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Background: In addition to the clinical burden, asthma is responsible for a high economic burden. However, little is known about the economic burden of asthma prior to death., Objective: We performed an economic analysis to describe the costs during 12 and 24 months prior to asthma death between 2013 and 2017 in France., Methods: An observational cohort study was established using the French national health insurance database. Direct medical and non-medical costs, as well as costs related to absence from the workplace, were included in the analysis., Results: In total, 3,829 patients were included in the final analysis. Over 24 and 12 months prior to death, total medical costs per patient were €27,542 [26,545-28,641] and €16,815 [16,164-17,545], respectively. Total medical costs clearly increased over 24 months prior to death. Over 12 months prior to death, costs increased significantly according to age categories, with mean total costs of €8,592, €15,038, and €17,845, respectively, for the categories <18 years old, 18-75 years old, and 75+ years old ( p  < 0.0001). Over 12 months prior to death, costs were statistically higher in patients with a dispensation of six or more SABA canisters compared to those with a dispensation of five or less canisters ( p  < 0.0001). In multivariate analysis, comorbidities, hospital as location of death, and dispensation of 12 or more canisters of SABA per year are independent factors of the highest costs., Conclusion: To conclude, the economic burden of asthma death is high and increases with time, age, and SABA dispensation., Competing Interests: LG has been an investigator in clinical trials for AstraZeneca, MSD and Novartis, reports grants or consultation fees from AstraZeneca, GlaxoSmithKline, Novartis and Sanofi-Regeneron, and consultation fees from Bayer, Chiesi, MSD, not related to the work submitted. AD reports consultation fees from AstraZeneca, GlaxoSmithKline, Novartis, Sanofi-Regeneron, Chiesi, ALK and Stallergenes, not related to the work submitted. LR reports consultations fees from Argenx, Neovacs and Novartis, not related to the work submitted. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guilleminault, Mounié, Sommet, Camus, Didier, Reber, Conte and Costa.)

