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BACKGROUND: Preoperative identification of patients with haemostasis abnormalities leading to an increased bleeding risk was based on routine haemostasis tests: prothrombin time (PT), activated prothrombin time (aPTT), and platelet count. Because of their low predictive performance, guidelines recommend replacing them with structured bleeding risk questionnaires, but none is validated in this population. OBJECTIVES: To assess the diagnostic accuracy of 3 strategies, performed at the pre-anaesthesia visit before scheduled interventions, to identify patients with haemostasis abnormalities leading to an increased bleeding risk PATIENTS AND METHODS: Multicenter study in 7 French academic hospitals, involving patients scheduled for surgical intervention, without antiplatelet/anticoagulant treatment. The 3 strategies consisted of 1-a structured screening questionnaire; 2-PT, aPTT, and platelet count ordered in selected patients; 3-systematic PT, aPTT, and platelet count. The reference standard comprised von Willebrand factor activity/antigen, factors VIII, IX, and XI, platelet-function analyser, and, when required, FII, FV, FX, and FVII and haemostasis consultation. RESULTS: Eighteen (1.2%) of 1484 patients had a haemostasis abnormality leading to an increased bleeding risk according to reference standard. In the overall cohort, sensitivity of the questionnaire-based strategy was 50% (95%CI, 26-74; specificity 87% (95%CI, 85-88); sensitivity was 0 (95%CI, 0-41) in men vs 82% (95%CI, 48- 98) in women. For selective routine tests, sensitivity was 33% (95%CI, 13-59) and specificity 97% (95% CI, 96-98). Corresponding values for systematic routine tests were 44% (95%CI, 22-69) and 93% (95%CI, 91-94). CONCLUSIONS: Sensitivity was low for all 3 strategies investigated. The structured screening questionnaire had clinically acceptable diagnostic accuracy only in women.
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AIM OF THE STUDY: The French National Health Data System (SNDS) comprises healthcare data that cover 99% of the population (over 67 million individuals) in France. The aim of this study was to present an overview of published pharmacoepidemiological studies using the SNDS in its maturation phase. METHODS: We conducted a systematic literature review of original research articles in the Pubmed and EMBASE databases from January 2012 until August 2018. RESULTS: A total of 316 full-text articles were included, with an annual increase over the study period. Only 16 records were excluded after screening because they did not involve the SNDS but other French healthcare databases. The study design was clearly reported in only 66% of studies of which 57% were retrospective cohorts and 22% cross-sectional studies. The reported study objectives were drug utilization (65%), safety (22%) and effectiveness (9%). Almost all ATC groups were studied but the most frequent ones concerned the nervous system in 149 studies (49%), cardiovascular system drugs in 104 studies (34%) and anti-infectives for systemic use in 50 studies (16%). CONCLUSION: The SNDS is of growing interest for studies on drug use and safety, which could be conducted more in specific populations, including children, pregnant women and the elderly, as these populations are often not included in clinical trials.
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BACKGROUND: Factors associated with the appropriateness of antibiotic prescribing in primary care have been poorly explored. In particular, the impact of computerised decision-support systems (CDSS) remains unknown. OBJECTIVES: We aim at investigating the uptake of CDSS and its association with physician characteristics and professional activity. METHODS: Since May 2022, users of a CDSS for antibiotic prescribing in primary care in France have been invited, when registering, to complete three case vignettes assessing clinical situations frequently encountered in general practice and identified as at risk of antibiotic misuse. Appropriateness of antibiotic prescribing was defined as the rate of answers in line with the current guidelines, computed by individuals and by specific questions. Physician's characteristics associated with individual appropriate antibiotic prescribing (< 50%, 50-75% and > 75% appropriateness) were identified by multivariate ordinal logistic regression. RESULTS: In June 2023, 60,067 physicians had registered on the CDSS. Among the 13,851 physicians who answered all case vignettes, the median individual appropriateness level of antibiotic prescribing was 77.8% [Interquartile range, 66.7%-88.9%], and was < 50% for 1,353 physicians (10%). In the multivariate analysis, physicians' characteristics associated with appropriateness were prior use of the CDSS (OR = 1.71, 95% CI 1.56-1.87), being a general practitioner vs. other specialist (OR = 1.34, 95% CI 1.20-1.49), working in primary care (OR = 1.14, 95% CI 1.02-1.27), mentoring students (OR = 1.12, 95% CI 1.04-1.21) age (OR = 0.69 per 10 years increase, 95% CI 0.67-0.71). CONCLUSION: Individual appropriateness for antibiotic prescribing was high among CDSS users, with a higher rate in young general practitioners, previously using the system. CDSS could improve antibiotic prescribing in primary care.
