PCSK9 inhibitors (PCSK9i) are indicated in combination with statins and/or ezetimibe to intensify LDL-cholesterol lowering and reduce the risks of atherosclerotic cardiovascular disease. We aimed at investigating PCSK9i (alirocumab and evolocumab) patterns of use in France by characterizing PCSK9i new-users and describing lipid-lowering agents (LLA) use before and after PCSK9i initiation. A cross-sectional study of PCSK9i users and a cohort study including PCSK9i new-users between 2018 and 2021 were conducted using the nationwide French healthcare insurance system database (SNDS). PCSK9i use increased greatly after the indication extension rapidly slowed by introduction of agreement prior to reimbursement in Dec-20. Among the 6891 PCSK9i new-users, 65.7% were men, 63.7% were at very-high cardiovascular risk, median age was 64 years (IQR: 56-71). Trajectories of cholesterol-lowering treatment prior to PCSK9i initiation showed high intensity treatment for 50.5% of patients, low/moderate treatment for 37.3% and no prior treatment for 12.2%. LLA discontinuation after PCSK9i initiation was most frequent in patients with no prior treatment (17.3%) than in those with prior low/moderate or high-intensity treatment (4.9 and 1.3% respectively). Agreement prior to reimbursement seemed effective in contributing to control the appropriate use of PCSK9i with almost two-thirds of patients at very-high cardiovascular risk, and high treatment persistence.

Importance:Although pharmacovigilance signals and a strong pathophysiological rationale have suggested a potential risk of arterial dissections or aneurysms associated with angiogenesis inhibitors, this association deserves to be further investigated through clinical practice evidence studies. Objective:To evaluate the association between exposure to angiogenesis inhibitors and the occurrence of arterial dissections or aneurysms in patients treated for metastatic colorectal cancer (mCRC). Design, Setting, and Participants:A nested case-control study was conducted within a cohort of adults initiating targeted therapy (angiogenesis or epidermal growth factor receptor inhibitors) for mCRC between January 1, 2012, and December 31, 2017. Data were analyzed from April 2021 through August 2023. Data were drawn from the French nationwide Système National des Données de Santé database, which combines health insurance and hospital discharge records. Cases of arterial dissection or aneurysm were identified through 2019 and matched with up to 10 controls by age, sex, and time since cohort entry. Exposures:The angiogenesis inhibitors indicated for mCRC in France (ie, bevacizumab, aflibercept, ramucirumab, and regorafenib) were considered. Exposure was defined using 3 criteria: exposure at any point (exposed vs unexposed), recency (current, past, or unexposed), and cumulative duration of exposure (quartiles). Exposure periods were estimated using recommended administration schedules or drug elimination times. Main Outcomes and Measures:The primary outcome was incident hospitalization for arterial dissection or aneurysm, identified through hospital discharge diagnoses. Conditional logistic regression models were applied to estimate the association between exposure to angiogenesis inhibitors and the occurrence of arterial dissections or aneurysms, expressed as odds ratios (ORs) with 95% CIs. Results:Of the 34 733 patients included in the cohort, 195 incident cases (0.6%) were matched with 1950 controls. The study population (2145 patients) included 1562 male patients (72.8%); the median (IQR) age was 69 (63-73) years for cases and 68 (62-73) years for controls. Considering exposure at any point, 141 cases (72.3%) and 1381 controls (70.8%) were exposed to angiogenesis inhibitors; after adjustment for cardiovascular risk level, no association was observed between exposure and the occurrence of arterial events (OR, 1.07; 95% CI, 0.75-1.52). No associations were found with either recency or cumulative duration of exposure, regardless of the exposure estimation method. Conclusions and Relevance:In this case-control study of arterial dissections or aneurysms in patients receiving targeted therapy for mCRC, the lack of association with angiogenesis inhibitor exposure was reassuring, given the established benefits of these drugs, particularly bevacizumab, for this indication.

