BACKGROUND:Potential drug-drug interactions (pDDIs) are frequent in clinical care, particularly among older patients. Accurate identification and management of pDDIs are essential for patient safety. Prescribers often rely on interaction checkers (ICs) to screen for pDDIs. However, these tools may provide inconsistent recommendations, potentially leading to suboptimal clinical decisions. OBJECTIVE:This study aimed to develop a standardized approach for classifying and prioritizing pDDIs based on the clinical relevance of their management recommendations and to compare how these pDDIs are categorized across ICs. METHODS:A scale was developed through a structured iterative process to classify pDDIs into four management categories (high priority, intermediate priority, low priority, data unavailable), based on the management recommendations extracted from six ICs. This scale was applied to 218 real-world pDDIs identified from 1923 patients, and the agreement was primarily assessed using Gwet's AC1. MAIN RESULTS:Overall agreement among the ICs was moderate (Gwet's AC1 = 0.44; 95% CI 0.39-0.50), with values ranging from 0.58 (0.51, 0.65) to 0.38 (0.31, 0.44) in leave-one-out analyses. The agreement was higher in binary analyses dichotomizing the scale into high- and intermediate-priority versus low-priority pDDIs (AC1 = 0.72; 95% CI 0.65-0.79), and in the classification of high-priority versus all other pDDIs (AC1 = 0.62; 95% CI 0.54-0.69). CONCLUSION:This study developed and tested a structured approach to systematically compare pDDI management across ICs and prioritize clinically relevant interactions. Its application revealed a generally limited agreement between ICs, pointing to the need for harmonized approaches and further studies to support more consistent, evidence-aligned pDDI management.

AIM:The French authorities mandated the use of secure prescriptions for pregabalin on May 2021. This study aimed to evaluate the impact of this measure on pregabalin use and misuse in Nouvelle-Aquitaine, a southwestern French region with around six million inhabitants. METHODS:This study was performed from the Nouvelle-Aquitaine regional databases of the French healthcare insurance system. It included all individuals who received at least one pregabalin reimbursement between 24 May 2020 and 24 May 2022. We analysed changes in the prevalence and incidence of pregabalin use and misuse, as well as the characteristics of pregabalin users. Misuse was defined as use exceeding 600 mg/day or engaging in doctor or pharmacy shopping. Two time periods were considered: 24 May 2020-23 May 2021 and 24 May 2021-24 May 2022. RESULTS:The implementation of secured prescriptions led to a 16.9% [16.5; 17.3] decrease in pregabalin prevalent use and in a 36.6% [36.1; 37.1] decrease in pregabalin incident use. Additionally, pregabalin misuse reduced by 7.7% [7.0; 8.4] for prevalent misuse and 71.5% [69.3; 73.6] for incident one. Most users were women aged over 60. Patients' characteristics changed between the two periods. Use of psychotropic and opioid treatment increased in prevalent users. CONCLUSIONS:The introduction of secured prescription forms was associated with a marked reduction in pregabalin use and misuse in Nouvelle-Aquitaine, especially in incident misuse.

We estimated the changes in the ambulatory use of antibiotics in France due to the COVID-19 pandemic in 2020-2022 by conducting time-series analyses using nationwide data from French health insurance databases. We examined all systemic antibiotics dispensed from January 1, 2010 through March 31, 2022. Use of most antibiotics decreased during the 3-month period following the start of first lockdown (March 17, 2020), and these decreases persisted 12 months later. Some initial increases indicated potential stockpiling for antibiotics used for chronic indications. Azithromycin constituted a noticeable exception. In a context of reduced circulation of non-COVID-19 viruses, the observed decreases compared with forecasts could partly reflect habitual overuse of certain antibiotics.