Individual appropriateness for antibiotic prescribing is high among CDSS users.CDSS use could passively improve antibiotic prescribing in primary care.Factors associated with appropriateness for antibiotic prescribing for primary care diseases are: prior use of CDSS, general practice speciality vs. other specialities, younger age and mentoring of students.
Subject(s)
Anti-Bacterial Agents , Inappropriate Prescribing , Practice Patterns, Physicians' , Primary Health Care , Humans , Anti-Bacterial Agents/therapeutic use , Practice Patterns, Physicians'/statistics & numerical data , Female , Male , Middle Aged , Inappropriate Prescribing/statistics & numerical data , France , Adult , Decision Support Systems, Clinical , Logistic Models , Multivariate AnalysisABSTRACT
COVID-19 is associated with heterogeneous outcome. Early identification of a severe progression of the disease is essential to properly manage the patients and improve their outcome. Biomarkers reflecting an increased inflammatory response, as well as individual features including advanced age, male gender, and pre-existing comorbidities, are risk factors of severe COVID-19. Yet, these features show limited accuracy for outcome prediction. The aim was to evaluate the prognostic value of whole blood transcriptome at an early stage of the disease. Blood transcriptome of patients with mild pneumonia was profiled. Patients with subsequent severe COVID-19 were compared to those with favourable outcome, and a molecular predictor based on gene expression was built. Unsupervised classification discriminated patients who would later develop a COVID-19-related severe pneumonia. The corresponding gene expression signature reflected the immune response to the viral infection dominated by a prominent type I interferon, with IFI27 among the most over-expressed genes. A 48-genes transcriptome signature predicting the risk of severe COVID-19 was built on a training cohort, then validated on an external independent cohort, showing an accuracy of 81% for predicting severe outcome. These results identify an early transcriptome signature of severe COVID-19 pneumonia, with a possible relevance to improve COVID-19 patient management.
Subject(s)
COVID-19 , SARS-CoV-2 , Transcriptome , Humans , COVID-19/blood , COVID-19/genetics , Male , Female , Middle Aged , Aged , Cohort Studies , Prognosis , Adult , Severity of Illness Index , Biomarkers/blood , Gene Expression Profiling , Membrane ProteinsABSTRACT
PURPOSE: Annually, the French Ministry of Health funds clinical research projects based on a national call for projects. Since 2013, the Ministry has prioritized funding of primary care. Projects selected for funding are made public without distinguishing the specific area of research. The objective of this study was to identify and describe the evolution of the primary care research projects funded by the Ministry of Health between 2013 and 2019. METHOD: We reviewed all of the 1796 medical research projects funded between 2013 and 2019 and categorized projects as primary care projects by using a list of specific keywords. This list was established through two approaches: (1) selected by an expert committee, the RECaP primary care working group, and (2) using an automated textual analysis of published articles in the field. The keywords were used to screen the titles of the medical research projects funded. The abstracts (at www. CLINICALTRIALS: gov ) or details (from project leaders) were then analyzed by two independent reviewers to determine true primary care projects. RESULTS: Finally, 49 primary care projects were identified, representing 2.7% of all medical research projects funded, without any significant change over the period. These projects were predominantly interventional (69%), with a median number of patients expected per project of 902. CONCLUSION: Despite the prioritization of primary care research in 2013 by the French ministry of health, the number and proportion of projects funded remains low, with no significant change over the years. TRIAL REGISTRATION: Not applicable.
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Biomedical Research , Financing, Government , Primary Health Care , France , Primary Health Care/economics , Primary Health Care/organization & administration , Humans , Biomedical Research/economics , Financing, Government/economics , Financing, Government/trendsABSTRACT
OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.
