Aurore Palmaro

Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France.

The epidemiology of immune thrombocytopenia (ITP) is not well known. The purpose of this study was to assess ITP incidence at a nationwide level (France) with recent data (mid-2009 to mid-2011; 129 248 543 person-years). The data source is the French health insurance database. We selected cases with diagnosis codes for in-hospital stays and long-term disease attributions, thus restricting our search to ITPs necessitating health care. We studied incidence by age, gender, calendar month, regions, and proportion of secondary ITPs, of ITPs becoming persistent or chronic, and of severe bleeding at disease onset. We identified 3771 incident ITP patients. Incidence was 2.9/100,000 person-years, with peaks among children and in those >60 years of age. ITP was more frequent among males in these subgroups. The incidence was lower in overseas Caribbean French departments, suggesting a lower incidence among Afro-American people. There was a north-south gradient in mainland France and seasonal variations (peak in winter and nadir in summer). Persistence or chronicity occurred in 36% of children compared with 67% of adults. Among adults, 18% of ITPs were secondary. Malignancy was the main cause (10.9%). Myelodysplastic syndromes were not rare (2.3%). Severe gastrointestinal or central nervous system bleeding at ITP onset was rare (<1%).

Analgesic drug consumption increases after knee arthroplasty: a pharmacoepidemiological study investigating postoperative pain.

Summary Preoperative pain intensity constitutes the main surgical indication of total knee arthroplasty. An increase in the use of different types of pain‐relieving drugs was found in 47% of patients during the year after surgery, providing new insights in the area of knee surgery. ABSTRACT Knee arthroplasty remains the gold standard in the treatment of severe osteoarthritis. Chronic postoperative pain has been reported with a prevalence ranging from 15% to 47%. The aim of this study was to compare analgesic drug consumption before and after surgery as an indicator of pain after knee surgery. A pharmacoepidemiological method comparing analgesics and antineuropathic issues 1 year before and 1 year after surgery was used. All patients who underwent knee arthroplasty in the Midi‐Pyrenees region (2.5 million inhabitants) were identified through the Health Insurance System Database. Increase of drug issues (all analgesics, antineuropathic drugs, strong opioids) was calculated and compared between several periods surrounding the surgery (12 months, 2 months, and 10 months before and after the knee arthroplasty). A multivariate logistic regression model was used to identify factors associated with chronic postoperative pain. The study included 1939 patients. An increase in analgesic, antineuropathic, and opioid drug consumption was observed the year after the surgery in 47.3%, 8.6%, and 5.6% of patients, respectively. Multivariate analysis found a significant association between type of surgery (total knee vs unicompartmental arthroplasty) and analgesic consumption 1 year after surgery, and between preoperative pain and psychiatric vulnerability and increase in neuropathic drug dispensing. Conversely, older age was considered as a protective factor. This study revealed that an increase in the issue of different analgesic drugs is present in half of patients 1 year after knee arthroplasty. Several associated factors of drug consumption (preoperative pain, type of surgery, and psychiatric disorder) were identified.

Off-label prescribing in pediatric outpatients.

OBJECTIVE: To study the characteristics of off-label prescribing and adverse drug reaction (ADR) occurrence in a sample of pediatric outpatients treated by general practitioners. METHODS: A survey on pediatric drug prescribing was implemented in 46 general practices in southwestern France. All consecutive patients aged 0 to 16 years were included. Patient characteristics, reasons for consultation, and drug prescribed (including indications) were collected. ADRs occurring ≤10 days after the date of consultation were recorded by the general practitioners (spontaneous notification). Off-label prescription was defined as prescribing outside the specifications of the Summary of Product Characteristics. RESULTS: Among the 2313 children seen between March 8, 2011 and July 31, 2011, 1960 were exposed to ≥1 prescribed drug. Mean age was 5.6 years, with a gender ratio of 1.1. Among children with prescriptions, 37.6% (n = 736) were exposed to ≥1 off-label prescription and 6.7% (n = 132) to ≥1 unlicensed drug. Off-label prescribing involved an unapproved indication in 56.4% of cases (n = 416), a lower dosage (26.5%, n = 195) or higher dosage (19.5%, n = 144) than specified, age not labeled (7.2%, n = 53), incorrect route of administration (3.5%, n = 26), and contraindication (0.3%, n = 2). A total of 23 ADRs were reported (1.5% of patients with off-label prescriptions). ADR occurrence was not significantly related to off-label drug prescribing. CONCLUSIONS: Despite the numerous initiatives implemented for promoting rational medicine use in children, the prevalence of off-label prescription in outpatient pediatric practice remains high.

