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Background and Purpose: The purpose was to describe the use patterns of pharmacological and non-pharmacological therapies and investigate potential determinants of riluzole use in patients newly diagnosed with amyotrophic lateral sclerosis (ALS) in three Italian regions., Methods: Amyotrophic lateral sclerosis patients were selected from administrative healthcare databases of Latium, Tuscany and Umbria from 1 January 2014 to 31 December 2019 based on hospital- and disease-specific co-payment exemption data. The first trace of ALS was considered the index date. Incident ALS cases were those without a trace of ALS during the 3-year look back. Patients were described in terms of demographics, clinical characteristics and drug use at baseline, and were classified into four categories based on riluzole use in the 2 years before and 1 year after the index date: prevalent, incident, former users and non-users. Use of symptomatic pharmacological and non-pharmacological therapies was described across these categories during 12 months after the index date. Determinants of riluzole use were also investigated., Results and Conclusions: A total of 1636 ALS incident subjects were detected in the three regions, mainly aged 65-74 years. Patients were generally fragile with a high prevalence of comorbidities at baseline. Riluzole was used by 27.4% of the overall study cohort at baseline and steeply increased in the first year after the index date differently between regions (Latium 61.2%, Tuscany 85.0%, Umbria 76.5%), with about half of the subjects being incident users. In the 12 months after the index date, also symptomatic therapies increased, in riluzole users and non-users. Determinants analysis showed that higher patient severity and complexity were associated with a lower likelihood of being treated with riluzole., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

We aim to estimate the incidence rates (IRs) of SARS-CoV-2 infections stratified by disease severity and comorbidities in pediatric population and to describe the COVID-19 vaccination coverage in children with and without comorbidities. A population-based cohort study was conducted in 6 electronic healthcare records databases from Italy, Spain, and Norway. The study lasted from 1 January 2020 to the latest databases' available data in each site, i.e., in Italian ARS Tuscany and PEDIANET: December 2021, in Spanish BIFAP: February 2022; SIDIAP: June 2022, and VID: December 2021. Finally, in Norwegian Health Registries: December 2021. Children and adolescents were included and stratified into three age categories (< 5, 5- < 12, and 12- < 18 years old). IRs (95% confidence intervals) per 100 person-years (PY) for non-severe (positive SARS-CoV-2 test or diagnosis without hospitalization) and severe COVID-19 (hospitalization, intensive care unit admission, and death after COVID-19) are reported. The cumulative COVID-19 vaccination rollout was stratified by population with and without comorbidities. The study population comprised 5,654,040 individuals < 18 years of age (51% females) across the six European databases (median age: 6 years), with 1.4 to 8.5% of them having at least one at-risk comorbidity for severe COVID-19. Incidence rates of severe COVID-19 were low (0-1 per 100 PY) but 3 to 4 times higher among children and adolescents with comorbidities during Omicron BA.1-2 wave in December 2021-January 2022. Percentages of vaccination rollout in the general population were between 13% in PEDIANET-IT and 64% in BIFAP-ICU-ES. In ARS-IT and SIDIAP-IT, vaccination rate in children with comorbidities was slightly lower than that in the general population., Conclusion: Severe COVID-19 was rare across databases, but up to 3 to 4 times higher in children with comorbidities during the predominance of Omicron BA.1-2 variant in winter 2021-2022. COVID-19 vaccination coverage was slightly lower in children with comorbidities in ARS (Tuscany) and SIDIAP (Catalonia) data sources. Our findings will inform future public policies aimed to protect the pediatric population, both within these countries and globally., What Is Known: • Pediatric population is susceptible to SARS-CoV-2 infection. • COVID-19 severity rates in children vary across study settings and context., What Is New: • This study confirms the low severity rates of COVID-19 in the pediatric population based on a large cohort of children and adolescents residing in Spain, Italy, and Norway. • Incidence of severe COVID-19 in children and adolescents with comorbidities was up to 3 to 4 times higher than in the general pediatric population during the SARS-CoV-2 high transmission wave of Omicron BA.1-2 variant in winter 2021-2022 in Italy and Spain., Competing Interests: Declarations Ethics approval Most data partners that provided data for the herein-presented results had passed the local ethical review process for the whole COVID-19 Vaccine Monitor study (EUPAS42467); Norwegian data (NHR): Regional Committee for Research Ethics (approval number 155294/REK Nord) and the Data Protection Officer at the University of Oslo (approval number 523275); Valencian data (VID): Comité Ético de Investigación con Medicamentos del Hospital General Universitario de Elche (approval number: PI-90/2021); Catalonian data (SIDIAP): Comitè Ètic d'Investigació amb medicaments (CEIm) de l'IDIAP Jordi Gol (approval number: 21/199-PCV); and BIFAP (several Spanish regions): Comité de Ética de la Investigación con Medicamentos del Hospital Universitario de la Princesa and Comité Científico de BIFAP (approval number: CEIm 14/21). There was no need of ethical committee approval for Italian databases (ARS and PEDIANET). This research adhered to the rules and principles of the European Network of Centers of Pharmacoepidemiology and Pharmacovigilance (ENCePP) Code of Conduct. Consent to participate This research was conducted using secondary heathcare data. Informed consent to participate was not obtained. The whole COVID-19 Vaccine Monitor study (EUPAS42467) was conducted following the ENCePP Code of Conduct. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To investigate seasonality, epidemiologic characteristics, and clinical severity variations of respiratory syncytial virus (RSV)-associated hospitalizations following the easing of COVID-19 restrictions in Tuscany, Italy, up to the 2022-2023 season., Methods: From 2017 to 2023, a dynamic cohort consisting of all resident children aged ≤2 years was followed up in regional registries. The person-time incidence rate of RSV-associated hospitalizations per 1,000 person-years and risk of severe hospitalization (intensive care unit, continuous positive airway pressure, or mechanical ventilation) per 100 RSV hospitalizations were calculated. RSV seasonality was investigated with retrospective methods., Results: A total of 193,244 children were followed up. After the easing of restrictions, RSV epidemics showed earlier seasonality and shorter duration compared with pre-pandemic (2017 to 2019), with this deviation decreased in 2022-2023. In 2021-2022 and 2022-2023, the incidence rate of RSV-associated hospitalizations significantly increased compared with pre-pandemic (2022-2023 risk ratio 3.6, 95% confidence interval 3.3-4.0), with larger increases among older age groups. Among hospitalized children, only those aged ≥12 months showed an increased risk of severe hospitalization, particularly during 2021-2022 (risk ratio 4.7, 95% confidence interval 1.5-24.3)., Conclusions: Our findings suggest a gradual return of RSV epidemics to the pre-pandemic pattern, although relevant increases in disease incidence persist. Reduced regular RSV exposure among older children may lead to declining immunity and increased severe outcome risks., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In epidemiological database studies, the occurrence of an event is measured with error through an indicator whose specificity is often maximised, at the expense of sensitivity. However, if the indicator has low sensitivity, measures of occurrence are underestimated. In association studies, risk difference is biased, and risk ratio may be biased as well, in either direction, if the sensitivity is differential across exposure groups. In this work, we show that if an auxiliary screening indicator can be defined to complement the main indicator, estimates of the positive predictive value of both indicators provide tools to estimate the sensitivity of the primary indicator, or a lower bound thereof. This mitigates bias in estimating the number of cases, prevalence, cumulative incidence, rate (particularly when the event is rare), and in association studies, risk ratio and risk difference. They also allow testing for non-differential sensitivity. While direct estimation of sensitivity is often infeasible, this novel methodology improves evidence based on data obtained from re-use of existing databases, which may prove critical for regulatory and public health decisions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Purpose: There is increasing recognition of the importance of transparency and reproducibility in scientific research. This study aimed to quantify the extent to which programming code is publicly shared in pharmacoepidemiology, and to develop a set of recommendations on this topic., Methods: We conducted a literature review identifying all studies published in Pharmacoepidemiology and Drug Safety (PDS) between 2017 and 2022. Data were extracted on the frequency and types of programming code shared, and other key open science practices (clinical codelist sharing, data sharing, study preregistration, and stated use of reporting guidelines and preprinting). We developed six recommendations for investigators who choose to share code and gathered feedback from members of the International Society for Pharmacoepidemiology (ISPE)., Results: Programming code sharing by articles published in PDS ranged from 1.8% in 2017 to 9.5% in 2022. It was more prevalent among articles with a methodological focus, simulation studies, and papers which also shared record-level data., Conclusion: Programming code sharing is rare but increasing in pharmacoepidemiology studies published in PDS. We recommend improved reporting of whether code is shared and how available code can be accessed. When sharing programming code, we recommend the use of permanent digital identifiers, appropriate licenses, and, where possible, adherence to good software practices around the provision of metadata and documentation, computational reproducibility, and data privacy., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Purpose: Metadata for data dIscoverability aNd study rEplicability in obseRVAtional studies (MINERVA), a European Medicines Agency-funded project (EUPAS39322), defined a set of metadata to describe real-world data sources (RWDSs) and piloted metadata collection in a prototype catalogue to assist investigators from data source discoverability through study conduct., Methods: A list of metadata was created from a review of existing metadata catalogues and recommendations, structured interviews, a stakeholder survey, and a technical workshop. The prototype was designed to comply with the FAIR principles (findable, accessible, interoperable, reusable), using MOLGENIS software. Metadata collection was piloted by 15 data access partners (DAPs) from across Europe., Results: A total of 442 metadata variables were defined in six domains: institutions (organizations connected to a data source); data banks (data collections sustained by an organization); data sources (collections of linkable data banks covering a common underlying population); studies; networks (of institutions); and common data models (CDMs). A total of 26 institutions were recorded in the prototype. Each DAP populated the metadata of one data source and its selected data banks. The number of data banks varied by data source; the most common data banks were hospital administrative records and pharmacy dispensation records (10 data sources each). Quantitative metadata were successfully extracted from three data sources conforming to different CDMs and entered into the prototype., Conclusions: A metadata list was finalized, a prototype was successfully populated, and a good practice guide was developed. Setting up and maintaining a metadata catalogue on RWDSs will require substantial effort to support discoverability of data sources and reproducibility of studies in Europe., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