The French health insurance data warehouse named SNDS is one of the largest medico-administrative in the world allowing for powerful pharmacoepidemiological studies, based on real-life data collected prospectively. In addition to the absolute necessity of a strong pharmacological rationale, recommendations have been thought to improve the quality of pharmacoepidemiological studies. These guidelines emphasize the importance of an accurate definition of the study population, outcome and exposure, especially for studies performed on medico-administrative databases. Compliance with certain guidelines, particularly those concerning the identification of a specific population or an outcome and the definition of risk periods or exposure periods, may be difficult when performing studies on the SNDS because of its structure and the nature of the data recorded. The objective of this article is to provide advice for the conduct of pharmacoepidemiological studies according to the recommendations when using the SNDS, given its specificities. The performing of reliable studies from this rich but complex data warehouse requires the expertise of researchers with deep knowledge both in the SNDS and in pharmacological reasoning., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The French health insurance data warehouse named SNDS is one of the largest medico-administrative in the world allowing for powerful pharmacoepidemiological studies, based on real-life data collected prospectively. In addition to the absolute necessity of a strong pharmacological rationale, recommendations have been thought to improve the quality of pharmacoepidemiological studies. These guidelines emphasize the importance of an accurate definition of the study population, outcome and exposure, especially for studies performed on medico-administrative databases. Compliance with certain guidelines, particularly those concerning the identification of a specific population or an outcome and the definition of risk periods or exposure periods, may be difficult when performing studies on the SNDS because of its structure and the nature of the data recorded. The objective of this article is to provide advice for the conduct of pharmacoepidemiological studies according to the recommendationswhen using the SNDS, given its specificities. The performing of reliable studies from this rich but complex data warehouse requires the expertise of researchers with deep knowledge both in the SNDS and in pharmacological reasoning., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: Pharmacokinetic interactions exist between apixaban or rivaroxaban, and CYP3A4 and P-glycoprotein inhibitors such as amiodarone, verapamil and diltiazem. We aimed to estimate the prevalence of exposure to this drug-drug association (DDA) and to assess the bleeding risk associated in patients with atrial fibrillation (AF)., Methods: We conducted a cohort study using a representative 1/97 th sample of the French healthcare insurance database between 2014 and 2019. Patients with AF receiving apixaban or rivaroxaban were included and followed-up until hospitalization for bleeding, death, discontinuation of apixaban or rivaroxaban, exposure to strong CYP3A4 inhibitor, or until December 31 st 2019, whichever came first. Primary outcome was hospitalization for bleeding registered as primary diagnosis. The association between the exposure to the DDA and hospitalization for bleeding was evaluated as a time-dependent variable in Cox model., Results: Between 2014 and 2019, the AF population under apixaban or rivaroxaban represented 10,392 patients. During the study period, the annual average prevalence of DDA exposure in this population was 38.9%. Among the 10,392 patients, 223 (2.1%) were hospitalized for bleeding, of which 75 (33.6%) received the association and 148 (66.4%) received apixaban or rivaroxaban alone. There was no association between DDA exposure and risk of hospitalization for bleeding (aHR = 1.19, [95% CI: 0.90, 1.58]). Age (HR 1.03 [1.02, 1.05]) and male gender (HR 1.72 [1.28, 2.30]) were associated with an increased risk of hospitalization for bleeding., Conclusion: Exposure to antiarrhythmic drugs was not associated with an increased risk of hospitalization for bleeding in patients with AF under rivaroxaban or apixaban., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF., Methods: Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias., Results: Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis., Conclusions: The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Population-based data on the epidemiology of progressive multifocal leukoencephalopathy, its predisposing conditions and mortality rate are lacking, although such data are crucial to raise awareness among clinicians and to lay foundations for future therapeutic trials in immunomodulating therapies. In our study, patients were identified by interrogating the French national healthcare reimbursement database from 1 January 2008 to 31 December 2017, using progressive multifocal leukoencephalopathy International Classification of Diseases code and a patient's selection algorithm. Overall incidence rate, 1-year all-cause mortality rate and survival patterns were calculated, and factors associated with death were identified using a multivariate Cox proportional hazards regression model. Our cohort is the largest to date, comprising 584 patients with incident progressive multifocal leukoencephalopathy. The overall incidence in France from 2010 to 2017 was stable during the study period at 0.11 per 100 000 person-years, 95% confidence interval [0.10-0.12]. Predisposing diseases were HIV infection (43.7%), followed by haematological malignancies (21.9%), chronic inflammatory diseases (20.2%), solid organ transplantation (4.3%), solid neoplasm (4.1%) and primary immune deficiency (1.5%). The 1-year mortality rate was 38.2%, with a 95% confidence interval (34.2-42.2). In multivariate analysis, factors independently associated with death were older age [adjusted hazard ratio 0.33 (0.20-0.53) for patients aged 20 to 40 compared with patients aged over 60], male gender [adjusted hazard ratio 0.73 (0.54-0.99) for females compared with males] and predisposing immunosuppressive disease, with the highest risk for solid neoplasms [adjusted hazard ratio 4.34 (2.25-8.37)], followed by haematological malignancies [adjusted hazard ratio 3.13 (1.85-5.30)] and HIV infection [adjusted hazard ratio 1.83 (1.12-3.00)], compared with chronic inflammatory diseases. Immune reconstitution inflammatory syndrome was notified in 7.0% of patients. In conclusion, incidence of progressive multifocal leukoencephalopathy is stable in France, and HIV infection remains the main predisposing disease. This large-size cohort uncovers a higher risk of mortality for male patients compared to females, and the worst prognosis for patients with solid neoplasm, while prognosis in patients with haematological malignancies appeared less dismal than in previous studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The advent of chronic myeloid leukaemia (CML) tyrosine-kinase inhibitors (TKI) has led to new paradigms including occupational rehabilitation., Objectives: This study aimed to characterize the impact of CML treatment on sick leaves within the 2 years following diagnosis in working-age patients., Methods: A cohort of all 18-60-year-old newly diagnosed CML patients initiating a TKI between January 1 st 2011 and December 31 st 2014 in France was identified in the French National Healthcare database (Système National des Données de Santé [SNDS]). Patients with a sick leave identified in the 24 months after TKI initiation were compared with sex and initiation date matched controls in a nested case-control design. Factors associated with sick leaves were identified through a conditional logistic regression model, providing adjusted odds-ratio (OR) with their 95% confidence interval (CI)., Results: Among 646 18-60-year-old patients, 268 were prescribed at least one sick leave in the study period, with 176 (27.2%) having their first sick leave prescribed after TKI initiation. The median number of sick days over the 2-years period was 115 per patient (interquartile range 25.5-384.5). In the nested case-control study (176 cases and 176 matched controls), sick leaves were more likely observed with second generation TKI (OR 4.11 [1.80-9.38]), whereas they were less likely observed in case if social deprivation (OR 0.07 [0.02-0.28]., Conclusion: More than 25% of working-age CML patients had at least one sick leave within 2 years of TKI initiation, with a higher impact of second generation TKI, and with a median duration of 115 days., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Concomitant nonsteroidal anti-inflammatory drug (NSAIDs) and antithrombotic drug use is associated with an increased risk of bleeding, mainly gastrointestinal. The goal of this study was to quantify the transient increase in the risk of hospitalization for bleeding associated with NSAID use in patients treated with antiplatelet agents or anticoagulants. We performed a unidirectional case-crossover study using the EGB (Échantillon généraliste de bénéficiaires), a permanent random sample of the French nationwide health database. Patients receiving antithrombotic therapy and hospitalized for bleeding between 2009 and 2017 were included. We compared their NSAID exposure during a 15-day hazard window immediately before hospital admission to 3 earlier 15-day control windows. The risk of hospitalization for bleeding associated with the recent use of NSAIDs was estimated using conditional logistic regression to estimate odds ratios (ORs). During the study period, 33 patients treated with anticoagulants and 253 treated with antiplatelet agents received NSAIDs and were included in the case-crossover analysis. We found an increased risk of hospitalization for gastrointestinal bleeding after exposure to NSAIDs, with an adjusted OR of 3.59 (95%CI, 1.58-8.17) in patients receiving anticoagulant therapy and 1.44 (95%CI, 1.07-1.94) in patients receiving antiplatelet therapy. The risk of nongastrointestinal bleeding was also increased after exposure to NSAIDs with an adjusted OR of 2.72 (95%CI, 1.23-6.04) in patients exposed to anticoagulant therapy. The risk of gastrointestinal and nongastrointestinal bleeding increases after NSAID use in patients treated with anticoagulants, while the risk of gastrointestinal bleeding increases, but to a lesser extent in those treated with antiplatelets., (© 2021, The American College of Clinical Pharmacology.)

