Background Antidepressant drugs (AD) are commonly used and prescribed. However, factors associated with their prescription and use have not yet been fully characterized. Objective To better characterize long-term utilization patterns of antidepressants, leverage data collected by naturalistic observation (i.e., routinely collected administrative prescription data, without experimental manipulation) across 5 years in two Italian regions. Methods Sociodemographic factors associated with prescription in a population of more than 2,000,000 individuals were explored (multivariate logistic regression). Multivariate survival analysis was employed to investigate factors associated with the time to drug discontinuation. Diverging patterns of use were described and empirically tested by logistic regression, performed on time series of drug utilization. Results A total of 219,351 incident users were observed. Older age and female sex were associated with a more likely prescription (age 45-64: incidence rate ratio [IRR] 1.63; age 65-84: IRR 3.266; age 85+: IRR 10.244; all p < 0.001: females vs. males IRR 1.740, Z-score 50.08, p < 0.001). Older age and the use of tricyclic or other antidepressants (compared to selective serotonin reuptake inhibitors [SSRIs]) were associated with lower discontinuation and thus longer treatment persistence (minimum hazard ratio [HR], 0.680, Z-score -36.08, p < 0.001). Predictive models could identify diverging patterns of use (area under the curve [AUC] >= 0.697). Conclusions The long-term pharmacoutilization of antidepressants was shown to be under the influence of structural and sociodemographic factors. Considering the recent directive by the European Commission on the European Health Data Space, implications for public health policies and future research may be considered.

Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease where diagnostic delays can worsen the clinical outcomes and increase the strain on healthcare systems. This study investigated the frequency of potentially missed UC diagnoses in tertiary care and their impact on treatment patterns and healthcare utilization.Methods We conducted a retrospective cohort study using Tuscany's regional healthcare database (2006-2020). Adults newly diagnosed with UC between 2011 and 2018 were included. A "possible missed diagnosis" was defined as a hospital or emergency department (ED) visit for gastrointestinal (GI) symptoms occurring 7-60 months before the UC diagnosis. We assessed the initiation of azathioprine and non-conventional therapies, as well as the rates of ED visits, hospital admissions, and surgery. Survival analyses and Cox regression models were applied.Results Among 3,804 patients with UC, 313 (8.3%) had prior GI-related tertiary care visits suggestive of a missed diagnosis. The mean time to diagnosis was 27.5 months. Compared with those who were timely diagnosed, these patients were not more likely to start azathioprine or non-conventional therapies. However, subjects with a possible missed diagnosis had higher rates of ED visits [adjusted hazard ratio (aHR) = 1.8, 95%CI = 1.5-2.0], hospitalizations (aHR = 1.4, 95%CI = 1.2-1.7), and combined urgent care encounters (aHR = 1.5, 95%CI = 1.3-1.7) compared with other patients.Conclusions Patients with a potentially missed UC diagnosis are more likely to need emergency and inpatient care, despite receiving similar treatments. Promoting earlier recognition of UC symptoms in tertiary care may reduce avoidable hospital use and improve disease management.

PURPOSE:In 2019, the Innovative Medicines Initiative funded the ConcePTION project to enhance monitoring of medication safety in pregnancy and breastfeeding. This paper describes how the ConcePTION Pregnancy Algorithm (PA) identified pregnancies in 10 diverse European electronic healthcare data sources and estimated their duration. METHODS:Data sources from six European countries were mapped to the ConcePTION Common Data Model. Any pregnancy-related record was retrieved from various available data banks, including birth register, primary care records, and hospital records, and reconciled into episodes of pregnancy (starting between 01/2015 and 12/2019), each with start date, end date, and type of end. A random forest model was used to estimate missing gestational ages for incomplete records. Parameters were tailored to data sources to address local variations in data availability, collection, and governance. Model performance was evaluated using cross-validated Root Mean Squared Error (RMSE). RESULTS:The PA identified ~2.7 million pregnancies, in over 2.2 million individuals. Most ended in live births (50%-83%), 1%-15% in elective terminations, and 4%-10% in spontaneous abortions, depending on data sources. Pregnancies with unknown type of end were also retrieved (2%-34%). Gestational age was predicted for 6%-89% of records (RMSE: 17-50 days). The median gestational age at first identified pregnancy record ranged from 47 to 280 days. CONCLUSIONS:We developed an open-source algorithm to identify and date pregnancies, including early-stage pregnancies with unknown end and/or ongoing at the time of data extraction. This algorithm may facilitate multinational studies, improving generation of timely real-world evidence about use and safety of medicinal products in pregnancy.