We test the robustness of the self-controlled risk interval (SCRI) design in a setting where time between doses may introduce time-varying confounding, using both negative control outcomes (NCOs) and quantitative bias analysis (QBA). All vaccinated cases identified from 5 European databases between 1 September 2020 and end of data availability were included. Exposures were doses 1-3 of the Pfizer, Moderna, AstraZeneca, and Janssen COVID-19 vaccines; outcomes were myocarditis and otitis externa (NCO). The SCRI used a 60-day control window and dose-specific 28-day risk windows, stratified by vaccine brand and adjusted for calendar time. The QBA included two scenarios: (i) baseline probability of the confounder was higher in the control window and (ii) vice versa. The NCO was not associated with any of the COVID-19 vaccine types or doses except Moderna dose 1 (IRR = 1.09, 95%CI 1.01-1.09). The QBA suggested even the strongest literature-reported confounder (COVID-19; RRmyocarditis = 18.3) could only explain away part of the observed effect from IRR = 3 to IRR = 1.40. The SCRI seems robust to unmeasured confounding in the COVID-19 setting, although a strong unmeasured confounder could bias the observed effect upward. Replication of our findings for other safety signals would strengthen this conclusion., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Purpose: The COVID-19 pandemic has impacted medication needs and prescribing practices, including those affecting pregnant women. Our goal was to investigate patterns of medication use among pregnant women with COVID-19, focusing on variations by trimester of infection and location., Methods: We conducted an observational study using six electronic healthcare databases from six European regions (Aragon/Spain; France; Norway; Tuscany, Italy; Valencia/Spain; and Wales/UK). The prevalence of primary care prescribing or dispensing was compared in the 30-day periods before and after a positive COVID-19 test or diagnosis., Results: The study included 294,126 pregnant women, of whom 8943 (3.0%) tested positive for, or were diagnosed with, COVID-19 during their pregnancy. A significantly higher use of antithrombotic medications was observed particularly after COVID-19 infection in the second and third trimesters. The highest increase was observed in the Valencia region where use of antithrombotic medications in the third trimester increased from 3.8% before COVID-19 to 61.9% after the infection. Increases in other countries were lower; for example, in Norway, the prevalence of antithrombotic medication use changed from around 1-2% before to around 6% after COVID-19 in the third trimester. Smaller and less consistent increases were observed in the use of other drug classes, such as antimicrobials and systemic corticosteroids., Conclusion: Our findings highlight the substantial impact of COVID-19 on primary care medication use among pregnant women, with a marked increase in the use of antithrombotic medications post-COVID-19. These results underscore the need for further research to understand the broader implications of these patterns on maternal and neonatal/fetal health outcomes., (© 2024. The Author(s).)