In the 2000s, newer generations of drugs appeared on the market called drugs of targeted therapy (TT) drugs. The introduction of TT in oncology has profoundly changed the prognosis of many cancers but also introduced a wide variety of adverse drugs reactions (ADR), including in particular dermatological adverse drug reactions (DADRs). We investigated the evolutions of the notifications of DADRs of anticancer drugs since 2000s in international pharmacovigilance data. For this purpose, we separated non-targeted therapy and targeted therapy. During the period from 01/01/2000 to 31/12/2017, 1,226,252 ICSRs (8.7%) were related to anticancer drugs, among them concerning anticancer drugs, 192,108 cases (15.6%) contained at least one MedDRA term for "skin and subcutaneous tissue disorders" system organ classes. The DADRs of anticancer drugs are in constant increase on the period 2000 to 2017, from 0.91% to 1.90% of the total ADR of Vigibase®. The number of DADRs drugs in the non-targeted therapies class remained stable during this period, while the DADRs of targeted therapy drugs increased and exceeded those of non-targeted therapy in recent years. Using a disproportionality analysis, we found that targeted therapy drugs are associated with a higher risk of reporting DADRs of the type: dermatitis acneiform, hair color changes, acne, and hyperkeratosis and skin toxicity. While, non-targeted therapy drugs are associated with a higher risk of reporting DADRs of the type: skin hyperpigmentation, nail discoloration, dermatitis exfoliative, Hyperhidrosis and alopecia. TT drugs are used more and more for cancer indications and even beyond. This problematic of DADR will become more and more common and should benefit from specialized support with the organization of a coordinated network of professionals., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Background: Although asthma mortality declined sharply until the mid-2000s, a stagnation in mortality has been observed over the past decade in different countries., Objective: The objective of this study is to describe healthcare resource consumption for patients who died from asthma in France., Method: This study was conducted using data from the French National Health Data System. Patients who died from asthma between 2013 and 2017 were identified by the ICD10 codes J45 and J46. Health care consumption data were collected. Patients were categorized into four categories according to age: ⩾75, (18-75), (12-18), (0-12). Daily doses of ICS were categorized according to GINA guidelines., Results: A total of 3829 patients were included. No ICS or an inadequate ICS dose was observed in 43.8%, 50.6%, 48.1%, and 54.0% of patients aged ⩾75, (18-74), (12-18), and (0-12) years, respectively. Dispensation of six or more SABA canisters was observed in 37.2%, 49.0%, and 70.3% of patients aged of ⩾75, (18-75), and (12-18) years, respectively. Omalizumab dispensation rate was very low [1.1% and 2.8% in patients aged ⩾75 and (18-75) years)]. The proportion of patients with a pulmonologist office visit was 13.8% and 14.6% in patients ⩾75 and (18-75) years, respectively. A lung function test was noted in only 18.6%, 28.3%, and 25.9% of patients ⩾75, (18-75) and (12-18) years, respectively., Conclusion: Half of the patients who died from asthma received inadequate ICS doses and only a small proportion had access to biological therapies. Less than 15% were referred to a specialist.

