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Background: Different methods have been proposed for assessing a possible causal link between a drug treatment and an adverse event in individual patients. They approximately belong to three main categories: expert judgement, operational algorithms and probabilistic approaches.Objective: To compare, in a set of actual drug adverse event reports, three different methods for assessing drug causality, each belonging to one of the three main categories: expert judgement, the algorithm used by the French pharmacovigilance centres since 1985, and a novel method based on the logistic function.Methods: Fifty drug-event pairs were randomly sampled from the database of the Bordeaux pharmacovigilance centre, France. To serve as the gold standard, the probability for drug causation, from 0 to 1, was first determined for each drug-event pair by a panel of senior experts until consensus was reached. Causality was then assessed by members of the Bordeaux pharmacovigilance centre by using the French algorithm and the logistic method. Results expressed as a probability with the logistic method and as a score from 0 to 4 with the French algorithm were then compared with consensual expert judgement, as were the sensitivity, specificity and positive and negative predictive values.Results: Probabilities ranged from 0.08 to 0.99 (median 0.58; mean 0.60) for experts versus 0.18-0.88 (median 0.73; mean 0.67) for the logistic method. Consensual expert judgement was not discriminant (p = 0.50) in ten cases. For the algorithm, only three of five causality scores were found, doubtful scores being clearly predominant (74%) followed by possible (16%) and probable (10%) scores. Sensitivity and specificity were 0.96 and 0.42, respectively, for the logistic method versus 0.42 and 0.92 for the algorithm. Positive and negative predictive values were 0.78 and 0.83, respectively, for the logistic method versus 0.92 and 0.42 for the algorithm.Conclusions: Agreement between the three approaches was poor, and only satisfactory for drug events judged as drug-induced by consensual expert judgement. The logistic method showed high sensitivity at the expense of poor specificity. Conversely, the algorithm had poor sensitivity but good specificity. The comparatively good sensitivity and positive predictive values of the logistic method suggest that it may be more useful in the routine or automated assessment of case reports of suspected but still unknown adverse drug reactions. With a substantial rate of false positives relative to true negatives (low specificity), the logistic method does not replace, but can be complemented by, critical clinical assessment of individual cases in evaluating drug-related risk. [ABSTRACT FROM AUTHOR]

Reimbursement databases are potentially invaluable tools to develop and conduct pharmacoepidemiological studies on drug use. However, two types of factors that may influence the performance of a database can be distinguished: firstly, factors related to the constitution of the database, and secondly, factors related to the data. For the latter, we think that two are important: the presence of the drug in the database and the capacity to capture real-life use, both of which are influenced by the marketing status (e.g., OTC) and whether reimbursement is possible. To illustrate and discuss to what extent reimbursement databases are relevant tools to conduct drug utilization studies with regard to the data on drugs. In order to illustrate the reliability of data in reimbursement databases, data from the main French national health insurance database (55 million individuals) were compared to national drug sales in France (units) during the same year. Depending on the ATC class, the capture in the database of drugs actually sold ranged from 32 to 81%. Capture of classes of drugs in the database may be explained by the specific characteristics of the French health insurance system (reimbursable drugs, OTC market share). These characteristics influence the studies that can be performed both in terms of the topic but also the methodology. This problem probably exists for the other reimbursement databases used worldwide. Studies should be designed according to the strengths and weaknesses of reimbursement databases that were not originally developed for pharmacoepidemiology. [ABSTRACT FROM AUTHOR]