Real-world data on biological drug use in pediatric patients with immune-mediated inflammatory diseases (IMIDs) are scarce. This retrospective, population-based, cohort study aimed to provide an overview of biological drug use among children and adolescents with IMIDs from 2010 to 2023 using the Italian VALORE distributed database network. As secondary aim, potential of such a network for evaluating the risk of serious infections related to biological drugs in pediatrics was investigated. The yearly prevalence of use of biological drugs in IMID pediatric patients was calculated. Among incident users, persistence to adalimumab, etanercept, infliximab, golimumab, tocilizumab, secukinumab, and abatacept was measured. A sample power analysis to estimate the person-years of exposure required to investigate the association with the risk of serious infection and individual biological drug was performed. The yearly prevalence of biological drug use increased over time (+427.3 %), and it was consistently higher among females than males and among 12-17-year-olds than younger children. A total of 6222 incident biological drug users were identified, with a median follow-up of 3.8 years, and juvenile idiopathic arthritis (JIA, 35.9 %) and inflammatory bowel diseases (IBDs, 35.9 %) were the most common indications for use. After one year from the treatment start, more than 70 % of JIA patients using either adalimumab or etanercept were still on treatment, while persistence rates in IBDs were lower (ranging from 57.4 % to 65.0 %). Findings of this study show the potential of the VALORE network to provide enough exposure data to investigate the risk of serious infections for adalimumab, etanercept, and infliximab.

BACKGROUND:The COVID-19 pandemic disrupted healthcare access, potentially impacting cardiovascular prevention by increasing and worsening interruptions in antihypertensive treatment. In this context, we aimed to assess whether the epidemic had modified the effect of antihypertensive interruptions on the risk of major cardiovascular events (MACE). METHODS:From the nationwide SNDS French health insurance databases (2018/01/01-2021/12/31), we identified patients with ≥1 year of continuous antihypertensive drug use. We then constituted a group of patients who interrupted an antihypertensive during the period (interrupters) i.e., who presented with a treatment gap for at least one antihypertensive (entry date: interruption date). Interruption length defined was defined as time to treatment restart. After 1:1 matching, we constituted a second group of patients with continuous antihypertensive treatment at interrupters entry date (persisters; entry date: interrupter entry date). Associations between MACE risk, antihypertensive drug interruption (all durations, ≥15 days, ≥30 days), COVID epidemic period, and the interaction between these were assessed using GEE multivariable models. RESULTS:A total of 2,072,672 interrupter/persister pairs were included (4,145,344 patients; 43.6% in COVID period). Risk of MACE was not found increased after interruptions overall (OR = 0.99; 95%CI [0.97-1.02]); it was when interruptions lasted at least fifteen days (OR = 1.03 [1.01-1.06]) and during the COVID period independently of the existence of interruptions (OR = 1.44 [1.39-1.50]; P-value for interaction: all interruptions 0.69, exceeding 15 days 0.65). CONCLUSIONS:The COVID epidemic period was associated with an increased risk of MACE or all-cause death in antihypertensive drug users without worsening the effect of antihypertensive drug interruptions.

Limited real-world data on biological drug use in older patients with immune-mediated inflammatory diseases (IMIDs) exist despite these drugs carrying serious risks in this population. We aimed to describe the frequency and persistence of biological drug use in older patients (≥ 65 years) with IMID, including inflammatory bowel diseases (IBDs), psoriatic arthritis/psoriasis, rheumatoid arthritis (RA), and ankylosing spondylitis, in a large Italian population. A retrospective cohort study using the VALORE distributed claims database network from 13 Italian regions in the years 2010–2022 was performed. Older patients with IMID receiving biological drugs were included. Yearly prevalence of biological drug use and treatment persistence among incident users, from first dispensing to discontinuation/switching to another drug, was measured. Multivariable logistic regression was employed to identify treatment discontinuation predictors. The prevalence of biological drug use in older patients with IMID increased dramatically from 2010 (0.44 per 1000 residents) to 2022 (2.48 per 1000 residents). Overall, 25,284 incident users of biological drugs were identified, with a female/male ratio of 1.6 and a mean age of 71.0 (standard deviation ± 5.2) years. The median duration of follow-up was 4.2 (2.5–6.6) years, and the most common indication for use was RA (n = 8371; 33.1