BACKGROUND:Different definitions of white-coat hypertension (WCH) may explain its variable outcome across studies. METHODS:In an Italian study started in 1986, we followed 3,153 people with (office blood pressure (BP) >=140/90 mmHg) and 457 without office hypertension for a mean of 10.4 years. None had previous cardiovascular disease. All underwent 24-h ambulatory BP (ABP) monitoring. We defined white-coat hypertension (WCH) as an average 24-h ABP < 130/80 mmHg or <125/75 mmHg. The primary outcome was a composite of major adverse cardiovascular events (MACE) and all-cause mortality. RESULTS:Baseline office BP was 156/97 mmHg in people with and 127/81 mmHg without hypertension. At follow-up, MACE events were 344 and 23, and all-cause deaths were 318 and 24 in people with and without hypertension, respectively. Compared to normotensive group, MACE risk was not higher in people with WCH and 24-h ABP < 125/75 mmHg (hazard ratio (HR), 0.94; 95% confidence interval (CI), 0.42-2.10). Compared to normotensive group, MACE risk was higher in people with WCH and 24-h ABP < 130/80 mmHg (HR: 1.79; 95% CI, 1.07-2.29). All-cause death did not differ between the normotensive group and people with WCH and 24-h ABP < 125/75 mmHg (HR 1.37; 95% CI, 0.68-2.73), but it was higher than in the normotensive group when WCH was defined by a 24-h ABP < 130/80 mmHg (HR 1.82; 95% CI, 1.55-3.58). CONCLUSIONS:WCH defined by an average 24-h ABP < 125/75 mmHg identifies people at low risk of MACE and death in the long term. Even modestly above these threshold values, the risk associated with WCH increases.

To assess the effect on prevalence estimates of using different algorithms to identify children with attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in healthcare data. Three algorithms were developed and run on administrative/research data in Finland, France (Haute Garonne), Italy (Emilia Romagna), Norway and Wales: (1) ≥ 1 ADHD or ASD diagnoses recorded in specialist settings, (2) ≥ 2 ADHD or ASD diagnoses recorded in primary care and (3) ≥ 1 prescription for medication to manage ADHD. Prevalence rates per 1000 children for each algorithm were calculated. 3,130,162 children (born 1996–2020) with 29,291,204 years of follow-up were included. ADHD prevalence per 1000 children in specialist settings ranged from 3.9 (Emilia Romagna) to 24.1 (Finland); and was 7.0 in primary care (Finland). Based on prescriptions, ADHD prevalence ranged from 0.1 (Emilia Romagna) to 9.9 (Haute Garonne). ASD prevalence in specialist settings ranged from 5.6 (Wales) to 9.7 (Finland), and in primary care from 1.0 (Finland) to 2.0 (Wales). Prevalence of ADHD and ASD was greater among children with longer follow-up. In Finland and Wales, 1.7

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.

Superiority trials are designed to test the hypothesis that a given diagnostic or therapeutic strategy is better than (i.e. "superior to") placebo or an active control. Conversely, non-inferiority trials test the hypothesis that a newer (i.e. alternative) strategy is not "unacceptably worse" than a control (i.e. "traditional", or "older") strategy. Non-inferiority trials are increasingly conducted in clinical medicine more often when a "newer" strategy is supposed to offer a relevant advantage in terms other than clinical efficacy (i.e. better tolerability, less cost, simpler regimen, etc.) versus a "gold standard" traditional strategy. The principle underlying non-inferiority trials is that the above advantage justifies the preferential use of the newer strategy in the clinical practice even if the clinical efficacy of the "new" appears to be a bit worse than that of the "old", albeit not unacceptably worse (i.e. not beyond a pre-specified value). The demonstration of non-inferiority requires that the confidence interval of the point estimate (e.g. the hazard ratio) does not cross a pre-specified limit. The definition of such pre-specified limit, the so called "non-inferiority margin", is a pivotal point when planning non-inferiority trials. It denotes the maximally tolerated worse effect of the alternative strategy, compared with the traditional one, required to conclude that an alternative strategy is non-inferior to the traditional "gold standard". The non-inferiority margin is derived from previous trials evaluating the efficacy of the traditional strategy vs placebo. We reviewed the principles and the practical aspects in the design and conduct of non-inferiority trials.