Subject(s)
Amantadine , Antiparkinson Agents , Parkinson Disease , Amantadine/therapeutic use , Amantadine/adverse effects , Humans , Male , Female , France/epidemiology , Aged , Antiparkinson Agents/adverse effects , Antiparkinson Agents/therapeutic use , Antiparkinson Agents/administration & dosage , Parkinson Disease/drug therapy , Parkinson Disease/epidemiology , Middle Aged , Prospective Studies , Dyskinesia, Drug-Induced/epidemiology , Dyskinesia, Drug-Induced/etiology , Cross-Sectional Studies , Levodopa/adverse effects , Levodopa/administration & dosage , Longitudinal Studies , Cohort StudiesABSTRACT
BACKGROUND AND AIMS: A recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection. METHODS: We conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal. RESULTS: We identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n = 17) and 39% (n = 9) of cases. The events reported were AML (n = 22), ALL (n = 11), AML and ALL (n = 1) and UAL (n = 15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL. CONCLUSION: This study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification.
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Antiviral Agents , Hepatitis C, Chronic , Leukemia, Myeloid, Acute , Humans , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/complications , Leukemia, Myeloid, Acute/chemically induced , Leukemia, Myeloid, Acute/epidemiology , Male , Middle Aged , Female , Aged , Adult , Pharmacovigilance , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiologyABSTRACT
Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.
Subject(s)
Asymptomatic Infections , COVID-19 , SARS-CoV-2 , Humans , COVID-19/genetics , COVID-19/immunology , SARS-CoV-2/immunology , Male , Female , Alleles , HLA Antigens/genetics , Middle Aged , Adult , Prospective Studies , Aged , Genetic Predisposition to DiseaseABSTRACT
In preparation for a new version of the CRAT (Centre de référence sur les agents tératogènes) website, an evaluation of user satisfaction was carried out. An invitation to complete an online questionnaire covering the various dimensions of the website (appearance, content, interactivity, ease of use, technical performance) was sent in April 2022 to healthcare professionals who referred to CRAT for clinical expertise over the previous two years. After sending out 3224 individual e-mail invitations, 758 evaluators completed the questionnaire in full (response rate: 23.5%). The evaluation revealed a high-level of overall satisfaction among site users (98.0% very satisfied or satisfied). Satisfaction with the site's appearance was also high, although comments were made about the site's lack of a modern web design. Health professionals recognized in their responses the reliable, relevant and up-to-date nature of the content of this free, public online resource, independent of the pharmaceutical industry. On the basis of these highly favorable assessments, with content that has been widely acclaimed and areas for improvement that have caught the attention of site users (evolution of its appearance, of the search tool, implementation of a mobile site), a new version of www.lecrat.fr was launched in the fall of 2023.
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OBJECTIVE: The management of antiseizure treatment in patients with epilepsy relies on the benefit-risk ratio. Data on antiseizure medication (ASM) use in children are limited. We described antiseizure medication use in children with epilepsy (CwE) in France, with a focus on the chronic use of benzodiazepines and related implications. METHODS: We conducted a 5-year cohort study from January 2012, using data from the French national health care data system (Système National des Données de Santé). We included CwE identified through International Classification of Diseases, 10th Revision codes and medications from January 2012 to December 2015 and followed them until December 2016. We described ASMs and assessed whether the risk of initiating a polytherapy after a bitherapy depends on whether benzodiazepine was included in the bitherapy. RESULTS: We identified 62 885 CwE. Valproate was the most reimbursed ASM (40%), followed by lamotrigine (17.6%), levetiracetam (9.3%), clobazam (6.1%), and carbamazepine (5.8%). Prescriptions were initiated at the hospital in 74.5% of CwE. We observed a decrease in the number of CwE with at least one benzodiazepine reimbursement from 15.3% in 2013 to 10.1% in 2016 (p < .0001). The prevalence of CwE with levetiracetam reimbursements increased, whereas that of CwE with valproate decreased. A switch from a bitherapy to a polytherapy was more likely when the bitherapy included a benzodiazepine (subdistribution hazard ratio [sHR] = 1.20 [1.03-1.39]). SIGNIFICANCE: The prevalence of CwE with at least one benzodiazepine reimbursement decreased during the study period. Benzodiazepines were associated with an increased use of subsequent ASM polytherapy.