Background The objective of this study was to assess the differential times of submission and approval of CFTR modulators in the United States (US) and the European Union (EU). Methods By collecting publicly available data from the websites of the Food and Drug Administration and the European Medicines Agency, we quantified differential times in submission, review duration, and approvals of initial marketing authorization and variation of indications of CFTR modulators in the US and the EU by December 31, 2023. Results Applications regarding marketing of 4 CFTR modulators were submitted 103 (SD ±143) days later in the EU than in the US: 31 (SD ±39) days later for initial approval, and 124 (SD ±155) days for supplemental indications. The regulatory review process was completed in 181 days [IQR, 179 - 182] in the US and 325 days [IQR, 276 - 382] in the EU: 167 days [IQR, 102 - 232] in the US and 346 days [IQR, 302 - 400] in the EU for first approvals, 181 days [IQR, 181 - 182] in the US and 324 days [IQR, 264 - 382] in the EU for supplemental indication approvals. CFTR modulators were approved 267 (SD 143) days later in the EU than in the US: 220 (SD ±76) days for initial approval and 280 (SD ±157) days for supplemental indications. Conclusion We found significant differences in times of submission and for approval of CFTR modulators between the US and EU, whereby initial approvals and subsequent indication approvals were always first granted in the US

Objective To determine whether the use of GLP-1 receptor agonists (RA) is associated with an increased risk of thyroid cancer. Research Design and Methods A nested case-control analysis was performed using the French national healthcare insurance system database (SNDS). Individuals with type 2 diabetes treated with second-line antidiabetic drugs between 2006 and 2018 were included in the cohort. All thyroid cancers were identified through hospital discharge diagnoses and medical procedures between 2014 and 2018. Exposure to GLP-1 RA was measured within the 6 years preceding a 6-month lag-time period and considered as current use and cumulative duration of use based on defined daily dose (≤1, 1 to 3, >3 years). Cases were matched with up to 20 controls on age, sex, and length of diabetes, using the risk-set sampling procedure. The risk of thyroid cancer related to the use of GLP-1 RA was estimated using a conditional logistic regression adjusted on goiter, hypothyroidism, hyperthyroidism, other antidiabetic drugs and social deprivation index. Results 2,562 cases of thyroid cancers were included in the study and matched to 45,184 controls. The use of GLP-1 RA for 1 to 3 years was associated with an increased risk of all thyroid cancer (adjusted hazard ratio: 1.58, 95% confidence interval: 1.27 to 1.95), and medullary thyroid cancer (aHR: 1.78, 95% CI: 1.04 to 3.05). Conclusions The present study found an increased risk of all thyroid cancer and medullary thyroid cancer with the use of GLP-1 RA, in particular after 1 to 3 years of treatment.

Background: The COVID-19 epidemic has disrupted care and access to care in many ways. It was accompanied by an excess of cardiovascular drug treatment discontinuations. We sought to investigate a deeper potential impact of the COVID-19 epidemic on antihypertensive drug treatment disruptions by assessing whether the epidemic induced some changes in the characteristics of disruptions in terms of duration, treatment outcome, and patient characteristics.Methods: From March 2018 to February 2021, a repeated cohort analysis was performed using French national health insurance databases. The impact of the epidemic on treatment discontinuations and resumption of antihypertensive medications was assessed using preformed interrupted time series analyses either on a quarterly basis.Results: Among all adult patients on antihypertensive medication, we identified 2,318,844 (18.7%) who discontinued their antihypertensive treatment during the first blocking period in France. No differences were observed between periods in the characteristics of patients who interrupted their treatment or in the duration of treatment disruptions. The COVID-19 epidemic was not accompanied by a change in the proportion of patients who fully resumed treatment after a disruption, neither in level nor in trend/slope [change in level: 2.66 (−0.11; 5.42); change in slope: −0.67 (−1.54; 0.20)]. Results were similar for the proportion of patients who permanently discontinued treatment within 1 year of disruption [level change: −0.21 (−2.08; 1.65); slope change: 0.24 (−0.40; 0.87)].Conclusion: This study showed that, although it led to an increase in cardiovascular drug disruptions, the COVID-19 epidemic did not change the characteristics of these. First, disruptions were not prolonged, and post-disruption treatment outcomes remained unchanged. Second, patients who experienced antihypertensive drug disruptions during the COVID-19 outbreak were essentially similar to those who experienced disruptions before it.

