Applying two approaches to detect unmeasured confounding due to time-varying variables in a self-controlled risk interval design evaluating COVID-19 vaccine safety signals, using myocarditis as a case example.

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.

Incretin-based therapy and the risk of diabetic foot ulcers and related events.

AIM: To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). METHODS: We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. RESULTS: We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. CONCLUSIONS: Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Prescribed Drug Use and Aneurysmal Subarachnoid Hemorrhage Incidence: A Drug-Wide Association Study.

BACKGROUND AND OBJECTIVES: Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial aneurysms thus remain untreated. Commonly prescribed drugs reducing aSAH incidence may provide leads for drug repurposing. We performed a drug-wide association study (DWAS) to systematically investigate the association between commonly prescribed drugs and aSAH incidence. METHODS: We defined all aSAH cases between 2000 and 2020 using International Classification of Diseases codes from the Secure Anonymised Information Linkage databank. Each case was matched with 9 controls based on age, sex, and year of database entry. We investigated commonly prescribed drugs (>2% in study population) and defined 3 exposure windows relative to the most recent prescription before index date (i.e., occurrence of aSAH): current (within 3 months), recent (3-12 months), and past (>12 months). A logistic regression model was fitted to compare drug use across these exposure windows vs never use, controlling for age, sex, known aSAH risk factors, and health care utilization. The family-wise error rate was kept at p < 0.05 through Bonferroni correction. RESULTS: We investigated exposure to 205 commonly prescribed drugs between 4,879 aSAH cases (mean age 61.4, 61.2% women) and 43,911 matched controls. We found similar trends for lisinopril and amlodipine, with a decreased aSAH risk for current use (lisinopril odds ratio [OR] 0.63, 95% CI 0.44-0.90, amlodipine OR 0.82, 95% CI 0.65-1.04) and an increased aSAH risk for recent use (lisinopril OR 1.30, 95% CI 0.61-2.78, amlodipine OR 1.61, 95% CI 1.04-2.48). A decreased aSAH risk in current use was also found for simvastatin (OR 0.78, 95% CI 0.64-0.96), metformin (OR 0.58, 95% CI 0.43-0.78), and tamsulosin (OR 0.55, 95% CI 0.32-0.93). By contrast, an increased aSAH risk was found for current use of warfarin (OR 1.35, 95% CI 1.02-1.79), venlafaxine (OR 1.67, 95% CI 1.01-2.75), prochlorperazine (OR 2.15, 95% CI 1.45-3.18), and co-codamol (OR 1.31, 95% CI 1.10-1.56). DISCUSSION: We identified several drugs associated with aSAH, of which 5 drugs (lisinopril and possibly amlodipine, simvastatin, metformin, and tamsulosin) showed a decreased aSAH risk. Future research should build on these signals to further assess the effectiveness of these drugs in reducing aSAH incidence. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that some commonly prescribed drugs are associated with subsequent development of aSAH.

A comparison of four self-controlled study designs in an analysis of COVID-19 vaccines and myocarditis using five European databases.

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.

Updated core competencies in pharmacoepidemiology to inform contemporary curricula and training for academia, government, and industry.

PURPOSE: The first paper to specify the core content of pharmacoepidemiology as a profession was published by an ISPE (International Society for Pharmacoepidemiology) workgroup in 2012 (Jones JK et al. PDS 2012; 21[7]:677-689). Due to the broader and evolving scope of pharmacoepidemiology, ISPE considers it important to proactively identify, update and expand the list of core competencies to inform curricula of education programs; thus, better positioning pharmacoepidemiologists across academic, government (including regulatory), and industry positions. The aim of this project was to update the list of core competencies in pharmacoepidemiology. METHODS: To ensure applicability of findings to multiple areas, a working group was established consisting of ISPE members with positions in academia, industry, government, and other settings. All competencies outlined by Jones et al. were extracted from the initial manuscript and presented to the working group for review. Expert-based judgments were collated and used to identify consensus. It was noted that some competencies could contribute to multiple groups and could be directly or indirectly related to a group. RESULTS: Five core domains were proposed: (1) Epidemiology, (2) Clinical Pharmacology, (3) Regulatory Science, (4) Statistics and data science, and (5) Communication and other professional skills. In total, 55 individual competencies were proposed, of which 25 were new competencies. No competencies from the original work were dropped but aggregation or amendments were made where considered necessary. CONCLUSIONS: While many core competencies in pharmacoepidemiology have remained the same over the past 10 years, there have also been several updates to reflect new and emerging concepts in the field.

Frequency and timing of adverse reactions to COVID-19 vaccines; A multi-country cohort event monitoring study.

