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1.  Management of Upper Respiratory Tract Infections by Different Medical Practices, Including Homeopathy, and Consumption of Antibiotics in Primary Care: The EPI3 Cohort Study in France 2007–2008 
PLoS ONE  2014;9(3):e89990.
Prescribing of antibiotics for upper respiratory tract infections (URTI) varies substantially in primary care.
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).
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.
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.
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.
PMCID: PMC3960096  PMID: 24646513
2.  Influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood-stabilizers 
To assess the influence of three definitions of antipsychotic exposure on the comparison between first generation (FGAP) and second generation (SGAP) antipsychotic drugs and ‘conventional’ mood stabilizers towards the risk of metabolic events using (i) a dichotomous measure (exposed/non-exposed over the follow-up), (ii) a categorical measure taking into account the chronology of exposure at the time of the metabolic event (current, recent and no use) and (iii) a continuous measure (cumulative duration).
A historical fixed cohort was identified from the 2004–2006 claims database of the French health insurance programme for self-employed workers, including 3172 patients aged 18 years and over who used conventional mood stabilizers over a 3 month period. A metabolic event was defined as an incident dispensing of an anti-diabetic or lipid-lowering drug.
A metabolic event occurred in 367 patients (11.6%). At least one FGAP had been prescribed in 29% of patients who did not develop a metabolic event and in 22% of patients who developed a metabolic event. In addition, at least one SGAP had been prescribed in 12% of patients who did not develop a metabolic event and in 7% of patients who developed a metabolic event. Compared with conventional mood stabilizers, the risk of a metabolic event was negatively associated with exposure to SGAPs over the follow-up period (HR 0.53, 95% CI 0.34, 0.82, P = 0.004), positively associated with recent, but not current, exposure to SGAPs (HR 2.1, 95% CI 1.2, 3.7, P = 0.006) and not associated with cumulative duration of SGAPs (HR 1.001, 95% CI 0.999, 1.003, P = 0.20).
The definition of exposure to antipsychotics in epidemiological studies exploring their metabolic impact is of paramount importance in understanding this association. Different definitions can lead to opposite and seemingly nonsensical results. Not taking into account past exposure, in order to minimize the depletion of susceptible effects, may lead to absurd results.
PMCID: PMC3394144  PMID: 22257309
adverse event; antipsychotic; drug exposure; health insurance database; metabolic
3.  Immunomodulatory and antitumour effects of abnormal Savda Munziq on S180 tumour-bearing mice 
Abnormal Savda Munziq (ASMq), a traditional uyghur medicine, has shown anti-tumour properties in vitro. This study attempts to confirm these effects in vivo and measure effects on the immune system.
Kunming mice transplanted with Sarcoma 180 cells were treated with ASMq (2–8 g/kg/day) by intra-gastric administration compared to model and cyclophosphamide (20 mg/kg/day). After the 14th day post tumour implant, thymus, liver, spleen and tumours were removed, weighed, and processed for histopathological analysis. Blood samples were also taken for haematological and biochemical analyses including TNF-α , IL-1 β and IL-2. Splenic lymphocyte function was measured with MTT; lymphocyte subpopulations were measured by flow cytometry.
ASMq treated animals had reduced tumour volume compared to model and increased concentrations of TNF-α, IL-1β and IL-2 compared to untreated and to cyclophosphamide-treated animals. No histopathological alterations were observed. The absence of viable S180 cells and the presence of necrotic cells and granulation tissue were observed in tumour tissue of treated animals. The effect on T lymphocytes was unclear.
ASMq confirmed in vivo anti-tumour effects observed in vitro, which may be at least in part mediated by increased immune activity.
PMCID: PMC3489790  PMID: 22978453
4.  Adherence with statins in a real-life setting is better when associated cardiovascular risk factors increase: a cohort study 
While the factors for poor adherence for treatment with statins have been highlighted, the impact of their combination on adherence is not clear.
To estimate adherence for statins and whether it differs according to the number of cardiovascular risk factors.
