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Pharmacovigilance reports of cerebral and cardiovascular events in those who use decongestants have triggered alerts related to their use. We aimed to assess the risk of stroke and myocardial infarction (MI) associated with the use of decongestants. We conducted a nested case-crossover study of patients with incident stroke and MI identified in France between 2013 and 2016 in two systematic disease registries. Decongestant use in the three weeks preceding the event was assessed using a structured telephone interview. Conditional logistic multivariable models were used to estimate the odds of incident MI and stroke, also accounting for transient risk factors and comparing week 1 (index at-risk time window, immediately preceding the event) to week 3 (reference). Time-invariant risk factors were controlled by design. In total, 1394 patients with MI and 1403 patients with stroke, mainly 70 years old or younger, were interviewed, including 3.2% who used decongestants during the three weeks prior to the event (1.0% definite exposure in the index at-risk time window, 1.1% in the referent time window; adjusted odds ratio (aOR), 0.78; 95%CI, 0.43-1.42). Secondary analysis yielded similar results for individual events (MI/stroke). We observed no increased risk of MI or stroke for patients 70 years of age and younger without previous MI or stroke who used decongestants.

The systematic case-referent method is a special case-referent design originally developed for pharmacoepidemiologic research purposes. It consists in the systematic collection of series of incident cases of various disorders and the assembling of a general reference pool, from which "controls" are secondarily selected to be matched to specific cases. Both series are collected independently from each other and with no a priori hypothesis to be investigated. The reference pool can be either general or limited to a subpopulation, representative of the source population of the cases. Based on clinical recruitment of cases and referents, the design allows a very high specificity of diagnosis and documentation of clinical variables. All cases and referents are systematically documented on all treatments received before the incidence of the cases or before identification of referents. This documentation is done preferentially using objective sources assembled independently (linkage to claims data, medical records, pharmacy records, prescription records, hospital discharge letters). It can be completed with patients' interviews using standardised research tools, in particular for over-the-counter drug use and self-medication, and for the documentation of adherence to treatment and specific time-windows of exposure. Likewise, all cases and all referents are systematically documented on a series of risk factors, which are common to most epidemiological studies and are not hypothesis-dependent. Whenever the documentation of a confounding factor specific to the disease at hand is necessary, additional questionnaires can be applied to all or a sample of patients. The method has been successfully implemented for the pharmacoepidemiologic study of myocardial infarction, stroke, lupus, multiple sclerosis, rheumatoid arthritis, Guillain Barré syndrome, idiopathic thrombocytopenic purpura, type 1 diabetes mellitus, suicide attempts, breast cancer, and other disorders, for the analysis of the risk or preventing action of NSAIDs, statins, antiplatelet agents, anticoagulants, insulins, vaccines and other drugs., (Copyright © 2018. Published by Elsevier Masson SAS.)

Objective: To compare ticagrelor and prasugrel with clopidogrel for recurrent fatal and non-fatal myocardial infarction (reMI) in real-life conditions., Methods: Case-referent study using the Pharmacoepidemiological General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Cases were patients with reMI from a cohort with index ACS or external to the cohort (same sites). Referents from the cohort, without recurrent event, were matched on index ACS type and date, age and sex with reMI cases. Multivariate conditional logistic regression assessed the OR (95% CI) for reMI associated with ticagrelor and prasugrel vs clopidogrel, adjusted for aspirin use and cardiovascular risk factors., Results: 1047 cases and 2234 matched referents were included. Compared with clopidogrel, ticagrelor and prasugrel were associated with respective ORs of 0.65 (95% CI 0.52 to 0.81) and 0.71 (95% CI 0.53 to 0.96) for reMI occurrence. ORs for ticagrelor and prasugrel vs clopidogrel were: 0.50 (95% CI 0.38 to 0.67) and 0.66 (95% CI 0.45 to 0.95), 0.39 (95% CI 0.24 to 0.62) and 0.44 (95% CI 0.26 to 0.75), 0.63 (95% CI 0.43 to 0.92) and 1.20 (95% CI 0.69 to 2.07), 1.11 (95% CI 0.72 to 1.72) and 0.82 (95% CI 0.44 to 1.54) when index ACS was a first MI, a first ST-elevated MI (STEMI), a first non-STEMI and a recurrent ACS, respectively, and 0.63 (95% CI 0.45 to 0.87) and 0.77 (95% CI 0.41 to 1.45) for patients aged ≥70  years., Conclusions: This real-world study showed a significant reduction of reMI with new antiplatelets compared with clopidogrel, ticagrelor being associated with a greater decrease of risk notably for first, either STEMI or non-STEMI. The larger magnitude of effect may be attributed to potential residual confounding or higher effectiveness compared with efficacy reported in trials (EMA Post Authorisation Study Registry Number EUPAS5905)., Competing Interests: Competing interests: LG-B is currently employed by PGRx, a company susceptible of collaborating with virtually all the pharmaceutical companies worldwide. NDa declares having received financial support from Abbott France, Amgen SAS, AstraZeneca, Bayer Healthcare SAS, Boehringer Ingelheim France, Bristol-Myers Squibb, GlaxoSmithKline France, Lilly France SAS, MSD France, Novo Nordisk, Pierre Fabre, Re-Imagine Health Agency, Sanofi-Aventis France and Servier during the conduct of the study. JD declares having received personal fees for participating in Scientific Boards from AstraZeneca, Bayer and MSD. BF reports personal fees from AstraZeneca during the conduct of the study. AF, OM, FL, FG and NDe declare no conflict of interest. YC declares having received financial support for participating in Scientific Boards and consulting for Bayer, Boehringer, Novartis, Pfizer and Servier outside the submitted work. LB declares having received financial support in the form of grants and/or personal fees from AstraZeneca during the conduct of the study and also outside the submitted work. EP declares having received fees for lectures and/or consulting from Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Lilly, MSD, The Medicine Company, Sanofi and Servier. JB declares having received financial support from Association pour le Développement de l’Enseignement et des Recherches auprès des universités des centres de recherches et des entreprises d’Aquitaine, AstraZeneca, Servier and LASER during the conduct of the study. LA is chairman and stock owner in Analytica LASER, a consultancy susceptible of collaborating with virtually all the pharmaceutical companies worldwide. PGRx has no commercial interests in any of the products studied. Members of the PGRx network have no interest in any drugs or other factors studied using data collected using PGRx., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Spontaneous reports of acute liver injuries (ALI) in patients taking dronedarone triggered an EMA alert in 2011. This study aimed to assess the risk of ALI for class III antiarrhythmic drugs controlling for the use of other potential ALI-inducing drugs., Methods: Between 2010 and 2014, consecutive ALI cases (≥50 years-old) were identified across Germany. ALI was defined as a new increase in at least one of the transaminases ≥3 times the upper limit of normal (ULN) or ≥2 ULN if alkaline phosphatase, with ("definite" case) or without ("biochemical" case) suggestive signs/symptoms of ALI, excluding other liver diseases. Recruited community controls were matched to cases on gender, age and inclusion date. Exposure to antiarrhythmic drugs and co-medication up to 2 years before ALI onset was informed by patients and confirmed by physicians' prescriptions. Adjusted Odds Ratios (aOR) were obtained from conditional multivariable logistic regressions, adjusted for a multivariate disease risk score and co-medication., Results: 252 cases and 1081 matched controls were included (59.1% females; mean age: 64 years). Exposure to class III antiarrhythmic drugs was 4.0% in cases and 1.5% in controls, aOR = 3.6 (95% CI: 1.6-8.4). Associations with exposure to dronedarone and amiodarone were respectively 3.1 (95% CI: 0.7-14. 8) and 5.90 (1.7-20.0). Restricting the analysis to definite or severe ALI cases did not change these results., Conclusions: Class III antiarrhythmic drugs were associated with ALI, amiodarone displaying the highest risk, and results were robust to case definitions. Continued vigilance is needed for patients taking these drugs., (Copyright © 2018. Published by Elsevier B.V.)

