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Summary Background Quadruple therapy using a single capsule formulation of bismuth, metronidazole and tetracycline (BMT; Pylera®), associated with omeprazole for the eradication of Helicobacter pylori, represents the reintroduction of bismuth in France after 40 years. Objective To describe the real-life patterns of use of BMT following a request from the French health authorities. Methods Patients with a first BMT dispensing (index date, ID), with one year of data before and after ID, were identified in the French nationwide claims database 1/97 sample. Misuse of BMT was defined as dispensing >1 pack of BMT at ID or absence of a diagnostic test in the preceding year. Results In total, 540 patients were included. Prescribers were gastroenterologists (n = 243; 45%) and general practitioners (n = 160; 30%). A proton pump inhibitor was co-dispensed to 504 patients (96%). Ten patients (2%) had contraindications to BMT. Fifty-nine patients (11%) met the misuse criteria: ten (2%) were dispensed > 1 pack of BMT and 49 (9%) had not had a diagnostic test for H. pylori in the previous year. During follow-up, 27 patients (5%) required retreatment (treatment failure). Conclusion In this real-life study, most patients were dispensed only one pack of BMT, consistent with recommendations. Misuse related principally to the absence of prior diagnostic test for H. pylori.

Background Diagnosis performances of case-identifying algorithms developed in healthcare database are usually assessed by comparing identified cases with an external data source. When this is not feasible, intra-database validation can present an appropriate alternative. Objectives To illustrate through two practical examples how to perform intra-database validations of case-identifying algorithms using reconstituted Electronic Health Records (rEHRs). Methods Patients with 1) multiple sclerosis (MS) relapses and 2) metastatic castration-resistant prostate cancer (mCRPC) were identified in the French nationwide healthcare database (SNDS) using two case-identifying algorithms. A validation study was then conducted to estimate diagnostic performances of these algorithms through the calculation of their positive predictive value (PPV) and negative predictive value (NPV). To that end, anonymized rEHRs were generated based on the overall information captured in the SNDS over time (e.g. procedure, hospital stays, drug dispensing, medical visits) for a random selection of patients identified as cases or non-cases according to the predefined algorithms. For each disease, an independent validation committee reviewed the rEHRs of 100 cases and 100 non-cases in order to adjudicate on the status of the selected patients (true case/ true non-case), blinded with respect to the result of the corresponding algorithm. Results Algorithm for relapses identification in MS showed a 95% PPV and 100% NPV. Algorithm for mCRPC identification showed a 97% PPV and 99% NPV. Conclusion The use of rEHRs to conduct an intra-database validation appears to be a valuable tool to estimate the performances of a case-identifying algorithm and assess its validity, in the absence of alternative.

Objectives: To assess the effectiveness of dimethyl fumarate (DMF) on annual rate of relapse (ARR) and disability progression in multiple sclerosis (MS) compared to injectable immunomodulators (IMM), teriflunomide (TERI) and fingolimob (FTY), in real life setting. Methods: A population-based cohort study was conducted using data of the French nationwide claims database, SNDS. All patients initiating IMM, TERI, FTY or DMF between July 1, 2015 and December 12, 2017, with 4.5 years of database history and 1 to 3.5 years of follow-up were included in this study. DMF patients were 1:1 matched to IMM, TERI or FTY using a high dimensional Propensity Score. Negative binomial regression and a logistic regression models were used to estimate the relative risk (RR ± [95% CI]) of ARR and the Odds Ratio (OR ± [95% CI]) of disability progression, respectively. Results: Overall, 9 304 subjects were identified: 29.0% initiated DMF, 33.2% TERI, 5.6% FTY and 32.2% an IMM. The matched cohorts consisted of 1779 DMF- IMM, patients, 1679 DMF-TERI patients, and 376 DMF-FTY patients. DMF significantly reduced ARR compared to IMM (RR 0.72 [0.61 - 0.86]) and TERI (0.81 [0.68 - 0.96]) and did not show any significant difference when compared with FTY The risk of the progression of MS specific disability was not significantly different for any matched cohorts. Interpretation: DMF is associated with lower risk of relapse for patients with RRMS than other first-line RRMS agents (TERI and IIM).

Clinical trials have indicated that the direct-acting oral anticoagulants dabigatran and rivaroxaban have better risk/benefit profiles than do vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (NVAF). Our objective was to compare the 1-year real-life risk of major clinical events with dabigatran or rivaroxaban versus VKAs for NVAF. This was a high-dimensional propensity score (hdPS)-matched cohort study of new users of dabigatran, rivaroxaban or VKAs for NVAF in the French national healthcare systems database in 2013 followed-up for 1 year [22]. Hazard ratios (HRs) with 95% confidence intervals (CIs) for clinical events and death were determined during exposure. In 2013, a total of 103,101 new anticoagulant users had definite NVAF: 44,653 VKA, 27,060 dabigatran, and 31,388 rivaroxaban. In matched populations, HRs were as follows for dabigatran versus VKAs (20,489 per group): stroke and systemic embolism (SSE) 0.75 (95% CI 0.63–0.88), clinically relevant bleeding (CRB) 0.58 (95% CI 0.51–0.66), hemorrhagic stroke (HS) 0.22 (95% CI 0.14–0.36), gastrointestinal bleeding (GIB) 0.98 (95% CI 0.80–1.19), acute coronary syndrome (ACS) 0.79 (95% CI 0.65–0.95), death 0.74 (95% CI 0.67–0.82), composite (any of the above) 0.71 (95% CI 0.66–0.76). For matched rivaroxaban versus VKA (23,053 per group) HRs were as follows: SSE 0.98 (95% CI 0.85–1.14), CRB 0.83 (95% CI 0.75–0.92), HS 0.65 (95% CI 0.49–0.87), GIB 1.08 (95% CI 0.90–1.30), ACS 0.84 (95% CI 0.71–1.00), death 0.77 (95% CI 0.71–0.84), composite 0.84 (95% CI 0.79–0.89). Numbers needed to treat to observe one fewer death were 49 ± 0.05 with dabigatran or rivaroxaban versus VKAs. Consistent with results from clinical trials and other observational studies, dabigatran and rivaroxaban were at least as effective and safer than VKAs for the prevention of thromboembolic events in NVAF over 1 year in the French population. European Medicines Agency EUPAS 13017 (www.encepp.eu) Clinicaltrials.gov id NCT02785354.