Purpose Various data sources may be used in pharmacoepidemiological studies. When they cannot be obtained from valid databases, medical data must be obtained from physicians or patients. In the CADEUS study, both patients and their prescribers reported medical data allowing investigation of the concordance between these sources. Methods CADEUS is a French national cohort study of traditional non-steroidal anti-inflammatory drug (NSAID) and coxib users conducted between September 2003 and August 2004 in France that employed self-administered questionnaires to obtain medical data from patients and their prescribers. The Kappa statistic ( κ) was used to measure concordance between patients and prescribers in 18 530 pairs with regard to previous medical history and index NSAID indication. Results For previous medical history, the proportion of agreement ranged from 70.7 to 99.2% and concordance was: substantial ( κ = 0.61-0.80) for hypertension, myocardial infarction, stroke and diabetes; moderate ( κ = 0.41-0.60) for angina pectoris, peripheral arterial disease and hypercholesterolaemia; fair ( κ = 0.21-0.40) for unstable angina, cardiac insufficiency, dyspepsia, gastroesophageal reflux and gastric ulcer; slight ( κ < 0.21) for upper gastrointestinal haemorrhage. For index NSAID indication, the proportion of agreement ranged from 84.3 to 99.4% and concordance was almost perfect ( κ = 0.81-1.00) for inflammatory rheumatism, flu-like symptoms, dysmenorrhoea and dental pain; substantial for arthritis, back pain and headache; moderate for osteoarticular pain. Conclusions Concordance was better for specific or serious conditions both regarding previous medical history and indication. Prescriber or patient perception and understanding may reduce concordance for certain items. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Some pharmaceutical tablets have an appearance that resembles that of ecstasy (a logo and often a name referring to it, a given shape and/or a colour). These are sometimes sold in the street as ‘ecstasy’. In order to assess the knowledge of this phenomenon, surveys were conducted among designer drug users (DDUsers), pharmacists and pharmaceutical firms. Three surveys were conducted: the first one was conducted among DDUsers by means of an anonymous questionnaire; the second one consisted of a 1-month postal survey within a network of 155 community pharmacies in the Aquitaine region, Southwestern France and the third one consisted of a postal questionnaire sent to 71 pharmaceutical firms. Nineteen users, 77 pharmacists and 25 pharmaceutical firms participated in the surveys. All DDUsers knew the existence of what they call ecstasy ‘swindles’, but less than one quarter of the pharmacists and one third of pharmaceutical firms were aware of the potential recreational and involuntary misuse of medicines. The phenomenon of ‘swindle’ in the illicit market is not new. However, the sale of medicines because of their appearance or logo seems to be quite rare. In order to limit this diversion, prevention should be reinforced. In addition, recommendations on the appearance of medicine tablets should be set up by regulatory agencies in charge of medicine approval. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Traditional or COX-2-specific (coxib) nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used. • Their use is associated with gastrointestinal toxicity and cardiovascular events. WHAT THIS STUDY ADDS • The low event rates observed for gastrointestinal bleeding and myocardial infarction in the real-life conditions of NSAID use (traditional and coxib) in France preclude their exploration using realistic field studies. • Large population healthcare databases are required to study such risks. AIMS To assess hospital admission rates for gastrointestinal (GI) or cardiovascular (CV) events in real-life use of nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS CADEUS is a real-life population-based cohort study of 23 535 coxib (celecoxib or rofecoxib) and 22 919 traditional NSAID (tNSAID) users. Each hospitalization reported between index day (NSAID delivery) and questionnaire submission (median = 75 days) was explored using hospital discharge summaries. An expert committee validated blindly serious GI and CV events according to predefined criteria. RESULTS Coxib users were older and had more GI history than tNSAID users. There were 21 hospitalizations for GI events, 12 in the coxib cohort and nine in the tNSAID cohort (respectively one and three upper GI haemorrhages and no ulcer perforations). Rates of GI events were 0.39 per 1000 patients [95% confidence interval (CI) 0.18, 0.75] for tNSAID users and 0.51 per 1000 patients (95% CI 0.26, 0.89) for coxib users. There were 21 hospitalizations for CV events, 13 in the coxib cohort and eight in the tNSAID cohort. None was fatal. Rates of CV events were, respectively, 0.59 (95% CI 0.24, 1.22), 0.51 (95% CI 0.19, 1.11) and 0.35 (95% CI 0.15, 0.69) per 1000 patients for celecoxib, rofecoxib and tNSAIDs. GI or CV event rates were not different between products even for patients >60 years old. CONCLUSIONS Hospitalization rates for GI bleeding were 10–20 times lower than expected from published randomized clinical trials, probably because of differences in drug usage and concomitant gastroprotection. CV event rates conformed to those expected from general population data. These results emphasize the necessity of developing population healthcare databases to explore such low event rates. [ABSTRACT FROM AUTHOR]

Purpose To describe the reimbursement databases available in France for pharmacoepidemiological research and their use. Methods France has a publicly funded health system that systematically covers the population. Within this system, three main insurance schemes provide health services to citizens in France and each have their own reimbursement database. Together these three databases cover almost 97% of the French population (respectively for 54.5, 3.6, and 3.3 million individuals, and a total of 61.4 million individuals). Data in these concern patients, prescribers, all the medical acts reimbursed, prescription and undertaking of laboratory tests (but without results), private hospital data, partial public hospital data and vital status. Their use is regulated but access is free and the data are anonymous. PubMed and Scopus were searched for relevant studies published from January 1988 to June 2009. Results 110 published studies were included. The topics and the study characteristics were extremely wide-ranging. The studies assessed patterns of drug use, have tested interventions, supported or improved prescribing practices, tested compliance with the French governmental Health guidelines, assessed physicians' prescribing practices and performed economic and cost-effectiveness assessments. The number of articles published increased greatly between 2002 and 2003. Conclusions The French reimbursement databases were greatly used over the last 20 years. They can provide data on exposure to drugs and can be used to study patterns of drug utilization although their limitations must be considered. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: The authors investigated the association between death of older people and use of psychotropic drugs before and during the Western European August 2003 heatwave. Method: A retrospective population-based case-control study was conducted using the French social security insurance national database. &posure to psychotropic drugs in cases aged 70 -100 years who died before (N = 2,093) and during (N = 9,531) the August 2003 heatwave was compared with those of survivors matched for age, gender, and presence of chronic illness, by using conditional logistic regressions. Results: The association between death and psychotropic drug use was modified by level of external temperature (Wald X² = 13.1, degree of freedom = 1, <0.001). Use of any psychotropic drug was associated with a 30% increased risk of death during the heatwave, with a signficant dose-response relationshijp between the number ofpsychotropic drugs and the risk of death (adjusted odds ratio [aOR] for linear trend 1.25, 95% confidence interval [95% C4 1.21-1.29). During the heatwave, therapeutic classes independently associated with an increased risk of death were ant/depressants (aOR 1.71,95% Ci 1.5 7-1.86) and antzpsychotics (aOR 209,95% (2k 1.89235), whereas exposure to anxiolytics/hypnotics use (aOR 085, 0.79-0.91) was associated with a decreased risk. Findings remained unchanged after adjustment on cardiotropic, ant/dementia, or anhi-parkinsonian drug use. Conclusion: Our findings suggest that a causal relationship may exist between psychotropic drug use during a heatwave and increased risk of death in older people. The risk/benefit ratio of antidepressant and antijpsychotic drugs should be carefully assessed in older people during a heatwave. (Am J Geriatr Psychiatry 2009; 17:1059-1067) [ABSTRACT FROM AUTHOR]