Superiority trials are designed to test the hypothesis that a given diagnostic or therapeutic strategy is better than (i.e. "superior to") placebo or an active control. Conversely, non-inferiority trials test the hypothesis that a newer (i.e. alternative) strategy is not "unacceptably worse" than a control (i.e. "traditional", or "older") strategy. Non-inferiority trials are increasingly conducted in clinical medicine more often when a "newer" strategy is supposed to offer a relevant advantage in terms other than clinical efficacy (i.e. better tolerability, less cost, simpler regimen, etc.) versus a "gold standard" traditional strategy. The principle underlying non-inferiority trials is that the above advantage justifies the preferential use of the newer strategy in the clinical practice even if the clinical efficacy of the "new" appears to be a bit worse than that of the "old", albeit not unacceptably worse (i.e. not beyond a pre-specified value). The demonstration of non-inferiority requires that the confidence interval of the point estimate (e.g. the hazard ratio) does not cross a pre-specified limit. The definition of such pre-specified limit, the so called "non-inferiority margin", is a pivotal point when planning non-inferiority trials. It denotes the maximally tolerated worse effect of the alternative strategy, compared with the traditional one, required to conclude that an alternative strategy is non-inferior to the traditional "gold standard". The non-inferiority margin is derived from previous trials evaluating the efficacy of the traditional strategy vs placebo. We reviewed the principles and the practical aspects in the design and conduct of non-inferiority trials.

Gli studi di non-inferiorità testano l’ipotesi che una procedura diagnostica o terapeutica alternativa sia migliore, oppure anche un po’ peggiore, rispetto ad una tradizionale, ma non peggiore oltre un certo limite predefinito (“margine di non-inferiorità”), indicato dall’estensione dell’intervallo di confidenza intorno alla stima puntuale dell’effetto. Tale margine denota il peggiore effetto possibile della procedura alternativa rispetto a quella tradizionale per poter concludere che la prima sia non-inferiore rispetto alla seconda. Tale margine viene ricavato da un’attenta analisi di studi precedenti che abbiano messo a confronto la strategia tradizionale con una non-strategia, ovvero con un placebo. Gli studi di non-inferiorità sono giustificati nei casi in cui la strategia alternativa sembri chiaramente preferibile rispetto a quella tradizionale per la previsione di minori effetti indesiderati, minore costo e maggiore praticità (somministrazione orale anziché parenterale, singola somministrazione anziché più somministrazioni nelle 24 h, minore durata del trattamento, migliore e più facile accessibilità della procedura, etc.). Il principio generale è che i presunti vantaggi della procedura alternativa rispetto alla tradizionale possano giustificare l’accettazione della procedura alternativa anche in presenza di un profilo di efficacia clinica non decisamente migliore, ma anche un po’ peggiore, rispetto alla procedura tradizionale. In questa rassegna abbiamo esaminato alcuni aspetti di natura essenzialmente pratica legati alla pianificazione ed interpretazione di questi studi.

Several outcome-based prospective investigations have provided solid data which support the prognostic value of 24 h ambulatory blood pressure over and beyond cardiovascular traditional risk factors. Average 24 h, daytime, and nighttime blood pressures are the principal components of the ambulatory blood pressure profile that have improved cardiovascular risk stratification beyond traditional risk factors. Furthermore, several additional ambulatory blood pressure measures have been investigated. The correct interpretation in clinical practice of ambulatory blood pressure monitoring needs a standardization of methods. Several algorithms for its clinical use have been proposed. Implementation of the results of ambulatory blood pressure monitoring in the management of individual subjects with the aim of improving risk stratification is challenging. We suggest that clinicians should focus attention on ambulatory blood pressure components which have been proven to act as the main independent predictors of outcome (average 24 h, daytime, and nighttime blood pressure, pulse pressure, dipping status, BP variability).

IntroductionDue to established teratogenicity of valproates, the EU risk minimisation measures (RMMs) with a pregnancy prevention programme (PPP) for valproate were updated in March 2018.ObjectivesTo investigate the effectiveness of the 2018 EU RMMs on valproate utilisation in five European countries/regions.MethodsA 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.ResultsWe 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).ConclusionThere 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.

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.

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.