Background Hypertension is a multifactorial disease involving both environmental and genetic Factros. G894 T eNOS polymorphism has been suggested to be responsible for reduced NO synthesis, and EH development. The objective of our case-control study is to evaluate the potential association of G894 T eNOS polymorphism with Essential Hypertension (EH) susceptibility, among a sample of Moroccan patients. Methods One hundred forty five hypertensive patients were recruited from the department of Cardiology, University Hospital Center Ibn Rochd, Casablanca, Morocco, and compared to 184 apparently healthy subjects. DNA samples were genotype by PCR-RFLP method using MboI restriction enzyme. Results Our results showed a positive correlation between G894 T eNOS distribution and Alcohol and Obesity rik factors (P = 0.009 and 0.02 respectively). Patients with elevated Cardio Vascular Risk (CVR) carried out the higher frequency of homozygous mutant genotype TT (62.2%) and T mutant allele (77.8%), compared to median and low CVR groups. G894 T eNOS distribution was significantly associated to a high risk of EH occurrence under the GT and TT genotypes (OR [95% CI] = 20.2 [7.7–52.4], P

Objective The aim of the present study was to investigate the association of I/D polymorphisms of ACE gene is associated with resistant hypertension and essential controlled hypertension. Results Our results show that the homozygous mutant genotype DD was more represented among resistant than controlled (58.1% vs 41.9% respectively), however the homozygote wild was more represented among controlled than resistant (70.6% vs 29.4% respectively). But more heterozygous ID among controlled than resistant patients (63.6% vs 36.4% respectively). The difference was statistically significant (p = 0.04). Analysis of clinical parameters indicated that physical activity contributes to resistant hypertension (P Based on our findings, the homozygous mutant for DD of ACE gene is associated with resistant hypertension in our population. Further studies with larger sample sizes are needed to confirm the results of this study.

Dabigatran and rivaroxaban at standard or reduced doses have been compared to warfarin in nonvalvular atrial fibrillation (NVAF), but not to each other. This was a new user study of standard dose and reduced dose dabigatran or rivaroxaban for NVAF in the French healthcare database, matched on gender, age, date of first dispensing, and high-dimensional propensity score, followed 2 years. Hazard ratios (HRs; 95% confidence intervals (CI)) of stroke or systemic embolism (SSE), major bleeding (MB), or death were computed. In matched standard-dose patients (8,290 per arm), mean age 67 years, HRs for dabigatran vs. rivaroxaban were SSE 0.92 (95% CI = 0.67-1.26), MB 0.59 (95% CI = 0.39-0.90), and death 0.84 (95% CI = 0.65-1.11). In reduced-dose patients (7,639 per arm), mean age 80 years, HRs for dabigatran vs. rivaroxaban were SSE 0.73 (95% CI = 0.59-0.94), MB 0.74 (95% CI = 0.57-0.96), and death 0.95 (95% CI = 0.83-1.09). In conclusion, at either dose, dabigatran had similar or better effectiveness than rivaroxaban but lower bleeding risk. Death rates were not different.

AIMS: We compared the 1‐year safety and effectiveness of dabigatran 110 mg (D110) or 150 mg (D150) twice daily to vitamin K antagonists (VKA) in patients with nonvalvular atrial fibrillation. METHODS: New user cohort study of patients dispensed D110 or D150 vs. VKA in 2013 for nonvalvular atrial fibrillation, followed 1 year in the French Système National des Données de Santé (66 million persons). D110 and D150 users were matched 1:1 with VKA users on sex, age, date of first drug dispensing and high‐dimensional propensity score. Hazard ratios [HR (95% confidence intervals)] for stroke and systemic embolism (SSE), major bleeding (MB) and death were computed using Cox proportional hazards or Fine and Gray models during exposure. RESULTS: In 14 442 matched D110 and VKA patients, mean age 79, 49% male, 91% with CHA(2)DS(2)‐VASc ≥2 and 8% with HAS‐BLED score >3, incidence rates of SSE were 1.9% and 2.6% person‐years [HR 0.69 (0.56–0.84)], MB 1.8% and 2.9% [0.62 (0.51–0.76)], death 7.2% and 8.6% [0.84 (0.76–0.94)]. In 8389 matched D150 and VKA patients, mean age 67, 67% male, 65% with CHA(2)DS(2)‐VASC ≥2; < 5% HAS‐BLED >3, incidence rates were for SSE 1.4% and 1.9% [0.76 (0.56–1.04)], MB 0.6% and 1.9% [0.30 (0.20–0.46)], death 1.6% and 3.6% [0.46 (0.35–0.59)]. Numbers needed to treat to observe one fewer death were 78 for D110, 88 for D150. CONCLUSION: In real life D110 and D150 were at least as effective, and safer than VKA.