Background: Phase III randomized controlled trials (RCT) typically exclude certain patient subgroups, thereby potentially jeopardizing estimation of a drug's effects when prescribed to wider populations and under routine care ("effectiveness"). Conversely, enrolling heterogeneous populations in RCTs can increase endpoint variability and compromise detection of a drug's effect. We developed the "RCT augmentation" method to quantitatively support RCT design in the identification of exclusion criteria to relax to address both of these considerations. In the present manuscript, we describe the method and a case study in schizophrenia., Methods: We applied typical RCT exclusion criteria in a real-world dataset (cohort) of schizophrenia patients to define the "RCT population" subgroup, and assessed the impact of re-including each of the following patient subgroups: (1) illness duration 1-3 years; (2) suicide attempt; (3) alcohol abuse; (4) substance abuse; and (5) private practice management. Predictive models were built using data from different "augmented RCT populations" (i.e., subgroups where patients with one or two of such characteristics were re-included) to estimate the absolute effectiveness of the two most prevalent antipsychotics against real-world results from the entire cohort. Concurrently, the impact on RCT results of relaxing exclusion criteria was evaluated by calculating the comparative efficacy of those two antipsychotics in virtual RCTs drawing on different "augmented RCT populations"., Results: Data from the "RCT population", which was defined with typical exclusion criteria, allowed for a prediction of effectiveness with a bias < 2% and mean squared error (MSE) = 5.8-6.8%. Compared to this typical RCT, RCTs using augmented populations provided improved effectiveness predictions (bias < 2%, MSE = 5.3-6.7%), while returning more variable comparative effects. The impact of augmentation depended on the exclusion criterion relaxed. Furthermore, half of the benefit of relaxing each criterion was gained from re-including the first 10-20% of patients with the corresponding real-world characteristic., Conclusions: Simulating the inclusion of real-world subpopulations into an RCT before running it allows for quantification of the impact of each re-inclusion upon effect detection (statistical power) and generalizability of trial results, thereby explicating this trade-off and enabling a controlled increase in population heterogeneity in the RCT design.

Objectives: To explore the impact upon estimation of drug effect as a result of applying exclusion criteria in randomized-controlled trials (RCT) measuring the efficacy of antipsychotics (AP) in schizophrenia., Methods: Three characteristics which may act as effect-modifiers of AP, while also common exclusion criteria in RCTs, were identified through literature review: schizophrenia duration, substance use disorder and poor adherence. The SOHO cohort was used to estimate the effect of initiating antipsychotic drugs "A", "B" or "C" (pooled) upon symptom evolution at 3months from baseline (CGI-S scale). "Estimated effectiveness" and "estimated efficacy" were drawn from the "SOHO" and "RCT-like" (patients with none of the above-listed exclusion criteria) samples, respectively. Effect-modification and impact of each exclusion criterion on AP effect estimates were explored using non-adjusted statistics., Results: The "SOHO sample" included 8250 patients initiating drug A, B or C at baseline, whose AP "estimated effectiveness" was ΔCGI-S=-0.78 (95% CI=-0.80, -0.76). The "RCT-like" sub-sample included 5348 (65%) patients whose AP "estimated efficacy" was ΔCGI-S=-0.73 (95% CI=-0.75, -0.70). Patients with short illness duration (≤3years since first AP; n=2436) experienced significant symptom improvement (ΔCGI-S=-0.89; 95%CI=-0.93, -0.85) compared to patients with duration >3years (mean ΔCGI-S=-0.73; 95%CI=-0.76, -0.71). Excluding patients with short illness duration led to a change in AP effect estimates but this was not the case for substance use disorder or poor adherence., Conclusion: Using certain exclusion criteria in RCTs may impact the drug's effect estimate, particularly when exclusion criteria are AP effect-modifiers representing frequent characteristics among patients with schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Reasons for using antipsychotic polypharmacy (APP) in routine clinical practice, despite a potentially unfavorable risk-benefit ratio, are poorly understood. This research aimed to determine (1) if severe courses of schizophrenia were associated with APP and (2) if a schizophrenia-related acute event would predict a switch to APP in the short term. Observational prospective data (at baseline and 6months) were drawn from a French nationwide cohort ("Cohorte Générale Schizophrénie"), which included 1859 inpatients and outpatients with schizophrenia. APP was defined as the prescription of ≥2 antipsychotic drugs (there being different active substances). Early-onset schizophrenia, legal guardianship, higher lifetime maximal severity of illness and comorbid antisocial personality were used as proxies for severe courses of schizophrenia. Schizophrenia-related acute events included hospitalization and recent suicide attempts. Logistic regression models were used to determine (1) whether the use of APP at baseline (vs. monotherapy) was associated with a severe course of schizophrenia or not, independent of acute events, and (2) if a switch to APP at 6months (vs. remaining on monotherapy) was associated with acute events, independent of severe courses of schizophrenia. Increased odds of APP use at baseline were independently associated with legal guardianship (OR=1.6; 95%CI=1.3, 2.0) and higher lifetime maximum severity of illness (OR=1.3; 95%CI=1.2, 1.5). A switch to APP at 6months was predicted by a hospitalization occurring since baseline (OR=6.1; 95%CI=3.9, 9.4). In routine clinical practice, APP is more likely prescribed to patients with severe courses of illness, possibly indicating the difficulty to manage these patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: A case study was conducted, exploring methods to identify drugs effects modifiers, at a health care center level., Patients and Methods: Data were drawn from the Schizophrenia Outpatient Health Outcome cohort, including hierarchical information on 6641 patients, recruited from 899 health care centers from across ten European countries. Center-level characteristics included the following: psychiatrist's gender, age, length of practice experience, practice setting and type, countries' Healthcare System Efficiency score, and psychiatrist density in the country. Mixed multivariable linear regression models were used: 1) to estimate antipsychotic drugs' effectiveness (defined as the association between patients' outcome at 3 months - dependent variable, continuous - and antipsychotic drug initiation at baseline - drug A vs other antipsychotic drug); 2) to estimate the similarity between clustered data (using the intra-cluster correlation coefficient); and 3) to explore antipsychotic drug effects modification by center-related characteristics (using the addition of an interaction term)., Results: About 23% of the variance found for patients' outcome was explained by unmeasured confounding at a center level. Psychiatrists' practice experience was found to be associated with patient outcomes ( p =0.04) and modified the relative effect of "drug A" ( p <0.001), independent of center- or patient-related characteristics., Conclusion: Mixed models may be useful to explore how center-related characteristics modify drugs' effect estimates, but require numerous assumptions., Competing Interests: Disclosure Lucien Abenhaim is the chairman of LASER Analytica, and Clementine Nordon has been employed by LASER Analytica, a research and consultancy company collaborating with virtually all pharmaceutical companies. LASER has no commercial interests in any of the products studied. Members of the LASER network have no interest in a drug or other factors studied. Josef Maria Haro works at the Sant Joan de Déu Health Park in Barcelona, Spain. Mark Belger is an employee of Eli Lilly and Company Limited. Helene Verdoux is a clinician at Bordeaux University Hospital. Constance Battin and Tjeerd van Staa report no conflicts of interest in this work.

Objectives: Nationwide prospective cohort study exploring (i) the factors associated with treatment initiation (vs. watchful waiting) in children with primary immune thrombocytopenia (ITP) followed in routine clinical practice and (ii) the predictors of chronicity at 12 months., Procedure: Between 2008 and 2013, 23 centers throughout France consecutively included 257 children aged 6 months-18 years and diagnosed with primary ITP over a 5-year period. Data on ITP clinical features along with medical management were collected at baseline and 12 months. Multivariate logistic regressions were used to determine (i) and (ii) as defined above, providing odds ratio (OR) with 95% confidence interval (95% CI)., Results: One hundred thirty-seven (53%) children were males, median age was 4.6 years, median platelet count was 7 × 109/l, and 214 (81%) patients initiated medication. Factors independently associated with treatment initiation included platelet counts <10 × 109/l (P < 0.0001) and mucocutaneous bleeding symptoms at baseline (P < 0.001). At 12 months, data were available for 211 (82%) children, of whom 160 (74%) had recovered. Predictors of chronicity included female gender (OR = 2.2; 95% CI = 1.0-4.8), age ≥10 years (OR = 2.6; 95% CI = 1.1-6.0), and platelet counts ≥10 × 10 9 /l (OR = 3.2; 95% CI = 1.5-6.9)., Conclusions: In routine clinical practice, the decision to apply a watchful waiting strategy seems to be driven by platelet counts even in the absence of bleeding symptoms, resulting in treatment being initiated in more than 80% of the children surveyed. Overall, younger children with ITP showed good prognosis, with lower platelet counts and, to a lesser extent, male gender predicting more favorable outcomes., (© 2016 Wiley Periodicals, Inc.)