INTRODUCTION: During the COVID-19 pandemic, EMA set-up a large-scale cohort event monitoring (CEM) system to estimate incidence rates of patient-reported adverse drug reactions (ADRs) of different COVID-19 vaccines across the participating countries. This study aims to give an up to date and in-depth analysis of the frequency of patient-reported ADRs after the 1st, 2nd, and booster vaccination, to identify potential predictors in developing ADRs and to describe time-to-onset (TTO) and time-to-recovery (TTR) of ADRs. METHODS: A CEM study was rolled out in a period ranging from February 2021 to February 2023 across multiple European countries; The Netherlands, Belgium, France, the United Kingdom, Italy, Portugal, Romania, Slovakia and Spain. Analysis consisted of a descriptive analyses of frequencies of COVID-19 vaccine-related ADRs for 1st, 2nd and booster vaccination, analysis of potential predictors in developing ADRs with a generalized linear mixed-effects model, analysis of TTO and TTR of ADRs and a sensitivity analysis for loss to follow-up (L2FU). RESULTS: A total of 29,837 participants completed at least the baseline and the first follow-up questionnaire for 1st and 2nd vaccination and 7,250 participants for the booster. The percentage of participants who reported at least one ADR is 74.32% (95%CI 73.82-74.81). Solicited ADRs, including injection site reactions, are very common across vaccination moments. Potential predictors for these reactions are the brand of vaccine used, the patient's age, sex and prior SARS-CoV-2 infection. The percentage of serious ADRs in the study is low for 1st and 2nd vaccination (0.24%, 95%CI 0.19--0.31) and booster (0.26%, 95%CI 0.15, 0.41). The TTO was 14 h (median) for dose 1 and slightly longer for dose 2 and booster dose. TTR is generally also within a few days. The effect of L2FU on estimations of frequency is limited. CONCLUSION: Despite some limitations due to study design and study-roll out, CEM studies can allow prompt and almost real-time observations of the safety of medications directly from a patient-centered perspective, which can play a crucial role for regulatory bodies during an emergency setting such as the COVID-19 pandemic.

Tools for assessing quality of studies investigating health interventions using real-world data: a literature review and content analysis.

OBJECTIVES: We aimed to identify existing appraisal tools for non-randomised studies of interventions (NRSIs) and to compare the criteria that the tools provide at the quality-item level. DESIGN: Literature review through three approaches: systematic search of journal articles, snowballing search of reviews on appraisal tools and grey literature search on websites of health technology assessment (HTA) agencies. DATA SOURCES: Systematic search: Medline; Snowballing: starting from three articles (D'Andrea et al, Quigley et al and Faria et al); Grey literature: websites of European HTA agencies listed by the International Network of Agencies for Health Technology Assessment. Appraisal tools were searched through April 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included a tool, if it addressed quality concerns of NRSIs and was published in English (unless from grey literature). A tool was excluded, if it was only for diagnostic, prognostic, qualitative or secondary studies. DATA EXTRACTION AND SYNTHESIS: Two independent researchers searched, screened and reviewed all included studies and tools, summarised quality items and scored whether and to what extent a quality item was described by a tool, for either methodological quality or reporting. RESULTS: Forty-nine tools met inclusion criteria and were included for the content analysis. Concerns regarding the quality of NRSI were categorised into 4 domains and 26 items. The Research Triangle Institute Item Bank (RTI Item Bank) and STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) were the most comprehensive tools for methodological quality and reporting, respectively, as they addressed (n=20; 17) and sufficiently described (n=18; 13) the highest number of items. However, none of the tools covered all items. CONCLUSION: Most of the tools have their own strengths, but none of them could address all quality concerns relevant to NRSIs. Even the most comprehensive tools can be complemented by several items. We suggest decision-makers, researchers and tool developers consider the quality-item level heterogeneity, when selecting a tool or identifying a research gap. OSF REGISTRATION NUMBER: OSF registration DOI (https://doi.org/10.17605/OSF.IO/KCSGX).

Incidence and individual risk prediction of post-COVID-19 cardiovascular disease in the general population: a multivariable prediction model development and validation study.

Aims: Previous studies suggest relatively increased cardiovascular risk after COVID-19 infection. This study assessed incidence and explored individual risk and timing of cardiovascular disease occurring post-COVID-19 in a large primary care database. Methods and results: Data were extracted from the UK's Clinical Practice Research Datalink. Incidence rates within 180 days post-infection were estimated for arterial or venous events, inflammatory heart disease, and new-onset atrial fibrillation or heart failure. Next, multivariable logistic regression models were developed on 220 751 adults with COVID-19 infection before 1 December 2020 using age, sex and traditional cardiovascular risk factors. All models were externally validated in (i) 138 034 vaccinated and (ii) 503 404 unvaccinated adults with a first COVID-19 infection after 1 December 2020. Discriminative performance and calibration were evaluated with internal and external validation. Increased incidence rates were observed up to 60 days after COVID-19 infection for venous and arterial cardiovascular events and new-onset atrial fibrillation, but not for inflammatory heart disease or heart failure, with the highest rate for venous events (13 per 1000 person-years). The best prediction models had c-statistics of 0.90 or higher. However, <5% of adults had a predicted 180-day outcome-specific risk larger than 1%. These rare outcomes complicated calibration. Conclusion: Risks of arterial and venous cardiovascular events and new-onset atrial fibrillation are increased within the first 60 days after COVID-19 infection in the general population. Models' c-statistics suggest high discrimination, but because of the very low absolute risks, they are insufficient to inform individual risk management.