Aims This study aimed to describe the real-life incidence of bleeding, arterial thrombotic events and death during vitamin K antagonist (VKA) treatment in atrial fibrillation (AF). Methods This was a cohort study in Echantillon Generaliste de Beneficiaires, the 1/97 sample of the French national healthcare claims and hospitalization database, of new VKA users with definite or probable AF and no other indication, and of patients without AF, from 2007 to 2011. Prespecified outcomes were all-cause death, hospitalization for bleeding, arterial thrombotic event (ATE), or acute coronary syndrome (ACS) or any of the above (composite outcome). Results Of 8894 new VKA users, 3345 had probable or certain AF, 51.7% were male, mean age was 75.1 years, 87.1% had a CHA2DS2-VASc score ≥ 2 and 11.6% a HAS-BLED score > 3. Among AF patients, during VKA exposure the incidence rate of bleeding was 2.8 [95% confidence interval (CI) 2.2, 3.4] per 100 patient-years, including 0.6 (95% CI 0.3, 0.8) cerebral, 1.0 (95% CI 0.7, 1.3) digestive and 1.4 (95% CI 1.0, 1.7) other bleeds. There were 1.6 (95% CI 1.2, 2.0) ACS, 1.5 (95% CI 1.1, 1.8) ATE and 3.8 (95% CI 3.2, 4.4) deaths per 100 patient-years. The incidence rate of the composite outcome was 9.1 per 100 patient-years (95% CI 8.2, 10.0). When patients stopped VKA, bleeding decreased (RR 0.67, 95% CI 0.43, 1.04)), but death or thrombosis increased (RR 3.06, 95% CI 2.46, 3.81 and 1.75, 95% CI 1.14, 2.70, respectively). During VKA exposure non-AF patients had similar rates of bleeding, but fewer deaths, ACS and ischaemic events. Conclusions Real-life rates for bleeding, arterial thrombotic events, ACS and deaths in AF patients treated with VKA were similar to those observed in clinical trials.

The AP-1 transcription factor complex is a key player in regulating inflammatory processes, cell proliferation, differentiation, and cell transformation. The aim of the present study is to investigate C-Jun (one of AP-1complex) expression and its proliferative role in skin samples of lichen planus, psoriasis as common inflammatory skin diseases and squamous cell carcinoma using immunohistochemical method. The present study was carried out on skin biopsies of 15 psoriatic patients, 15 lichen planus patients, 15 SCC, and 15 normal skin biopsies. Nuclear expression of C-Jun was detected in basal and few suprabasal layers of epidermis of normal skin. C-Jun was expressed in the whole epidermal layers of both psoriasis (14/15) and lichen planus (15/15) in addition to its expression in lymphocytic infiltrate in the latter in about half of cases (8/15). C-Jun was also expressed in 93.3% (14/15) of SCC in a percentage lower than that of psoriasis, lichen planus, and normal skin. The percentage of C-Jun expression in SCC was significantly associated with an early stage (p = 0.000), free surgical margins (p = 0.022), and small tumour size (p = 0.003).The marked reduction of C-Jun in SCC in comparison to normal skin and inflammatory skin dermatoses may refer to its tumour suppressor activity. C-Jun expression in SCC carries favourable prognosis. Absence of significant association between C-Jun and Ki-67 either in SCC or inflammatory skin diseases indicates that it does not affect proliferative capacity of cells.

Objective Estimate the effect of lifestyle adjustment activities in patients with metabolic syndrome treated by prescribed balneotherapy. Methods Observational pilot cohort study with 12-month follow-up after multidimensional lifestyle training (physical, dietary, educational) during 3-week standard stay in the spa town of Eugenie-les-Bains. Results Of 145 eligible patients, 97 were included; 63 were followed and analysable. At inclusion all had ≥ 3 National cholesterol education program-Adult treatment panel III (NCEP-ATPIII) criteria defining metabolic syndrome, 76.2% were female, mean age was 61.2 years. At the end of follow-up (median:10.4 months, Inter-Quartile Range: [6.7;11.4]), 48 of these 63 patients (76.2%) no longer had metabolic syndrome (95%CI [65.7;86.7]). These 48 patients without metabolic syndrome at the end of follow-up represented 49.5% of the 97 included (95%CI [39.5;59.4]). Conclusions Future studies of lifestyle interventions taking advantage of the spa environment can be expected to find least one third of patients free of metabolic syndrome at the end of 12-month follow-up in the intervention group.

The aim of the present study was to describe the real-life usage patterns of paracetamol.The Echantillon Généraliste de Bénéficiaires (EGB) database, the permanent 1/97 representative sample from the French national healthcare insurance system, was searched in 2011 to identify usage patterns, concomitant chronic diseases and use of cardiovascular medication in users prescribed single-ingredient (SP) and combination (CP) paracetamol, representing 85% of all sales.Of 526 108 subjects aged ≥15 years in the EGB, 268 725 (51%) had paracetamol dispensed on ≥1 occasion; of these, 207 707 (77%) were dispensed only SP and 61 018 (23%) received CP with or without SP. SP users were younger (48.3 years vs. 50.5 years), and 57% of SP users vs. 58% of CP users were female. Chronic comorbidities were more common in CP than SP users. SP users had, on average, 3.4 dispensings per year vs. 5.0 for CP users, for 36 defined daily doses (DDD, 3 g) of SP vs. 53 DDD per year for CP; 49% SP users bought 14 DDD or fewer; 15% bought60 DDD. Use of paracetamol increased with age from about 16 DDD per year in 15-30-year-olds to over 90 DDD per year in patients above the age of 75; 53% of patients ≤60 years bought fewer than 14 DDD per year, whereas 55% of those60 bought more than 30 DDD per year. More than half the dispensings exceeded the legal per-box limit of 8 g.Over 50% of the French adult population were dispensed paracetamol at least once over the course of a year, generally for short-term use. Considering recent misgivings on the real efficacy and safety of paracetamol, such widespread use might have important public health consequences.