The objective was to study the current narcotics regulations which are the most restrictive regarding prescription and dispensation practice in France, and their evolution over the period 1992–2007. This is an example of regulation in a European member state regarding medicines with a risk of abuse or dependence. Narcotics regulations were studied in the French public health code. Status and indications of medicines concerned were found on the French medicine agency website, and the retrospective part of the study was conducted using the French public statute law website. Seventeen medicines were found. Three were psychotropics and fourteen narcotics. The prescription rules could be different for a given substance according to the route of administration or indication. In 2007, half of the narcotic opioids could be prescribed for 28 days, whereas in 1992, most of them could be prescribed for only 7 days. These results show the adaptation of French narcotics regulations, with the development of medicines indicated in acute or chronic pain treatment or opioid maintenance treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Spontaneous reporting is a valuable way to provide early detection for safety signals related to drug use. • Due to the increasing size of pharmacovigilance databases, data-mining and other automated methods for signal generation are more and more often used. • Even if these methods are very useful, they do not allow, for every particular association, an automated exploration of the multiple sources of confounding. WHAT THIS STUDY ADDS • An association between angiotensin receptor blockers use and hypoglycaemia was found in the French pharmacovigilance database. • This signal disappeared after stratification on antidiabetic drug use, suggesting confounding by indication. • The association between hypoglycaemia and angiotensin receptor blocker use was actually less than expected in concomitant antidiabetic drug users. AIMS To study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding. METHODS The French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This association was also tested in patients taking or not taking antidiabetic agents (ADAs) using reporting odds ratios (ROR). RESULTS Hypoglycaemia was mentioned in 807 of the 174 595 reports entered during the study period. Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6, 8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively). CONCLUSION A signal indicating an association between ARB use and hypoglycaemia was found in the French pharmacovigilance database. This signal disappeared after stratification on ADA use, thus suggesting confounding by indication. Moreover, the association between ARB use and hypoglycaemia was negative in ADA users. [ABSTRACT FROM AUTHOR]

In pharmacoepidemiology studies where patients are selected by prescribers, there is concern that the patients of responding prescribers are not necessarily an unbiased sample of all patients. However, this usually cannot be explored. In the CADEUS study, patients and prescribers were independently contacted so that data are available for patients irrespective of whether their prescriber responded or not. Our objective was to compare the characteristics of patients whose prescriber did or did not respond.The CADEUS study included patients treated with COX-2 inhibitors (celecoxib, rofecoxib) or traditional NSAIDs from September 2003 to August 2004. Redeemed prescriptions were randomly sampled on a monthly basis within the database of the French national healthcare insurance system for salaried persons during 1 year. Patients and prescribers were questioned independently. Data from patients and from the database were used to compare patients whose prescriber responded and those whose prescriber did not.Of 45,217 patients, 26,618 had prescriber data. Patients whose prescriber responded were similar to patients whose prescriber did not respond for the main study outcomes: age (56.8 ± 16.3 years vs. 56.1 ± 16.3 years), sex (66.0% female vs. 64.8%), cardiovascular disease history (52.2% vs. 52.0%), gastrointestinal disease history (39.5% vs. 39.4%), concomitant prescription of gastroprotective agents (22.4% vs. 23.7%), and NSAID indication, prescription type, use, and duration.We found no evidence for a difference between patients whose prescriber responded and patients whose prescriber did not participate in the study. [ABSTRACT FROM AUTHOR]

What is already known about this subject • In pharmacovigilance, many methods have been proposed for causality assessment of adverse drug reactions. • Expert judgement is commonly used to evaluate the causal relationship between a drug treatment and the occurrence of an adverse event. This form of judgement relies either explicitly or implicitly on causality criteria. What this study adds • Our study compares the judgements of five senior experts using global introspection about drug causation and seven causality criteria on a random set of putative adverse drug reactions. • Even if previous publications have shown poor agreement between experts using global introspection, few have compared judgements of well trained pharmacologists, familiar with using a standardized causality assessment method. Aims To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation. Methods A sample of 31 adverse event-drug pairs was constituted. For each pair, five experts separately assessed (i) the probability of drug causation, which was secondarily divided into seven causality levels: ruled out (0–0.05), unlikely (0.06–0.25), doubtful (0.26–0.45), indeterminate (0.46–0.55), plausible (0.56–0.75), likely (0.76–0.95), and certain (0.96–1); and (ii) seven causality criteria. To test discrepancies between experts, the kappa index was used. Results The agreement of the five experts was very poor (kappa = 0.05) for the probability of drug causation. Among the seven levels of causality, only ‘doubtful’ showed a significant rate of agreement (kappa = 0.32, P < 0.001). For all criteria, the kappa index was significant except for the item ‘risk(s) factor(s)’ (kappa = 0.09). Agreement between experts was good (0.64, P < 0.001) only for the criterion ‘reaction at site of application or toxic plasma concentration of the drug or validated test’. However, the rate of agreement with kappa indices of the causality criteria ranged from 0.12 to 0.38. Conclusions This study confirms that in the absence of an operational procedure, agreement between experts is low. This should be considered when designing a causality assessment method. In particular, criteria inducing a low level of agreement should have their weight reduced. [ABSTRACT FROM AUTHOR]

Abstract: Background and Objective: The many methods proposed for causality assessment of adverse drug reaction (ADR) generally rely on algorithms. They have no clear relationship to probabilities, however, a situation we attempted to improve. Study Design and Setting: Thirty ADR cases corresponding to 32 suspect drugs were randomly selected from the French pharmacovigilance database. The statistical weighting was performed by using a multilinear regression with logit(p) as the dependent variable and seven judgment criteria as independent variables. The best model (i.e., giving the best correlation with the gold standard) was retained for the new causality assessment method. Results: The weights [logit(p)] for the 21 choices, on average three for each of the seven criteria, ranged from −3.95 to 0.86, secondarily rounded to multiples of 0.5. The correlation between the probability obtained from the final method and the gold standard was quite good (R 2 = .92). Conclusion: This method based on the rational weighting of seven causality criteria is straightforward to use and provides very good agreement with experts'' judgment. Moreover, unlike most classical algorithms, it respects one basic rule of probabilities—namely, a symmetrical probability distribution for drug causation around the .5 neutral position (maximum uncertainty). [Copyright &y& Elsevier]