Background: Long-acting injectable (LAI) atypical antipsychotics are associated with improved adherence and reduced relapse rates in schizophrenia but reminder-based interventions may further improve outcomes., Objectives: To assess an institutional medication adherence program's (IMAP) effectiveness on adherence and psychiatric hospitalizations among schizophrenia patients taking risperidone LAI (RLAI)., Methods: Between 2009 and 2010, we recruited patients meeting DSM-IV criteria for schizophrenia treated with RLAI receiving outpatient care from psychiatric centres in France. The IMAP consisted of calling patients 48 hours prior to their scheduled RLAI injections and within 3 days of a missed appointment. Centres applying the IMAP to ≥50% of scheduled patient injections were deemed compliant. Patients were followed up to one year for adherence (≥80% of scheduled RLAI injections received within 5 days of the scheduled date) and psychiatric hospitalizations., Results: Among 506 patients recruited from 36 centres, the hospitalization rate was 32.5 per 100 person-years. 15 centres treating 243 patients were IMAP compliant and 21 centres treating 263 patients were not. IMAP compliance was associated with lower psychiatric hospitalization rates (crude RR: 0.64 [95% CI: 0.44-0.93]; adjusted RR: 0.78 [95% CI: 0.47-1.27]). Nearly 75% of patients were adherent to RLAI. While patient adherence had little impact on hospitalization rates (adjusted RR: 0.92 [95% CI: 0.59-1.44]), IMAP compliance was more effective among non-adherent (adjusted RR: 0.45 [95% CI: 0.16-1.28]) than adherent (adjusted RR: 0.88 [95% CI: 0.51-1.53]) patients., Conclusions: IMAPs may improve patient adherence and reduce psychiatric hospitalizations, particularly among patients with difficulties adhering to LAI antipsychotics., (© 2017 Journal of Population Therapeutics and Clinical Pharmacology. All rights reserved.)

Background: Safety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization., Objectives: To assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France., Methods: Systematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11-25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barré syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008-2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations., Results: With a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41-0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results., Conclusion: Exposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Randomized-controlled trials and claims databases suggest that antiepileptic drug (AED) use may increase the risk of suicide attempts (SA). The present case-control study explores the impact of underlying indications on this potential association., Methods: Physicians collected the medical history; prior 12-month drug use was obtained from standardized telephone interviews with patients. The association between AED use and SA was explored using multivariate conditional logistic regression. The analyses were replicated after stratification on depression and neurological disorders (epilepsy, migraine, and chronic neuropathic pain)., Results: Between 2008 and 2012, 506 adults with an incident SA were recruited in suicide treatment centers from across France and socio-demographically matched to 2829 controls from primary care settings. The association between AED use and odds of SA was not significant overall (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.9-2.4). No association was observed for patients with neurological disorders (OR, 1.1; 95%CI, 0.5-2.4) as opposed to patients with depression (OR, 1.6; 95%CI, 1.0-2.5), but unmeasured confounding was suspected., Conclusions: Our results suggest that the association observed between AED use and increased odds of non-fatal SA in patients with either a lifetime history of depression or no neurological disorder may be explained by the presence of an underlying psychiatric disorder. Accounting for underlying indications is crucial in drug safety studies, as these can cause a reported association (or lack thereof) to be misleading. This may require the prospective collection of medical data at a patient level. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: To evaluate the real-life impact of ezetimibe on cardiovascular (CV) morbidity and mortality in France., Objective: To estimate the number of non-fatal and fatal CV events that could be prevented and corresponding number of patients needed to treat (NNT) with ezetimibe to prevent one CV event over 5 years., Methods: Non-interventional 48-month follow-up cohort conducted in hypercholesterolemic patients starting on ezetimibe <3 months at study entry, either as monotherapy or combined with statins. Prediction modeling using discrete event simulation with calibrated Framingham CV risk equations was applied to data from pivotal clinical trials on ezetimibe and real-life data derived from the cohort., Results: A total of 3215 patients in the cohort accumulated 9314 person-years of follow-up for an average of 2.9 years. Mean age was 61.5 (standard deviation [SD] = 10.7), 54.6% were males, and 27.0% had a history of CV disease. Baseline LDL-cholesterol averaged 4.1 mmol/L (159 mg/dL; SD = 1.0) and HDL-C 1.6 mmol/L (62 mg/dL; SD = 0.5). LDL-C decreased in the first 12 months in ezetimibe-LLT (lipid-lowering therapy) initiators, switchers (monotherapy), and combination therapy with a statin by respectively 21.3%, 6.4%, and 29.1%. The corresponding predicted rate reductions of CV events (non-fatal and fatal) compared to no treatment or to a statin (combination therapy) were respectively 8, 2, and 12 per 1000 patients treated over 5 years, with a global NNT of 143 patients over 5 years., Conclusion: These results, accounting for observed CV event rates, risk factors evolution over time and adherence to treatment in real life, were consistent with those from clinical trials., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

This prospective observational cohort study aimed to explore the clinical features of incident immune thrombocytopenia in adults and predictors of outcome, while determining if a family history of autoimmune disorder is a risk factor for immune thrombocytopenia. All adults, 18 years of age or older, recently diagnosed with immune thrombocytopenia were consecutively recruited across 21 hospital centers in France. Data were collected at diagnosis and after 12 months. Predictors of chronicity at 12 months were explored using logistic regression models. The association between family history of autoimmune disorder and the risk of developing immune thrombocytopenia was explored using a conditional logistic regression model after matching each case to 10 controls. One hundred and forty-three patients were included: 63% female, mean age 48 years old (Standard Deviation=19), and 84% presented with bleeding symptoms. Median platelet count was 10×10(9)/L. Initial treatment was required in 82% of patients. After 12 months, only 37% of patients not subject to disease-modifying interventions achieved cure. The sole possible predictor of chronicity at 12 months was a higher platelet count at baseline [Odds Ratio 1.03; 95%CI: 1.00, 1.06]. No association was found between outcome and any of the following features: age, sex, presence of either bleeding symptoms or antinuclear antibodies at diagnosis. Likewise, family history of autoimmune disorder was not associated with incident immune thrombocytopenia. Immune thrombocytopenia in adults has been shown to progress to a chronic form in the majority of patients. A lower platelet count could be indicative of a more favorable outcome., (Copyright© Ferrata Storti Foundation.)

Background: The purpose of the study was to compare utilization of conventional psychotropic drugs among patients seeking care for anxiety and depression disorders (ADDs) from general practitioners (GPs) who strictly prescribe conventional medicines (GP-CM), regularly prescribe homeopathy in a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho)., Methods: This was one of three epidemiological cohort studies (EPI3) on general practice in France, which included GPs and their patients consulting for ADDs (scoring 9 or more in the Hospital Anxiety and Depression Scale, HADS). Information on all medication utilization was obtained by a standardised telephone interview at inclusion, 1, 3 and 12 months., Results: Of 1562 eligible patients consulting for ADDs, 710 (45.5 %) agreed to participate. Adjusted multivariate analyses showed that GP-Ho and GP-Mx patients were less likely to use psychotropic drugs over 12 months, with Odds ratio (OR) = 0.29; 95 % confidence interval (CI): 0.19 to 0.44, and OR = 0.62; 95 % CI: 0.41 to 0.94 respectively, compared to GP-CM patients. The rate of clinical improvement (HADS <9) was marginally superior for the GP-Ho group as compared to the GP-CM group (OR = 1.70; 95 % CI: 1.00 to 2.87), but not for the GP-Mx group (OR = 1.49; 95 % CI: 0.89 to 2.50)., Conclusions: Patients with ADD, who chose to consult GPs prescribing homeopathy reported less use of psychotropic drugs, and were marginally more likely to experience clinical improvement, than patients managed with conventional care. Results may reflect differences in physicians' management and patients' preferences as well as statistical regression to the mean.