AIM OF THE STUDY:Post-mRNA coronavirus diseases 2019 (COVID-19) vaccines myocarditis emerged as a rare adverse effect, particularly in adolescents and young adults, and was labeled as such for both vaccines in the summer of 2021. This study aims to summarize the timeline and process of signal detection, substantiation, and quantification of myocarditis cases related to mRNA vaccines in France. METHODS:The intensive monitoring plan for COVID-19 vaccine safety was based on case-by-case analysis of all cases collected in the French spontaneous reporting database (Base nationale de pharmacovigilance, BNPV). Cases were evaluated by drug safety medical professionals and discussed at a national level for signal detection purposes. Reported cases were compared to the number of vaccine-exposed persons up to September 30th, 2021. Reporting rates (Rr) of myocarditis per 100,000 injections were calculated and stratified according to age, gender, and injection rank of BNT162b2 and mRNA-1273 vaccines. Poisson distribution was used to compute Rrs 95% Confidence Interval (95% CI). RESULTS:The case-by-case analysis detected a possible cluster of myocarditis in April 2021 (5 cases, 4 after the 2nd injection). In June 2021, the signal was substantiated with 12 cases (9 related to BNT162b2, and 3 to mRNA-1273). As of September 2021, almost 73 million BNT162b2 and 10 million mRNA-1273 doses had been injected. The Rr per 100,000 injections was 0.5 (0.5-0.6) for BNT162b2 and 1.1 (95% CI 0.9-1.3) for mRNA-1273. The difference among vaccines was more pronounced after the second injection, particularly in men aged 18-24 years (4.3 [3.4-5.5] for BNT162b2 vs. 13.9 [9.2-20.1] for mRNA-1273) and aged 25-29 years (1.9 [1.2-2.9] vs. 7.0 [3.4-12.9]). CONCLUSION:The study highlighted the role of the spontaneous reporting system in the detection, assessment, and quantification of myocarditis related to m-RNA vaccines. It suggested from September 2021 that mRNA-1273 was reasonably related to a higher risk of myocarditis than BNT162b2 in people under 30, particularly after the second injection.

Since pandemic start, patients may have faced difficulties in accessing to care and treatment. This study aimed at assessing the impact of COVID-19 pandemic and its control measures on the use of drugs indicated in cardiovascular prevention and diabetes mellitus in France. From 09/17/2018 to 09/20/2020, a repeated cohort analysis was performed using the French nationwide health insurance databases. The pandemic impact was assessed using time-series analyses and unobserved components model for the weekly number of patients with (i) drug dispensing, (ii) ongoing treatment, (iii) treatment initiation, (iv) treatment disruption. Overall, 14,822,132 patients with cardiovascular drug dispensings and 3,231,618 with antidiabetic ones were identified. After a sharp spike in the amount of dispensings in the week the first national lockdown was announced, the period was marked by decreased levels and trends. Altogether, the estimated impact of the pandemic on dispensings appeared limited over the lockdown period (1–3

Little is known about psychoactive substance use in students, apart from tobacco, alcohol, and cannabis. This study investigated the prevalence of substance use and overlap between various psychoactive substances in students. This cross-sectional study was conducted in 10 066 students included in the i-Share cohort between January 1, 2015, and December 31, 2017. The baseline questionnaire was the key source of information. Psychoactive substances of interest (PSI) were cannabis, cocaine, amphetamines, nitrous oxide, poppers, and MDMA. Their patterns of use were categorized as lifetime, past year, and current use. The use of other psychoactive substances including alcohol and tobacco was described in PSI users and non-users. Most participants were female (75%), and their average age was 21 years. Lifetime use of at least one PSI was reported by 65.5% of participants. Cannabis was the most frequently used substance both over lifetime (57% of students) and past year (35%), followed by poppers and nitrous oxide (28% and 26% of students over lifetime, respectively). Among polydrug users (n = 1242), 65% used only nitrous oxide and poppers, showing a strong link between these two substances. Regular alcohol use, binge drinking, and current tobacco use were higher in PSI users than in non-users. Substance use was higher than previously found in both French and European studies in young people. Nitrous oxide use was particularly high. Regular alcohol use, binge drinking, and tobacco use could be used as markers to identify students at risk of PSI use to be targeted by prevention programs.

(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for nonsquamous-NSCLC, it was 22.3% (2009-2011) and 30.6% (2018-2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018-2019 vs. 2009-2011 was found (non-squamous: HR: 0.95 CI95%: 0.92-0.98; squamous: HR: 0.94 CI95%: 0.90-0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed.

