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Bernard Bégaud

Publications and source records attributed to Bernard Bégaud.

At least 19 recordsLinked to original sources
PubMed2006

A new method for assessing drug causation provided agreement with experts' judgment.

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).

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Agreement of expert judgment in causality assessment of adverse drug reactions.

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 (kappa). RESULTS: The overall agreement between experts was poor (kappa=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 (kappa=0.03, 0.03, -0.01, and 0.13, respectively) than for VAS extremes: excluded, likely, and certain (kappa=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.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

[Medical and socio-economical impact of drug-induced adverse reactions].

OBJECTIVE: To analyse the nature of adverse drug reactions, their frequency, the drugs incriminated, their outcome, the different ways to treat them and their cost. METHODS: Descriptive, prospective and non-comparative study, based on spontaneous reporting. Each patient was followed-up over a 6-month period. RESULTS: One hundred and fifteen adverse events were reported in 113 patients (58 men and 55 women), with a mean age of 59.5 years. Cutaneous and haematological reactions predominated, with a majority of cardiovascular and psychotropic agents incriminated. Sixty-three percent of adverse reactions were serious: 49% led to (or prolonged) hospitalisation, 6% led to death, 4% to after effects, 3% were life-threatening and 1% led to congenital malformation. The mean duration of an adverse reaction was of 37.4 days. The total cost of these 115 adverse reactions was an estimated 610.110 Euros, with a mean global cost of 5.305 Euros per event. CONCLUSION: This study shows the individual and collective extent of the impact of adverse individual and collective reactions.

Adolescent↗
PubMed2005

Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study.

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 questionnaires. 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.

Aged↗
PubMed2005

An easy to use method to approximate Poisson confidence limits.

Despite the ever larger choice of softwares and statistical packages allowing fast and accurate computation of binomial and Poisson confidence limits, there is always a need for a simple and reliable formula allowing non-computerized computations. The method proposed in this paper is derived from the Freeman and Tukey's variance stabilizing transformation for a random Poisson variable and adjusted for giving the best fit with the exact Poisson values. Despite its simplicity, allowing its use in any circumstances, this method provides very satisfactory results and a much better fit than classical formula based on the normal approximation, even if a continuity correction is used. It allows computation of Poisson confidence limits both for count or rates and proportions.

Biometry↗
PubMed2005

Effects of armagnac or vodka on platelet aggregation in healthy volunteers: a randomized controlled clinical trial.

BACKGROUND: Cardiovascular mortality is especially low in southwest France (the French Paradox). In previous experimental studies, we found that alcohol-free extracts of armagnac could inhibit human platelet function in vitro and experimental thrombosis in vivo. To test the possible relevance of these findings, we tested the effects of daily use of small quantities of armagnac against same alcohol strength, polyphenol-free vodka in healthy volunteers. METHOD: Randomized controlled trial comparing 5-year old armagnac (30 ml/day for 2 weeks) to same alcoholic strength vodka, in 20 healthy volunteers, on platelet aggregation induced by ADP, collagen, and thrombin, as well as bleeding time, partial thromboplastin time (pTT), and plasma lipids during and after consumption. Platelet testing was done blind. RESULTS: After 14 days, ADP-induced platelet aggregation was inhibited more in armagnac (-31+/-3.2% compared to pretreatment values, p<.01) than in vodka (-11.0+/-6.8%, NS) users (p<.05, armagnac vs. vodka). A rebound increase of aggregation was found 2 weeks later in vodka but not in armagnac users. The same pattern was found for thrombin-induced aggregation, including post-treatment rebound. No effect was found on collagen-induced aggregation, bleeding time, pTT, or plasma lipids. CONCLUSION: The chronic ingestion of moderate quantities of armagnac modified platelet aggregation to ADP in healthy volunteers. The difference with the effects of same alcohol degree vodka is in favour of an effect of the nonalcoholic fraction in the effects of armagnac, rather than just alcohol. All spirits may not be equal for cardioprotection.

Adenosine Diphosphate↗
PubMed2005

Evaluation of statistical association measures for the automatic signal generation in pharmacovigilance.

Pharmacovigilance aims at detecting the 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.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Potential impact of oral contraceptive choice on myocardial infarction mortality and deep vein thrombosis.

OBJECTIVES: To summarise the epidemiological evidence on the relationship between second- (OC2) and third-generation (OC3) oral contraceptives (OC) and the mortality associated with deep vein thrombosis (DVT) and myocardial infarction (MI), and to extrapolate and balance the evidence for these risks to the population of French OC users. METHODS: All studies published on the risk of MI during OC2 and OC3 use were analysed. For DVT the Committee for Proprietary Medicinal Products public assessment report published in 2001 and more recent studies published on this topic were used. The estimates of odds ratios (OR) for risk of death from DVT or MI were extracted from the published manuscripts. ORs were used to calculate the aetiological fraction of risk for death from DVT and MI in the population; the relative impact of OC3 compared to OC2 use was expressed as an excess risk of death overall and by age group for French women. RESULTS: Compared with OC2, the use of OC3 would prevent a maximum of 24 deaths from MI per year and induce a maximum of 16 deaths. Conversely, OC3 would induce 282-940 excess cases of DVT per year, resulting in 28-94 pulmonary embolisms and 3-19 deaths in the 4.7 million French OC users. CONCLUSION: Balancing the evidence, it is difficult to conclude that the overall cardiovascular risk is significantly lower for either of the two OC schemes.