Purpose: Real-world evidence (RWE) is increasingly used for medical regulatory decisions, yet concerns persist regarding its reproducibility and hence validity. This study addresses reproducibility challenges associated with diversity across real-world data sources (RWDS) repurposed for secondary use in pharmacoepidemiologic studies. Our aims were to identify, describe and characterize practices, recommendations and tools for collecting and reporting diversity across RWDSs, and explore how leveraging diversity could improve the quality of evidence., Methods: In a preliminary phase, keywords for a literature search and selection tool were designed using a set of documents considered to be key by the coauthors. Next, a systematic search was conducted up to December 2021. The resulting documents were screened based on titles and abstracts, then based on full texts using the selection tool. Selected documents were reviewed to extract information on topics related to collecting and reporting RWDS diversity. A content analysis of the topics identified explicit and latent themes., Results: Across the 91 selected documents, 12 topics were identified: 9 dimensions used to describe RWDS (organization accessing the data source, data originator, prompt, inclusion of population, content, data dictionary, time span, healthcare system and culture, and data quality), tools to summarize such dimensions, challenges, and opportunities arising from diversity. Thirty-six themes were identified within the dimensions. Opportunities arising from data diversity included multiple imputation and standardization., Conclusions: The dimensions identified across a large number of publications lay the foundation for formal guidance on reporting diversity of data sources to facilitate interpretation and enhance replicability and validity of RWE., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Introduction: The aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis., Methods: We used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures., Results: We included 1,757 cases of myocarditis. For analyses of the first dose of the Pfizer vaccine, to which all databases contributed information, we found results consistent with a null effect in both of the SCRI and extended SCCS, but some indication of a harmful effect in a standard SCCS. For the second dose, we found evidence of a harmful association for all study designs, with relatively similar effect sizes (SCRI pre = 1.99, 1.40 - 2.82; SCRI post 2.13, 95 %CI - 1.43, 3.18; standard SCCS 1.79, 95 %CI 1.31 - 2.44, extended SCCS 1.52, 95 %CI = 1.08 - 2.15). Adjustment for calendar time did not change these conclusions. Findings using all designs were also consistent with a harmful effect following a second dose of the Moderna vaccine., Conclusions: In the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: University Medical Center Utrecht in collaboration with the Vaccine Monitoring Collaboration for Europe network (VAC4EU). reports financial support was provided by European Medicines Agency. Anna Schultze reports a relationship with GSK that includes: funding grants. Ian Douglas reports a relationship with GSK that includes: equity or stocks and funding grants. Fabio Riefolo reports a relationship with TEAMIT Institute, a research management organisation that participates in financially supported studies for the European Medicines Agency and related healthcare authorities, pharmaceutical companies, and the European Union that includes: employment. Felipe Villalobos, Meritxell Palleja-Millan, Carlo Alberto Bissacco and Elena Segundo reports a relationship with IDIAPJGol, which receives institutional research funding from public and private partners, pharmaceutical companies and regulatory agencies that includes: employment. Miriam Sturkenboom reports a relationship with University Medical Center Utrecht, which conducts studies for the European Medicines Agency, the European Commission and medicine manufacturers, all according to the ENCePP code of conduct that includes: employment. Carlos E. Duran reports a relationship with University Medical Center Utrecht, which receives institutional research funding from pharmaceutical companies and regulatory agencies that includes: employment. Rosa Gini and Davide Messina reports a relationship with ARS Tuscany, which reports funding from the Innovative Medicines Initiative, RTI, PHARMO, University of Southern Denmark, University of Utrecht, Eli Lilly, Pfizer, Novartis, AstraZeneca, Galapagos, and LeoPharma that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier India Pvt Ltd. All rights reserved.)

To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients' characteristics and median treatment duration of biologics approved for IMIDs between RCTs' and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8-1.9) compared to RCTs (F/M ratio: 0.5-0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4-100 vs. 6-167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients., Competing Interests: Declaration of Competing Interest G.T. participated to advisory boards and seminars as lecturer on topics not related to the paper and sponsored by the following pharmaceutical companies in the last two years: Eli Lilly; Sanofi; Amgen; Novo Nordisk; Sobi; Gilead; Celgene; Daiichi Sankyo, Takeda and MSD. He is also scientific coordinator of the pharmacoepidemiology team at the University of Verona and of the academic spin-off “INSPIRE srl” that carried out in the last two years observational studies/systematic reviews on topics not related to the content of this article and which were funded by PTC Pharmaceutics, Kyowa Kirin, Shionogi, Shire, Chiesi and Daiichi Sankyo. Y.I. is the CEO of the academic spin-off “INSPIRE srl”, which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.) and from pharmaceutical Companies (Chiesi Italia, Kyowa Kirin s.r.l., Daiichi Sankyo Italia S.p.A.)., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Using 4 data-sources (Spain, Italy, United Kingdom) data and a 1:1 matched cohort study, we aimed to estimate vaccine effectiveness (VE) in preventing SARS-CoV-2 infections with hospitalisations (±30 days) and death (±56 days) in general population and clinical subgroups with homologous/heterologous booster schedules (Comirnaty-BNT and Spikevax-MOD original COVID-19 vaccines) by comparison with unboosted individuals, during Delta and beginning of Omicron variants. Hazard Ratio (HR, by Cox models) and VE ([1-HR]*100) were calculated by inverse probability weights. Between December 2020-February 2022, in adults without prior SARS-CoV-2 infection, we matched 5.5 million people (>1 million with immunodeficiency, 343,727 with cancer) with a booster (3rd) dose by considering doses 1 and 2 vaccine brands and calendar time, age, sex, region, and comorbidities (immunodeficiency, cancer, severe renal disease, transplant recipient, Down Syndrome). We studied booster doses of BNT and MOD administered after doses 1 and 2 with BNT, MOD, or Oxford-AstraZeneca during a median follow-up between 9 and 16 weeks. BNT or MOD showed VE ranging from 70 to 86% across data sources as heterologous 3rd doses, whereas it was 42-88% as homologous 3rd doses. Depending on the severity and available follow-up, 3rd-dose effectiveness lasted between 1 and 5 months. In people with immunodeficiency and cancer, protection across data sources was detected with both heterologous (VE = 54-83%) and homologous (VE = 49-80%) 3rd doses. Overall, both heterologous and homologous 3rd doses with BTN or MOD showed additional protection against the severe effects of SARS-CoV-2 infections for the general population and for patients at potentially high risk of severe COVID-19 (elderly, people with immunodeficiency and cancer) in comparison with two doses schemes during Delta or early Omicron periods. The early VE after vaccination may be due to less testing among vaccinated pairs and unknown confounders, deserving cautious interpretation. The VE wane over time needs further in-depth research to properly envisage when or whether a booster of those vaccines should be administered., Competing Interests: Declaration of Competing Interest All the authors declare financial support was provided by European Medicines Agency and the following financial interests/personal relationships which may be considered as potential competing interests: Elisa Martin Merino (corresponding author): Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) and Agencia Española de Cooperación Internacional para el Desarrollo (AECID) paid a presentation in a course ‘Farmacovigilancia de las vacunas frente a la COVID-19’; Unpaid collaboration in observational studies with Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) for the “Grupo de Trabajo de Efectividad Vacunación COVID-19. Spanish Ministry of Health. ISCIII.CNE. Spanish Agency of Medicines and Medical Devices.” Riefolo Fabio is an employee of TEAMIT Institute, consulting research company that participates in financially supported studies for European Medicines Agency and related healthcare authorities, pharmaceutical companies, and the European Union. Ylenia Ingrasciotta is the CEO of the academic spin-off “INSPIRE srl” of the University of Messina, which has received funding for conducting observational studies from contract research organizations (RTI Health Solutions, Pharmo Institute N.V.) and from pharmaceutical Companies (Chiesi Italia, Kyowa Kirin s.r.l., Daiichi Sankyo Italia S.p.A.). Karin Swart-Polinder is an employee of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for the government and related healthcare authorities and several pharmaceutical companies., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: To describe the pattern of anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP mAbs) utilization in the Tuscany region, Italy, and the variation of triptan consumption after treatment initiation., Background: Given the recent commercialization of anti-CGRP mAbs as migraine preventive medications, real-world evidence on their patterns of utilization and their impact on migraine abortive medication use is still limited., Methods: A retrospective, descriptive, cohort study on the real-world utilization of anti-CGRP mAbs was performed using the population-based regional administrative database of Tuscany. Patients with ≥1 anti-CGRP mAb dispensing (namely erenumab, galcanezumab, fremanezumab) between April 1, 2019, and September 30, 2021, were identified. The first dispensing was the cohort entry (CE). New users (NUs) were patients with no anti-CGRP mAb dispensing before CE. Kaplan-Meier (KM) curves were plotted to describe the cumulative probability of remaining with the initial anti-CGRP mAb during a 15-month follow-up period as a measure of treatment persistence. Among NUs with ≥2 triptan dispensings during the 6 months before CE (i.e., baseline), the mean monthly number of triptan dosage units dispensed was measured in five consecutive follow-up time windows (months 1-3, 4-6, 7-9, 10-12, 13-15) and the difference from the baseline was calculated., Results: A total of 624 NUs (erenumab = 295, galcanezumab = 223, fremanezumab = 106) were identified, of whom 188 (78%) were women. Mean age was 49.2 years (standard deviation [SD] = 12.6). The survival to discontinuation at 6, 12, and 15 months was about 69%, 48%, and 6%, respectively. The survival to switch was about 6% at 15 months. The observed variation of triptan consumption at 3/6/9/12/15 months and the corresponding SD was -4.4 [8.2]/-5.2 [9.0]/-5.5 [9.2]/-5.4 [9.2]/-4.5 [10.0], respectively., Conclusion: Patient demographics reflect the place of these medications in therapy. Overall, findings seem to indicate a favorable tolerability and effectiveness profile. Further studies are warranted to better establish the long-term comparative effectiveness, safety, and cost effectiveness of anti-CGRP mAbs compared to other preventive medications., (© 2023 American Headache Society.)