A cohort study was conducted using data from the main French national health insurance system reimbursement database. Newly treated patients with statins between September 1 and December 31, 2004 were included. Patients were followed up 15 months. The cohort was split into three groups according to their number of additional cardiovascular risk factors that included age and gender, diabetes mellitus and cardiovascular disease (using co-medications as a proxy). Adherence was assessed for each group by using four parameters: (i) proportion of days covered by statins, (ii) regularity of the treatment over time, (iii) persistence, and (iv) the refill delay.
16,397 newly treated patients were identified. Of these statin users, 21.7% did not have additional cardiovascular risk factors. Thirty-one percent had two cardiovascular risk factors and 47% had at least three risk factors. All the parameters showed a sub-optimal adherence whatever the group: days covered ranged from 56% to 72%, regularity ranged from 23% to 33% and persistence ranged from 44% to 59%, but adherence was better for those with a higher number of cardiovascular risk factors.
The results confirm that long-term drug treatments are a difficult challenge, particularly in patients at lower risk and invite to the development of therapeutic education.
PMCID: PMC3160410  PMID: 21791073
Hydroxymethylglutaryl-CoA Reductase Inhibitors; Risk factors; Medication adherence; Databases, Factual; Pharmacoepidemiology; Insurance, Health, Reimbursement
5.  Hospitalizations for gastrointestinal and cardiovascular events in the CADEUS cohort of traditional or Coxib NSAID users 
To assess hospital admission rates for gastrointestinal (GI) or cardiovascular (CV) events in real-life use of nonsteroidal anti-inflammatory drugs (NSAIDs).
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.
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.
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.
PMCID: PMC2829700  PMID: 20233201
cardiovascular events; cohort; coxib; gastrointestinal toxicity; NSAID
6.  Who seeks primary care for musculoskeletal disorders (MSDs) with physicians prescribing homeopathic and other complementary medicine? Results from the EPI3-LASER survey in France 
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).
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.
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 were1.75; 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.
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.
PMCID: PMC3034723  PMID: 21247493
7.  The CADEUS study: burden of nonsteroidal anti-inflammatory drug (NSAID) utilization for musculoskeletal disorders in blue collar workers 
The aim of this study was to compare patterns of utilization of NSAIDs for musculoskeletal disorders (MSD) by occupation in a general employed population.
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’.
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.
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.
PMCID: PMC2668092  PMID: 19133061
drug utilization; nonsteroidal anti-inflammatory drugs; occupations; pharmacoepidemiology
8.  A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding 
To study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding.
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).
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).
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.
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.
PMCID: PMC2485248  PMID: 18507660
angiotensin receptor blockers; confounding; diabetes mellitus; pharmacoepidemiology; pharmacology; pharmacovigilance
9.  Inter-expert agreement of seven criteria in causality assessment of adverse drug reactions 
What is already known about this subjectIn 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 addsOur 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.
To evaluate agreement between five senior experts when assessing seven causality criteria and the probability of drug causation.
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.
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.
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.
PMCID: PMC2048553  PMID: 17711539
adverse drug reactions; causality assessment
11.  Differences between clinical trials and postmarketing use 
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.
PMCID: PMC1884419  PMID: 14678345
clinical trials; drug safety; drug utilization; effectiveness; postapproval
12.  Does age increase the risk of adverse drug reactions? 
PMCID: PMC1874473  PMID: 12445039
adverse drug reactions; age; pharmacovigilance; risk factor
13.  Drug reimbursement: Indicators of inappropriate resource allocation 
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.
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.
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.
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.
PMCID: PMC1874470  PMID: 12445033
drug utilization; evidence-based medicine; pharmacoeconomics; reimbursement policy
16.  Benzodiazepines and hip fractures in elderly people: case-control study 
BMJ : British Medical Journal  2001;322(7288):704-708.
To determine whether benzodiazepines are associated with an increased risk of hip fracture.
Case-control study.
All incident cases of hip fracture not related to traffic accidents or cancer in patients over 65 years of age. 245 cases were matched to 817 controls.
Emergency department of a university hospital.
Main outcome measures
Exposure to benzodiazepines and other potential risk or protective factors or lifestyle items.