Benzodiazepines and risk of death: Results from two large cohort studies in France and UK

Benzodiazepines are widely prescribed for the treatment of anxiety or insomnia, but their impact on mortality is still debated. This study investigated the impact of benzodiazepine use on short term mortality. Exposed-unexposed cohorts were constructed with the Clinical Practice Research Datalink (CPRD) in the UK and with the General Sample of Beneficiaries (EGB) in France. Benzodiazepine incident users were matched to incident users of antidepressants/non-benzodiazepine sedatives and to controls (non-users of antidepressants or anxiolytics/hypnotics) according to age and gender in both sources (and practice for the CPRD only). Survival at one year was studied using Cox regression model. In the CPRD, the final population comprised 94 123 patients per group (57 287 in the EGB). In the CPRD, adjusted HR was 3.73 in benzodiazepine users (95% CI, 3.43-4.06), and 1.61 (1.47-1.76) in antidepressant/non-benzodiazepine users compared to controls. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.70 (1.36-2.12). In the EGB, adjusted HR was 1.26 in benzodiazepine users (95% CI, 1.08-1.48), and 1.07 (95% CI, 0.91-1.27) in antidepressant/non-benzodiazepine users. When considering benzodiazepine use as a time-dependent covariate, adjusted HR for current use at 12 months was 1.03 (0.74-1.44). Using two nationally representative databases, we found a significant while moderate increase in all-cause mortality in relation to benzodiazepines, in a population of incident and mostly occasional users. This issue need to be monitored given the extensive use of these drugs.

First French Experience of ADR Reporting by Patients After a Mass Immunization Campaign with Influenza A (H1N1) Pandemic Vaccines

AbstractBackground: Available data concerning the contribution of patient adverse drug reaction (ADR) reporting in practice are scarce. Few studies have compared patients’ reports with reports from healthcare professionals (HCPs). During the 2009–10 mass immunization campaign with A (H1N1)v2009 pandemic influenza vaccines, a reinforced pharmacovigilance plan was introduced in France according to European Medicines Agency recommendations. For the first time, patients were offered the opportunity to report suspected ADRs to pandemic vaccines directly to regional pharmacovigilance centres. Objective: The aim of the study was to compare the characteristics of patient and HCP ADR reports in order to assess the qualitative and quantitative contribution of patient reporting to the French Pharmacovigilance System. Methods: All spontaneous ADRs registered into the French Pharmacovigilance Database from 21 October 2009 to 15 June 2010, in which either one of the most frequently administered pandemic vaccines (i.e. Panenza® or Pandemrix®) was involved, were analysed. ADRs were classified as ‘serious’, ‘medically serious’ and ‘non-serious’. This study focused on ‘serious’ and ‘medically serious’ ADRs. An ADR was ranked as ‘medically serious’ when it required medical intervention or hospitalization within less than 24 hours. In each level of seriousness, frequency of ‘unlabelled’ ADRs, ADRs of ‘special interest’, imputability scores and category of ADRs according to Medical Dictionary for Regulatory Activitives (MedDRA®) primary System Organ Class were compared between patient and professional reports. Results: Among the 4746 reports received during the study period, 1006 (21.2%) originated from patients. HCPs reported significantly more ‘medically serious’ or ‘serious’ ADRs than patients (15.1% [565/3740] vs 8.4% [85/1006], respectively; p < 0.001). No difference was found in ‘unlabelled, serious’ ADRs between patients and HCPs (56.5% [n= 13] vs 56.7% [n= 136], respectively). Conclusions: In this first French experience of formal patient participation to ADR reporting, patient contribution to the total number of ADRs reached 21.2%. This study revealed no major qualitative difference between patient and HCP reports. ADR profiles reported by patients appeared to be consistent with those from professionals. Further investigations are necessary to assess the intrinsic quality of notification forms coming from non-professional reporters. However, this study is of particular interest in the context of publication of the first governmental decree that will formally integrate patient participation to the current French ADR reporting scheme.