Background: A missed diagnosis of Crohn's disease (CD) can delay treatment initiation with consequences on disease course., Aims: To measure the possible impact of missed diagnoses on drug utilization and access to healthcare facilities in a real-world cohort of CD patients., Methods: This retrospective observational study has been conducted on the regional administrative databases of Tuscany (Italy). We included patients with a first record of CD diagnosis between 06/11/2011 and 06/30/2016. Possible missed diagnosis (exposure) was defined by hospital presentation for gastrointestinal symptoms consistent with CD diagnosis that occurred in the 7-60 months preceding CD diagnosis. We compared exposed and non-exposed patients by assessing time-free from biologic drugs and from Emergency Department (ED) or hospital access. Hazard ratio (HR) was calculated using Cox models., Results: Among 3342 CD patients, 584 (17.5%) had a possible missed diagnosis. A risk of being treated with biologic drugs [adjusted HR (aHR): 2.17, 95% CI: 1.75-2.71] and of access to ED or hospitalization (aHR: 1.59, 95% CI: 1.44-1.75) was observed in patients with a possible missed diagnosis as compared to those without., Conclusion: Tertiary care caregivers should be trained in the identification of early CD symptoms, to timely identify CD diagnosis and optimize pharmacological treatment and disease management., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: The disease activity associated with the drug-utilization patterns of biologic Disease Modifying Anti-Rheumatic Drugs (DMARDs) is poorly investigated in real-world studies on rheumatoid arthritis (RA) patients. To investigate the relationship between biologic DMARD initiation/discontinuations in RA patients identified in the healthcare administrative databases of Tuscany and the Disease Activity Score 28 (DAS28) reported in the medical charts. Methods: This retrospective population-based study included RA's first-ever biologic DMARD users of the Pisa University Hospital from 2014 to 2016. Patients were followed up until 31 December 2019. We evaluated the DAS28 recorded before (T0) and after (T1) the biologic DMARD initiation and before (TD0) and after (TD1) discontinuations. Patients were classified as "off-target" (DAS28 > 3.2) or "in-target" (DAS28 ≤ 3.2). We described the disease activity trends at initiation and discontinuation. Results: Ninety-five users were included (73 women, mean age 59.6). Among 70 patients (74%) with at least three DAS28 measures, 28 (40.0%) were off-target at T0 and 38 (54.3%) in-target at T1. Thirty-three (47%) patients had at least one discontinuation, among those with at least three DAS28 assessments. In the disease activity trend, disease stability or improvement was observed in 28 out of 37 (75.7%) patients at initiation and in 24 out of 37 (64.9%) at discontinuation. Discussion: Biologic DMARD discontinuations identified in the healthcare administrative databasese of Tuscany are frequently observed in situations of controlled RA disease. Further studies are warranted to confirm that these events can be used in studies using healthcare administrative databases as proxies of treatment effectiveness., 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 © 2023 Convertino, Cazzato, Tillati, Giometto, Gini, Valdiserra, Cappello, Ferraro, Bonaso, Bartolini, Paoletti, Lorenzoni, Trieste, Filippi, Turchetti, Cristofano, Blandizzi, Mosca, Lucenteforte and Tuccori.)

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use., 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 © 2023 Durán, Riera-Arnau, Abtahi, Pajouheshnia, Hoxhaj, Gamba, Alsina, Martin-Perez, Garcia-Poza, Llorente-Garcia, Gonzalez-Bermejo, Ibánez, Sabaté, Vidal, Ballarín, Sanfélix-Gimeno, Rodríguez-Bernal, Peiró, García-Sempere, Sanchez-Saez, Ientile, Ingrasciotta, Guarneri, Tanaglia, Tari, Herings, Houben, Swart-Polinder, Holthuis, Huerta, Gini, Roberto, Bartolini, Paoletti, Limoncella, Girardi, Hyeraci, Andersen, Kristiansen, Hallgreen, Klungel and Sturkenboom.)