Aims/hypothesis Using the Echantillon Généraliste de Bénéficiaires: random 1/97 permanent sample of the French national healthcare insurance system database (EGB), we investigated whether, as previously suspected, the risk of cancer in insulin glargine (A21Gly,B31Arg,B32Arg human insulin) users is higher than in human insulin users. The investigation period was from 1 January 2003 to 30 June 2010. Methods We used Cox proportional hazards time-dependent models that were stratified on propensity score quartiles for use of insulin glargine vs human insulin, and adjusted for insulin, biguanide and sulfonylurea possession rates to assess the risk of cancer or death in all or incident exclusive or predominant (≥80% use time) users of insulin glargine compared with equivalent human insulin users. Results Only type 2 diabetic patients were studied. Exposure rates varied from 2,273 and 614 patient-years for incident exclusive users of insulin glargine or human insulin, respectively, to 3125 and 2341 patient-years for all patients predominantly using insulin glargine or human insulin, respectively. All-type cancer HRs with insulin glargine vs human insulin ranged from 0.59 (95% CI 0.28, 1.25) in incident exclusive users to 0.58 (95% CI 0.34, 1.01) in all predominant users. Cancer risk increased with exposure to insulin or sulfonylureas in these patients. Adjusted HRs for death or cancer associated with insulin glargine compared with human insulin ranged from 0.58 (95% CI 0.32, 1.06) to 0.56 (95% CI 0.36, 0.87). Conclusions/interpretation There was no excess risk of cancer in type 2 diabetic patients on insulin glargine alone compared with those on human insulin alone. The overall risk of death or cancer in patients on insulin glargine was about half that of patients on human insulin, thereby excluding a competitive risk bias.

Background Imatinib has dramatically improved the prognosis of advanced gastrointestinal stromal tumours (GISTs). Clinical trial data showed that patients with trough imatinib plasma concentrations (Cmin) below 1100 ng/ml (quartile 1) had shorter time to progression, but no threshold has been defined. The main objective of this study was to investigate in advanced GIST whether a Cmin threshold value associated with a longer progression-free survival (PFS) could be specified. This would be the first step leading to therapeutic drug monitoring of imatinib in GIST. Patients and methods Advanced GIST patients (n = 96) treated with imatinib 400 mg/d (41 stomach, 34 small bowel, and 21 other primary site localisations) were prospectively included in this real-life setting study. Routine plasma level testing imatinib (Cmin) and clinical data of were recorded prospectively. Results Small bowel localisation was associated with an increased relative risk of progression of 3.09 versus stomach localisation (p = 0.0255). Mean Cmin (±standard deviation) was 868 (±536) ng/ml with 75% inter-individual and 26% intra-patient variability. A Cmin threshold of 760 ng/ml defined by log-rank test was associated with longer PFS for the whole population (p = 0.0256) and for both stomach (p = 0.043) and small bowel (p = 0.049) localisations when analysed separately. Multivariate Cox regression analysis found that Cmin above 760 ng/ml was associated with 65% reduction risk of progression (p = 0.0271) in the whole population independently of the anatomical localisation. Conclusion Concentration of imatinib significantly influences duration of tumour control treatment in GIST patients with a Cmin threshold of 760 ng/ml associated with prolonged PFS in real-life setting.