Pharmacovigilance aims at detecting tile adverse effects of marketed drugs. It is generally based on the spontaneous reporting of events thought to be the adverse effects of drugs. Spontaneous Reporting Systems (SRSs) supply huge databases that pharmacovigilance experts cannot exhaustively exploit without data mining tools. Data mining methods; i.e., statistical association measures in conjunction with signal generation criteria, have been proposed in the literature but there is no consensus regarding their applicability and efficiency, especially since such methods are difficult to evaluate on the basis of actual data. The objective of this paper is to evaluate association measures on simulated datasets obtained with SRS modeling. We compared association measures using the percentage of false positive signals among a given number of the most highly ranked drug-event combinations according to the values of the association measures. By considering 150 drugs and 100 adverse events, these percentages of false positives, among the 500 most highly ranked drug-event couples, vary from 1.1% to 53.4% (averages over 1000 simulated datasets). As the measures led to very different results, we could identify which measures appeared to be the most relevant for pharmacovigilance. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the risk factors, rate of occurrence, onset, nature and impact of mild to moderate muscular symptoms with high-dosage HMG-CoA reductase inhibitor (statin) therapy in general practice. Methods: The Prédiction du Risque Musculaire en Observationnel (Prediction of Muscular Risk in Observational conditions, PRIMO) survey was an observational study of muscular symptoms in an unselected population of 7924 hyperlipidemic patients receiving high-dosage statin therapy in a usual care, outpatient setting in France. Information on patient demographics, treatment history and muscular symptoms was obtained by question-naires. Results: Multivariate analysis revealed the strongest predictors for muscular symptoms to be a personal history of muscle pain during lipid-lowering therapy (odds ratio, OR, 10.12, 95% CI 8.23–12.45; P < 0.0001), unexplained cramps (OR 4.14; 95% CI 3.46–4.95; P < 0.0001) and a history of creatine kinase (CK) elevation (OR 2.04; 95% CI 1.55–2.68; P < 0.0001). Overall, muscular symptoms were reported by 832 patients (10.5%), with a median time of onset of 1 month following initiation of statin therapy. Muscular pain prevented even moderate exertion during everyday activities in 315 patients (38%), while 31 (4%) were confined to bed or unable to work. Fluvastatin XL was associated with the lowest rate of muscular symptoms (5.1%) among individual statins. Conclusion: PRIMO demonstrated that mild to moderate muscular symptoms with high-dosage statin therapy may be more common and exert a greater impact on everyday lives than previously thought. Knowledge of the risk factors for muscular symptoms will allow identification and improved management of high-risk patients. The risk of muscular symptoms with fluvastatin XL treatment may be lower than with high dosages of other statins. [ABSTRACT FROM AUTHOR]

Background: Global introspection is, with operational algorithms and Bayes' theorem, one of the three main approaches used to assess the causal relationship between a drug treatment and the occurrence of an adverse event. Objective: To analyze and compare the judgments of five senior experts using global introspection about drug causation on a random set of putative adverse drug reactions. Methods: A random sample of 150 drug-effect pairs was constituted. For each pair, five senior experts had to independently assess the probability of drug causation from 0 to 1 by using a 100 mm visual analog scale (VAS). For analysis, those probabilities were secondarily split into seven levels of causality: excluded (0–0.05); unlikely (0.06–0.25); doubtful (0.26–0.45); unassessable/ unclassifiable (0.46–0.55); plausible (0.56–0.75); likely (0.75–0.95); and certain (0.95–1). Agreement among the five experts was assessed using kappa coefficients (κ). Results: The overall agreement between experts was poor (κ=0.20), although significantly different from chance, and varied according to the level of causality. It was lower for the unlikely, doubtful, unassessable/ unclassifiable, and plausible categories (κ=0.03, 0.03, -0.01, and 0.13, respectively) than for VAS extremes: excluded, likely, and certain (κ=0.40, 0.32, and 0.30, respectively). Conclusion: This study confirms that experts express marked disagreements when assessing drug causality independently. The agreement rate was lower for intermediate levels of causality, especially when strong evidence was lacking for confirming or ruling out drug causality. Therefore, in a decision-making context, a step-by-step consensual approach such as the Delphi method seems necessary to make the assessment of such cases more reliable. [ABSTRACT FROM AUTHOR]