Introduction: Due to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018., Objectives: To investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions., Methods: A multi-database, times series study of females of childbearing potential (12-55 years) was conducted using electronic medical records from five countries/regions (01.01.2010-31.12.2020): Denmark, Tuscany (Italy), Spain, the Netherlands, and the UK. Clinical and demographic information from each database was transformed to the ConcePTION Common Data Model, quality checks were conducted and a distributed analysis was performed using common scripts. Incident and prevalent use of valproate, proportion of discontinuers and switchers to alternative medicine, frequency of contraception coverage during valproate use, and occurrence of pregnancies during valproate exposure were estimated per month. Interrupted time series analyses were conducted to estimate the level or trend change in the outcome measures., Results: We included 69,533 valproate users from 9,699,371 females of childbearing potential from the five participating centres. A significant decline in prevalent use of valproates was observed in Tuscany, Italy (mean difference post-intervention -7.7%), Spain (-11.3%), and UK (-5.9%) and a non-significant decline in the Netherlands (-3.3%), but no decline in incident use after the 2018 RMMs compared to the period before. The monthly proportion of compliant valproate prescriptions/dispensings with a contraceptive coverage was low (<25%), with an increase after the 2018 RMMs only in the Netherlands (mean difference post-intervention 12%). There was no significant increase in switching rates from valproates to alternative medicine after the 2018 intervention in any of the countries/regions. We observed a substantial number of concurrent pregnancies during valproate exposure, but with a declining rate after the 2018 RMMs in Tuscany, Italy (0.70 per 1000 valproate users pre- and 0.27 post-intervention), Spain (0.48 and 0.13), the Netherlands (0.34 and 0.00), and an increasing rate in UK (1.13 and 5.07)., Conclusion: There was a small impact of the 2018 RMMs on valproate use in the studied European countries/regions. The substantial number of concurrent pregnancies with valproate exposure warrants a careful monitoring of implementation of the existing PPP for valproate in clinical practice in Europe, to see if there is any need for additional measures in the future., (© 2023. The Author(s).)

Purpose: Several case reports of acquired hemophilia A (AHA) following COVID-19 vaccines were recently published. A possible increased incidence of AHA during the COVID-19 vaccination campaign was also suggested. We aimed at generating evidence for the preliminary assessment of the association between AHA and COVID-19 vaccination through an ecological study in one Italian region, Tuscany., Methods: An ecological study was performed using the population-based administrative data source of Tuscany. Per each year between 2017 and 2021, we included patients aged 5+ and active into the database as of January 1. Temporal patterns of annual incidence of possible AHA cases and AHA-tested patients were respectively observed. The rates of possible AHA cases per AHA-tested patients were calculated in 2021 and 2017-2019, respectively (calendar year 2020 was excluded because non-representative of the pre-pandemic era). Age-sex standardization was applied. Poisson's 95% confidence intervals (95% CI) were estimated. Statically significant differences were defined as absence of 95% CI overlap., Results: In 2021, standardized incidence of both possible AHA cases (5.6/million subjects/year; 95% CI = 3.4-8.7) and AHA-tested patients (60.7/1000 subjects/year; 95% CI = 60.4-60.9) showed the lowest point estimates, though only the latter was statistically different compared to previous calendar years. The standardized rate of possible AHA cases per AHA-tested patients was 9.2/100000 (95% CI = 5.6-14.3) in 2021 and 12.5/100000 (95% CI = 8.2-18.1) during 2017-2019., Conclusions: These preliminary findings do not support the hypothesis of an increased incidence of AHA cases during the COVID-19 vaccination campaign. However, in 2021, the still ongoing healthcare access restrictions might have contributed to the low incidence of AHA and laboratory tests observed. Therefore, large-scale multi-database studies are warranted., (© 2023 John Wiley & Sons Ltd.)

Introduction: Italian administrative healthcare databases are frequently used for studies on real-world drug utilization. However, there is currently a lack of evidence on the accuracy of administrative data in describing the use of infusive antineoplastics. In this study, we used rituximab as a case study to investigate the validity of the regional administrative healthcare database of Tuscany (RAD) in describing the utilization of infusive antineoplastics., Methods: We identified patients aged 18 years or older who had received ≥1 rituximab administration between 2011 and 2014 in the onco-haematology ward of the University Hospital of Siena. We retrieved this information from the Hospital Pharmacy Database (HPD-UHS) and linked the person-level information to RAD. Patients who had received ≥1dispensing of rituximab, single administration episodes, and patients treated for non-Hodgkin Lymphoma (nHL) or Chronic Lymphocytic Leukemia (CLL) were identified in RAD and validated using HPD-UHS as the reference standard. We identified the indications of use using algorithms based on diagnostic codes (ICD9CM codes, nHL=200*, 202*; CLL=204.1). We tested 22 algorithms of different complexity for each indication of use and calculated sensitivity and positive predictive value (PPV), with 95% confidence intervals (95%CI), as measures of validity., Results: According to HPD-UHS, 307 patients received rituximab for nHL (N=174), CLL (N=21), or other unspecified indications (N=112) in the onco-haematology ward of the University Hospital of Siena. We identified 295 rituximab users in RAD (sensitivity=96.1%), but PPV could not be assessed due to missing information in RAD on dispensing hospital wards. We identified individual rituximab administration episodes with sensitivity=78.6% [95%CI: 76.4-80.6] and PPV=87.6% [95%CI: 86.1-89.2]. Sensitivity of algorithms tested for identifying nHL and CLL ranged from 87.7% to 91.9% for nHL and from 52.4% to 82.7% for CLL. PPV ranged from 64.7% to 66.1% for nHL and from 32.4% to 37.5% for CLL., Discussion: Our findings suggest that RAD is a very sensitive source of information for identifying patients who received rituximab for onco-haematological indications. Single administration episodes were identified with good-to-high accuracy. Patients receiving rituximab for nHL were identified with high sensitivity and acceptable PPV, while the validity for CLL was suboptimal., Competing Interests: CB, RG are employed and AG, GR are collaborator by ARS, a public health agency that conducts or participates in pharmacoepidemiology studies compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. 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 © 2023 Bartolini, Roberto, Girardi, Moscatelli, Spini, Barchielli, Bocchia, Fabbri, Donnini, Ziche, Monti and Gini.)