Subject(s)
Benzodiazepines , Epilepsy , Humans , Child , Benzodiazepines/therapeutic use , Valproic Acid , Levetiracetam , Cohort Studies , Epilepsy/drug therapy , Epilepsy/epidemiology , Delivery of Health Care , Anticonvulsants/adverse effectsABSTRACT
OBJECTIVES: The use of secondary databases has become popular for evaluating the effectiveness and safety of interventions in real-life settings. However, the absence of important confounders in these databases is challenging. To address this issue, the high-dimensional propensity score (hdPS) algorithm was developed in 2009. This algorithm uses proxy variables for mitigating confounding by combining information available across several healthcare dimensions. This study assessed the methodology and reporting of the hdPS in comparative effectiveness and safety research. STUDY DESIGN AND SETTING: In this methodological review, we searched PubMed and Google Scholar from July 2009 to May 2022 for studies that used the hdPS for evaluating the effectiveness or safety of healthcare interventions. Two reviewers independently extracted study characteristics and assessed how the hdPS was applied and reported. Risk of bias was evaluated with the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. RESULTS: In total, 136 studies met the inclusion criteria; the median publication year was 2018 (Q1-Q3 2016-2020). The studies included 192 datasets, mostly North American databases (n = 132, 69%). The hdPS was used in primary analysis in 120 studies (88%). Dimensions were defined in 101 studies (74%), with a median of 5 (Q1-Q3 4-6) dimensions included. A median of 500 (Q1-Q3 200-500) empirically identified covariates were selected. Regarding hdPS reporting, only 11 studies (8%) reported all recommended items. Most studies (n = 81, 60%) had a moderate overall risk of bias. CONCLUSION: There is room for improvement in the reporting of hdPS studies, especially regarding the transparency of methodological choices that underpin the construction of the hdPS.
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Algorithms , Comparative Effectiveness Research , Propensity Score , Humans , Research DesignABSTRACT
OBJECTIVES: Overtreatment with glucose-lowering treatment (GLT) is frequent and a source of high morbidity and mortality in older adults with type 2 diabetes mellitus (T2DM). This study aimed to identify and synthesize barriers and enablers for deprescribing GLT in older adults (≥65 years) with T2DM. DESIGN: Systematic review of qualitative and mixed-methods studies. SETTING AND PARTICIPANTS: Older adults with T2DM, any participants [patients, health care providers (HCPs), caregivers], any settings. METHODS: Two researchers (and a referred third researcher at all stages) independently screened original articles reporting qualitative and mixed-methods studies exploring barriers and enablers for deprescribing GLT in older adults published during 2010-2023, identified from MEDLINE, Embase, CINAHL, and gray literature. Quality of the included studies was assessed with the Mixed-Methods Appraisal Tool. Verbatim statements on barriers and enablers were extracted, and determinants of behaviors were identified with the Theoretical Domains Framework (TDF) version 2, and related intervention functions (targets for future interventions) were proposed according to the Behavior Change Wheel (BCW). RESULTS: We identified only 4 studies from 2 countries (United States and the Netherlands), all recently published (2019-2023), that primarily reported barriers to GLT deprescribing from interviews or focus groups of patients or HCPs practicing outpatient medicine. Knowledge, fear, poor communication, inertia, and trust with HCPs were the main determinants of behaviors that influenced deprescribing, and education, training, persuasion and environmental restructuring were the main intervention functions for proposing future interventions. Studies did not cover financial aspects, physician characteristics, or caregiver and family viewpoints. CONCLUSIONS AND IMPLICATIONS: The use of a behavioral theory and a validated implementation framework provided a comprehensive approach to identifying barriers and enablers for deprescribing GLT in older adults (≥65 years) with T2DM. The behavioral determinants identified may be useful in tailoring interventions to improve the implementation of GLT deprescribing in older adults in ambulatory settings.