L’étude pharmacoépidémiologique EPIGRAM a été mise en place auprès de médecins généralistes (MG) prescripteurs d’orlistat (Xenical®) dans le but de décrire, en situation réelle, la prise en charge des patients obèses ou en surpoids et le suivi sur un an des patients traités par orlistat. Sept cent quatorze MG ont participé à cette étude et ont inclus 6801 patients dont 40 % traités par orlistat, 76 % étaient des femmes et 63 % souffraient de comorbidités. Avec un indice de masse corporelle (IMC) moyen de 33,1 ± 5,1 kg/m2, les patients traités par orlistat correspondaient pour 85 % aux indications du médicament. La comparaison des patients traités ou non par orlistat n’a permis d’identifier aucun facteur majeur prédictif de la prescription du traitement. Les patients traités par orlistat à l’inclusion et revus au moins une fois par leur médecin ont été suivis par celui-ci 11 mois en moyenne avec un maximum de 23 mois. Entre 64 % et 77 % des patients ont arrêté le traitement par orlistat sur la période de suivi. Le coût thérapeutique était une raison d’arrêt plus fréquente avec 50 % des cas. La perte de poids était en moyenne de 5 % et 9 % à 3 mois et 12 mois de traitement, respectivement. Mots clés : obésité, orlistat, pharmacoépidémiologie, observance, médecine générale Abstract The EPIGRAM pharmacoepidemiological study was conducted in general practitioners (GPs) prescribing orlistat (Xenical®) in order to describe, under real clinical conditions, the management of obese or overweight patients, as well as a 1-year follow-up of a patient cohort treated with orlistat. A total of 714 GPs participated in this study and recruited a total of 6801 patients. Forty percent were treated with orlistat, 76% were women and 63% presented with a comorbidity. With a mean body mass index of 33.1 ± 5.1 kg/m2, 85% of the patients treated with orlistat were in agreement with the indications of this drug. Comparison of patients treated and not treated with orlistat did not allow identification of any key factor able to predict prescription of the treatment. Patients treated with orlistat on inclusion and reviewed at least once by their doctor were followed up for an average of 11 months and a maximum of 23 months. Between 64% and 77% of patients stopped treatment with orlistat during the follow-up period. The treatment cost was the main reason for definitive treatment discontinuation for more than 50% of the patients. The average weight loss was 5% and 9% after 3 and 12 months of treatment, respectively. Keywords: obesity, orlistat, pharmacoepidemiology, compliance, general practice Texte reçu le 27 octobre 2003 ; accepté le 29 avril 2004 [ABSTRACT FROM AUTHOR]

Objectif : L’objectif de cette étude est de décrire les sujets débutant un traitement par célécoxib et l’évolution de ce traitement au cours des 6 mois suivant son initiation. Méthode : Elle a été conduite sur 14 323 sujets ayant eu une première délivrance de célécoxib en décembre 2000, identifiés dans la base de sécurité sociale d’Acquitaine. L’âge moyen est de 61,9 ans et le sex ratio homme/femme de 0,45. Soixante et un pour cent sont d’anciens consommateurs d’autres anti-inflammatoires non stéroïdiens (AINS) et 38 % d’anti-ulcéreux. Résultats : Sur la même ordonnance que célécoxib ou dans les 30 jours suivants, 23 % ont une délivrance d’anti-ulcéreux et 15 % d’autres AINS. Au cours des 6 mois suivant l’inclusion, le célécoxib a été renouvelé par 41 % des sujets. En cas de renouvellement, au cours des 6 mois avant et après l’inclusion, la délivrance d’anti-ulcéreux est respectivement de 40,9 % et de 44,1 %. En cas de non-renouvellement, ces proportions sont de 32,2 % et de 33,7 %. Discussion : La prescription de célécoxib s’adresse essentiellement à des sujets anciens consommateurs d’autres AINS. Elle ne modifie pas ou peu la prise en charge des sujets traités et, en particulier, ne fait pas diminuer l’utilisation des anti-ulcéreux. Mots clés : célécoxib, inhibiteur de la cyclo-oxygénase 2, pharmacoépidémiologie Abstract Objective: The objective of this study was to describe the characteristics of subjects beginning celecoxib treatment and the evolution of treatment over a 6-month period. Methods: All the subjects (n = 14 323) for whom reimbursement of celecoxib was submitted to the “Sécurité Sociale” d’Acquitaine in December 2000 were included in the study. Their mean age was 61.9 years, and the male/female sex ratio was equal to 0.45. Almost two-thirds of the subjects were previous typical nonsteroidal anti-inflammatory drug users (NSAIDs-typical). Results: Fifteen percent of the subjects had a gastroprotective agent prescribed, either on the same form as celecoxib or during the following 30 days. New reimbursements of celecoxib involved 41% of the subjects. Among the subjects who received a repeat prescription of celecoxib, 41% had used a gastroprotective agent at least once during the 6 months before study inclusion and 44% during the 6 months after inclusion. Among the subjects who did not renew their celecoxib prescription, the respective proportions were 32.2% and 33.7%. Discussion: These results show that celecoxib is mainly prescribed to previous NSAIDs-typical users. The small difference in the prescription of gastroprotective agents between the period preceding and that following the initiation of celecoxib treatment does not indicate an advantage of celecoxib in terms of a lower rate of use of gastroprotective agents. Keywords: celecoxib, type 2 cyclo-oxygenase inhibitors, pharmacoepidemiology Texte reçu le 18 décembre 2003 ; accepté le 10 juin 2004 [ABSTRACT FROM AUTHOR]