Background: Anti-tumour necrosis factor (TNF) agents, through their intense immunoregulatory effect, have been suspected to increase the risk of malignant lymphoma. However, the classical epidemiological approaches conducted over about the last 10 years have not totally succeeded in addressing the question of a causal or artifactual association. Therefore, the analysis of a substantial set of case reports, although usually considered as poorly generalizable to the general population, could be particularly informative. Two main sources of case reports in postmarketing settings are available; publications in medical journals and reports to pharmacovigilance systems. Objective: The aim of the study was to compare the characteristics of case reports from both these sources in order to understand whether they provided the same information for the investigation of the causal link between lymphoma and anti-TNF agents. Methods: All case reports of malignant lymphoma in patients treated with an anti-TNF agent published in MEDLINE and all reports to the French pharmacovigilance system up to 1 February 2010 were identified. Cases of malignant lymphoma identified in postmarketing surveillance from both sources were compared regarding the following variables: age, sex, anti-TNF agent involved, indication for use, type of lymphoma, prior or concomitant immunosuppressive drugs and time to onset of lymphoma. Results: A total of 81 published case reports and 61 cases reported to the French pharmacovigilance system were compared. In published reports, patients were younger (p = 0.03) and more frequently receiving a first anti-TNF treatment (p = 0.03), particularly infliximab (p = 0.03). Conversely, in the pharmacovigilance system reports, a succession of different anti-TNFs (p = 0.03) and adalimumab (p< 0.0001) were more frequently reported. Lymphomas in patients treated with anti-TNF agents for Crohn’s disease were more prevalent in published cases than in pharmacovigilance reports (p< 0.0001), and in particular involved hepatosplenic T-cell lymphoma. Conversely, rheumatoid arthritis was the main indication for anti-TNF agents in pharmacovigilance reports (p = 0.01). Time to onset was markedly shorter in published cases (median 12 months) than in pharmacovigilance reports (median 30 months; p = 0.0001). Conclusions: Characteristics of published cases and those reported to the French pharmacovigilance system differed markedly for all characteristics tested, except sex and the use of prior or concomitant immunosuppressive drugs. Published case reports favoured convincing arguments for drug causation whereas cases reported to the pharmacovigilance system were more disparate but could describe more accurately the reality of lymphoma occurrence in this particular population. These results argue for the use of the pharmacovigilance reports when case reports are used to investigate the causal link between lymphoma and anti-TNF agents at the population level. Data from cases notified to the French pharmacovigilance system did not indicate an increased risk of lymphoma during the early phase of anti-TNF treatment. To confirm this hypothesis, a study combining pharmacovigilance reports from several countries, or, if feasible, a cohort study both with a large sample size and a long duration of follow-up would be required.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • To our knowledge, no study has ever described the intensity of nonsteroidal anti-inflammatory drug (NSAID) utilization in an employed population by occupation. • As the use of NSAIDs carries a well-known risk of adverse effects, this risk adds to the burden of musculoskeletal disorders in employed populations. • Information on utilization of NSAIDs in this context will help to better characterize and prevent this risk. WHAT THIS STUDY ADDS • In spite of a previous history of dyspepsia, blue collar workers had the highest rate of chronic and continuous utilization of nonselective NSAIDs. • No clustering of cyclooxygenase-2 selective NSAID utilization according to a previous history of dyspepsia was observed among blue collar workers. • The association between chronicity of NSAID utilization and occupation was independent of medical indication for the prescription and other lifestyle factors. AIM The aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population. METHODS This was a secondary analysis of the CADEUS cohort study on 5651 actively employed patients, who submitted at least one claim for the reimbursement of a NSAID dispensation for a MSD between August 2003 and July 2004, in the French National Healthcare Insurance database. Questionnaires were sent to prescribing physicians to obtain diagnoses and the medical history, and to patients for their occupation, height and weight and smoking status. Multivariate logistic regression was used to study the determinants of a heavy use of NSAIDs defined as ‘over four dispensations in one year with less than two months between any two’. RESULTS Factors associated with heavy use of NSAIDs were age (Odds ratio (OR): 1.8 (ten years), 95% confidence interval (CI): 1.6–1.9), osteoarthritis (versus back pain) (OR: 1.8, 95% CI: 1.5–2.1), body mass index (superior to 30) (OR: 1.8, 95% CI: 1.5–2.2), and occupation (blue collar versus white collar workers) (OR: 1.4, 95% CI: 1.2–1.6). Blue collar workers also had a 20% higher prevalence of 5-year history of dyspepsia. No difference was observed between sexes or in the use of COX-2 selective inhibitors between occupations. CONCLUSION Factors associated with occupational constraints that contribute to the severity of MSDs, may explain the heavier use of NSAIDs among blue collar workers in spite of a concurrent and past medical history of adverse reactions to this type of medication.

Purpose We describe drug–drug interactions (DDIs) encountered with antifungals in clinical practice. Methods Retrospective observational study of hospitalized adults receiving systemic antifungal treatment in the intensive care unit (ICU) and in the infectious diseases unit (IDU) of the University Hospital of Bordeaux, France between 1996 and 2001. All treatment episodes with antifungal agent were examined and all prescribed concomitant medication identified for potential drug–drug interactions (PDDI)-serious events occurring during treatment were adjudicated for clinical DDI. Results There were 150 treatment episodes with antifungal agent in 105 patients. Fluconazole was used in 48% of the treatment episodes, amphotericin B in 46%, itraconazole in 4.7% and flucytosine in 1.3%. One hundred and sixteen PDDIs were identified related to the use of amphotericin B (81.0%), fluconazole (17.2%) or itraconazole (1.7%). Of these, 22 were associated with a clinical evidence of adverse interaction (hypokalemia, increased creatininemia or nephrotoxicity). All these clinical drug–drug interactions (CDDIs) were with amphotericin B. They were due to furosemide (36.4%), cyclosporine (31.8%) and hydrocortisone (18.2%). PDDIs were mostly associated with leukaemia (40.4%), HIV infection (24.6%) and cancer (10.5%). Conclusions In ICU and IDU, systemic antifungal treatments lead to many PDDIs, mainly related to the type of antifungal used and to the pathology treated. Clinical DDI seem more common with amphotericin. Copyright © 2007 John Wiley & Sons, Ltd.

To evaluate the prevalence of nocturnal symptoms in a large sample of asthmatic patients, and to assess the agreement between patients' complaints and general practitioners' (GPs') reports in primary care.Cross-sectional survey involved 3,526 GPs and 751 specialists (pulmonologists and allergists) and included 13,493 patients with persistent asthma. Symptoms, treatment, and social and medical data were collected in real time by the patients and their GPs.France.Prevalence of nocturnal symptoms was 60%. A total of 7,989 patients with nocturnal symptoms had complete data for both patients and GPs; 3,849 (48.1%) had perfect agreement between GP and their complaints for nocturnal symptoms (agreement group; [kappa = 1]); 3,376(42.2%) declared having no symptoms during the night, but these were detected by the GP during the visit (underestimated by patients and detected by GPs); 773(9.6%) declared having nocturnal symptoms, but these were not detected by GPs. Patients with a good agreement with their GP's opinion were significantly more frequently followed-up by a specialist than other patients (p = 0.002).Nocturnal symptoms appear to be underdeclared by patients. GPs should therefore systematically ask their patients about nocturnal symptoms to increase control of asthma and to adequately manage its treatment.