Rheumatoid arthritis (RA) is commonly treated with Janus kinase inhibitors (JAKis) and anti-tumor necrosis factor-α (anti-TNFα), but the cardiovascular safety profiles of these drugs remain unclear. The aim of this study was to describe the individual case safety reports of major adverse cardiac events (MACE) or stroke and to determine whether there was a difference in the frequency of reporting of cardiovascular events between JAKis and anti-TNFα used in RA. A case/non-case study was conducted using the WHO VigiBase® database. Descriptive analysis was performed, the time to onset (TTO) of MACE was calculated, and the reporting odds ratio (ROR) was used to estimate the frequency of MACE reports associated with JAKis versus anti-TNFα in RA. A total of 18,099 cases of MACE were identified, of which 2543 (14

Introduction Le mécanisme d'action des antiangiogéniques, qui fournit un rationnel physiopathologique compatible avec une atteinte artérielle, et des séries de cas et études de pharmacovigilance ont fait naitre des interrogations concernant la sécurité de ces médicaments. L'objectif de cette étude était d’étudier l'association entre l'utilisation d'antiangiogéniques et la survenue de dissection ou d'anévrisme artériel chez les patients traités pour cancer colorectal métastatique (CCRm). Méthodes Une étude cas-témoins nichée dans une cohorte d'adultes ayant débuté une thérapie ciblée indiquée dans le CCRm (antiangiogéniques, anti-EGFR) entre 2012 et 2017, et sans antécédent de dissection et anévrisme artériel a été menée dans le SNDS. Les patients hospitalisés pour dissection ou anévrisme artériel entre 2012 et 2019 constituaient les cas, appariés jusqu’à 10 témoins sur l’âge, le sexe, et la durée depuis l'inclusion. L'analyse principale a considéré l'exposition aux antiangiogéniques globalement (exposition, non exposition). Les analyses secondaires ont considéré l'ancienneté (en cours, passée, non exposition) et la durée cumulée d'exposition, les périodes d'exposition étant calculées selon deux méthodes (schéma d'administration, demi-vie d’élimination). L'association a été estimée à l'aide de modèles de régression logistique conditionnelle ajustés sur le niveau de risque cardiovasculaire défini par la présence de comorbidités cardiovasculaires. Résultats Parmi les 34 733 patients de la cohorte, 195 cas (0,6 %) ont été identifiés et appariés à 1950 témoins. La population était majoritairement masculine (73 %) avec un âge médian de 69 ans (IIQ : 63-73) pour les cas et 68 ans (62-73) pour les témoins. Dans l'analyse principale, 141 (72,3 %) cas et 1381 (70,8 %) témoins étaient exposés aux antiangiogéniques et aucune association avec la survenue de dissection ou anévrisme artériel n'a été retrouvée (RC [IC95%]=1,09 [0,76;1,54], RCa [IC95%]=1,07 [0,75;1,52]). L'absence d'association a été retrouvée dans les analyses secondaires quelles que soient la méthode de calcul des périodes d'exposition et la définition d'exposition utilisées. Conclusion L'incidence très faible de dissection ou anévrisme artériel et l'absence d'association avec l'exposition aux antiangiogéniques dans cette étude apportent des éléments rassurants compte tenu de leur bénéfice attendu dans le CCRm.