La prescription des antidépresseurs a évolué depuis la mise sur le marché de nouvelles molécules comme les inhibiteurs de la recapture de la sérotonine (IRS). Qu’en est-il de leurs effets indésirables (EI) chez la personne âgée ? Nous avons analysé les notifications d’EI sous antidépresseurs chez les sujets de ≥ 75 ans, dans la base de données de pharmacovigilance française entre 1985 et 2001. La répartition globale des 2381 notifications recensées semble refléter les chiffres de vente avec 44 % des EI sous IRS, 25 % sous imipraminiques, 2 % sous inhibiteurs de la monoamine oxydase et 27 % sous antidépresseurs divers. Le profil des EI de chaque classe d’antidépresseurs est différent avec une prédominance des EI métaboliques, hydroélectrolytiques pour les IRS et des EI psychiatriques et cardiovasculaires pour les imipraminiques. Cependant, les conséquences d’EI tels que l’hyponatrémie sont loin d’être négligeables chez le sujet âgé. Mots clés : antidépresseurs, sujet âgé, effets indésirables, pharmacovigilance Abstract The prescription of antidepressants in the elderly has changed since the marketing of new antidepressants such as selective serotonin reuptake inhibitors (SSRIs). We analysed the adverse effects associated with antidepressants in subjects aged ≥75 years reported to the pharmacovigilance centres in France. Among the 2381 cases recorded between 1985 and 2001, the distribution of adverse effects may reflect sales figures: 1040 for SSRIs (44%), 586 for tricyclic and related antidepressants (25%), 46 for monoamine oxidase inhibitors (2%) and 654 for other antidepressants (27%). Adverse effect patterns differed according to antidepressant class. For SSRIs, hyponatraemia was predominant (30%), followed by psychiatric (13%) and nervous system (10%) effects. For tricyclic antidepressants, psychiatric effects (confusion, agitation) [21%] were the most frequent followed by cardiovascular effects (15%). However, the consequences of adverse effects such as hyponatraemia are far from negligible in the elderly. Keywords: antidepressants, elderly, adverse effects, pharmacovigilance Texte reçu le 25 février 2004 ; accepté le 10 juin 2004 [ABSTRACT FROM AUTHOR]

Syncope and sudden death are features of schizophrenia that can be attributed to ischaemic heart disease, the use of antipsychotics (because of proarrhythmia or other reasons such as pharyngeal dyskinesia) or the psychiatric disease itself. Cases have been described with most antipsychotics and have led to the withdrawal, temporary suspension from the market or restricted use of antipsychotics, such as sultopride, droperidol, sertindole or thioridazine. Reviewing the available data shows that all antipsychotics tested affect the cardiac potassium channel, with the concentration that produces 50% inhibition (IC50) ranging from 1 nmol/L (haloperidol) to 6 μmol/L (olanzapine). Experimental in vitro or in vivo electrophysiological studies have shown a dose-dependent increase in the duration of the action potential with various degrees of indicators of serious arrhythmogenicity. However, this does not always translate clinically into an increased duration of the QT interval or increased risk of torsade de pointes or sudden death in clinical trials or pharmacoepidemiological studies. In turn, QT prolongation in clinical trials does not always translate to an increased risk of torsade de pointes or sudden death. The reasons for these apparent discrepancies are unclear and could be related to insufficiently powered field studies, low plasma and tissue drug concentrations with reference to in vitro data or drug effects on other receptors or ion channels that have a protective effect. Alternatively, risks that were not apparent from preclinical or clinical data could be related to the use of the drug in high-risk patients, metabolic interactions or other factors that would only be encountered in large postmarketing populations. The assessment of cardiovascular safety, both preclinical and during premarketing clinical trials, needs to be supported by appropriately powered pharmacoepidemiology studies. [ABSTRACT FROM AUTHOR]

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Recent in vitro studies, clinical trials and epidemiological studies have suggested possible interactions between aspirin and other cyclo-oxygenase (COX) inhibitors, such as ibuprofen of the COX-2 inhibitors celecoxib and rofecoxib. The objective of this study was to test the effects of aspirin (1, 2.5 and 5 mg/kg), and ibuprofen (4 and 15 mg/kg), diclofenac (2.5 mg/kg), flurbiprofen (2 mg/kg), celecoxib (7.5 mg/kg), and rofecoxib (1 mg/kg), alone or combined on a rat model of arterial thrombosis. Drugs were given orally daily for 7 days, before insertion of an arterio-venous shunt thrombosis system, left in place for 15 min. Main parameter was thrombus weight. Five to 12 rats were used per experiment, and 35 controls overall. Aspirin inhibited thrombus formation in a dose-dependent manner. All NSAIDS given alone also inhibited thrombus formation to approximately the same level as aspirin 1 mg/kg/day. Ibuprofen, celecoxib and rofecoxib inhibited the effects of aspirin, but not diclofenac or flurbiprofen. The interactions with aspirin do not seem to affect all NSAIDs to equal levels. The clinical impact of this needs to be confirmed in adequately powered clinical trials or pharmaco-epidemiological studies. [ABSTRACT FROM AUTHOR]

Because extrapolation of adverse event rates from clinical trials to the general population relies on the assumption of similar drug-usage patterns, we have studied usage patterns for nonsteroidal anti-inflammatory drugs (NSAIDs) from the National Health Insurance claims database. Reimbursement patterns of NSAIDs and analgesics were studied in a cohort of 232 users, half selected from authorisations of reimbursed spa cures, and the other half - strictly matched according to age and gender - who had redeemed at study onset at least one prescription for NSAIDs, analgesics or other antirheumatic drugs. Drug utilisation was measured as the total number of defined daily doses (DDD) bought over the 9-month study period. Over this time, the patients bought a median 45 DDD of NSAIDs out of the 270 needed to cover the whole period. Only two patients bought 270 DDD or more. Median paracetamol use (alone or combined) was 26 days. This study shows that patients use NSAIDs either intermittently or at lower than recommended doses, which is consistent with a primarily symptomatic use. Intermittent or on-demand use of NSAIDs, or at doses lower than full, could partly explain the lower rates of gastrointestinal bleeding and other ulcer complications in postmarketing epidemiological studies than could be expected from the findings of clinical trials. Keywords: NSAIDs, gastrointestinal bleeding, marketing, adverse effect Résumé L’extrapolation des fréquences des effets indésirables des médicaments à la population générale à partir des données des essais cliniques présume d’une utilisation similaire des produits. Nous avons donc étudié les remboursements d’anti-inflammatoires non stéroïdiens (AINS) par l’Assurance Maladie dans une population de 232 sujets, dont la moitié avait été acceptée pour une cure thermale de traitement de l’arthrose. L’autre moitié était appariée sur l’age exact et le sexe, et sur le remboursement d’au moins un produit similaire au cours de la période d’inclusion. Toutes les délivrances d’AINS, d’antalgiques, de myorelaxants et d’anti-arthrosiques d’action lente ont été recueillies pendant les 3 mois précédant la cure et les 6 mois suivants, ou la période équivalente chez les non-curistes. Pendant ces 9 mois, ces patients ont acheté une médiane de 45 jours de traitement d’AINS, alors qu’il en faudrait 270 pour couvrir tous les jours de la période d’étude. Seuls deux sujets ont acheté plus de 270 jours de traitement. Pour le paracétamol (seul ou associé), la médiane d’achat était de 26 jours. Notre étude montre que les patients utilisent les AINS de façon intermittente ou à des posologies inférieures aux posologies recommandées, ce qui n’est pas étonnant compte tenu du contexte de traitement symptomatique. L’utilisation intermittente ou à la demande des AINS, ou l’utilisation à des posologies inférieures aux posologies recommandées, pourraient expliquer dans les études épidémiologiques post-AMM (autorisation de mise sur le marché) une incidence de saignements gastro-intestinaux et d’autres complications moindre que celle retrouvée dans les essais cliniques. Mots clés : AINS, hémorragies gastro-intestinales, marketing, effet indésirable Texte reçu le 22 septembre 2003 ; accepté le 20 janvier 2004 [ABSTRACT FROM AUTHOR]