Role of serotonin 5-HT2C and histamine H1 receptors in antipsychotic-induced diabetes: A pharmacoepidemiological-pharmacodynamic study in VigiBase.

Pharmacodynamic mechanisms of diabetes induced by antipsychotic drugs remain unclear, while numerous receptors have been suspected to be involved in the genesis of this Adverse Drug Reaction (ADR). We investigated potential relationships between antipsychotics׳ receptor occupancy (serotonin 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, muscarinic M3, adrenergic α1, α2 or dopaminergic D2 D3 occupancies) and reports of diabetes using VigiBase(®), the World Health Organization (WHO) global Individual Case Safety Report (ICSR) database. All ADR reports from 15 first and second generation antipsychotic drugs recorded in VigiBase(®) were extracted. Logistic regression models, completed by disproportionality analysis, were used to determine the associations between antipsychotics׳ receptor occupancy and ICSRs of diabetes on VigiBase(®). During the study period, 94,460 ICSRs involved at least one of the 15 antipsychotics of interest. Diabetes was reported in 1799 (1.9%) patients. Clozapine was the most frequently suspected drug (n=953; 53.0%). A significant and positive association was found between histamine H1, muscarinic M3 and serotonin 5-HT2C, 5-HT2A receptor occupancies and reports of diabetes. A multivariable stepwise regression model showed that only serotonin 5-HT2c (AOR=2.13, CI 95% 1.72-2.64) and histamine H1 (AOR=1.91, CI 95% 1.38-2.64) predicted the risk for diabetes mellitus (p<0.001). Using an original pharmacoepidemiology-pharmacodynamic (PE-PD) approach, our study supports that antipsychotic drugs blocking simultaneously histamine H1 and serotonin 5-HT2C receptors are more frequently associated with diabetes reports in VigiBase(®) than other antipsychotics. These findings should encourage investigation of histamine H1 and serotonin 5-HT2C properties for predicting the risk of glycemic effects in candidate antipsychotics.

Corticosteroid Risk Function of Severe Infection in Primary Immune Thrombocytopenia Adults. A Nationwide Nested Case-Control Study.

Corticosteroid (CS)-related infection risk in immune thrombocytopenia (ITP) is unknown. The aim of this study was to assess the adjusted CS risk function of severe infection in persistent or chronic primary ITP adults. We designed a nested case-control study in the FAITH cohort. This cohort is built through the French national health insurance database named SNIIRAM and includes all treated incident persistent or chronic primary ITP adults in France (ENCePP n°4574). Patients who entered the FAITH cohort between 2009 and 2012 were eligible (n = 1805). Cases were patients with infection as primary diagnosis code during hospitalization. Index date was the date of first hospitalization for infection. A 2:1 matching was performed on age and entry date in the cohort. Various CS exposure time-windows were defined: current user, exposure during the 1/3/6 months preceding index date and from the entry date. CS doses were converted in prednisone equivalent (PEQ). The cumulative CS doses were averaged in each time-window to obtain daily PEQ dosages. Each CS exposure definition was assessed using multivariate conditional regression models. During the study period, 161 cases (9 opportunistic) occurred. The model with the best goodness of fit was CS exposure during the month before the index date (OR: 2.48, 95% CI: 1.61–3.83). The dose-effect relation showed that the risk existed from averaged daily doses ≥5 mg PEQ (vs. <5 mg: 2.09, 95% CI: 1.17–3.71). The risk of infection was mainly supported by current or recent exposure to CS, even with low doses.