Introduction Bien que l'accès au SNDS ait été largement ouvert, son utilisation reste aujourd'hui freinée par la complexité de la base de données et de son architecture informatique. L'objectif de cette boite à outils est de fournir des programmes permettant l'extraction de données et la constitution de référentiels patients pour la conduite d’études observationnelles à partir d'accès permanent au SNDS. Méthodes La documentation SNDS (recommandations de nettoyage des données et bonnes pratiques de codage SAS) a été utilisée afin de développer des macros d'extraction permettant d'optimiser la préparation des données à partir de différents champs : %xtr_pha_dcir et %xtr_ucd_dcir pour les médicaments (DCIR) ; %xtr_hsp_dcir diagnostics des séjours hospitaliers (PMSI MCO, HAD, PSY et/ou SSR) ; %xtr_ald_dcir ALD ; %xtr_cam_dcir actes médicaux (DCIR, PMSI) ; %xtr_lpp_dcir dispositifs médicaux (DCIR). Ces macros appellent %multi_like une macro permettant d'enchainer des opérateurs like et réduisant ainsi la complexité des requêtes. Les six macros de constitution du référentiel patient permettent de réaliser successivement la sélection et le nettoyage des données pour aboutir à une table contenant un identifiant unique par patient, l'ensemble des variables nécessaires aux jointures, les données sociodémographiques, et les indicateurs annuels de présence aux différents régimes d'affiliation. Pour illustrer l'utilisation de ces macros SAS, la constitution d'un référentiel patients et l'extraction des délivrances d’ézétimibe a été réalisée pour permettre d’évaluer la prévalence d'utilisation en 2022 en France. Résultats Les macros sont disponibles à l'adresse : https://gitlab.com/Drugs-Safe-R/Outils_SNDS. Les deux premières macros référentiel ont permis d'identifier 156 155 088 pseudo-identifiants considérés normaux ou provisoires correspondant à 106 355 507 sujets après exclusion des jumeaux et mauvaises associations. La macro d'extraction des délivrances d’ézétimibe en 2022 a abouti à 2 087 572 lignes (28 min). Les quatre macros référentiel restantes ont abouti à identifier 468 514 patients ayant une délivrance de ce médicament en 2022 (30 min). Conclusion L'ouverture de ces outils à la communauté des utilisateurs du SNDS devrait permettre d'améliorer l'accès et l'exploitation des données via les accès permanents ainsi que la reproductibilité des études qui y sont conduites.

Introduction Les inhibiteurs de la proprotéine convertase subtilisine/kexine de type 9 (antiPCSK9) sont indiqués en association avec des statines et/ou de l'ézétimibe pour intensifier la réduction du cholestérol LDL, et réduire le risque de maladie cardiovasculaire athéroscléreuse. L'objectif de cette étude était de décrire les profils d'utilisation des antiPCSK9. Méthodes Une étude de cohorte, incluant les nouveaux utilisateurs d'antiPCSK9 entre 2018 et 2021, a été menée à partir du Système national des données de santé (SNDS). Les trajectoires d'intensité du traitement hypocholestérolémiant dans les deux ans précédant l'initiation des antiPCSK9 ont été modélisées à l'aide d'un modèle mixte à processus latent sans effet aléatoire. L'intensité du traitement a été évaluée mensuellement en se basant sur quatre états : (1) absence de délivrance; (2) statine d'intensité faible, ou ézétimibe; (3) statine d'intensité modérée, ou faible + ézétimibe; (4) statine de forte intensité, ou d'intensité modérée + ézétimibe. Pour chaque trajectoire identifiée, l'utilisation des hypolipémiants au cours des six mois de suivi a été représentée à l'aide de graphiques en tapis de séquences. Résultats La majorité des 6891 nouveaux utilisateurs d'antiPCSK9 était des hommes (65,7 %), d’âge médian 64 ans (IIQ : 56-71); 63,7 % étaient à très haut risque cardiovasculaire. Huit trajectoires ont été retenues : traitement hypocholestérolémiant intensif (33,8 %), faible/modéré à intensif (6,8 %), nul à intensif (3,4 %), faible/modéré (22,0 %), nul à modéré (8,7 %), intensif à faible/modéré (6,5 %), faible/modéré à nul (6,6 %), et nul (12,2 %). Les patients non traités avant l'initiation avaient plus souvent une délivrance unique (10,0 %). L'utilisation des hypolipémiants au cours des six mois de suivi dépendait de l’état atteint en fin de trajectoire; les patients non traités interrompaient plus fréquemment leur traitement hypolipémiant (17,3 %) que ceux ayant un traitement d'intensité faible/modérée, ou forte (respectivement 4,9 % et 1,3 %). Conclusion Les nouveaux utilisateurs d'antiPCSK9 étaient majoritairement à très haut risque cardiovasculaire. Peu de patients étaient traités en première intention, mais ces derniers étaient ceux pour lesquels la persistance au traitement hypolipémiant était la moins bonne.