Our aim was to explore the agreement between clinically collected information on purported drug intake and plasma data in intentional drug overdose. We included all subjects with intentional drug overdose above 15 years of age consecutively admitted to the Emergency Department of the University Hospital during 4 months. Information about drugs used and sources of this information was collected and compared to presence of drug in plasma, concerning four drugs with high toxic potential (tricyclic antidepressants, meprobamate, paracetamol and ethanol). Sensitivity, specificity, predictive positive and negative values of all sources of information pooled were assessed for each drug. 413 intentional drug overdoses were included, 66% with more than one drug. According to clinical information, 8% took tricyclic antidepressants, 11% meprobamate, 9% paracetamol and 41% ethanol. Systematic plasma assays confirmed this in 59% of cases for tricyclic antidepressants, 76% for meprobamate and ethanol, and 77% for paracetamol. Plasma concentrations were considered toxic in 28% of cases for tricyclic antidepressants, 65% for meprobamate, 43% for ethanol and never for paracetamol. Tricyclic antidepressants and meprobamate were found unexpectedly in 3%, paracetamol in 7% and ethanol in 6%. Toxic concentrations were found only with meprobamate. The risk of erroneous, clinically collected information was greater by excess (25 to 40% false positives) than by lack (3 to 7% false negatives). Thus, the consequences of erroneous, clinically collected information were probably more excess cost for the institution than medical risk for the patients. However these results found at the population level may not be true at an individual level. [ABSTRACT FROM AUTHOR]

Clinical trials constitute the gold standard to assess the efficacy and safety of new medicines. However, because they are conducted in standardized conditions far from the real world of prescription and use, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks. On the basis of three examples, our objectives were to study the differences between the characteristics of treated populations and treatment patterns in clinical trials and in postmarketing settings and to discuss the potential consequences on actual efficacy and safety. Treated populations were compared with patients included in premarketing clinical trials. Comparisons were made on the basis of demographic characteristics and treatment patterns. Whatever the indicator and the drug studied, differences were observed: from 0.04% to 63% for tacrine, from 0% to 37% for celecoxib and from 6% to 52% for simvastatin, with possible consequences on the effectiveness and safety of the drug concerned. Our results confirm the under-representation of women and elderly patients in premarketing clinical trials, e.g. an M : F ratio of 4.6 in clinical trails of simvastatin vs 1.0 in the joint population. Moreover, the concomitant use of medicines was made extremely restrictive by the protocols of these trials while this was not the case in the postmarketing phase. This has possible consequences on the effectiveness and safety of the drug concerned. These results plead for systematic ad hoc observational postmarketing studies for any novel and/or expensive medicine to assess the relevance of premarketing data. [ABSTRACT FROM AUTHOR]

Dix ans après leur apparition en thérapeutique, les statines posent encore des questions en France. Que donnerait la transposition des essais contrôlés d’efficacité ? Cette transposition est-elle licite ? Le bénéfice du traitement est-il supérieur à ses risques ? Quels malades doivent être traités par les statines ? Dans quelle mesure la prescription de statines se substitue-t-elle à la correction d’autres facteurs de risque ? Quelles sont les performances des statines dans les conditions réelles de leur utilisation ? Les statines sont-elles efficaces en l’absence d’hypercholestérolémie ? Quel est le coût des statines ? Si les statines sont des médicaments incontestables dans des situations précises et lorsqu’elles sont correctement prescrites, la réponse à ces questions serait indispensable pour légitimer ou infirmer la large utilisation qui en est faite en France. Mots clés : statines, hypolipémiants, hypocholestérolémiants, prévention des accidents cardiovasculaires Texte reçu le 18 octobre 2002 ; accepté le 19 décembre 2002 Abstract More than ten years after the statins became available in therapeutics, some questions remain unanswered. What would be the populational impact if the results of clinical trials were applied to a country such as France? Is the extrapolation licit? Does the benefit of the statins actually exceed the risk? What is the relevant target population? Are statins more effective than agents acting on other cardiovascular risk factors? How efficient are the statins really? Are the statins effective in non-hypercholesterolaemic patients? What is the overall cost of the statins? Despite the fact that the statins are the drug of choice in many situations, it is still important for these questions to be answered before we accept the widespread use of statins in the general population, such as the large numbers of patients that the drug may be prescribed for in France. Keywords: statins, lipid-lowering drugs, prevention of cardiovascular events [ABSTRACT FROM AUTHOR]