Purpose: To examine the robustness of findings of case-control studies on the association between acute liver injury (ALI) and antibiotic use in the following different situations: (i) Replication of a protocol in different databases, with different data types, as well as replication in the same database, but performed by a different research team. (ii) Varying algorithms to identify cases, with and without manual case validation. (iii) Different exposure windows for time at risk., Methods: Five case-control studies in four different databases were performed with a common study protocol as starting point to harmonize study outcome definitions, exposure definitions and statistical analyses., Results: All five studies showed an increased risk of ALI associated with antibiotic use ranging from OR 2.6 (95% CI 1.3-5.4) to 7.7 (95% CI 2.0-29.3). Comparable trends could be observed in the five studies: (i) without manual validation the use of the narrowest definition for ALI showed higher risk estimates, (ii) narrow and broad algorithm definitions followed by manual validation of cases resulted in similar risk estimates, and (iii) the use of a larger window (30 days vs 14 days) to define time at risk led to a decrease in risk estimates., Conclusions: Reproduction of a study using a predefined protocol in different database settings is feasible, although assumptions had to be made and amendments in the protocol were inevitable. Despite differences, the strength of association was comparable between the studies. In addition, the impact of varying outcome definitions and time windows showed similar trends within the data sources., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: The concept of the "efficacy-effectiveness gap" (EEG) has started to challenge confidence in decisions made for drugs when based on randomized controlled trials alone. Launched by the Innovative Medicines Initiative, the GetReal project aims to improve understanding of how to reconcile evidence to support efficacy and effectiveness and at proposing operational solutions., Objectives: The objectives of the present narrative review were 1) to understand the historical background in which the concept of the EEG has emerged and 2) to describe the conceptualization of EEG., Methods: A focused literature review was conducted across the gray literature and articles published in English reporting insights on the EEG concept. The identification of different "paradigms" was performed by simple inductive analysis of the documents' content., Results: The literature on the EEG falls into three major paradigms, in which EEG is related to 1) real-life characteristics of the health care system; 2) the method used to measure the drug's effect; and 3) a complex interaction between the drug's biological effect and contextual factors., Conclusions: The third paradigm provides an opportunity to look beyond any dichotomy between "standardized" versus "real-life" characteristics of the health care system and study designs. Namely, future research will determine whether the identification of these contextual factors can help to best design randomized controlled trials that provide better estimates of drugs' effectiveness., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: Utilization of sedative hypnotic drugs for sleeping disorders (SD) raises concerns, particularly among older people. This study compared utilization of conventional psychotropic drugs for SD among patients seeking care from general practitioners (GPs) who strictly prescribe conventional medications (GP-CM), regularly prescribe homeopathy in a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho)., Methods: This was a French population-based cohort study of GPs and their patients consulting for SD, informed through the Pittsburgh sleep quality index (PSQI) questionnaire. Information on psychotropic drugs utilization was obtained from a standardized telephone interview at inclusion, one, three and 12 months., Results: 346 patients consulting for SD were included. Patients in the GP-Ho group experienced more often severe SD (41.3%) than patients in the GP-CM group (24.3%). Adjusted multivariate analyses showed that patients who chose to be managed by GP-Ho were less likely to use psychotropic drugs over 12 months as opposed to the GP-CM group, with Odds ratio (OR) = 0.25; 95% confidence interval (CI): 0.14 to 0.42. Patients in the GP-Mx group also used less psychotropic drugs but the result was not statistically significant (OR = 0.67; 95% CI: 0.39-1.16). Rates of clinical improvement of the SD did not differ between groups., Conclusions: Patients with SD who chose to consult GPs certified in homeopathy consumed less psychotropic drugs and had a similar evolution of their condition to patients treated with conventional medical management. This result may translate in a net advantage with reduction of adverse events related to psychotropic drugs., (Copyright © 2015 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.)

Background: Gout therapy includes xanthine oxidase inhibitors (XOI) and colchicine, which have both been associated with decreased cardiovascular risk. However, their effects on major cardiac events, such as myocardial infarction (MI), need to be investigated further., Objectives: To investigate whether XOIs and colchicine are associated with decreased risk of MI., Methods: This case-control study compared patients with first-ever MI and matched controls. Cases were recruited from the Pharmacoepidemiological General Research on MI registry. Controls were selected from a referent population (n=8444) from general practice settings., Results: The study sample consisted of 2277 MI patients and 4849 matched controls. Use of allopurinol was reported by 3.1% of cases and 3.8 of controls, and 1.1% of cases and controls used colchicine. The adjusted OR (95% CI) for MI with allopurinol use was 0.80 (0.59 to 1.09). When using less stringent matching criteria that allowed for inclusion of 2593 cases and 5185 controls, the adjusted OR was 0.73 (0.54 to 0.99). Similar results were found on analysis by sex and hypertension status. Colchicine used was not associated with a decreased risk of MI (aOR=1.17 (0.70 to 1.93))., Conclusions: Allopurinol may be associated with a reduced risk of MI. No decreased risk of MI was found in colchicine users. Besides its urate-lowering property, allopurinol might have a cardioprotective effect., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Studies have suggested that systemic lupus erythematosus (SLE) may be triggered by vaccinations. We undertook this study to investigate the relationship between vaccination and onset of SLE., Methods: This international case-control study was conducted between April 2008 and June 2012 in 36 specialist referral centers (34 in France and 2 in Quebec, Canada) and recruited patients ≤60 years old recently diagnosed as having either definite SLE (meeting ≥4 American College of Rheumatology [ACR] criteria including at least 1 immunologic criterion) or probable SLE (meeting 3 ACR criteria including at least 1 immunologic criterion). Controls were recruited from general practice settings through a closely monitored protocol and matched to patients by age, sex, region of residence, and date of recruitment. Vaccinations and other potential risk factors for SLE were assessed using a standardized telephone interview. We compared proportions of patients and controls who were vaccinated 12 and 24 months before the index date (date of first clinical symptom presented by the patient) using odds ratios (ORs) from conditional logistic regression., Results: We assessed 105 patients (89 with definite SLE and 16 with probable SLE) and 712 controls. Twenty-two of the 105 patients (21.0%) and 181 of the 712 controls (25.4%) had received at least 1 vaccination within 24 months before the index date (adjusted OR 0.9 [95% confidence interval 0.5-1.5]). The proportions of patients and controls vaccinated within the previous 12 months were also similar., Conclusion: Our study showed no association between exposure to vaccination and risk of developing SLE., (Copyright © 2014 by the American College of Rheumatology.)

Objectives: The aim of this study was to investigate whether the quadrivalent human papillomavirus (HPV) vaccine Gardasil is associated with a change in the risk of autoimmune disorders (ADs) in young female subjects., Design: Systematic case-control study of incident ADs associated with quadrivalent HPV vaccination in young women across France., Participants and Setting: A total of 113 specialised centres recruited (from December 2007 to April 2011) females aged 14-26 years with incident cases of six types of ADs: idiopathic thrombocytopenic purpura (ITP), central demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes mellitus and autoimmune thyroiditis. Control subjects matched to cases were recruited from general practice., Analysis: Multivariate conditional logistic regression analysis; factors included age, geographical origin, smoking, alcohol consumption, use of oral contraceptive(s) or vaccine(s) other than Gardasil received within 24 months before the index date and personal/family history of ADs., Results: Overall, 211 definite cases of ADs were matched to 875 controls. The adjusted odds ratio (OR) for any quadrivalent HPV vaccine use was 0.9 [95% confidence interval (CI) 0.5-1.5]. The individual ORs were 1.0 (95% CI 0.4-2.6) for ITP, 0.3 (95% CI 0.1-0.9) for MS, 0.8 (95% CI 0.3-2.4) for connective disorders and 1.2 (95% CI 0.4-3.6) for type 1 diabetes. No exposure to HPV vaccine was observed in cases with either Guillain-Barré syndrome or thyroiditis., Conclusions: No evidence of an increase in the risk of the studied ADs was observable following vaccination with Gardasil within the time periods studied. There was insufficient statistical power to allow conclusions to be drawn regarding individual ADs., (© 2013 The Association for the Publication of the Journal of Internal Medicine.)

Background: Prescribing of antibiotics for upper respiratory tract infections (URTI) varies substantially in primary care., Objectives: To describe and compare antibiotic and antipyretic/anti-inflammatory drugs use, URTI symptoms' resolution and occurrence of potentially-associated infections in patients seeking care from general practitioners (GPs) who exclusively prescribe conventional medications (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho)., Method: The EPI3 survey was a nationwide population-based study of a representative sample of 825 GPs and their patients in France (2007-2008). GP recruitment was stratified by self-declared homeopathic prescribing preferences. Adults and children with confirmed URTI were asked to participate in a standardized telephone interview at inclusion, one-, three- and twelve-month follow up. Study outcomes included medication consumption, URTI symptoms' resolution and potentially-associated infections (sinusitis or otitis media/externa) as reported by patients. Analyses included calibration to account for non-respondents and groups were compared using multivate analyses adjusting for baseline differences with a propensity score., Results: 518 adults and children with URTI (79.3% rhinopharyngitis) were included (36.9% response rate comparable between groups). As opposed to GP-CM patients, patients in the GP-Ho group showed significantly lower consumption of antibiotics (Odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.27-0.68) and antipyretic/anti-inflammatory drugs (OR = 0.54, 95% CI: 0.38-0.76) with similar evolution in related symptoms (OR = 1.16, 95% CI: 0.64-2.10). An excess of potentially-associated infections (OR = 1.70, 95% CI: 0.90-3.20) was observed in the GP-Ho group (not statistically significant). No difference was found between GP-CM and GP-Mx patients., Conclusion: Patients who chose to consult GPs certified in homeopathy used less antibiotics and antipyretic/anti-inflammatory drugs for URTI than those seen by GPs prescribing conventional medications. No difference was observed in patients consulting GPs within mixed-practice. A non-statistically significant excess was estimated through modelling for associated infections in the GP-Ho group and needs to be further studied.