Subject(s)
Deprescriptions , Diabetes Mellitus, Type 2 , Medicine , Humans , Aged , Diabetes Mellitus, Type 2/drug therapy , Educational Status , GlucoseABSTRACT
OBJECTIVE: We assess the clinical and structural impact at two years of progressively spacing tocilizumab (TCZ) or abatacept (ABA) injections versus maintenance at full dose in patients with rheumatoid arthritis in sustained remission. METHODS: This multicenter open-label noninferiority (NI) randomized clinical trial included patients with established rheumatoid arthritis in sustained remission receiving ABA or TCZ at a stable dose. Patients were randomized to treatment maintenance (M) at full dose (M-arm) or progressive injection spacing (S) driven by the Disease Activity Score in 28 joints every 3 months up to biologics discontinuation (S-arm). The primary end point was the evolution of disease activity according to the Disease Activity Score in 44 joints during the 2-year follow-up analyzed per protocol with a linear mixed-effects model, evaluated by an NI test based on the one-sided 95% confidence interval (95% CI) of the slope difference (NI margin 0.25). Other end points were flare incidence and structural damage progression. RESULTS: Overall, 202 of the 233 patients included were considered for per protocol analysis (90 in S-arm and 112 in M-arm). At the end of follow-up, 16.2% of the patients in the S-arm could discontinue their biologic disease-modifying antirheumatic drug, 46.9% tapered the dose and 36.9% returned to a full dose. NI was not demonstrated for the primary outcome, with a slope difference of 0.10 (95% CI 0.10-0.31) between the two arms. NI was not demonstrated for flare incidence (difference 42.6%, 95% CI 30.0-55.1) or rate of structural damage progression at two years (difference 13.9%, 95% CI -6.7 to 34.4). CONCLUSION: The Towards the Lowest Efficacious Dose trial failed to demonstrate NI for the proposed ABA or TCZ tapering strategy.
Subject(s)
Antibodies, Monoclonal, Humanized , Antirheumatic Agents , Arthritis, Rheumatoid , Humans , Abatacept/therapeutic use , Treatment Outcome , Arthritis, Rheumatoid/drug therapy , Antirheumatic Agents/therapeutic useABSTRACT
Background: Older studies uncovered an increased risk of cancer in patients with rheumatoid arthritis between 10% and 30% compared to the general population, with a lack of data concerning infrequent cancers. In recent year, major therapeutic breakthroughs might have affected this risk of cancer by mitigating disease activity or on the contrary by impairing antitumoral immune response. The objectives of this study are to compare cancer risk in patients with treated rheumatoid arthritis to the general population, in all treated patients and according to treatment exposure. Methods: This is a nationwide population-based study within the French national claims database "Système National des Données de Santé" (SNDS) between January 1st 2010 and December 31st 2020, to estimate the age and sex-standardized incidence ratios of cancer (all sites and site specific) of treated rheumatoid arthritis patients, with the French population as reference (by use of the French Network of Population-Based Cancer Registries [FRANCIM]). Findings: During the study period, 257,074 treated patients with rheumatoid arthritis contributed to a total of 2,098,238 person-years for the main analysis. The all-cancer risk was increased in rheumatoid arthritis patients, with a SIR (Standardized Incidence Ratio) of 1.20 (95% CI [1.17-1.23]). This risk was increased particularly for lung (SIR 1.41, 95% CI [1.36-1.46], bladder (SIR 2.38 95% CI [2.25-2.51]), cervix (SIR 1.80, 95% CI [1.62-2.01]), prostate (SIR 1.08, 95% CI [1.04, 1.13]) cancers, melanoma (SIR 1.37, 95% CI [1.29-1.46]), diffuse large B cell lymphoma (SIR 1.79, 95% CI [1.63-1.96], multiple myeloma (SIR 1.42, 95% CI [1.27-1.60]) and Hodgkin's lymphoma (SIR 2.73, 95% CI [2.31-3.23]). Some cancers were less frequent than in the general population such as pancreatic (SIR 0.90, 95% CI [0.83-0.97]) as well as breast and endometrial cancers (SIR 0.91, 95% CI [0.88-0.94] and SIR 0.77, 95% CI [0.71-0.84] respectively). Although we observed a modest but significant relative increase of all-cancer risk over-time in rheumatoid arthritis patients, there was a trend towards a decrease in risk of non-Hodgkin's lymphoma. Patients treated with rituximab were the patients displaying the highest risk of cancer. Interpretation: Compared to the general population, treated rheumatoid arthritis patients were at greater risk of all-cancer and some site specific cancers, except for breast, pancreatic and endometrial cancers which were less frequent than in the general population. Funding: This work was supported by unrestricted grants from the InCA (national institute against cancer) and AP-HP (Assistance Publique des Hôpitaux de Paris).