Despite the risks associated with their use, benzodiazepines remain used more widely than wisely. In this context, a better understanding of how their patterns of use can be associated with an increased risk of death appears essential. Indeed, the studies that investigated this association so far are inconsistent and question the influence of potential biases. The objective of this study was to investigate the association of various patterns of benzodiazepine use with all-cause mortality. A nationwide cohort of non-prevalent benzodiazepine users aged ≥ 65 years was identified using French healthcare insurance system claims databases. Exposure to benzodiazepines considered short-term, chronic (defined as a cumulated ≥ 6-month period over the previous 12 months), ongoing, and discontinued use. Using a Cox model, adjusted hazard ratios for all-cause mortality were estimated according to benzodiazepine patterns of use; exposure and confounders were treated as time-dependent variables. In the cohort of 54,958 individuals aged ≥ 65 years, adjusted hazard ratios for all-cause mortality and benzodiazepines were 2.26 (95% confidence interval 1.96–2.61) for short-term use, 3.86 (3.04–4.90) for chronic use—discontinued, and 3.05 (2.17–4.29) for chronic use—ongoing. At age 80 years, these were 1.62 (1.48–1.79), 2.00 (1.82–2.19) and 1.13 (1.02–1.26), respectively. Adjusted hazard ratios show similar decreases with age for all patterns of benzodiazepine use. These findings confirm the existence of an excess risk of mortality associated with benzodiazepine use and provide pattern- and age-specific estimates. Higher risks were observed for patients aged < 80 years, short-term use, or chronic use recently interrupted. If the two latter can relate to an indication bias, the associations found for ongoing chronic use and short-term use conversely support a potential causal hypothesis.

Dementia is a major public health issue worldwide and chronic use of benzodiazepine, which is very frequent in northern countries, was found to be a risk factor of dementia. This work aims at evaluating the impact of a reduction in chronic use of benzodiazepine on the future burden of dementia in France. Using estimations of dementia incidence and of benzodiazepine use and nation-wide projections of mortality and population sizes, a Monte Carlo approach based on an illness-death model provided projections of several indicators of dementia burden. With no change in benzodiazepine consumption, the prevalence of dementia between age 65 and 99 in France in 2040 was estimated at 2.16 millions (95% confidence interval (CI) 1.93–2.38), with a life expectancy without dementia at 65 years equal to 25.0 years (24.7–25.3) for women and 23.8 years (23.5–24.2) for men. Assuming a disappearance of chronic use of benzodiazepine in 2020, the prevalence would be reduced by about 6.6% in 2040 and the life expectancy without dementia would increase by 0.99 (0.93–1.06) year among women and 0.56 (0.50–0.62) among men. To conclude, a modest but significant reduction in future dementia burden could be obtained by applying current recommendation for duration of benzodiazepine use.

Context: Ticagrelor was related to bradycardia in DISPERSE-II trial. This risk has been integrated into the European risk-management plan, and its use is warned in at-risk patients. Nevertheless, this risk was not systematically assessed nor measured. Objectives: To estimate the risk of bradyarrhythmia associated with ticagrelor. Study design:Systematic review and meta-analysis. Data-source: MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, ISI web of Science, clinicaltrial.gov, clinicaltrialsregister.eu. Study selection: Randomized controlled trials (RCTs) and observational studies in patients treated with ticagrelor or comparator(s). Meta-analysis: Risk of bias in each RCT was assessed using Cochrane tool. Relative Risks (RR) with 95 % confidence intervals (95 %CI) were calculated for each RCT, and pooled using fixed-effect or random-effects models, when appropriate. Subgroup and sensitivity analyses were performed. A potential publication bias was searched. Results: Among 82 eligible studies, event data were missing for 56 studies, due to detected reporting bias (i.e. inability to confirm zero events). Fifteen RCTs were selected and the combined RR of bradyarrhythmia was 1.15 (95 %CI 1.05-1.26), and 1.29 (1.02-1.65) for severe bradyarrhythmia. The risk appeared to be dose dependent. Restricting the analysis only to RCTs performed in patients without previous bradyarrhythmia resulted in a non-increased risk. Conclusion: This meta-analysis confirmed the risk of bradyarrhythmia or severe bradyarrhythmia related to ticagrelor, and its use in patients without previous bradycardia was effective in preventing it. The evidence coming from this meta-analysis was low to moderate due to missing outcome in 2/3 of eligible studies. Waiting for access to these data, the use of ticagrelor in patients with risk factors of bradycardias should be avoided.