OBJECTIVE Several studies have been published in 2009 suggesting a possible association between insulin glargine and increased risk of malignancies, including breast cancer. The objective of this study was to assess the relation between the individual insulins (glargine, aspart, lispro, and human insulin) and development of breast cancer. RESEARCH DESIGN AND METHODS Seven hundred seventy-five incident cases of primary invasive or in situ carcinoma breast cancer occurring in women with diabetes from 92 centers in the U.K., Canada, and France were matched to a mean of 3.9 diabetic community control subjects (n = 3,050; recruited from 580 general practices) by country, age, recruitment date, and diabetes type and management. The main risk model was a multivariate conditional logistic regression model with case/control status as the dependent variable and individual insulin use, 8 years preceding the index date, as the independent variable, controlling for past use of any insulin, oral antidiabetes drugs, reproductive factors, lifestyle, education, hormone replacement therapy and history of contraceptive use, BMI, comorbidities, diabetes duration, and annual number of physician visits. Glargine was also compared with every other insulin by computing all ratios using the variance-covariance matrix of logistic model parameters. RESULTS Adjusted odds ratios of breast cancer for each type of insulin versus no use of that insulin were 1.04 (95% CI 0.76-1.44) for glargine, 1.23 (0.79-1.92) for lispro, 0.95 (0.64-1.40) for aspart, and 0.81 (0.55-1.20) for human insulin. Two-by-two comparisons found no difference between glargine and the different types of insulins. Insulin dosage or duration of use and tumor stage did not change the results. CONCLUSIONS This international study found no difference in the risk of developing breast cancer in patients with diabetes among the different types of insulin with short- to mid-term duration of use. Longer-term studies would be of interest.

Background: Homeopathic care has not been well documented in terms of its impact on patients' utilization of drugs or other complementary and alternative medicines (CAM). The objective of this study was to describe and compare patients who visit physicians in general practice (GPs) who prescribe only conventional medicines (GP-CM), regularly prescribe homeopathy within a mixed practice (GP-Mx), or are certified homeopathic GPs (GP-Ho)., Material and Methods: The EPI3-LASER study was a nationwide observational survey of a representative sample of GPs and their patients from across France. Physicians recorded their diagnoses and prescriptions on participating patients who completed a self-questionnaire on socio-demographics, lifestyle, quality of life Short Form 12 (SF-12) and the complementary and alternative medicine beliefs inventory (CAMBI)., Results: A total of 6379 patients (participation rate 73.1%) recruited from 804 GP practices participated in this survey. Patients attending a GP-Ho were slightly more often female with higher education than in the GP-CM group and had markedly healthier lifestyle. They did not differ greatly in their comorbidities or quality of life but exhibited large differences in their beliefs in holistic medicine and natural treatments, and in their attitude toward participating to their own care. Similar but less striking observations were made in patients of the GP-Mx group., Conclusion: Patients seeking care with a homeopathic GP did not differ greatly in their socio-demographic characteristics but more so by their healthier lifestyle and positive attitude toward CAM. Further research is needed to explore the directionality of those associations and to assess the potential economic benefits of homeopathic management in primary care., (Copyright © 2013 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.)

Background: Evidence on the real effectiveness of statins on acute coronary syndrome (ACS) incidence is scarce. We assessed the effectiveness of real-life statins on the risk of first non-fatal ACS in a low-cardiovascular-risk country., Methods: Systematic case-control study was conducted in 60 cardiology centres and 371 general practices from across France. A total of 2238 cases with first ACS within 1 month from recruitment and 2238 controls without history of ACS were included; controls were matched to ACS cases on sex, age, frequency of visits to GPs, date of recruitment and personal history of chronic diseases. Statin exposure and risk factors were documented through patient telephone interviews and validated against medical records. The index date was the date of ACS for cases. Adjusted odds ratios (OR) of first ACS and statin use were estimated by multiple conditional logistic regression models controlled for risk factors and propensity score for statin exposure., Results: Statin use was associated with lower ACS risk, with an adjusted matched OR of 0.67; 95% confidence interval (CI): 0.56 to 0.79 for current use (within 2 months) and 0.73; 95% CI: 0.62 to 0.86 for any use within 24 months [atorvastatin: 0.83 (0.63-1.10), fluvastatin: 0.75 (0.43-1.30), pravastatin: 0.98 (0.72-1.34), rosuvastatin: 0.49 (0.35-0.68) and simvastatin: 0.62 (0.46-0.84)]. The preventive effect of statins on non-fatal ACS reached its maximum after one to four years of use., Conclusion: A similar magnitude of effect for statin use was observed in real life, as compared to randomised clinical trials in France., (© 2013.)

Purpose: Patients' self-reported vaccine exposure (PS) may be subject to memory errors and other biases. Physicians' prescription records and other medical records (MR) do not capture noncompliance with vaccination. This study compared PS with MR for influenza, 23-valent pneumococcal, and human papillomavirus (HPV) vaccines., Methods: The Pharmacoepidemiologic General Research Extension (PGRx) database uses a network of over 300 general practitioners across France, who systematically recruit an age- and sex-stratified sample of patients (≥ 14 years old), without reference to their diagnoses or prescriptions. Patients received a structured telephone interview, combined with an interview guide listing vaccines commonly given. Patients' self-reported vaccination in the 3 years before their recruitment was compared with medical records kept by the physician or the patient., Results: Concordance between PS and MR was assessed for 7613 patients for whom both sources of information were available. Agreement within 3 years before the recruitment date was substantial for influenza vaccines (prevalence and bias-adjusted kappa [PABAK] = 0.74, sensitivity PS relative to MR 81.5%) and high for 23-valent pneumococcal vaccines (PABAK = 0.98, sensitivity PS 49.6) and HPV vaccines (PABAK = 0.92, sensitivity PS 91.6). In adjusted analyses, agreement varied with sociodemographic and health-related factors, particularly for influenza and 23-valent pneumococcal vaccines., Conclusions: The PGRx method for drug exposure assessment is a new tool in pharmacoepidemiology that shows substantial to high agreement between PS and MR for exposure to various vaccines. Our finding of high agreement between PS and MR for HPV vaccination status in young women is a significant addition to the literature., (Copyright © 2013 John Wiley & Sons, Ltd.)

Mild encephalopathy with reversible splenial lesions has mainly been associated with influenza A and B virus infection. Patients present with neurologic symptoms 1 to 3 days after a prodromal illness and recover completely within a few days. Magnetic resonance imaging typically shows reversible lesions with reduced diffusion in the corpus callosum, predominantly in the splenium. We report on a 5-year old Caucasian boy who was referred with recurrent seizures and decreased level of consciousness after a 2-day prodromal fever and cough. Magnetic resonance imaging showed cytotoxic edema of the entire corpus callosum and the adjacent periventricular white matter with diffusion restriction and faint T(2)-hyperintensity. Parainfluenza virus type 1-3 infection was documented by direct immunofluorescence in the initial nasopharyngeal swab, but polymerase chain reaction for parainfluenza virus type 1-4 in the cerebrospinal fluid remained negative. This is-to our knowledge-the first description of mild encephalopathy with reversible splenial lesions in association with parainfluenza virus infection. The pathogenesis of mild encephalopathy with reversible splenial lesions, however, still remains unclear, and further studies investigating detailed mechanisms that lead to the typical brain lesions are warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Omalizumab has been shown to decrease the risk of hospitalization or ED visits in patients with uncontrolled severe allergic asthma compared with placebo. This longitudinal study observed the conditions under which omalizumab is prescribed in real-life settings and assessed whether its use as an add-on therapy alongside standard treatments decreases the risk of severe asthmatic exacerbations., Methods: A cohort of adult patients with uncontrolled severe asthma despite optimal treatment with inhaled and oral corticosteroids and a long-acting b 2 -agonist but no treatment with omalizumab upon entry was assembled. Risk of hospitalization or ED visits for asthma exacerbation was assessed using the Andersen-Gill extension of the Cox model for repeated events, controlling for age, sex, smoking history, BMI, gastroesophageal reflux, allergic status, allergic rhinitis, treatment, and hospitalization or ED visits for asthma in the 2 months prior to omalizumab treatment., Results: Overall, 163 physicians recruited 767 patients, of whom 374 took omalizumab at least once (mean observation period, 20.4 months). Omalizumab use was associated with an adjusted relative risk of 0.57 (95% CI, 0.43-0.78) for hospitalization or ED visits for asthma. In users of omalizumab, the adjusted relative risk of hospitalization or ED visits for asthma during omalizumab treatment vs nontreatment periods was 0.40 (95% CI, 0.28-0.58)., Conclusions: Add-on omalizumab is associated with a significantly decreased risk of hospitalization or ED visits in patients with uncontrolled severe asthma in real-life practice.