Purpose: Intraocular pressure increase (IOPi) after intravitreal injections of vascular endothelial growth factor inhibitors (VEGFis) might be different among different VEGFis (bevacizumab, aflibercept, ranibizumab). The purpose of this study was to evaluate the risk of IOPi among new users of bevacizumab, ranibizumab, and aflibercept in nondiabetic patients in Tuscany, Italy., Design: Retrospective cohort study., Methods: Tuscan regional administrative database was used to identify subjects with a first VEGFi intravitreal injection between 2011 and 2020, followed to first incidence of IOPi. Diabetic subjects, those with pre-existing IOPi, or previous use of dexamethasone implants were excluded. Multivariable Cox regression analyses (intention-to-treat and as treated) were conducted to evaluate risk of IOPi among aflibercept, bevacizumab, and ranibizumab, adjusting for potential confounding variables. IOPi was defined as the first record of International Classification of Diseases, Ninth Revision (ICD-9-CM) code 365 or use of 2 glaucoma drugs dispensations within 180 days of each other., Results: We identified 6585 new users of VEGFis: 1749 aflibercept, 1112 bevacizumab, and 3724 ranibizumab. Women made up 60% of the cohort, with a mean age of 73.6 years. In the intention-to-treat analysis, the adjusted hazard ratio (HR) for incident IOPi, compared with aflibercept, was higher for bevacizumab (HR = 2.20, 95% CI = 1.64-2.95) and ranibizumab users (HR = 1.88, 95% CI = 1.46-2.42), respectively. The HRs remained robust after exclusion of patients with proxy of retinal vascular occlusion. As treated analysis confirmed such results (bevacizumab: HR = 3.76, 95% CI = 2.30-6.17; ranibizumab: HR = 2.49, 95% CI = 1.62-3.82)., Conclusions: This study found an increased risk of IOPi among nondiabetic patients with ranibizumab and bevacizumab compared with aflibercept. Future studies are needed to validate these findings., (Copyright © 2022. Published by Elsevier Inc.)

This study is aimed at describing tofacitinib and baricitinib users by characterizing their prescription and healthcare histories, drug and healthcare utilization patterns, and direct costs from a healthcare system perspective. This retrospective cohort study was performed using Tuscan administrative healthcare databases, which selected two groups of Janus kinase inhibitors (JAKi) incident users (index date) from 1st January 2018 to 31 December 2019 and from 1 January 2018 to 30 June 2019. We included patients ≥18 years old, at least 10 years of data, and six months of follow-up. In the first analysis, we describe mean time, standard deviation (SD), from the first-ever disease-modifying antirheumatic drug (DMARD) to the JAKi, and costs of healthcare facilities and drugs in the 5 years preceding the index date. In the second analysis, we assessed Emergency Department (ED) accesses and hospitalizations for any causes, visits, and costs in the follow-up. In the first analysis, 363 incident JAKi users were included (mean age 61.5, SD 13.6; females 80.7%, baricitinib 78.5%, tofacitinib 21.5%). The time to the first JAKi was 7.2 years (SD 3.3). The mean costs from the fifth to the second year before JAKi increased from 4325 € (0; 24,265) to 5259 € (0; 41,630) per patient/year, driven by hospitalizations. We included 221 incident JAKi users in the second analysis. We observed 109 ED accesses, 39 hospitalizations, and 64 visits. Injury and poisoning (18.3%) and skin (13.8%) caused ED accesses, and cardiovascular (69.2%) and musculoskeletal (64.1%) caused hospitalizations. The mean costs were 4819 € (607.5; 50,493) per patient, mostly due to JAKi. In conclusion, the JAKi introduction in therapy occurred in compliance with RA guidelines and the increase in costs observed could be due to a possible selective prescription., Competing Interests: M.T., C.B., E.L., V.L., G.T., R.G. are involved as investigators of this observational study funded by Galapagos in compliance with the ENCEPP code of conduct. R.G., C.B., O.P. are employed by ARS, a public health agency that conducts or participates in pharmacoepidemiology studies compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. I.C., S.B., S.F., G.V., E.C., E.F., M.B. have no relevant financial or non-financial interests to disclose.

Objective: To describe the pattern of triptan use by gender in Tuscany, Italy, focusing on special user populations in which evidence on triptan safety is still not conclusive., Background: Growing evidence supports the role of gender differences in migraine pathophysiology and treatment. However, gender impact on triptan real-word utilization has been poorly investigated., Methods: A retrospective, descriptive, cohort study was performed using the population-based Administrative Healthcare Database of Tuscany region (Italy). Subjects registered in the database on the January 1 of each year between 2008 and 2018 were identified. New users (NU) of triptans (ATC:N02CC*) were patients with one or more triptan dispensation during the year of interest and none in the past. Age, cardiovascular comorbidities representing an absolute or a possible contraindication to triptan utilization, concomitant serotonergic medications, and pattern of triptan use during 1-year follow-up were described by gender., Results: A total of 86,109 patients who received one or more triptan dispensing were identified. Of 64,672 NU (men = 17,039; women = 47,633), 10.2% (6823/64,672) were aged >65 years, who were mostly women (n = 4613). Among NU, men and women with absolute cardiovascular contraindications were 4.3% (740/17,039) and 2.1% (1022/47,633), respectively, while those concomitantly taking serotonergic medications were 17.2% (267/1549) and 21.9% (949/4330), respectively (949/4330). Regular users (two or more dispensing with ≥3 months between first and last observed dispensing) accounted for 26.4% of women (12,597/47,633) and 19.11% of men (3250/17,039); frequent users (≥15 dosage units/month during ≥3 consecutive months) were overall 0.1% (94/64,672) and 62.0% (58/94) of them concomitantly received serotonergic medications., Conclusion: Considering gender differences in triptan use highlighted here, large scale observational studies are warranted to better define what populations are safe to use triptans and whether it is appropriate to tighten or relax certain recommendations on triptan use. In the meantime, any suspected adverse drug reaction observed in the special user populations highlighted in this study should be promptly reported., (© 2023 American Headache Society.)