Aims In many countries, governments and third parties find themselves paying for (reimbursing) unproven, inadequate products limiting their ability to invest in therapies with evidence of relevant patient benefit. We examined how three characteristics, level of therapeutic evidence, susceptibility of inappropriate prescribing, and intercountry variation can be used to identify inefficiencies in pharmaceutical reimbursement among four European Union countries, Austria, Belgium, the Netherlands and Sweden. Methods Specific classes of medicines were chosen to provide useful examples of how healthcare resources could be reallocated. A high level of therapeutic evidence was defined as a substantial body of evidence in at least one indication with clear-cut support of relevant patient benefit. The susceptibility of inappropriate prescribing was defined as the likelihood of prescribing a drug outside the scenario for which clear-cut evidence (if any) has been documented to produce relevant benefit for the patient. The intercountry variation represents the variation in utilization of reimbursed drugs across the four countries. Results The combination of these characteristics provides a useful tool for assessing appropriate reimbursement decisions. It would be beneficial to healthcare payers as well as patients to move resources from products that have a low level of therapeutic evidence and a high susceptibility of inappropriate prescribing to products with a high level of therapeutic evidence and low susceptibility of inappropriate prescribing, and to use intercountry variation as a signal of drug classes that should be subject to further scrutiny. Conclusions A method is presented to help policy-makers identify inefficiencies in the spending of limited health care resources, and to reallocate resources to products that have been shown to improve patient care through evidence-based medicine. [ABSTRACT FROM AUTHOR]

Presents letters to the editor. Patient complaints and risk of being sued; Tobacco advertising and freedom of speech; Rates of spontaneous reporting of adverse drug reactions in France.

Objectives: The objective of this study was to describe determinants of current and subsequent benzodiazepine use in an elderly population, the Paquid cohort Methods: The study was conducted on a cohort of 2792 community-dwelling subjects 65 years of age or more living in the Gironde department, southwestern France. Benzodiazepine use and its correlates were studied with data collected at inclusion in the cohort. Longitudinal analysis over a 5-year period of follow-up was done to identify baseline predictors of subsequent use. Results: At baseline, prevalence rate of benzodiazepine use was 31.9%. It was associated with female gender [odds ratio (OR)=2.0; 95% confidence interval (CI): 1.66, 2.46], previous psychiatric disease (OR =2.87; 95% CI: 2.31, 3.56), concomitant antidepressant use (OR=2.45; 95% CI: 1.59, 3.78), depressive symptomatology (OR=1.70; 95% CI: 1.28, 2.26), multiple drug use (OR=1.82; 95% CI: 1.50, 2.21), multiple chronic diseases (OR=1.37; 95% CI: 1.12, 1.67) and poor self-perceived health (OR=1.63; 95% CI: 1.33, 2.0). For the 1926 benzodiazepine non-users at inclusion and followed during 5 years, incidence rate of subsequent use was 5.37 per 100 person-years (95% CI: 4.76, 5.98). In multivariate Cox proportional hazards regression analysis, previous psychiatric diseases, poor self-perceived life satisfaction and polymorbidity were significantly associated with subsequent benzodiazepine use. Conclusions: Elderly people are heavy users of benzodiazepines. Independently from mental health status, those in poor health were most at risk of benzodiazepine use. [ABSTRACT FROM AUTHOR]

Background Although rotavirus vaccines have proven to prevent the risk of rotavirus gastroenteritis (RVGE) in children under 5 years old, they are also associated with an increased transient risk of intussusception (IS). Several quantitative benefit-risk models (qBRm) are performed to measure this balance in hospitalizations and deaths prevented versus the ones induced. Method In this study, our objective was to provide a complete overview of qBRm used for rotavirus vaccination. We systematically searched 3 medical literature databases to identify relevant articles, in English, that were published between 2006 and 2019. Results Of the 276 publications screened, 14 studies using qBRm for rotavirus vaccination were retained, based on preselected criteria. Four were performed in low- and middle-income countries. Almost all (13 of 14) displayed the following characteristics: force of infection assumed to be constant over time (static model), indirect effect of rotavirus vaccination (herd effect) not considered, closed model (individuals not allowed to enter and/or exit the model over time), and aggregated level (no tracking of individual's behavior). Most of the models were probabilistic (9 of 14) and reported sensitivity and/or scenario analyses (12 of 14). Input parameter values varied across studies. Selected studies suggest that, depending on the models used, for every IS hospitalization and death induced, vaccination would prevent, respectively, 190–1624 and 71–743 RVGE-related hospitalizations and deaths. Conclusions The benefits of rotavirus vaccination were shown to largely exceed the increased risk of IS, across all studies. Future research aiming to harmonize qBRm for rotavirus vaccination should ensure the comparability of studies and provide additional information for regulatory authorities, physicians, and patients. [ABSTRACT FROM AUTHOR]

The author reflects on the differences between the conditions of pre-marketing trials and actual marketing practices of pharmaceutical product. According to the author, variances between clinical trials and utilization in naturalistic conditions need to be identified due to their clinical and economic impact.

The article presents a study by M. Olfson related to comprehensive study of the use of benzodiazepines in the U. S. Topics discussed include use of benzodiazepines in elders for long periods of time, potential use of drugs in acute episodes of insomnia or transient anxiety in young persons and use of Benzodiazepines for very short periods or avoided altogether in elderly individuals who are susceptible to cognitive impairment or to falls and fractures.