The use of benzodiazepines as determined from questionnaires, medical records, or plasma samples at admission to hospital was not associated with an increased risk of hip fracture (odds ratio 0.9, 95% confidence interval 0.5 to 1.5). Hip fracture was, however, associated with the use of two or more benzodiazepines, as determined from questionnaires or medical records but not from plasma samples. Of the individual drugs, only lorazepam was significantly associated with an increased risk of hip fracture (1.8, 1.1 to 3.1).
Except for lorazepam, the presence of benzodiazepines in plasma was not associated with an increased risk of hip fracture. The method used to ascertain exposure could influence the results of case-control studies.
What is already known on this topicBenzodiazepines increase the risk of elderly people falling in a dose dependent wayTheir role in hip fracture remains disputed, with increased risk sometimes attributed to drugs with a longer half life or those used to induce sleepWhat this study addsBenzodiazepines were not associated with hip fracture either as a group or according to half life or to characterisation as hypnotic or anxiolyticPatients using two or more benzodiazepines may be at higher riskPatients using lorazepam or certain other benzodiazepines may also be at a higher risk of fracture
PMCID: PMC30096  PMID: 11264208
17.  The link between sunshine and phototoxicity of sparfloxacin 
To test the association between reporting rates for sparfloxacin-induced phototoxicity and sunlight u.v. exposure, and the effects of regulatory action.
The reporting rates for phototoxicity with sparfloxacin to the French Pharmacovigilance System or to the Drug Manufacturer were compared with concurrent national mean u.v. exposure obtained from Météo-France, before and after the regulatory restrictions and warnings.
There were 371 severe phototoxic reaction reports during the first 9 months of marketing (reporting rate of 0.4 per thousand treated patients), approximately four to 25 times that reported for other fluoroquinolones. The reporting rate correlated highly (r = 0.873, P < 0.001) with the mean monthly u.v. exposure from sunlight (from Météo-France). Regulatory action including warnings for physicians, and restricted indications dramatically decreased the number of reports, but not the reporting rate.
This is the first demonstration of a strong association between sunlight exposure in a population and drug-induced phototoxicity. Regulatory action had no effect on the reporting rate (individual exposed patient risk), though it solved the public health issue.
PMCID: PMC2015040  PMID: 10848726
phototoxicity; sparfloxacin; sunshine
18.  Patterns of neuroleptic drug prescription: a national cross-sectional survey of a random sample of French psychiatrists 
To describe the psychiatric indications of neuroleptics (especially the relative share of schizophrenic and other psychotic disorders) and the usage patterns of these drugs (dose, duration, coprescriptions).
A one-day national cross-sectional survey in a random sample of 723 French psychiatrists was carried out in 1996. Each psychiatrist was asked to complete a standardized questionnaire for the first three patients seen the day of the survey to whom at least one neuroleptic was prescribed (initiated or renewed).
One thousand seven hundred and fifty-four questionnaires were returned. Three quarters of the patients (74%) were psychotic (664 with schizophrenia, and 636 other psychosis), 19.3% were depressive and 6.7% had other psychiatric disorders. Phenothiazines were the most often prescribed (40.8%), followed by butyrophenones (22.5%), benzamides (15.8%), other neuroleptics (14.8%) and thioxanthenes (6.1%). Among schizophrenic subjects, an average number of 1.54 (95% CI: 1.50–1.60) neuroleptics were prescribed per patient, compared with 1.4 (95% CI: 1.32–1.41) and 1.2 (95% CI: 1.14–1.23) in other psychotic and depressive subjects, respectively. Regardless of the indication, non-neuroleptic psychotropic drugs were coprescribed in 75.4%, mainly benzodiazepines (75.7%). Adjuvant drugs used in prevention or treatment of side-effects were coprescribed in 46.7%, mostly anticholinergic antiparkinsonians (86.1%).
Neuroleptics are mainly prescribed for psychotic disorders and especially schizophrenia. However, current recommendations are not always followed.