The cause of immune thrombocytopenia (ITP) remains unknown. Studies have suggested immunizations as possible triggering factors of ITP through molecular mimicry. This case-control study explored potential associations between adult ITP and various routinely administered vaccines. A network of internal medicine and hematology centers across France recruited 198 incident (ie, newly diagnosed) cases of ITP between April 2008 and June 2011. These cases were compared with 878 age- and sex-matched controls without ITP recruited in general practice. Information on vaccination was obtained from patients' standardized telephone interviews. Sixty-six of 198 cases (33.3%) and 303 of 878 controls (34.5%) received at least 1 vaccine within the 12 months before the index date. We found no evidence of an increase in ITP after vaccination in the previous 6 or 12 months (adjusted odds ratio [OR] for the previous 12 months = 1.0; 95% confidence interval, 0.7-1.4). When the 2-month time window was used, higher ORs were observed for all vaccines (OR = 1.3). This increase was mainly attributable to the vaccination against diphtheria-tetanus-pertussis-poliomyelitis (OR = 1.5) and was not statistically significant. The results of the present study show that in an adult population, the exposure to common vaccines is on average not associated with an observable risk of developing ITP.

Objectives: To describe and compare patients seeking treatment for sleep, anxiety and depressive disorders (SADD) from physicians in general practice (GPs) with three different practice preferences: strictly conventional medicine (GP-CM), mixed complementary and conventional medicine (GP-Mx) and certified homeopathic physicians (GP-Ho)., Design and Setting: The EPI3 survey was a nationwide, observational study of a representative sample of GPs and their patients, conducted in France between March 2007 and July 2008., Participants: 1572 patients diagnosed with SADD., Primary and Secondary Outcomes: The patients' attitude towards complementary and alternative medicine; psychotropic drug utilisation., Results: Compared to patients attending GP-CM, GP-Ho patients had healthier lifestyles while GP-Mx patients showed similar profiles. Psychotropic drugs were more likely to be prescribed by GP-CM (64%) than GP-Mx (55.4%) and GP-Ho (31.2%). The three groups of patients shared similar SADD severity., Conclusion: Our results showed that patients with SADD, while differing principally in their sociodemographic profiles and conventional psychotropic prescriptions, were actually rather similar regarding the severity of SADD in terms of comorbidities and quality of life. This information may help to better plan resource allocation and management of these common health problems in primary care.

Objective: The objective of this study was to assess the effect of physician practicing preferences (PPP) in primary care for homeopathy (Ho), CAM (Complementary and alternative medicines) with conventional medicine (Mx) or exclusively conventional medicine (CM) on patients with musculoskeletal disorders (MSDs), with reference to clinical progression, drug consumption, side effects and loss of therapeutic opportunity., Methods: The EPI3-MSD study was a nationwide observational cohort of a representative sample of general practitioners (GP) and their patients in France. Recruitment of GP was stratified by PPP, which was self-declared. Diagnoses and comorbidities were recorded by GP at inclusion. Patients completed a standardized telephone interview at inclusion, one, three and twelve months, including MSD-functional scales and medication consumption., Results: 1153 MSD patients were included in the three PPP groups. Patients did not differ between groups except for chronicity of MSDs (>12 weeks), which was higher in the Ho group (62.1%) than in the CM (48.6%) and Mx groups (50.3%). The twelve-month development of specific functional scores was identical across the three groups after controlling for baseline score (p > 0.05). After adjusting for propensity scores, NSAID use over 12 months was almost half in the Ho group (OR, 0.54; 95%CI, 0.38-0.78) as compared to the CM group; no difference was found in the Mx group (OR, 0.81; 95% CI: 0.59-1.15)., Conclusion: MSD patients seen by homeopathic physicians showed a similar clinical progression when less exposed to NSAID in comparison to patients seen in CM practice, with fewer NSAID-related adverse events and no loss of therapeutic opportunity., (Copyright © 2012 John Wiley & Sons, Ltd.)

PURPOSE: The use of prescription records for the assessment of exposure to nonsteroidal anti-inflammatory drugs (NSAIDs) does not capture over-the-counter drug use. This study compared patients' self-reported use to physician's prescriptions for NSAIDs and other drugs used to treat musculoskeletal disorders (MSDs). METHODS: The international Pharmacoepidemiologic General Research eXtension database includes a network of general practitioners recruiting patients without reference to diagnoses or prescriptions. Data on all drug use across France within the 2 years preceding the date of inclusion (index date) were obtained from both patients' self-reports (PSRs) and physicians' prescription reports (PPRs). Patients' reports were obtained using a structured telephone interview combined with an interview guide containing a list of drugs commonly used. Comparisons were made on exposure to four categories of MSD drugs and three time windows up to 24 months before the index date. RESULTS: Agreement between physician and patient reports was assessed on 4152 patient-physician pairs. Bias- and prevalence-adjusted kappa values showed fair agreement for nonaspirin NSAIDs, moderate to fair for nonnarcotic analgesics, high for osteoarthritis and moderate to substantial for muscle relaxants. Over-the-counter drug use was associated with greater disagreement (OR = 2.21, 95%CI = 1.05-1.38). Age was not associated with disagreement. CONCLUSION: Differences between PSR and PPR in estimating the prevalence of MSD drug use varied by the type of drug and the elapsed time from the index date. The patient-assisted interview method used in this study showed better agreement with PPR compared with standard interviews, especially for long time windows and patients older than 65 years. Copyright © 2012 John Wiley & Sons, Ltd., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: The primary aim of this study was to compare the impact of risperidone long-acting injectable (R-LAI) to other antipsychotics on rates of hospitalisation in real-life settings., Method: The Cohort for the General study of Schizophrenia (CGS) followed 1859 patients diagnosed with schizophrenia (DSM-IV) from 177 psychiatric wards of public and private hospitals across France over a mean period of 12months. These patients were ambulatory or had been hospitalised for less than 93days at study entry. Recruitment was stratified for long-acting second-generation antipsychotic use. A multivariate Poisson regression adjusted for confounding with propensity scores and allowing for autocorrelation was used for the calculation of relative rates of hospitalisation with 95% confidence intervals., Results: The mean age of participants was 37.65years, 68.3% were male and 36.7% were hospitalised for less than 93days at study entry. Altogether, participants accumulated 796 hospital stays (53.4 per 100 person-years). R-LAI patients were slightly younger and had been hospitalised more often in the past 12months compared to non-R-LAI users. The adjusted Poisson regression analysis showed R-LAI use to be associated with a lower rate of future hospitalisation: 0.66 [0.46-0.96] compared to non-R-LAI use, and 0.53 [0.32-0.88] compared to use of other LAIs., Conclusion: Use of R-LAI was associated with lower rates of hospitalisation compared to non-use of R-LAI., (Copyright © 2011. Published by Elsevier B.V.)