To describe adverse events occurring after mass vaccination with conjugate and nonconjugate vaccines and to assess the incidence of serious adverse effects. A mass immunisation campaign against meningococcal C disease was conducted in two French administrative areas, Landes and Pyrenees atlantiques, for 2 months (from October to December 2002). Adverse events were reported by families and physicians by means of a specific reporting form returned to the pharmacovigilance centre 15 days after vaccination. The target population was 260,630 individuals aged between 2 months and 24 years. About 179,000 children and young adults were vaccinated. A total of 92,711 report forms were received by the pharmacovigilance centre, and 12,695 subjects presented at least one adverse event. The most frequently involved systems/disorders were application site disorders (48.4%), whole-body general disorders (21.8%), central and peripheral nervous system disorders (14.6%), and gastrointestinal system disorders (4.7%). Most of these adverse events were transient and not serious. There were 13 serious adverse events: one each of syncope, fever, headache with fever, neuralgia, serum sickness, arthritis, purpura, facial paralysis, multiple sclerosis, lipoma, and meningism, and two cases of bronchospasm. No significant difference was found in rates of adverse event reports between both vaccines. The estimated incidence of serious adverse effect reports was 7 per 100,000. This campaign was the second immunisation campaign undertaken in France involving both physicians and families as reporters. Although unlabeled adverse effects were identified during this campaign, they were mostly nonserious and have been known to occur with other vaccines.

Objective: To assess whether current use of psychoactive substance(s) is a prognostic factor during hospitalization for intentional drug overdose (IDO). Method: Current intoxication with psychoactive substance(s) [cannabis, opiate, buprenorphine, amphetamine/ecstasy, cocaine, lysergic acid diethylamide (LSD)] was identified using toxicological urinalysis in 671 patients with IDO. An IDO was a priori defined as serious if associated with one of the following events: death, hospitalization in intensive care unit longer than 48 h, respiratory support, use of vasopressive drugs, cardiac massage or dialysis. Results: Subjects positive for toxicological assays were twice as likely to present with serious IDO (OR = 1.9, 95% CI: 1.3–2.8, P = 0.001), independently from a large range of confounding factors. The risk of serious IDO was especially marked in subjects using LSD, buprenorphine or opiates. Conclusion: Systematic investigation of substance use could be important to adapt medical management of subjects with IDO in general hospital, but also in primary care and psychiatric settings.

Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However, it seems difficult to relate these in vitro and in vivo preclinical models to clinical findings, in part, because the relationship between concentrations used and in vivo tissue concentrations during treatment in man is not known. Consequently, we established the myocardium to plasma concentration ratios for a series of antipsychotic drugs by intraperitoneal administration of different level doses to the guinea pig. Then, we compared these values to their ability to induce arrhythmia or torsade de pointes in clinical practice. The myocardium to plasma concentration ratios were 2.2 for clozapine, 2.7 for olanzapine, 3.1 for sertindole, 4.5 for risperidone, and 6.4 for haloperidol. These data suggest that when the ratio is higher than 4, arrhythmia and sudden death may be expected. On the contrary, when the ratio is less than 3, little effect may be predicted. These results underscore the importance of interpreting HERG channel data and electrophysiological data in the context of other pharmacokinetic parameters such as myocardium to plasma distribution.

Most risks of nonsteroidal anti-inflammatory drugs (NSAIDs) are pharmacological, dose and duration dependent. Usage patterns of prescription-only (POM) or 'over-the-counter (OTC)' NSAIDs may influence risks, but are not commonly described.The Echantillon Généraliste de Bénéficiaires database, the permanent 1/97 representative sample from the French national healthcare insurance systems, was queried over 2009-2010 to identify usage patterns, concomitant chronic diseases and cardiovascular medication in OTC and POM NSAID users.Over 2 years, 229 477 of 526 108 patients had at least one NSAID dispensation; 44 484 patients (19%) were dispensed only OTC NSAIDs (93% ibuprofen) and 121 208 (53%) only POM NSAIDs. The OTC users were younger (39.9 vs. 47.4 years old) and more often female (57 vs. 53%); 69% of OTC users and 49% of POM users had only one dispensation. A mean of 14.6 defined daily doses (DDD) were dispensed over 2 years for OTC vs. 53 for POM; 93% OTC vs. 60% POM patients bought ≤ 30 DDD over 2 years, and 1.5 vs. 12% bought ≥ 90 DDD. Chronic comorbidities were found in 19% of OTC users vs. 28% of POM users; 24 vs. 37% had at least one dispensation of a cardiovascular drug over the 2 years.Most of the use of NSAIDs appears to be short term, especially for OTC-type NSAIDs, such as ibuprofen. The validity of risk estimates for NSAIDs extrapolated from clinical trials or from observational studies not including OTC-type usage may need to be revised.