Mortality Associated With Time in and Out of Buprenorphine Treatment in French Office-Based General Practice: A 7-Year Cohort Study

In France, most cases of opioid use disorder are treated with buprenorphine by general practitioners in private practice. Using reimbursement data of a representative sample of the French population, Echantillon Généraliste des Bénéficiaires, we investigated mortality during periods when patients were in and out of treatment in a cohort of 713 new users of buprenorphine having a mean (SD) follow-up of 4.5 (1.5) years. The mortality rate was 0.63 per 100 person-years (95% CI, 0.40–0.85) overall. In a multivariate Cox regression model, compared with being in treatment, being out of treatment was associated with a markedly increased risk of death (hazard ratio = 29.04; 95% CI, 10.04–83.99). Buprenorphine appears to be a strong protective factor against mortality.

Risk of hormonotherapy in transgender people: Literature review and data from the French Database of Pharmacovigilance.

OBJECTIVE After the diagnosis of transsexualism, hormone therapy is an established stage of gender identity disorder treatment for inducing secondary sex characteristic development of the target gender while reducing that of the birth sex. The aim of this study was to review existing data about the risk of hormone therapy in transsexual people. METHODS A PubMed search was done to identify relevant data about adverse drug reactions (ADRs) and mortality associated to hormones exposure. Furthermore, case reports of hormonal therapy-induced ADRs were identified in the French Pharmacovigilance DataBase (FPDB). RESULTS Review of currently available data showed an increase of thromboembolic effects and hyperprolactinemia with oestrogens. Both oestrogens and testosterone derivatives could induce hepatic effects. Currently, there is no significant association between hormone exposure and cancer or mortality in transsexual people. Five ADRs were found in FPDB, and two of them were related to misuse (voluntary overdose and prescription error). CONCLUSION Potential for under-reporting and under-identification in the FPDB of hormonal therapy-induced ADRs in transsexual people should be underlined. Technical improvement of the FPDB could facilitate further identification of reports concerning the risk associated with hormonal therapy in transsexual subjects.

Efficacy and safety of biologics in relapsing polychondritis: a French national multicentre study

Objectives To assess the efficacy and the safety of biologics in a cohort of patients with relapsing polychondritis (RP). Methods We conducted a French multicentre retrospective cohort study including patients treated with biologics for RP. Efficacy outcomes were clinical response (partial or complete) and complete response during the first 6 months of exposure, plus daily corticosteroid dose at 6 months. Other outcomes were adverse drug reactions (ADRs), persistence of biologics and factors associated with a response. Results This study included 41 patients exposed to 105 biologics (tumour-necrosis factor (TNF) inhibitors, n=60; tocilizumab, n=17; anakinra, n=15; rituximab, n=7; abatacept, n=6). Overall response rate during the first 6 months of exposure was 62.9%. Complete response rate was 19.0%. Reduced corticosteroid doses were highly variable among patients. ADRs were mostly infections (n=42). Reasons for biologic withdrawal (73.3%) were insufficient efficacy (34.3%; ranging from 23.5% for tocilizumab to 72.7% for etanercept), loss of efficacy (18.1%) and ADRs (20.9%; mostly for anakinra: 46.7%). Persistence was comparable among biologic classes. Among TNF inhibitors, the highest persistence was observed with adalimumab. Differences in clinical response rates were observed depending on biologics and organ involvement. There were trends towards a lower response rate in cases with associated myelodysplastic syndrome and for a higher response rate for nasal/auricular chondritis, sternal chondritis and concomitant exposure to non-biologic disease-modifying antirheumatic drugs. Conclusions This study describes the efficacy of biologics for refractory RP. However, the number of complete responses was low and there were concerns about the risk of ADRs, particularly infections.