We analyzed demographic characteristics, comorbidities and patterns of treatment with tyrosine kinase inhibitors (TKIs) in a cohort of 3,633 incident cases of chronic myeloid leukemia (CML) identified across France from 1 January 2011 to 31 December 2014. Patients were identified through a specific algorithm in the French Healthcare Data System and were followed up 12 months after inclusion in the cohort. The estimated incidence rate of CML for this period in France was 1.37 per 100,000 person-years (95% Confidence Interval 1.36-1.38) and was higher in men, with a peak at age 75-79 years. At baseline, the median age of the cohort was 60 years (Inter Quartile Range 47-71), the Male/Female ratio was 1.2, and 25% presented with another comorbidity. Imatinib was the first-line TKI for 77.6% of the patients, followed by nilotinib (18.3%) and dasatinib (4.1%). Twelve months after initiation, 86% of the patients remained on the same TKI, 13% switched to another TKI and 1% received subsequently three different TKIs. During the follow-up, 23% discontinued and 52% suspended the TKI. Patients received a mean of 16.7 (Standard Deviation (SD) 9.6) medications over the first year of follow-up, and a mean of 2.7 (SD 2.3) concomitant medications on the day of first TKI prescription: 24.4% of the patients received allopurinol, 6.4% proton pump inhibitors (PPI) and 6.5% antihypertensive agents. When treatment with TKI was initiated, incident CML patients presented with comorbidities and polypharmacy, which merits attention because of the persistent use of these concomitant drugs and the potential increased risk of drug-drug interactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pajiep, Conte, Huguet, Gauthier, Despas and Lapeyre-Mestre.)

Purpose: Infections are frequent and often result in serious complications in patients with multiple myeloma (MM). Prophylactic vaccination is recommended for influenza virus, Streptococcus pneumoniae (SP) , and Hemophilus influenzae b (Hib) . The aims of this study were to measure the vaccination rates within 24 months after the diagnosis of multiple myeloma and to identify factors associated with vaccine use., Methods: MM patients were selected through the French national health insurance database from 1 January 2010 to 31 December 2015. Patients with a previous history of MM were excluded., Results: Vaccination rates against influenza, SP, and Hib among 22,831 newly diagnosed MM patients were, respectively, 28.5%, 10.3%, and 1.4%. Only 0.7% received all three vaccines. Factors associated with vaccination were young age, male gender, an absence of comorbidity, a history of higher medication and vaccine consumption, Herpes simplex virus (HSV), Varicella zoster virus (VZV), and the use of pneumocystis prophylaxis., Conclusion: The low rates of vaccination indicate the need to improve physician and MM patient adherence and education regarding vaccination.

Purpose: Drug-drug interactions (DDIs) require monitoring in an aging population with increasing polypharmacy exposure. We aimed to estimate the prevalence of exposure to potential DDIs using the French healthcare insurance system database, for six DDIs with various clinical relevance: angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs (ARBs-ACEIs + NSAIDs), antiplatelet agents and NSAIDs (AAP + NSAIDs), serotonergic drugs and tramadol (SD + T), statins and macrolides (S + M), oral anticoagulant and NSAIDs (OAC + NSAIDs), and colchicine and macrolides (C + M)., Methods: We used exhaustive healthcare data from a 1/97th random sample of the population covered by the French health insurance system (EGB) between 2006 and 2016. Exposure to a DDI was defined as overlapping exposure to two interacting drugs. The prevalence of exposure was estimated by year., Results: Prevalence of exposure in 2016 was estimated at 3.7% for ARBs-ACEIs + NSAIDs, 1.5% for AAP + NSAIDs, 0.76% for SD + T, 0.36% for S + M, 0.24% for AOC + NSAIDs, and 0.02% for C + M. In 26% to 58% of episodes of exposure, the two interacting drugs were prescribed by the same physician and dispensed by the same pharmacy the same day. Between 2006 and 2016, the yearly prevalence was increasing for SD + T and for DDIs involving NSAIDs, and it was decreasing for those involving macrolides., Conclusion: Exposures to potential DDIs in France are not uncommon with a high proportion resulting from a co-prescription by the same physician. Monitoring the prevalence of exposure to DDIs is needed to implement prevention measures. Administrative data enable this surveillance in large and representative cohorts.