Background A highly effective therapy involving elexacaftor, tezacaftor, and ivacaftor (ETI) for cystic fibrosis (CF) patients has recently raised safety concerns regarding potential psychiatric disorders. The manuscript reports cases of suicide attempts in patients receiving ETI and investigates putative causality using the WHO spontaneous reporting database. Methods First, four cases of suicide attempts/self-injury are described. Second, a disproportionality analysis was conducted using spontaneous reports collected in Vigibase through the standardised MedDRA Query (narrow version) "Suicide/Self-injury" and ETI exposure. Reporting Odds Ratio (ROR) was calculated for the main and subgroup (i/suicide attempt, ii/suicidal ideation) analyses. Sensitivity analyses were performed with variations in exposure, to ivacaftor/lumacaftor to assess the intrinsic psychiatric risk of CF patients, and paracetamol as a positive control for suicide attempt and a negative one for suicidal ideation. Exposure to reduced-dose ETI was studied to evaluate the dose-gradient effect. Results Four cases of suicide attempt/self-injury occurred 3 to 13 months after ETI initiation in CF patients and were reported to the Bordeaux Pharmacovigilance centre. Aside, in Vigibase, ETI is associated with an increased likelihood of reporting suicidal behaviour (ROR 2.5, 95 % CI[2.1; 2.8]). A signal of disproportionate reporting was found for the subgroup of suicide attempts (1.4, 95 % CI[1.2; 1.8]), unlike ivacaftor/lumacaftor, which was associated only with the risk of reporting suicidal ideation. Significant ROR values were also found for reduced-dose ETI for all psychiatric effects studied except suicide attempt. Conclusions ETI exposure is related with increased reporting of suicidal behaviour. A potential dose-dependent effect merits further investigation.

Background: Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce.Objectives: This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings.Methods: We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients >= 18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors.Results: Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]).Conclusions: In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.

In 2021, the massive Covid-19 vaccination campaign in France was accompanied by an intensified pharmacovigilance monitoring of their potential adverse drug reactions. The importance of this reporting might have led to an important selective reporting and overloading of Pharmacovigilance Centres, delaying the recording of some reports in the national pharmacovigilance database. In this context, we aimed to evaluate the impact of the Covid-19 vaccination campaign in France and related reports on spontaneous reporting of adverse drug reactions that were not related to the Covid-19 vaccine. We performed time-series analyses considering the monthly number of adverse drug reactions reported between January 1, 2018 and April 30, 2022 using the French Pharmacovigilance database. The impact of the Covid-19 vaccination campaign on the monthly reporting not Covid-19 vaccine related was estimated using interrupted time-series. January 2021, marking the start of the campaign, was the intervention date in the models. Analyses were run globally first considering all adverse drug reaction reports, and second according to notifier type and to case seriousness. We included 170,294 reports registered in the French Pharmacovigilance database between January 1, 2018 and April 30, 2022 that were not Covid-19 vaccine-related. Among these, 77,067 (45.3

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.

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.

BackgroundPathological anxiety is responsible for major functional impairments and resistance to conventional treatments in anxiety disorders (ADs), posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Focal neuromodulation therapies such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS) are being developed to treat those disorders.MethodsWe performed a dimensional systematic review and meta-analysis to assess the evidence of the efficacy of TMS, tDCS and DBS in reducing anxiety symptoms across ADs, PTSD and MDD. Reports were identified through systematic searches in PubMed/Medline, Scopus and Cochrane library (inception to November 2020), followed by review according to the PRISMA guidelines. Controlled clinical trials examining the effectiveness of brain stimulation techniques on generic anxiety symptoms in patients with ADs, PTSD or MDD were selected.ResultsNineteen studies (RCTs) met inclusion criteria, which included 589 participants. Overall, focal brain activity modulation interventions were associated with greater reduction of anxiety levels than controls [SMD: −0.56 (95% CI, −0.93 to−0.20, I2 = 77%]. Subgroup analyses revealed positive effects for TMS across disorders, and of focal neuromodulation in generalized anxiety disorder and PTSD. Rates of clinical responses and remission were higher in the active conditions. However, the risk of bias was high in most studies.ConclusionsThere is moderate quality evidence for the efficacy of neuromodulation in treating pathological anxiety.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=233084, identifier: PROSPERO CRD42021233084. It was submitted on January 29th, 2021, and registered on March 1st, 2021. No amendment was made to the recorded protocol. A change was applied for the subgroup analyses based on target brain regions, we added the putative nature (excitatory/inhibitory) of brain activity modulation.