Introduction: Safe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections., Methods and Analysis: BRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed., Ethics and Dissemination: The study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals., Trial Registration Number: EUPAS30280., Competing Interests: Competing interests: MR and PBJ report participation in research funded by LEO Pharma A/S (no personal fees). participation in studies funded by Alcon, Almirall, Astellas, AstraZeneca, Boehringer-Ingelheim, Novo Nordisk, Servier, Pfizer, Menarini Pharmaceuticals, and LEO Pharma, all regulator mandated phase IV studies, all with funds paid to the institution (no personal fees). JH has received teaching fees from Atrium. HS reports participation in research funded by LEO Pharma A/S (no personal fees). He has received personal consulting fees from Bristol-Myers-Squibb, Novartis, Roche, Merck and Pfizer outside the submitted work. He has received teaching fees from Atrium. KF and ØK reports participation in research projects funded by Novo Nordisk and LEO Pharma, all regulator mandated phase IV studies, all with funds paid to the institution (no personal fees). ES, EH and RH are employees of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies. AE has received research funding from Pfizer, Eli Lilly, Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the Simon Spies Foundation and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker from AbbVie, Almirall, Leo Pharma, Zuellig Pharma, Galápagos NV, Sun Pharmaceuticals, Samsung Bioepis, Pfizer, Eli Lilly and Company, Novartis, Union Therapeutics, Galderma, Dermavant, UCB, Mylan, Bristol-Myers Squibb, Horizon Therapeutics and Janssen Pharmaceuticals. UK, Alessandro Cesare Rosa, and Valeria Belleudi are employees of the Department of Epidemiology ASL Roma1, Lazio Regional Health Service in Rome, Italy. Our publicly funded department performs epidemiological research and receives grants from public national and international organisations. In case of financial support from private organisations, an ethical code of conduct is signed to guarantee transparency and independence. KG, DH and JR are employees of the Centre for Pharmacoepidemiology of the Karolinska Institutet in Sweden, which receives grants from regulatory authorities, pharmaceutical companies, and contract research organisations for performance of drug safety and drug utilisation studies. UH, WS and SS are working at an independent, non-profit research institute, the Leibniz Institute for Prevention Research and Epidemiology-BIPS. Unrelated to this study, BIPS occasionally conducts studies financed by the pharmaceutical industry. Almost exclusively, these are postauthorisation safety studies (PASS) requested by health authorities. GT declares participation to advisory boards on topics not related to this paper and sponsored by the following pharmaceutical companies in the last two years: Eli Lilly; Sanofi; Amgen; Novo Nordisk; Sobi; Gilead; Celgene; Daikii Sankyo. RG is employed by ARS, a public research centre participating in pharmacoepidemiology studies funded by public or private institutions and compliant with the ENCePP Code of Conduct. The budget of ARS is partially sustained by such studies. Lise Skov Ranch is a full time employee of LEO Pharma A/S., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A high degree of adherence to direct oral anticoagulants is essential for reducing the risk of ischaemic stroke and systemic embolism in patients with atrial fibrillation, owing to the rapid decline in anticoagulation activity when doses are omitted (i.e. rebound effect)., Objective: We aimed to assess the relationship between non-adherence and non-persistence with direct oral anticoagulants and the incidence of ischaemic stroke in patients with atrial fibrillation., Methods: A nested case-control study was conducted in the Netherlands, Italy and Germany among patients with atrial fibrillation starting direct oral anticoagulants between the drug approval date and the end of database availability. Patients with an ischaemic stroke during the follow-up were selected as cases and compared with matched controls (matched on age ± 5 years, sex, year of cohort entry date and CHA 2 DS 2 -VASc-score at cohort entry date). The cohort entry date was the first dispensing date. Study patients were those aged ≥ 45 years, with ≥ 1 year database history, ≥ 1 year follow-up and at least two direct oral anticoagulant dispensings after the cohort entry date. Adherence and persistence to direct oral anticoagulant treatment were defined as the proportion of days covered ≥ 80% or direct oral anticoagulant continuous use between the cohort entry date and the index date (i.e. date of ischaemic stroke), respectively., Results: In The Netherlands, Italy and Germany, 105 cases and 395 controls, 1580 cases and 6248 controls, and 900 cases and 3570 controls were included, respectively. Odds ratios (ORs) for stroke among current users who were non-adherent compared to adherent users were 0.43 (95% confidence interval [CI] 0.09-1.96) in The Netherlands, 1.11 (95% CI 0.98-1.26) in Italy and 1.21 (95% CI 1.01-1.45) in Germany. The risk of stroke was significantly higher among non-persistent users compared with persistent users in all three databases [OR 1.56 (95% CI 1.00-2.44), OR 1.48 (1.32-1.65) and OR 1.91 (95% CI 1.64-2.22), respectively]. In The Netherlands and Germany, the risk of stroke was higher the longer a patient had stopped using direct oral anticoagulants., Conclusions: Both non-adherence (in Germany) and non-persistence increased the risk of stroke, either using a once-daily or twice-daily regime., (© 2022. The Author(s).)

Background: Estimates of the association between COVID-19 vaccines and myo-/pericarditis risk vary widely across studies due to scarcity of events, especially in age- and sex-stratified analyses. Methods: Population-based cohort study with nested self-controlled risk interval (SCRI) using healthcare data from five European databases. Individuals were followed from 01/01/2020 until end of data availability (31/12/2021 latest). Outcome was first myo-/pericarditis diagnosis. Exposures were first and second dose of Pfizer, AstraZeneca, Moderna, and Janssen COVID-19 vaccines. Baseline incidence rates (IRs), and vaccine- and dose-specific IRs and rate differences were calculated from the cohort The SCRI calculated calendar time-adjusted IR ratios (IRR), using a 60-day pre-vaccination control period and dose-specific 28-day risk windows. IRRs were pooled using random effects meta-analysis. Findings: Over 35 million individuals (49·2% women, median age 39-49 years) were included, of which 57·4% received at least one COVID-19 vaccine dose. Baseline incidence of myocarditis was low. Myocarditis IRRs were elevated after vaccination in those aged < 30 years, after both Pfizer vaccine doses (IRR = 3·3, 95%CI 1·2-9.4; 7·8, 95%CI 2·6-23·5, respectively) and Moderna vaccine dose 2 (IRR = 6·1, 95%CI 1·1-33·5). An effect of AstraZeneca vaccine dose 2 could not be excluded (IRR = 2·42, 95%CI 0·96-6·07). Pericarditis was not associated with vaccination. Interpretation: mRNA-based COVID-19 vaccines and potentially AstraZeneca are associated with increased myocarditis risk in younger individuals, although absolute incidence remains low. More data on children (≤ 11 years) are needed., 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 © 2022 Bots, Riera-Arnau, Belitser, Messina, Aragón, Alsina, Douglas, Durán, García-Poza, Gini, Herings, Huerta, Sisay, Martín-Pérez, Martin, Overbeek, Paoletti, Pallejà-Millán, Schultze, Souverein, Swart, Villalobos, Klungel and Sturkenboom.)