Psychotropic drugs (PD) are often used close to a cancer diagnosis and may be considered as a way of coping. We aimed to determine the incidence of anxiolytics, hypnotics, antidepressants, and antipsychotics initiation around a diagnosis of chronic myelogenous leukemia (CML). Population-based cohort: Data were extracted from Systeme National des données de Santé (SNDS, the French health insurance database) at the regional level (Midi-Pyrenees area, 2.9 million inhabitants). All newly diagnosed patients treated by a CML tyrosine kinase inhibitor (TKI) between 10/01/2011 and 04/01/2014 were included. Pre-CML (9 months before to 3 months before first TKI prescription-F-TKI) and CML (3 months before to 9 months after F-TKI) phases were defined. The main evaluation criterion was the initiation of PD during CML phase. Determinants associated with this incident PD use were studied through a logistic regression model. We compared pre-CML and CML healthcare consumption. The cohort included 103 patients (mean age of 60.8 years). PD initiation rate was 35.9%, anxiolytics being the most initiated PD (59.5%). Advanced age was associated with PD initiation (adjusted OR = 1.029, 95% CI = 1.001-1.056). The number of consultations during the pre-CML phase and female gender tended to be associated with increased risk of PD initiation in univariate analysis. For PD initiators, healthcare consumption was greater in CML but not in pre-CML phase. PD initiation is a frequent finding around a CML diagnosis. Its risk increases with age. It could be a way to identify a subgroup with higher healthcare consumption., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

In adults, statins safety profile is well known. However, literature data on their adverse drug reactions (ADRs) remain scarce in children in real-life setting. In order to better characterize ADRs related to 'real-life' use of statins in children, we reviewed statin-related ADRs recorded in the World Health Organization (WHO) global database of individual case safety reports (ICSRs), VigiBase. Methods. Individual case safety reports (ICSRs) in children (2-11 years) and adolescents (12-17 years) associated with statins from January 1, 1987, to July 18, 2017, were extracted from VigiBase. Characteristics of ICSRs, type of ADRs according to MedDRA classification (SOC and PT), and ICSR seriousness were described using SAS 9.4. A total of 311 ICSRs were identified for 8 statins with 712 ADRs. Musculoskeletal disorders (n = 85, 27.3%) were the first registered ADRs followed by general disorders (n = 67, 21.5%; mainly asthenia and pain). More than 1 out of 5 ADRs were 'injury, poisoning and procedural complications' (n = 67), mainly accidental or intentional exposures (n = 44, 14.1%), overdoses (n = 14, 4.5%), or off-label use (n = 11, 3.5%). Overall, 133 (42.8%) reports were 'serious', including 11 deaths. Deaths mainly involved adolescents with intentional overdose and completed suicide with other associated drugs in 75% of reports. Our study identified rare but serious safety issues (rhabdomyolysis, myalgia, and hepatocellular injury). These ADRs can impact quality of life or lead to life-threatening complications in children. Our results should be supplemented with other data sources. Spontaneous statin ADR reports in children to pharmacovigilance networks must be promoted., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Background: Potential relationships between β-adrenergic drugs and α-synuclein synthesis in Parkinson's disease (PD) have been recently suggested., Objective: This study investigated the putative association between β-adrenoceptor drug exposure and PD occurrence., Methods: A nested case-control study was performed in the Echantillon Généraliste des Bénéficiaires (EGB) (a 1/97th random sample of affiliates to the French Insurance System). Incident PD patients diagnosed between 01/01/2008 and 31/12/2017 (index date) were matched 1:1 to controls by gender, birth year, and insurance scheme. Exposure to any β-agonist and to any β-antagonist was compared between cases and controls within 1-2 years before the index date, and exposure to salbutamol and to propranolol was individualized. The association between PD and β-adrenoceptor drugs was investigated through conditional logistic regression models adjusted for potential confounding factors. Because of a statistical interaction between β-agonists and diabetes, results were stratified according to the presence of diabetes., Results: Among the 2225 incident PD patients identified in the EGB (mean age 75.6 ± 10.2 years, sex ratio 1.04), no significant association was found between PD and β-antagonists (adjusted odds ratio [aOR] 1.05 [95% confidence interval 0.91-1.20]), except for propranolol (aOR 2.11 [1.38-3.23]). For β-agonists, a protective association in non-diabetic patients (aOR 0.75 [0.60-0.93]) and an opposite and significant association in diabetic patients (aOR 1.61 [1.02-2.55]) were observed. Similar results were found with salbutamol., Conclusion: This study did not identify an increased risk of PD occurrence after β-antagonist exposure, except for propranolol (potential protopathic bias). The discordant results observed with β-agonists in patients with or without diabetes deserve further exploration of the influence of diabetic comorbidity on PD occurrence and evolution.