AIM:Drug shortages are a growing global health issue. The aim of the study was to evaluate the consequences of drug shortages on patient safety based on data recorded in the French National Pharmacovigilance Database. METHODS:All cases involving drug shortages reported from 1985 to the end of 2019 were extracted from the database. RESULTS:Following the selection process, 462 cases were included. The number of cases increased significantly from 2004 to 2019. Cases mainly involved drugs from the nervous system (22.1%, 95% confidence interval [CI] 17.5-27.0%), the cardiovascular system (16.4%, 95% CI 11.9-21.4%) and anti-infectives for systemic use (14.3%, 95% CI 9.7-19.2%) ATC classes. Most of the cases reported an adverse drug reaction (ADR) belonging to the SOC nervous system (21%, 95% CI 18-24%), skin and subcutaneous (14%, 95% CI 11-17%), general (13%, 95% CI 10-17%) and gastrointestinal (8%, 95% CI 5-11%) disorders. Disease worsening was observed in 15.9% of the cases, mostly related to a lack of efficacy of the replacement drug. Half of the cases were considered as serious. Evolution was favourable in 79.4% of the cases. Death and/or life-threatening situations were reported in 5.8% of the cases. Medication errors (MEs) were identified in 51 cases (11%), mostly occurring at the administration step and involving a human factor. CONCLUSION:This study emphasizes the clinical impact of drug shortage in terms of ADRs, ME and inefficiency. These observations underline the importance of a global health policy programme to limit the occurrence of drug shortages and to reinforce the information provided to patients and health care professionals in this context to limit risk.

L'utilisation problématique des opioïdes est une préoccupation mondiale à l'origine d'une augmentation massive des cas de troubles de l'usage et de décès. Bien que tous les opioïdes aient le même potentiel de mésusage, ceux impliquant les opiacés faibles ont été peu évalués. L'objectif de cette étude était de décrire l'utilisation en première intention et le mésusage potentiel des opiacés faibles à partir des bases de données médico-administratives françaises. Des cohortes d'utilisateurs incidents d'opiacés faibles ont été constituées annuellement entre 2012 et 2017. L’évolution des fréquences d'utilisation en première intention et de mésusage des opiacés faibles a été décrite au cours de la période d’étude. Les indicateurs de mésusage incluaient principalement l'utilisation d'opiacés faibles dans un contexte de contre-indication (par exemple, asthme sévère ou insuffisance respiratoire). Le tramadol et la codéine étaient les opiacés faibles les plus fréquemment prescrits en première intention (autour de 30 %). Les proportions d'utilisation en première intention d'opium et de dihydrocodéine atteignaient 25 % en 2017, après une augmentation d'un peu moins de 10 % pour l'opium et de près de 30 % pour la dihydrocodéine. La fréquence de mésusage était stable pour le tramadol, la codéine et l'opium (2-3 %). Elle était plus importante chez les utilisateurs de dihydrocodéine, variant de 5 % à 7 % au cours de la période. L'utilisation d'opiacés faibles dans un contexte d'asthme ou d'insuffisance respiratoire et l'utilisation concomitante de plusieurs opioïdes étaient les situations de mésusage les plus fréquentes. Cette étude fournit une image globale de l'utilisation et du mésusage des opiacés faibles en France. À l'exception de la dihydrocodéine, l'utilisation en première intention et le mésusage des opiacés faibles sont stables. Les opiacés faibles sont largement utilisés et bien que leur mésusage soit faible, il implique des situations évitables, soulignant ainsi la nécessité de poursuivre la sensibilisation à l'usage des opioïdes. Les auteurs déclarent ne pas avoir de liens d'intérêts.