Objectives: Existing individual-level human data cover large populations on many dimensions such as lifestyle, demography, laboratory measures, clinical parameters, etc. Recent years have seen large investments in data catalogues to FAIRify data descriptions to capitalise on this great promise, i.e. make catalogue contents more Findable, Accessible, Interoperable and Reusable. However, their valuable diversity also created heterogeneity, which poses challenges to optimally exploit their richness., Methods: In this opinion review, we analyse catalogues for human subject research ranging from cohort studies to surveillance, administrative and healthcare records., Results: We observe that while these catalogues are heterogeneous, have various scopes, and use different terminologies, still the underlying concepts seem potentially harmonizable. We propose a unified framework to enable catalogue data sharing, with catalogues of multi-center cohorts nested as a special case in catalogues of real-world data sources. Moreover, we list recommendations to create an integrated community of metadata catalogues and an open catalogue ecosystem to sustain these efforts and maximise impact., Conclusions: We propose to embrace the autonomy of motivated catalogue teams and invest in their collaboration via minimal standardisation efforts such as clear data licensing, persistent identifiers for linking same records between catalogues, minimal metadata 'common data elements' using shared ontologies, symmetric architectures for data sharing (push/pull) with clear provenance tracks to process updates and acknowledge original contributors. And most importantly, we encourage the creation of environments for collaboration and resource sharing between catalogue developers, building on international networks such as OpenAIRE and research data alliance, as well as domain specific ESFRIs such as BBMRI and ELIXIR., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (IMIA and Thieme. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Purpose: To develop and validate a case-finding algorithm for the identification of Non-Small Cell Lung Cancer (NSCLC) cases in a region-wide Italian pathology registry (PR)., Materials and Methods: Data collected between 2009 and 2017 in the PR and the Pharmacy Database of the University Hospital of Siena and the PR of Tuscany region were used. A NSCLC-identification algorithm based on free-text keywords and SNOMED morphology and topography codes was designed and tested on data from Siena: indication for drug use (i.e. NSCLC) was the reference standard for sensitivity (SE); positive predictive value (PPV) was estimated through manual review. Algorithm modifications were then tested to improve algorithm performance: PPV was calculated against validated dataset from PR of Siena; a range of SE [min-max] was estimated in PR of Tuscany using analytical formulae that assumed NSCLC incidence equal either to 80% or 90% of overall lung cancer incidence recorded in Tuscany. The algorithm modification with the best performance was chosen as the final version of the algorithm. A random sample of 200 cases was extracted from the PR of Tuscany for manual review., Results: The first version of the algorithm showed a PPV of 74.7% and SE of 79% in PR of Siena. The final version of the algorithm had a SE in PR of Tuscany that grew with calendar time (2009 = [24.7%-28%]; 2017 = [57.9%-65.1%]) and a PPV of 93%., Conclusions: The final NSCLC-finding algorithm showed with very high PPV. SE was in line with the expected contribution of PR to overall cases captured in the regional Cancer Registry, with a trend of increase over calendar time. Given the promising algorithm validity and the wide use of SNOMED terminology in electronic pathology records, the proposed algorithm is expected to be easily adapted to other electronic databases for (pharmaco)epidemiology purposes., Competing Interests: The authors have declared that no competing interests exist.

Our study aims at providing evidence on patterns of use of biologic drugs for psoriasis in Tuscany, Italy. We conducted a drug-utilization study based on administrative databanks of Tuscany (EUPAS45365) from 2011 to 2019. We selected new users of etanercept, infliximab, adalimumab, ustekinumab, or secukinumab between 1 January 2011 and 31 December 2016. We considered subjects with psoriasis and followed subjects until the end of the study period (three years after the first dispensation of biologic drug for psoriasis) or the patient's death, whichever came first. We censored subjects for pregnancy or neoplasia. For each subject, we defined the state as the weekly coverage of one of the biologic drugs of interest. We then defined the switch as the change from a state to another one. A total of 7062 subjects with a first dispensation of a PSObio drug in the inclusion period was identified, and 1839 (52.9% female, 51.6 mean age) patients were included in the analysis. Among new users of adalimumab (N = 770, 41.9%), one third showed a continuous behaviour whereas the others moved to etanercept and ustekinumab. New users of etanercept (N = 758, 41.2%), had the highest proportion of switchers, with adalimumab most often being the second choice. New users of infliximab (N = 159, 8.6%) experienced the highest proportion of treatment discontinuation. The present study suggests that the majority of patients treated with PSObio drugs do not switch from one active ingredient to another. However, patients who started biological therapy with etanercept had the highest frequency of switching to other PSObio drugs, whereas those who started with secukinumab or ustekinumab had the lowest.

Background: The European post-authorisation study (EU PAS) register is a repository launched in 2010 by the European Medicines Agency (EMA). All EMA-requested PAS, commonly observational studies, must be recorded in this register. Multi-database studies (MDS) leveraging secondary data have become an important strategy to conduct PAS in recent years, as reflected by the type of studies registered in the EU PAS register., Objectives: To analyse and describe PAS in the EU PAS register, with focus on MDS., Methods: Studies in the EU PAS register from inception to 31st December 2018 were described concerning transparency, regulatory obligations, scope, study type (e.g., observational study, clinical trial, survey, systematic review/meta-analysis), study design, type of data collection and target population. MDS were defined as studies conducted through secondary use of >1 data source not linked at patient-level. Data extraction was carried out independently by 14 centres with expertise in pharmacoepidemiology, using publicly available information in the EU PAS register including study protocol, whenever available, using a standardised data collection form. For validation purposes, a second revision of key fields for a 15% random sample of studies was carried out by a different centre. The inter-rater reliability (IRR) was then calculated. Finally, to identify predictors of primary data collection-based studies/versus those based on secondary use of healthcare databases) or MDS (vs. non-MDS), odds ratios (OR) and 95% confidence intervals (CI) were calculated fitting univariate logistic regression models., Results: Overall, 1426 studies were identified. Clinical trials (N = 30; 2%), systematic reviews/meta-analyses (N = 16; 1%) and miscellaneous study designs (N = 46; 3%) were much less common than observational studies (N = 1227; 86%). The protocol was available for 63% (N = 360) of 572 observational studies requested by a competent authority. Overall, 36% (N = 446) of observational studies were based fully or partially on primary data collection. Of 757 observational studies based on secondary use of data alone, 282 (37%) were MDS. Drug utilisation was significantly more common as a study scope in MDS compared to non-MDS studies. The overall percentage agreement among collaborating centres that collected the data concerning study variables was highest for study type (93.5%) and lowest for type of secondary data (67.8%)., Conclusions: Observational studies were the most common type of studies in the EU PAS register, but 30% used primary data, which is more resource-intensive. Almost half of observational studies using secondary data were MDS. Data recording in the EU PAS register may be improved further, including more widespread availability of study protocols to improve transparency., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Direct oral anticoagulants are available for patients with atrial fibrillation., Objective: This study compared adherence and persistence of once-daily (QD) vs twice-daily (BID) direct oral anticoagulants in patients with atrial fibrillation., Methods: A cohort study was conducted in three databases in the Netherlands, Italy and Germany. Patients with AF starting direct oral anticoagulants after drug approval date were included. The index date was the date of first dispensing. Study patients were restricted to those aged ≥ 18 years, ≥ 1 year database history and ≥ 1 year follow-up. Adherence to treatment was defined as the proportion of days covered ≥ 80% between the index date and the date of last dispensing of the index regimen (i.e. exposure period). The proportion of days covered was also determined during the 12-month follow-up. Persistence was defined as continuous use from index to treatment discontinuation., Results: In the Netherlands, Italy and Germany, respectively, 6068, 32,260 and 167,445 patients were included. The mean age of the patients was 70, 77 and 74 years, and 31%, 40% and 61% were QD users, all respectively. Among QD/BID users, 93/90%, 88/86% and 77/58%, respectively were adherent during the exposure period. Persistence rates at 1 year in QD/BID users were 60/59%, 13/14% and 46/31%, respectively., Conclusions: Adherence to treatment was high. In Germany, adherence was markedly higher in QD users compared with BID users. In Italy and the Netherlands, these differences were marginal. Persistence was low in all countries, but discontinuation was temporary. Only in Germany, persistence was markedly lower in BID users vs QD users., (© 2022. The Author(s).)