Background: Lymphomas are costly diseases that suffer from a lack of detailed economic information, notably in a real-world setting. Decision-makers are increasing the search for Real-World Evidence (RWE) to assess the impact, in real-life, of healthcare management and to support their public decisions. Thus, we aimed to assess the real-world net costs of the active treatment phases of adult Hodgkin Lymphoma (HL), Follicular Lymphoma (FL) and Diffuse Large B Cell Lymphoma (DLBCL). Methods: We performed a retrospective cohort study using population-based data from a national representative sample of the French population covered by the health insurance system. Cost analysis was performed from the French health insurance perspective and took into account direct and sick leave compensation costs (€2,018). Healthcare costs were studied over the active treatment phase. We used multivariate modeling to adjust cost differences between lymphoma subtypes. Results: Analyses were performed on 224 lymphoma patients and 896 controls. The mean additional monthly costs due to HL, FL and DLBCL patients were respectively €5,188, €3,242 and €7,659 for the active treatment phase. The main additional cost driver was principally inpatient stay (hospitalization costs and costly cancer-related drugs), followed by outpatient medication and productivity loss. When adjusted, DLBCL remains significantly the most costly lymphoma subtype. Conclusion: This study provides an accurate assessment of the main lymphoma subtypes related cost with high magnitude of details in a real-world setting. We underline where potential cost saving could be realized via the use of biosimilar medication, and where lymphoma management could be improved with the early management of adverse events.KEY POINTSThis is one of the first studies which assess the additional cost of lymphoma in Europe, according the main sub-types of lymphoma and with real-world database.The additional monthly cost due to HL, FL and DLBCL patients were respectively €5,188, €3,242 and €7,659 for the active treatment phase and the main additional cost driver was principally inpatient stay (i.e. hospitalization costs and additional inpatient medicines, notably rituximab), followed by outpatient medication and productivity loss.This study provides an accurate and detailed lymphoma subtype cost description and comparison which supply data for efficiency evaluations and will allow French health policy to improve lymphoma management.

Background: Previous studies have suggested that lymphoma survivors commonly display altered Health-Related Quality of Life (HRQoL). Because these were predominantly cross-sectional studies, the dynamic of events as well as the factors which influence HRQoL remain to be determined., Methods: We conducted a prospective study on a cohort of 204 Hodgkin and non-Hodgkin lymphoma survivors who remained disease-free 2 years after undergoing chemotherapy (referred to the M0-M12-M24 periods)., Results: We found that although Physical and Mental Component Scores (PCS and MCS) of HRQoL significantly improved from M0 to M24 in the vast majority of patients (favorable group), approximately 20% of patients displayed severe alterations in HRQoL (global SF-36 scores < 50) extending over the 2-year period (unfavorable group). Low M24 PCSs were associated with Post-Traumatic Stress Disorder (PTSD), depression, cardiovascular events and neuropathy. In contrast social determinants, comorbidity and infections, as well as several other parameters related to the disease or to the treatment itself were not associated with low M24 PCSs. Low M24 MCSs were associated with a low educational level, aggressive histology, infections, cardiovascular events and PTSS. However, the most predictive risk factor for low SF-36 scores at M24 was a low SF-36 score at M12. The unfavorable group also displayed a low incidence of return to work., Conclusions: Although the HRQoL of lymphoma survivors generally improved over time, persistent and severe HRQoL alterations still affected approximately one fifth of patients, resulting in important social consequences. This specific group, which presents with identifiable risk factors, may benefit from early, targeted psycho-social support.

Patients suffering from B-cell non-Hodgkin lymphomas (B-NHL) have an increased likelihood of being exposed to proton pump inhibitors (PPIs), related to several factors which have been reported in the literature. PPIs are among the drugs most likely to be prescribed inappropriately. Consequently, B-NHL patients could be particularly at risk of inappropriate PPI prescription, with potential adverse drug reactions. We aimed to evaluate the incidence of PPIs use and to identify factors associated with PPIs initiation during the active treatment phase of B-NHL. We conducted a new-user cohort study using regional data from the French national health insurance database in the Midi-Pyrénées region (southwestern France). Incident B-NHL patients were selected according to an algorithm of selection, validated with data from a cancer registry. Our study revealed that 48.9% (95% confidence interval [CI]: 45.2-52.6) of patients initiated PPIs during chemotherapy after B-NHL diagnosis. According to information available in the SNDS, recommended indications for PPI prescriptions were identified in 21.1% of cases. Median duration of treatment was 65.3 days (CI: 35-112). Determinants of PPIs initiation were peptic ulcer disease, gastroprotection (appropriate or not) for medications considered at risk (NSAIDs, glucocorticoids and anticoagulants), age, nonfollicular lymphoma, polypharmacy, gastroenterologists' consultations and being hospitalized in a university hospital. Around 50% of patients initiated PPI treatment during the chemotherapy phase with only one-fifth identified as appropriate prescriptions and with long durations of treatment in most cases. Given this background, appropriate PPI prescription should be promoted in B-NHL to avoid potential inappropriate chronic use and related adverse events., (© 2018 Société Française de Pharmacologie et de Thérapeutique.)