PMCID: PMC2014886  PMID: 10606841
antipsychotic drugs; cross-sectional study; drug utilization study; France; pharmacoepidemiology
20.  Is reporting rate a good predictor of risks associated with drugs? 
Uncertainty as to relative under-reporting plagues the comparisons of spontaneous reporting rates as a tool for decision-making in pharmacovigilance. However, it is generally accepted that under-reporting should be reasonably similar for similar drugs sharing the same indication, country and period of marketing. To test this, we compared the adverse drug reaction reporting rates to the French regional pharmacovigilance centres for six pairs of identical drug marketed at the same time by different companies under different brand names (co-marketing).
All reaction reports were related to sales, to compute reporting rate; within each pair, the reporting rate ratio and its confidence interval were calculated.
The rate ratios were all between 0.76 and 1.33. Two of them were significantly different from 1 (1.28; 95% C.I. [1.01; 1.60] and 1.33; 95% C.I. [1.06; 1.74]).
These small differences in reporting rates would not warrant regulatory action and support the usual assumption of similar reporting for similar drugs.
PMCID: PMC2014220  PMID: 10215758
pharmacovigilance; spontaneous reporting; decision-making; pharmacoepidemiology; drugs
21.  Reports of hypoglycaemia associated with the use of ACE inhibitors and other drugs: a case/non-case study in the French pharmacovigilance system database 
Aims To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database.
Methods The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA).
Results 428 of 93338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33–48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25–2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57–112)), disopyramide (OR 32 (22–46)), nifedipine (OR 2.16 (1.32–3.51)), diltiazem (OR 1.76 (1.01–3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16–3.16)) and frusemide (OR 1.89 (1.31–1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5–1.4) and 1.2 (0.7–2.2), respectively). The same was found for other drugs except cibenzoline.
Conclusion The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.
PMCID: PMC2042872  PMID: 9384470
spontaneous reporting databases; case-non-case methodology; hypoglycaemia; ACE inhibitors; diabetics
22.  Temporal trends in spontaneous reporting of unlabelled adverse drug reactions 
Aims Trends in spontaneous reporting during the first years on the market were analyzed from a sample of selected drugs, with special attention to unlabelled effects.
Methods Ten drugs were selected giving rise to approximately 100 spontaneous reports each during the first 4 years of marketing. Case reports were identified from the national pharmacovigilance database. A bibliographical score assigned at the time of reporting was used to identify unlabelled effects. Results were expressed as reporting rates.
Results The average reporting rate peaked during the first year of marketing (54.6 per million treatment-months; s.d.:62.8), then progressively decreased during the following years. Unlabelled effects represented 63% of all the spontaneous reports during the first year.
Conclusions Unlabelled adverse effects represent a high proportion of spontaneous reports during the early years of marketing.
PMCID: PMC2042840  PMID: 9296328
spontaneous reporting; unlabelled effects
24.  Benzodiazepine use and risk of dementia: prospective population based study 
Objective To evaluate the association between use of benzodiazepines and incident dementia.
Design Prospective, population based study.
Setting PAQUID study, France.
Participants 1063 men and women (mean age 78.2 years) who were free of dementia and did not start taking benzodiazepines until at least the third year of follow-up.
Main outcome measures Incident dementia, confirmed by a neurologist.
Results During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case-control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users.
Conclusions In this prospective population based study, new use of benzodiazepines was associated with increased risk of dementia. The result was robust in pooled analyses across cohorts of new users of benzodiazepines throughout the study and in a complementary case-control study. Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against.
PMCID: PMC3460255  PMID: 23045258
25.  Benzodiazepine use and risk of Alzheimer’s disease: case-control study 
Objectives To investigate the relation between the risk of Alzheimer’s disease and exposure to benzodiazepines started at least five years before, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment.
Design Case-control study.
Setting The Quebec health insurance program database (RAMQ).
Participants 1796 people with a first diagnosis of Alzheimer’s disease and followed up for at least six years before were matched with 7184 controls on sex, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09.
Main outcome measure The association between Alzheimer’s disease and benzodiazepine use started at least five years before diagnosis was assessed by using multivariable conditional logistic regression. Ever exposure to benzodiazepines was first considered and then categorised according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half life.
Results Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).
Conclusion Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.
PMCID: PMC4159609  PMID: 25208536

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