Concerns have been raised regarding sub-optimal utilization of analgesics and psychotropic drugs in the treatment of patients with chronic musculoskeletal disorders (MSDs) and their associated co-morbidities. The objective of this study was to describe drug prescriptions for the management of spinal and non-spinal MSDs contrasted against a standardized measure of quality of life. A representative population sample of 1,756 MSDs patients [38.5% with spinal disorder (SD) and 61.5% with non-spinal MSDs (NS-MSD)] was drawn from the EPI3-LASER survey of 825 general practitioners (GPs) in France. Physicians recorded their diagnoses and prescriptions on that day. Patients provided information on socio-demographics, lifestyle and quality of life using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than 12 weeks duration of the current episode. Chronic SD and NS-MSD patients were prescribed less analgesics and non-steroidal anti-inflammatory drugs than their non-chronic counterpart [odds ratios (OR) and 95% confidence intervals (CI), respectively: 0.4, 0.2-0.7 and 0.5, 0.3-0.6]. They also had more anxio-depressive co-morbidities reported by their physicians (SD: 16.1 vs.7.4%; NS-MSD: 21.6 vs. 9.5%) who prescribed more antidepressants and anxiolytics with a difference that was statistically significant only for spinal disorder patients (OR, 95% CI: 2.0, 1.1-3.6). Psychotropic drugs were more often prescribed in patients in the lower quartile of SF-12 mental score and prescriptions of analgesics in the lower quartile of SF-12 physical score (P < 0.001). In conclusion, anxiety and depressive disorders were commonly reported by GPs among chronic MSD patients. Their prescriptions of psychotropic and analgesic drugs were consistent with patients' self-rated mental and physical health.

Objective To assess the burden of diseases and quality of life (QOL) of patients for a large variety of diseases within general practice. Design In a representative nationwide cross-sectional study, a total of 825 general practitioners (GPs) were randomly selected from across France. Independent investigators recruited 8559 patients attending the GPs' practices. Data on QOL (12-Item Short Form questionnaire) and other individual characteristics were documented by the independent investigators for all participants in the waiting room. Medical information was recorded by GPs. Sampling was calibrated to national standards using the CALMAR (CALage sur MARges) weighting procedure. Associations of lower scores (ie, below vs above the first quartile) of physical and mental component scores (physical component summary score (PCS) and mental component summary score (MCS), respectively) with main diseases and patients characteristics were estimated using multivariate logistic regression. Weighted morbidity rates, PCS and MCS were computed for 100 diagnoses using the International Classification of Diseases (9th version). Results Overall mental impairment was observed among patients in primary care with an average MCS of 41.5 (SD 8.6), ranging from 33.0 for depressive disorders to 45.3 for patients exhibiting fractures or sprains. Musculoskeletal diseases were found to have the most pronounced effect on impaired physical health (OR=2.31; 95% CI 2.08 to 2.57) with the lowest PCS (45.6 (SD 8.8)) and ranked first (29.0%) among main diagnoses experienced by patients followed by cardiovascular diseases (26.7%) and psychological disorders (22.0%). When combining both prevalence and QOL, musculoskeletal diseases represented the heaviest burden in general practice. Conclusions Etude épidémiologique de l'Impact de santé public sur 3 groupes de pathologies (EPI3) is the first study to provide reference figures for burden of disease in general practice across a wide range of morbidities, particularly valuable for health-economics and healthcare-system evaluation.

Objective: The objective of this study was to explore the association of non-steroidal anti-inflammatory drugs (NSAID) with ST-segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI)., Design, Setting & Patients: A matched case-control study comparing patients with incident non-fatal myocardial infarction (MI) collected by cardiologists with controls. Cases were retrieved from the Pharmacoepidemiological General Research on Myocardial Infarction (PGRx-MI) registry, a French nationwide registry consisting of 55 cardiology centres, whereas controls were selected from general practice settings. Both cases and controls were recruited from the same geographically diverse areas across continental France., Main Outcome Measures: The association between NSAID and MI was assessed by matched adjusted OR from conditional logistic regression., Results: Between 2007 and 2009, 1125 incident cases were included (67.3% and 32.7% for STEMI and NSTEMI, respectively), with 2790 controls matched to MI cases by age and sex. Current use (previous 2 months) of either diclofenac or naproxen and other arylpropionic acid NSAID was not associated with STEMI (OR 0.9, 95% CI 0.4 to 1.9 and OR 1.0, 95% CI 0.6 to 1.7, respectively), instead it showed significant association with NSTEMI (OR 2.8, 95% CI 1.2 to 6.4 and OR 0.4, 95% CI 0.2 to 0.9, respectively). Our study confirms results from previously published analyses on the association of MI with NSAID (OR 1.5, 0.9, and 1.0 for diclofenac, naproxen and related NSAID, and all NSAID combined, respectively)., Conclusions: Our study shows that the MI risk modification associated with NSAID is limited to NSTEMI.

Purpose: To analyse the mortality and its causes, especially cancer, among French cement production workers., Methods: A cohort of all workers employed at least 1 year in one of the main four cement companies in France was assembled (9,118 workers, 122,124 person-years of follow-up between 1990 and 2005). A common job titles classification was used to analyse occupational risk factors. We conducted a standardized mortality ratio analysis based on age, gender and calendar-period-specific national mortality rates and explored the combined effect of job titles and duration through an internal Cox regression analysis., Results: The number of deaths during the follow-up period was 430 (4.7%). Malignant neoplasm was the cause of 48.1% of deaths. Overall, a deficit in all-causes mortality (standardized mortality ratio (SMR): 0.68, 95% confidence interval (CI) 0.61-0.74) and in cancer mortality (SMR: 0.80, CI 0.69-0.92) was observed. Working in the quarry, yard and shipping sectors was associated with a 50% higher all-causes mortality risk in comparison with the administrative sector., Conclusions: This cohort study does not support previous observations that cement workers are at higher risk of cancer mortality than the general population. The length of follow-up should be increased, and specific exposures deserve analysis.

Background: There is a paucity of information describing patients with musculoskeletal disorders (MSDs) using complementary and alternative medicines (CAMs) and almost none distinguishing homeopathy from other CAMs. The objective of this study was to describe and compare patients with MSDs who consulted primary care physicians, either certified homeopaths (Ho) or regular prescribers of CAMs in a mixed practice (Mx), to those consulting physicians who strictly practice conventional medicine (CM), with regard to the severity of their MSD expressed as chronicity, co-morbidity and quality of life (QOL)., Methods: The EPI3-LASER study was a nationwide observational survey of a representative sample of general practitioners and their patients in France. The sampling strategy ensured a sufficient number of GPs in each of the three groups to allow comparison of their patients. Patients completed a questionnaire on socio-demographics, lifestyle and QOL using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than twelve weeks duration of the current episode. Diagnoses and co-morbidities were recorded by the physician., Results: A total of 825 GPs included 1,692 MSD patients (predominantly back pain and osteoarthritis) were included, 21.6% in the CM group, 32.4% Ho and 45.9% Mx. Patients in the Ho group had more often a chronic MSD (62.1%) than the CM (48.6%) or Mx (50.3%) groups, a result that was statistically significant after controlling for patients' characteristics (Odds ratio = 1.43; 95% confidence interval (CI): 1.07 - 1.89). Patients seen by homeopaths or mixed practice physicians who were not the regular treating physician, had more often a chronic MSD than those seen in conventional medicine (Odds ratios were 1.75; 95% CI: 1.22 - 2.50 and 1.48; 95% CI: 1.06 - 2.12, respectively). Otherwise patients in the three groups did not differ for co-morbidities and QOL., Conclusion: MSD patients consulting primary care physicians who prescribed homeopathy and CAMs differed from those seen in conventional medicine. Chronic MSD patients represented a greater proportion of the clientele in physicians offering alternatives to conventional medicine. In addition, these physicians treated chronic patients as consulting rather than regular treating physicians, with potentially important impacts upon professional health care practices and organisation.

Objective: This population-based survey was conducted to provide a formal description of upper gastrointestinal bleeding (UGIB) in children on a nationwide basis and assess the contribution of risk factors, principally nonsteroidal anti-inflammatory drugs (NSAID)., Methods: A case-crossover study of UGIB patients aged between 2 months and 16 years was conducted in France. Medical data were collected by physicians, and personal risk factors and exposure to drugs during the month preceding the onset of the bleeding was ascertained by a standardised telephone interview with parents. The odds ratios for UGIB and NSAID was assessed by comparing exposure during the 7 days preceding the date of hospitalisation and the 21st to the 28th days before that date., Results: A total of 177 children with UGIB were included over 2 years. Eighty-three children had taken at least one NSAID before the index date, among which 58 were ibuprofen, 26 aspirin and nine others. The adjusted odds ratio (OR) of exposure was 8.2 [95% confidence interval (CI) 2.6-26.0] for NSAIDs altogether, and this was 10.0 (95% CI 2.0-51.0) for ibuprofen and 7.3 (95% CI 0.9-59.4) for aspirin. There was no increased risk associated with NSAIDS for oesophageal lesion [OR = 1.0 [(5% CI:0.2-7.2)]., Conclusion: The study confirms that UGIB is rare but that some cases may be avoided, as one third of the cases was attributable to exposure to NSAID at doses used for analgesic or antipyretic purposes, which may be attained with alternative therapy. The findings from this study call for more caution in prescribing NSAIDS to children.