Adult↗
PubMed2005

Atypical antipsychotics: from potassium channels to torsade de pointes and sudden death.

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 micromol/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.

Animals↗
PubMed2005

Trends in spontaneous adverse drug reaction reports to the French pharmacovigilance system (1986-2001).

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

Adult↗
PubMed2004

Assessment of doctor-shopping for high dosage buprenorphine maintenance treatment in a French region: development of a new method for prescription database.

PURPOSE: To assess the extent of doctor-shopping for buprenorphine maintenance therapy in a French region with a specific indicator. METHODS: Use of a quasi-exhaustive prescription database in a French region (information system of the French General Health Insurance Scheme). Extraction of all buprenorphine prescriptions between September 1999 and December 2000. Definition and calculation of three quantities for each patient: delivered, prescribed and doctor-shopping quantity. The calculation of these three quantities is done by an automated and reproducible method determining the overlaps in prescription periods of different physicians for a given patient. Calculation of the corresponding daily dose was done for each quantity. RESULTS: A total of 64 326 prescriptions of buprenorphine by 1313 physicians to 3259 patients were extracted. Quantities and doses were calculated for 2587 patients. The total doctor-shopping quantity represented 18.6% of the delivered quantity. Doctor-shopping involved a minority of patients and was highly concentrated: 87 patients with doctor-shopping doses superior to 16 mg/day were responsible for 45.4% of the total doctor-shopping quantity. CONCLUSIONS: Doctor-shopping appears to be an important problem for buprenorphine maintenance treatment in France but may be resolved by regulatory interventions. The use of adequate indicators on prescription databases may help to limit the effects of such interventions on legitimate care. The method presented here may be used with slight adaptations for other medications to assess their abuse potential.

Buprenorphine↗
PubMed2004

Patterns and correlates of benzodiazepine use in the French general population.

OBJECTIVE: To investigate the prevalence of current use of benzodiazepines (BZDs) and related drugs in the French general population and factors associated with this use. METHODS: National cross-sectional telephone survey conducted between 25 April 2001 and 8 May 2001 in a representative sample of non-institutionalized adults of BZD use and duration, prescriber specialty, socio-demographic data and mood and anxiety disorders, using a structured diagnostic interview. RESULTS: The prevalence of current use of BZD was 7.5%. It was higher among women (9.7%) than men (5.2%). It increased with age and was higher in the jobless (10.9). Duration of BZD use was more than 6 months in 75.9% of users and increased with age. Of the 711 (17.7%) subjects with at least one mood or anxiety disorder, 122 (17%) used BZD compared with 180 (5.5%) of the 3296 subjects without mood or anxiety disorders. In multivariate analysis, factors associated with BZD use were age [odds ratio (OR): 3.6; 95% confidence interval (CI) 2.0-5.6], 6.5 (4.1-10.3) and 10.9 (6.9-17.1), respectively, for ages 35-44 years, 45-59 years and over 60 years compared with below 34 years, female gender (OR: 1.7; 95% CI 1.3-2.1), anxiety only (OR: 2.2; 95% CI 1.5-3.2), mood disorder only (OR: 4.4; 95% CI 2.7-7.1) or both mood and anxiety disorders (OR: 8.8; 95% CI 5.9-12.6). CONCLUSION: Despite precautions, warnings and attempts to limit use, there remains a high proportion of long-term BZD users in the general French population, especially in the elderly. Our findings add to the weight of opinion that messages concerning proper use of BZDs certainly need to be clarified and amplified.

Adult↗
PubMed2004

Incidence of agranulocytosis in Southwest France.

BACKGROUND: Updated knowledge of background event rates is fundamental to risk assessment. OBJECTIVE: To estimate the incidence of agranulocytosis in the general population in Southwest France. METHODS: All definite cases of acute non-cancer drug-related agranulocytosis in subjects aged more than 16 years were systematically retrieved weekly from Medical departments or labs in the catchment area (approximately 3.5 millions inhabitants). Event rates were compared to population figures from 1999 census data, and Poisson 95% confidence intervals computed. RESULTS: From January 1st 1997 to December 31st 1998, 87 cases of agranulocytosis were identified, 58 being validated by an independent ad hoc panel of experts. The overall annual incidence rate was 9.2 per million inhabitants (95%CI: 6.9;13.0); 7.7 (95%CI: 4.8;11.7) per million in men, and 10.5 (95%CI: 7.2; 14.8) per million in women. These rates of all-cause acute agranulocytosis can be used as expected background reference rate for specific risk assessment.

Acute Disease↗
PubMed2004

Differences between clinical trials and postmarketing use.

AIMS: 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. METHODS: Treated populations were compared with patients included in premarketing clinical trials. Comparisons were made on the basis of demographic characteristics and treatment patterns. RESULTS: 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. CONCLUSIONS: These results plead for systematic ad hoc observational postmarketing studies for any novel and/or expensive medicine to assess the relevance of premarketing data.

Adult↗
PubMed2004

Interactions between aspirin and COX-2 inhibitors or NSAIDs in a rat thrombosis model.

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.

Administration, Oral↗
PubMed2004

Comparison of patient questionnaires and plasma assays in intentional drug overdoses.

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.

Acetaminophen↗