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INTRODUCTION: In older adults with type 2 diabetes (T2D), overtreatment with hypoglycaemic drugs (HDs: sulfonylureas, glinides and/or insulins) is frequent and associated with increased 1-year mortality. Deintensification of HD is thus a key issue, for which evidence is though limited. The primary objective of this study will be to estimate the effect of deintensifying HD on clinical outcomes (hospital admission or death) within 3 months in older adults (≥75 years) with T2D. METHODS: We will emulate with real-world data a target trial, within The Health Improvement Network cohort, a large-scale database of data collected from electronic medical records of 2000 general practitioners in France. From 1 January 2010 to 28 February 2019, we will include eligible patients ≥75 years who will have T2D, a stable dose of HDs, glycated haemoglobin A1c (HbA1c) value <75 mmol/mol (9.0%) and no deintensification in the past year. The target trial will be sequentially emulated (ie, eligibility assessed) every month in the database. Patients will be classified at baseline of each sequential trial in the intervention arm (deintensification of HDs: decrease of ≥50% in the total dose of HDs, including complete cessation) or control arm (no deintensification of HDs). The pooled dataset for all sequential emulated trials will be analysed. The primary outcome will be time to first occurrence of hospital admission or death, within 3 months. Secondary outcomes will be hospitalisation, death, appropriateness of glycaemic control and occurrence of HbA1c >75 mmol/mol within 1 year. Participants will be followed from baseline to 12 months after randomisation, administrative censoring, or death, whichever occurs first. A pooled logistic regression will be used to estimate the treatment effect on the incidence of the outcomes. DISSEMINATION AND ETHICS: No ethical approval is needed for using retrospectively this fully anonymised database. The results will be disseminated during conferences and through publications in scientific journals.
Subject(s)
Diabetes Mellitus, Type 2 , Aged , Humans , Diabetes Mellitus, Type 2/drug therapy , France/epidemiology , Glycated Hemoglobin , Hypoglycemic Agents/therapeutic use , Retrospective Studies , Treatment OutcomeABSTRACT
Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris-Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.
Subject(s)
Antineoplastic Agents, Immunological , Myocarditis , Myositis , Neoplasms , Humans , Immune Checkpoint Inhibitors/adverse effects , Myocarditis/chemically induced , Antineoplastic Agents, Immunological/adverse effects , Myotoxicity/drug therapy , Myositis/chemically induced , Myositis/drug therapy , Myositis/pathology , Neoplasms/drug therapyABSTRACT
BACKGROUND: Mortality is high in older patients hospitalized with COVID-19. Previous studies observed lower mortality during the Omicron wave, yet no data is available on older patients. The objective was to compare in-hospital mortality between the Omicron and previous waves in older patients hospitalized with COVID-19. METHODS: This retrospective observational multicenter cohort study used the Greater Paris University Hospitals Group's data warehouse (38 hospitals). Patients aged ≥ 75 years with a confirmed COVID-19 diagnosis and hospitalized from March 2020 to January 2022 were included. The study period was divided into five waves. The fifth wave (January 1st to 31st 2022) was considered as the Omicron wave as it was the predominant variant (≥ 50%), and was compared with waves 1 (March-July 2020), 2 (August-December 2020), 3 (January-June 2021) and 4 (July-December 2021). Primary outcome was in-hospital mortality. Secondary outcome was occurrence of ICU admission or in-hospital death. Multivariate logistic regression was performed, with a sensitivity analysis according to variant type. RESULTS: Of the 195,084 patients hospitalized with COVID-19, 19,909 patients aged ≥ 75 years were included (median age 85 [IQR 79-90] years, 53% women). Overall in-hospital mortality was 4,337 (22%), reaching 345 (17%) during wave 5. Waves 1 and 3 were significantly associated with increased in-hospital mortality in comparison with wave 5 (adjusted Odds Ratios aOR 1.42 [95%CI 1.21-1.66] and 1.56 [95%CI 1.33-1.83] respectively). Waves 1 to 3 were associated with an increased risk of occurrence of ICU admission or in-hospital death in comparison with wave 5: aOR 1.29 [95% CI 1.12 to 1.49] for wave 1, aOR 1.25 [95% CI 1.08 to 1.45] for wave 2 and aOR 1.56 [95% CI 1.36 to 1.79] for wave 3. Sensitivity analysis found that Omicron variant was associated with decreased mortality, in comparison with previous variants. CONCLUSIONS: Mortality was lower during the 5th Omicron wave in the older population, but remained high, implying that this variant could be considered as "milder" but not "mild". This persistently high mortality during the 5th Omicron wave highlights the importance of including older patients in clinical trials to confirm the benefit/risk balance of COVID-19 treatments in this fragile population.