Some concerns have emerged about the evidence of benefits on survival outcomes or quality of life of new anticancer drugs. In parallel, the decreased cancer mortality leads to an increased number of patients exposed to cancer treatment-related consequences. In this context, pharmacoepidemiology is crucial to assess anticancer drug use, effectiveness and safety in real life conditions. We aimed to describe strengths, limitations and considerations associated with the use of the French national health insurance database (système national des données de santé [SNDS]) to conduct pharmacoepidemiological studies in oncology. The SNDS represents a powerful tool in pharmacoepidemiology owing to its extensive coverage, accurate description and quantification of drug exposure and individual data on patients. The main limitations of this database ensue from the administrative nature resulting in technical difficulties in its management and gaps in availability of data. Another limitation is the lack of accurate identification of diseases, comorbidities or outcomes and potential confounding with notably the lack of data regarding cancer stage, prognosis or risk factors. Finally, the accurate identification of the nature of chemotherapy received by patients is sometimes complex. To minimize these limitations, several approaches and statistical methods could be used as highlighted by national or international initiatives. First, the SNDS may be linked with cancer registry or clinical data. Then, several data sources could be combined using meta-analytical methods. The development of methodological tools and the use of standardized methods are crucial to enhance the quality of studies that can impact clinical practice and guide public decision. Pharmacoepidemiological approaches and pharmacovigilance represent an important cornerstone in oncology for signal detection or long-term follow up of cancer patients. In this context, validated methods to identify cancer patients and to describe chemotherapy regimens within these data should be promoted and remain too scarce despite international guidelines. Moreover, limits and strength of each data sources should be systematically discussed according to the research question. Optimized and framed use of claims database represents a future challenge in onco-pharmacoepidemiology., (Copyright © 2019 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: This study explored the use of non-cancer drugs in lymphoma survivors during the early trajectory (0 to 2 years) of cancer survivorship and determined the factors that influenced this consumption., Methods: Between January and March 2014, a cross-sectional survey was conducted to assess drug consumption in adult lymphoma survivors at the Toulouse University Hospital. This study was based on a questionnaire consisting of ten open questions related to medical prescription and/or self-medication occurring within the last 3 months., Results: A total of 83/103 lymphoma survivors returned the questionnaire. This study showed that 91.6% of patients were drug consumers (about twice more than the general French population). Twenty percent of patients were treated with≥5 drugs. Overall drug consumption mainly concerned analgesics, anti-inflammatory drugs and psychotropics. The presence of comorbidity, urban residence and female gender were associated with overall drug consumption. Moreover, half of survivors required at least one self-medication. Finally, only seven survivors (8.4%) reported no use of any medication., Conclusion: This study shows that, at least during the early trajectory of cancer survivorship, lymphoma patients are heavily treated with non-cancer drug therapy. This drug consumption profile may have serious implications in terms of safety, overall benefit and health economics., (Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

The use of claims database to study lymphomas in real-life conditions is a crucial issue in the future. In this way, it is essential to develop validated algorithms for the identification of lymphomas in these databases. The aim of this study was to assess the validity of diagnosis codes in the French health insurance database to identify incident cases of lymphomas according to results of a regional cancer registry, as the gold standard.Between 2010 and 2013, incident lymphomas were identified in hospital data through 2 algorithms of selection. The results of the identification process and characteristics of incident lymphomas cases were compared with data from the Tarn Cancer Registry. Each algorithm's performance was assessed by estimating sensitivity, predictive positive value, specificity (SPE), and negative predictive value.During the period, the registry recorded 476 incident cases of lymphomas, of which 52 were Hodgkin lymphomas and 424 non-Hodgkin lymphomas. For corresponding area and period, algorithm 1 provides a number of incident cases close to the Registry, whereas algorithm 2 overestimated the number of incident cases by approximately 30%. Both algorithms were highly specific (SPE = 99.9%) but moderately sensitive. The comparative analysis illustrates that similar distribution and characteristics are observed in both sources.Given these findings, the use of claims database can be consider as a pertinent and powerful tool to conduct medico-economic or pharmacoepidemiological studies in lymphomas., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