The recommended pharmacotherapy for secondary prevention of acute coronary syndrome (ACS) is long-term treatment with a combination of four therapeutic classes: beta-blockers, antiplatelet agents (including aspirin), statins or other lipid-lowering agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The aim of this study was to describe use and persistence of the recommended drug combination after the first occurrence of ACS in France.This was a database cohort study of patients with first registration for ACS between 2004 and 2007 in a representative sample of the French healthcare insurance database (Echantillon Généraliste de Bénéficiaires, EGB). The drugs of interest were those recommended. Persistence was assessed for patients dispensed three or all four drug classes within 2 months following ACS. Discontinuation was defined by a gap of more than 6 weeks between two dispensations. The follow-up period was 24 months after ACS occurrence.Of 2,057 patients with incident ACS, 872 (42.4 %) had at least one dispensation of each of the four recommended drug classes, and 684 (33.3 %) had three of the four classes. Persistence to treatment at 24 months was 57.4 % (95 % CI [54.0-60.6]) for patients with four classes, and 55.5 % (95 % CI [51.6-59.1]) with three classes. Discontinuation of initial combination was higher in patients aged ≥ 65 years at ACS occurrence, those with associated ongoing chronic disease, and in those who did not suffer myocardial infarction.Post-ACS secondary prevention in France is not optimal, especially in patients who did not have myocardial infarction.

To determine healthcare claim patterns associated using nonsteroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis (RA).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.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).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.

A retrospective, observational, cohort study in primary care. To determine the total direct medical and non-medical cost of chronic low back pain (LBP) in France and its associated factors. Chronic LBP affects 5-10% of the population its burden in France is unknown. Ninety-eight randomly selected general practitioners included 796 adult patients with chronic LBP between October 2001 and December 2002. Direct costs due to physician visits, investigations, medications, hospitalizations, and other medical and non-medical resource use were collected for the 6 months prior to study visit. Costs both reimbursed and not by the French health insurance system were considered. Quality of life (QoL) and disease severity were measured using Short Form (SF)-8 and Roland-Morris disability questionnaire (RMDQ), respectively. Costs were updated to represent 2007 prices. Men represented 50.6% of the 796 patients, mean age was 53 +/- 11.3 years, and the duration of LBP was more than 1 year in 80.9% of patients. The total mean cost per patient over six months was 715.6 euro (95% CI: 644.2-797.8). Of these costs, 22.9% related to care provided by physiotherapists and allied specialists, 19.5% to medications, 17.4% to hospitalizations, 9.6% to investigations, and 12.5% to physician fees. In multivariate analysis, the factors associated with the cost of chronic LBP were disease severity (RMDQ score) and age of the patients. LBP is a disease that is both common and costly.

To investigate the effect of chronic oral arginine aspartate on the growth hormone (GH), GH-releasing hormone (GHRH), insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) secretions in healthy volunteers. Twenty-three healthy non-athlete volunteer males were administered arginine aspartate (30 g) orally once daily at 21:00 h for 21 consecutive days. Subjects were hospitalized on days 0, 1, 3, 5, 7, 14 and 21 of treatment. At each hospitalization, concentrations of GHRH, GH, IGF-1 and IGFBP-3 were measured over 4 h after arginine aspartate intake. GH, IGF-1 and IGFBP-3 concentrations were also determined over 12 h at days 0, 1 and 21. Compared with day 1, 4 h GH levels dropped at day 5 and subsequently rose to levels not significantly different from initial ones. The latter was substantiated by 12 h GH levels that did not significantly change from days 1 to 21. GHRH levels were not statistically different, although there was a trend in median values that seemed to inversely mirror those of GH. This dynamic over the course of the study for GH and GHRH was accompanied by a general decrease in IGF-1 and IGFBP-3. In healthy volunteers, a chronic oral treatment with 30 g/day arginine aspartate is followed by a decrease in IGF-1 and IGFBP-3 secretions.

The aims of the present study were to assess the prevalence and comorbidity of psychiatric disorders in subjects with intentional drug overdose and to explore whether there were gender differences in prevalence and comorbidity. A standardized psychiatric evaluation was performed in 100 randomly selected subjects, 18 years old and older, with intentional drug overdose referred to an emergency department. The prevalences of psychiatric morbidity and comorbidity were very high in both genders: 88% presented with at least one psychiatric diagnosis, and three-quarters presented with comorbid psychiatric disorders. Affective and anxiety disorders were the most prevalent diagnoses. One patient out of three presented with alcohol or substance misuse. Compared to females, males suffered five times more often from substance misuse and three times more often from psychotic syndrome and were three times less likely to present with anxiety disorder. When subjects are referred to hospital for intentional drug overdose, medical management should systematically involve a psychiatric assessment in order to identify not only affective and anxiety disorders, but also alcohol and substance misuse, due to the high prevalence of these disorders, especially in male subjects.

To investigate the prevalence of current use of benzodiazepines (BZDs) and related drugs in the French general population and factors associated with this use. National cross-sectional telephone survey conducted between 25 April 2001 and 8 May 2001 in a representative sample of non-institutionalized adults of BZD use and duration, prescriber specialty, socio-demographic data and mood and anxiety disorders, using a structured diagnostic interview. The prevalence of current use of BZD was 7.5%. It was higher among women (9.7%) than men (5.2%). It increased with age and was higher in the jobless (10.9). Duration of BZD use was more than 6 months in 75.9% of users and increased with age. Of the 711 (17.7%) subjects with at least one mood or anxiety disorder, 122 (17%) used BZD compared with180 (5.5%) of the 3296 subjects without mood or anxiety disorders. In multivariate analysis, factors associated with BZD use were age [odds ratio (OR): 3.6; 95% confidence interval (CI) 2.0–5.6], 6.5 (4.1–10.3) and 10.9 (6.9–17.1), respectively, for ages 35–44 years, 45–59 years and over 60 years compared with below 34 years, female gender (OR: 1.7; 95% CI 1.3–2.1), anxiety only (OR: 2.2; 95% CI 1.5–3.2), mood disorder only (OR: 4.4; 95% CI 2.7–7.1) or both mood and anxiety disorders (OR: 8.8; 95% CI 5.9–12.6). Despite precautions, warnings and attempts to limit use, there remains a high proportion of long-term BZD users in the general French population, especially in the elderly. Our findings add to the weight of opinion that messages concerning proper use of BZDs certainly need to be clarified and amplified.

