corresponding codes in each terminology. A common database model was used to share and pool data and verify the semantic basis of the event extraction queries. Feedback from the database holders was obtained at various stages to refine the extraction queries. MEASUREMENTS: Standardized and age specific incidence rates (IRs) were calculated to facilitate benchmarking and harmonization of event data extraction across the databases. This was an iterative process. RESULTS: The study population comprised overall 19 647 445 individuals with a follow-up of 59 929 690 person-years (PYs). Age adjusted IRs for the five events of interest across the databases were as follows: (1) AMI: 60-148/100 000 PYs; (2) ARF: 3-49/100 000 PYs; (3) AS: 2-12/100 000 PYs; (4) BE: 2-17/100 000 PYs; and (5) RHABD: 0.1-8/100 000 PYs. CONCLUSIONS: The iterative harmonization process enabled a more homogeneous identification of events across differently structured databases using different coding based algorithms. This workflow can facilitate transparent and reproducible event extractions and understanding of differences between databases.

Objectives The aim of this research was to automate the search of publications concerning adverse drug reactions (ADR) by defining the queries used to search MEDLINE and by determining the required threshold for the number of extracted publications to confirm the drug/event association in the literature. Methods We defined an approach based on the medical subject headings (MeSH) ‘descriptor records’ and ‘supplementary concept records’ thesaurus, using the subheadings ‘chemically induced’ and ‘adverse effects’ with the ‘pharmacological action’ knowledge. An expert-built validation set of true positive and true negative drug/adverse event associations (n=61) was used to validate our method. Results Using a threshold of three of more extracted publications, the automated search method presented a sensitivity of 90% and a specificity of 100%. For nine different drug/event pairs selected, the recall of the automated search ranged from 24% to 64% and the precision from 93% to 48%. Conclusions This work presents a method to find previously established relationships between drugs and adverse events in the literature. Using MEDLINE, following a MeSH approach to filter the signals, is a valid option. Our contribution is available as a web service that will be integrated in the final European EU–ADR project (Exploring and Understanding Adverse Drug Reactions by integrative mining of clinical records and biomedical knowledge) automated system.

Background The health of the agricultural population has been previously explored, particularly in relation to the farming exposures and among professionally active individuals. However, few studies specifically focused on health and aging among elders retired from agriculture. Yet, this population faces the long-term effects of occupational exposures and multiple difficulties related to living and aging in rural area (limited access to shops, services, and practitioners). However, these difficulties may be counter-balanced by advantages related to healthier lifestyle, richer social support and better living environment. The general aim of the AMI cohort was to study health and aging in elderly farmers living in rural area through a multidisciplinary approach, with a main focus on dementia. Methods/design The study initially included 1 002 participants, randomly selected from the Farmer Health Insurance rolls. Selection criteria were: being 65 years and older; living in rural area in Gironde (South-Western France); being retired from agriculture after at least 20 years of activity and being affiliated to the Health Insurance under own name. The study started in 2007, with two follow-up visits over 5 years. Baseline visits were conducted at home by a neuropsychologist then by a geriatrician for all cases suspected of dementia, Parkinson’s disease and depression (to confirm the diagnosis), and by a nurse for others. A large panel of data were collected through standardised questionnaires: complete neuropsychological assessment, material and social living environment, psychological transition to retirement, lifestyle (smoking, alcohol and diet), medications, disability in daily living, sensory impairments and some clinical measures (blood pressure, depression symptomatology, anxiety, visual test, anthropometry…). A blood sampling was performed with biological measurements and constitution of a biological bank, including DNA. Brain MRI were also performed on 316 of the participants. Finally, the three-year data on health-related reimbursements were extracted from the Health System database (medications, medical and paramedical consultations, biological examinations and medical devices), and the registered Long-Term Diseases (30 chronic diseases 100% covered by the Insurance System). Discussion AMI is the first French longitudinal study on health and aging set up in a population of elderly farmers living in rural area through a multidisciplinary approach.

Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

International audience; BACKGROUND: The French pharmacovigilance system is based on a network of 31 regional centres located in teaching hospitals and coordinated by the French Medicines Agency ("Agence Française de Sécurité Sanitaire des Produits de Santé" [Afssaps]). Since 1984, they have shared a common database of adverse drug reactions (ADRs) that are spontaneously reported by healthcare professionals. The objective of this study is to describe the characteristics of the reports and the reporting trends in the French pharmacovigilance spontaneous reporting database from 1986 to 2001. METHODS: All the reports from January 1986 to December 2001 were included. Drugs and ADRs were translated to anatomical therapeutic chemical (ATC) codes and MedDRA classifications, respectively. RESULTS: The total number of reports was 197 580 over the 16-year period, with linearly increase over time. The median (interquartile range [IQR]) age of the patients was 53 (34-70) and the male/female ratio was 0.82. The median (IQR) time between the date of occurrence of the ADR and the date of report was 73 days (34-166). The reporter was a specialist in 74% of the reports and a general practitioner in 17%. The annual rate of reporting according to medical demography strongly increased for the specialists, especially since 1994. At least one ADR was considered as serious in 44.8% of the reports. The ADRs were most frequently related to nervous system drugs (23%), followed by cardiovascular drugs (19%) and systemic anti-infectives (17%). The latter class had the fastest progression mostly due to antiretroviral therapy since 1996. According to the Medical Dictionary for Regulatory Activities (MedDRA) coding, the system organ most often reported was skin and subcutaneous tissue disorders (29%), followed by nervous system disorders (19%), gastrointestinal disorders (12%), blood and lymphatic system disorders (12%), vascular disorders (12%) and general disorders and administration site conditions (12%). DISCUSSION: All spontaneous reporting systems are affected by under-reporting. One of their goals is to generate early signals, which might be more affected by reporting bias than by under-reporting. Some improvements should be made in the design of the French database, but data collected since 1986 constitute an essential tool for the routine work of the 31 pharmacovigilance centres. CONCLUSION: This first description of the data of the French pharmacovigilance database involving all drugs and ADRs shows an increasing tendency to reporting over time, especially in specialists and for systemic anti-infective drugs. The database that uses hierarchical international classifications for drugs and adverse reactions may be used for further studies and could be the basis for an automatic signal generation system.