This study aimed to assess the performance of several algorithms based on hospital diagnoses and the long-term diseases scheme to identify multiple myeloma patients.Potential multiple myeloma patients in 2010 to 2013 were identified using the presence of hospital records with at least 1 main diagnosis code for multiple myeloma (ICD-10 "C90"). Alternative algorithms also considered related and associated diagnoses, combination with long-term conditions, or at least 2 diagnoses. Incident patients were those with no previous "C90" codes in the past 24 or 12 months. The sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) were computed, using a French cancer registry for the corresponding area and period as the criterion standard.Long-term conditions data extracted concerned 11,559 patients (21,846 for hospital data). The registry contained 125 cases of multiple myeloma. Sensitivity was 70% when using only main hospital diagnoses (specificity 100%, PPV 79%), 76% when also considering related diagnoses (specificity 100%, PPV 74%), and 90% with associated diagnoses included (100% specificity, 64% PPV).In relation with their good performance, selected algorithms can be used to study the benefit and risk of drugs in treated multiple myeloma patients.

Purpose: Patients with B cell non-Hodgkin's lymphomas (B-NHLs) are known to be at risk of developing psychological disorders. The aims of this study were to measure the incidence of psychotropic drug use during the diagnosis and the active treatment phase in comparison with controls from the general population, and to identify factors associated with this use., Methods: B-NHL patients were selected through the French national health insurance database in the Midi-Pyrénées region (southwestern France) from January 1, 2011, to April 31, 2013. Patients with a previous history of B-NHL and/or psychotropic drug treatment were excluded., Results: Among 745 newly diagnosed B-NHL patients, psychotropic treatment was initiated in 31.5 % (95 % CI [28.1-34.9]), compared to 7.6 % (95 % CI [7.57-7.64]) in the general population during the same period. This incidence was comparable in colorectal cancer patients (33.5 %) but higher than that in patients with myocardial infarction (23.5 %) or with a first knee replacement surgery (22.4 %). Anxiolytics and hypnotics were the most frequently used drugs. Median duration of treatment was 37 days for anxiolytics and 58 days for hypnotics, with 20.8 % of patients remaining under treatment at 8 months. Factors associated with psychotropic drug initiation were young age, health care consumption in the year before diagnosis, and initial care at a university hospital., Conclusion: The high rate of psychotropic drug initiation reflects a high level of anxiety at the initial phase of B-NHL patients' trajectory. This pharmacoepidemiological study reveals inappropriate use in some patients, which should now be investigated in lymphoma survivorship.

Background: To prevent abdominal organs' traumas in crash situations, the definition of efficient safety devices should be based on a detailed knowledge of human tolerance, i.e., injury mechanisms and related injury criteria. This knowledge should be based on experimental observation of these mechanisms through damage and failure analysis., Methods: In this study, 10 human cadaveric livers are uniaxially compressed using three different loading velocities (0.0013, 0.2, and 1 m/s). Injuries induced are analyzed at two observation levels through a macroscopic study of internal and external cracks and a histologic study of damage initiation., Results: Liver global behavior is similar for the three loading velocities, but loading rate seems to influence the stiffness and the severity of failure process. Macroscopic injury analysis showed four patterns of laceration because of organ spreading during its compression exhibiting liver structure incidence. Histologic analysis shows two different damage occurrences: microcracking and cavitation. The crack propagation is observed to occur preferentially within the lobules. Influence of the vascular system is also highlighted. Both macroscopic and histologic injuries obtained are relevant with those clinically observed under trauma situations., Conclusion: Based on experimental investigation of human liver under compression, this work provides a multiscale evaluation of injury process coupling mechanical and histologic analysis. Injury mechanisms postulated involve vascular structures and capsule. All this information is essential for the design of dedicated behavior laws and finite element models.

To prevent traumas to abdominal organs, the selection of efficient safety devices should be based on a detailed knowledge of injury mechanisms and related injury criteria. In this sense, finite element (FE) simulation coupled with experiment could be a valuable tool to provide a better understanding of the behaviour of internal organs under crash conditions. This work proposes a methodology based on inverse analysis which combines exploration process optimisation and robustness study to obtain mechanical behaviour of the complex structure of the liver through FE simulation. The liver characterisation was based on Mooney-Rivlin hyperelastic behaviour law considering whole liver structure under uniform quasi-static compression. With the global method used, the model fits experimental data. The variability induced by modelling parameters is quantified within a reasonable time.