The correct use of inhalation devices is an inclusion criterion in many comparative studies. However, patients can make errors, thus compromising the effectiveness of their own inhaler. The aim of the study is to evaluate inhaler use by patients with chronic obstructive pulmonary disease (COPD) [n = 984]. General practitioners assessed inhalation technique, using a specific checklist previously established for each inhaler model (Aerolizer, Autohaler, Diskus, a pressurised metered-dose inhaler (pMDI) or a Turbuhaler). A total of 24% of the patients using a pMDI did not make an error compared with 34-40% of those using breath-actuated devices. The frequency of critical errors varied according to the device: 11.5-14.9% of the subjects using an Aerolizer, Autohaler or Diskus versus 37.4% and 38.1% of the patients using a pMDI and a Turbuhaler, respectively. The proper use of the Turbuhaler is often overestimated (24.7%) compared with the pMDI (2.1%). The development of educational programmes for patients and prescribers is needed to improve the management of COPD.

To assess the accuracy of self-reported substance use and toxicological assays in subjects admitted for Intentional Drug Overdose (IDO), using as a reference diagnosis of substance use disorder.Self-reported substance use was collected and toxicological assays were carried out in urine samples in 507 patients with IDO. A standardized psychiatric evaluation was performed in 100 randomly selected subjects.In routine practice, the emergency department staff did not investigate substance use in nearly one of two patients. Patients' statements and toxicological assays were more specific than sensitive, with lower scores for toxicological assays. Patients' statements made it possible to detect nearly 80% of subjects with substance use disorder.Identification of substance use disorder in subjects with IDO has strong clinical consequences regarding treatment and prevention of suicidal behaviour. Thus, emergency department staff should be made aware of the value of more systematically exploring self-reported substance use.

The correct use of inhalation devices is an inclusion criterion for all studies comparing inhaled treatments. In real life, however, patients may make many errors with their usual inhalation device, which may negate the benefits observed in clinical trials. Our study was undertaken to compare inhalation device handling in real life. A total of 3811 patients treated for at least 1 month with an inhalation device (Aerolizer, Autohaler, Diskus, pressurized metered dose inhaler (pMDI), or Turbuhaler) were included in this observational study performed in primary care in France between February 1st and July 14th, 2002. General practitioners had to assess patient handling of their usual inhaler device with the help of a checklist established for each inhaler model, from the package leaflet. Seventy-six percent of patients made at least one error with pMDI compared to 49-55% with breath-actuated inhalers. Errors compromising treatment efficacy were made by 11-12% of patients treated with Aerolizer, Autohaler, or Diskus compared to 28% and 32% of patients treated with pMDI and Turbuhaler, respectively. Overestimation of good inhalation by general practitioners was maximal for Turbuhaler (24%), and lowest for Autohaler and pMDI (6%). Ninety percent of general practitioners felt that participation in the study would improve error detection. These results suggest that there are differences in the handling of inhaler devices in real life in primary care that are not taken into account in controlled studies. There is a need for continued education of prescribers and users in the proper use of these devices to improve treatment efficacy.

OBJECTIVES. This project aimed to compare the independent and combined effectiveness of two implementation interventions of guidelines for ordering thyroid function tests: a Memorandum Pocket Card (MPC) and a Test RequestForm (TRF). RESEARCH DESIGN. Intervention groups were wards. The study used an experimental 2*2 factorial design with matching hospitals according to size and activity and wards according to preintervention appropriateness for test ordering. Four ward groups were established: the dual intervention group, the order form group, the pocket card group and the control group. Physicians in all groups received guidelines and were invited to a local information meeting. MEASURES. The main outcome measure of effectiveness was the Guideline Conformity Rate (GCR). RESULTS. Six hospitals participated in the study (two middle-sized hospitals, two small-sized hospitals and two psychiatric hospitals). A total of 1412 orders for thyroid function tests were collected. GCR was 78% in the dual intervention group, 83% in the order form group, 73% in the pocket card group and 62% in the control group. The interaction between TRF and MPC was not significant (β = -0.70; P = 0.21). Compared with simple information, TRF was effective in increasing GCR (OR, 2.65; 95% CI, 1.52-4.62), unlike MPC (OR, 1.28; CI, 0.75-2.19). CONCLUSIONS. Using a robust design, our study shows the greater effectiveness of TRF than MPC and their association in implementing thyroid function test guidelines.

For toxicological purposes, a HPLC assay was developed for the simultaneous determination of risperidone and 9-hydroxyrisperidone in human plasma. After a single-step liquid-liquid extraction, both compounds were separated on a C(18) column and measured at 280 nm. A good inter-assay accuracy (116%) was achieved with inter-assay precision less than 12%. Quantification limits were 10 ng/ml. This rapid method (run time5 min) is currently used for poison management.