Purpose: Patients' self-reported drug exposure is subjected to memory errors and different sources of bias. Utilization of prescription records is impaired with non-compliance and over-the-counter (OTC) drug utilization. This study compared patients' self-report (PS) to physician's prescriptions of cardiovascular drugs (CVDs)., Methods: The PGRx database is constituted by networks of specialized centers that recruited cases of 15 different diseases including myocardial infarction (MI) cases, and a network of general practitioners recruiting a pool of potential referents. For MI cases and referents, data on all drug utilization within the 2 years preceding the index date were obtained from PS and from physician's report of their prescriptions (PP). Patients' reports were obtained using a structured telephone interview complemented with an interview guide containing names of diseases and pictures of drug packages. Comparisons were made on exposure to each class of CVDs, for different time-windows, 2 months, 3-12 months and 13-24 months prior to the index date., Results: The concordance between physician and patient report was assessed on 2702 patient-physician pairs. Agreement was excellent overall (kappa = 0.83, 95% confidence interval (CI): 0.81-0.85). Prevalences of exposure were very close between PS and PP for all classes of prescription CVDs., Conclusion: Using a standardized and systematic collection of information on drug exposure directly from patients appeared to provide similar information to using physician prescription records over a 2-year recall period.

Purpose: Based on contemporary epidemiological and pathological characteristics of prostate cancer we explain the rationale for and concerns about focal therapy for low risk prostate cancer, review potential methods of delivery and propose study design parameters., Materials and Methods: Articles regarding the epidemiology, diagnosis, imaging, treatment and pathology of localized prostate cancer were reviewed with a particular emphasis on technologies applicable for focal therapy, defined as targeted ablation of a limited area of the prostate expected to contain the dominant or only focus of cancer. A consensus summary was constructed by a multidisciplinary international task force of prostate cancer experts, forming the basis of the current review., Results: In regions with a high prevalence of prostate specific antigen screening the over detection and subsequent overtreatment of prostate cancer is common. The incidence of unifocal cancers in radical prostatectomy specimens is 13% to 38%. In many others there is an index lesion with secondary foci containing pathological features similar to those found incidentally at autopsy. Because biopsy strategies and imaging techniques can provide more precise tumor localization and characterization, there is growing interest in focal therapy targeting unifocal or biologically unifocal tumors. The major arguments against focal therapy are multifocality, limited accuracy of staging, the unpredictable aggressiveness of secondary foci and the lack of established technology for focal ablation. Emerging technologies with the potential for focal therapy include high intensity focused ultrasound, cryotherapy, radio frequency ablation and photodynamic therapy., Conclusions: Early detection of prostate cancer has led to concerns that while many cancers now diagnosed pose too little a threat for radical therapy, many men are reluctant to accept watchful waiting or active surveillance. Several emerging technologies seem capable of focal destruction of prostate tissue with minimal morbidity. We encourage the investigation of focal therapy in select men with low risk prostate cancer in prospective clinical trials that carefully document safety, functional outcomes and cancer control.

Background: Reports have linked anorexigen intake to an increased risk of pulmonary arterial hypertension (PAH). With the rise in anorexigen use in the latter half of the last decade, we established a surveillance network within the United States to monitor temporal trends in the number of reported cases of PAH. We also studied whether use of anorexigens and other drugs differed among patients with pulmonary hypertension of different etiologies., Methods: Newly diagnosed subjects (N = 1335) at 13 tertiary pulmonary hypertension centers were enrolled between January 1998 and June 2001. Patient-reported medication use was obtained by a telephone interview. Patients were classified as to the type of pulmonary hypertension. Poisson regression models were fitted to monthly case counts, and logistic regression methods were used to assess the association between type of pulmonary hypertension and medication use., Results: The average monthly number of reported cases of PAH and other categories of pulmonary hypertension did not change over the study period. Fenfluramine or dexfenfluramine use during the 5 years before the time of the interview was preferentially associated with PAH. Fenfluramine/dexfenfluramine use was particularly common in cases referred but found not to have pulmonary hypertension., Conclusions: No epidemic of anorexigen-related PAH was evident during the study period. As persons who had taken fenfluramine or dexfenfluramine were particularly likely to be referred for evaluation of pulmonary hypertension, it is unlikely that the failure to detect an anorexigen-induced rise in primary pulmonary hypertension was because of underascertainment. The association between fenfluramine derivatives and PAH is consistent with the risk elevations previously reported.

Background: It is not known whether burden-of-illness differs in chronic venous disease patients with prior venous thromboembolism compared with patients with other forms of chronic venous disease., Objective: To compare severity of disease and quality of life in chronic venous disease patients with and without prior venous thromboembolism., Patients and Methods: The VEINES Study population is an international cohort of 1531 outpatients with chronic venous disease in Belgium, France, Italy and Canada. Clinical severity of chronic venous disease graded using the seven-category 'CEAP' scale, and quality of life using standardized generic (SF-36) and venous disease-specific (VEINES-QOL/Sym) questionnaires were compared in patients with and without venous thromboembolism. Multivariable analyses with adjustment for known confounders were used to examine associations between venous thromboembolism and quality of life., Results: One hundred and fifty-one (10%) patients had prior venous thromboembolism. These patients had more severe chronic venous disease than those without venous thromboembolism (P <0.0001), including a higher frequency of healed or active ulcers (29% vs. 7%, respectively). Multivariable analyses controlling for age, sex, country, education, body mass index, years of chronic venous disease and comorbid conditions demonstrated that prior venous thromboembolism was an independent predictor of poorer generic quality of life (SF-36 Mental Component Summary score, P=0.047; SF-36 Physical Component Summary score, P=0.012) and venous disease-specific quality of life (VEINES-QOL, P = 0.0002; VEINES-Sym, P=0.009)., Conclusions: Disease severity is worse and quality of life poorer in chronic venous disease patients with prior venous thromboembolism compared with patients with other forms of chronic venous disease. Our findings support the need for further research of interventions to prevent and treat the long-term complications of venous thromboembolism.

Objective: A wave of bombings struck France in 1995 and 1996, killing 12 people and injuring more than 200. The authors conducted follow-up evaluations with the victims in 1998 to determine the prevalence of and factors associated with posttraumatic stress disorder (PTSD)., Method: Victims directly exposed to the bombings (N=228) were recruited into a retrospective, cross-sectional study. Computer-assisted telephone interviews were conducted to evaluate PTSD, per DSM-IV criteria, and to assess health status before the attack, initial injury severity and perceived threat at the time of attack, and psychological symptoms, cosmetic impairment, hearing problems, and health service use at the time of the follow-up evaluation. Factors associated with PTSD were investigated with univariate logistic regression followed by multiple logistic regression analyses., Results: A total of 196 respondents (86%) participated in the study. Of these, 19% had severe initial physical injuries (hospitalization exceeding 1 week). Problems reported at the follow-up evaluation included attack-related hearing problems (51%), cosmetic impairment (33%), and PTSD (31%) (95% confidence interval=24.5%-37.5%). Results of logistic regression analyses indicated that the risk of PTSD was significantly higher among women (odds ratio=2.54), participants age 35-54 (odds ratio=2.83), and those who had severe initial injuries (odds ratio=2.79) or cosmetic impairment (odds ratio=2.74) or who perceived substantial threat during the attack (odds ratio=3.99)., Conclusions: The high prevalence of PTSD 2.6 years on average after a terrorist attack emphasizes the need for improved health services to address the intermediate and long-term consequences of terrorism.

Exogenous substances such as the appetite suppressant fenfluramine are known to be causally related to the development of pulmonary arterial hypertension (PAH). In these cases, the clinical course as well as the pulmonary vascular disease pathologically is indistinguishable from idiopathic PAH. Other exogenous substances, such as amphetamines, cocaine, and meta-amphetamines, have been considered to be potential risk factors for inducing PAH. SOPHIA (the study of pulmonary hypertension in America), in addition to confirming previous reports of a causal association between the appetite suppressant fenfluramine and PAH, unexpectedly found a significantly increased risk for the development of PAH with exposure to over-the-counter antiobesity agents containing phenylpropanolamine. The first case is reported of fatal PAH in a child heavily treated with cold remedies containing phenylpropanolamine, which, in addition to the results of SOPHIA, strengthens the hypothesis that phenylpropanolamine is a risk factor for the development of PAH.