Cross-Regional Data Initiative for the Assessment and Development of Treatment for Neurological and Mental Disorders.

Purpose: To describe and categorize detailed components of databases in the Neurological and Mental Health Global Epidemiology Network (NeuroGEN). Methods: An online 132-item questionnaire was sent to key researchers and data custodians of NeuroGEN in North America, Europe, Asia and Oceania. From the responses, we assessed data characteristics including population coverage, data follow-up, clinical information, validity of diagnoses, medication use and data latency. We also evaluated the possibility of conversion into a common data model (CDM) to implement a federated network approach. Moreover, we used radar charts to visualize the data capacity assessments, based on different perspectives. Results: The results indicated that the 15 databases covered approximately 320 million individuals, included in 7 nationwide claims databases from Australia, Finland, South Korea, Taiwan and the US, 6 population-based electronic health record databases from Hong Kong, Scotland, Taiwan, the Netherlands and the UK, and 2 biomedical databases from Taiwan and the UK. Conclusion: The 15 databases showed good potential for a federated network approach using a common data model. Our study provided publicly accessible information on these databases for those seeking to employ real-world data to facilitate current assessment and future development of treatments for neurological and mental disorders.

Effectiveness of homologous/heterologous booster COVID-19 vaccination schedules against severe illness in general population and clinical subgroups in three European countries.

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.

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis.

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.

The associations of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as add-on to metformin with fracture risk in patients with type 2 diabetes mellitus.

AIM: To investigate whether sodium-glucose cotransporter-2 (SGLT2) inhibitor use as compared to dipeptidyl peptidase-4 (DPP-4) inhibitor use as add-on to metformin is associated with the risk of any fracture or major osteoporotic fractures (MOFs). METHODS: A cohort study using the Clinical Practice Research Datalink (CPRD) Aurum database was conducted. All patients aged 18 years and older with a first-ever prescription for a DPP-4 inhibitor or an SGLT2 inhibitor as add-on to metformin between January 1, 2013 and June 30, 2020 were selected. Patients starting with SGLT2 inhibitors were matched (up to 1:3) on propensity scores to patients starting with DPP-4 inhibitors. Propensity scores were calculated based on sex, age, body mass index, comorbidities, comedication and lifestyle factors. Cox proportional hazard models were used to estimate the risk of fracture with SGLT2 inhibitor use as compared to DPP-4 inhibitor use. RESULTS: A total of 13 807 SGLT2 inhibitor users (age 55.4 ± 10.6 years, 36.7% female) were included in this study, matched with 28 524 DPP-4 inhibitor users (age 55.4 ± 8.0 years, 36.4% female). The risk of any fracture with current SGLT2 inhibitor use was similar compared with current DPP-4 inhibitor use (adjusted hazard ratio [aHR] 1.09, 95% confidence interval [CI] 0.91-1.31), as was the risk of MOFs (aHR 0.89, 95% CI 0.64-1.22) and the risk of fractures at any of the individual MOF sites. Additionally, no association was found with duration of SGLT2 inhibitor use (longest duration >811 days) for any of the individual SGLT2 inhibitor agents, or after stratification by sex and age. CONCLUSION: Use of SGLT2 inhibitors was not associated with the risk of any fracture, MOFs or fracture at the individual MOF sites when compared to DPP-4 inhibitor use.

Impact of 2018 EU Risk Minimisation Measures and Revised Pregnancy Prevention Programme on Utilisation and Prescribing Trends of Medicinal Products Containing Valproate: An Interrupted Time Series Study.

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.

Improving 10-year cardiovascular risk prediction in apparently healthy people: flexible addition of risk modifiers on top of SCORE2.

AIMS: In clinical practice, factors associated with cardiovascular disease (CVD) like albuminuria, education level, or coronary artery calcium (CAC) are often known, but not incorporated in cardiovascular risk prediction models. The aims of the current study were to evaluate a methodology for the flexible addition of risk modifying characteristics on top of SCORE2 and to quantify the added value of several clinically relevant risk modifying characteristics. METHODS AND RESULTS: Individuals without previous CVD or DM were included from the UK Biobank; Atherosclerosis Risk in Communities (ARIC); Multi-Ethnic Study of Atherosclerosis (MESA); European Prospective Investigation into Cancer, The Netherlands (EPIC-NL); and Heinz Nixdorf Recall (HNR) studies (n = 409 757) in whom 16 166 CVD events and 19 149 non-cardiovascular deaths were observed over exactly 10.0 years of follow-up. The effect of each possible risk modifying characteristic was derived using competing risk-adjusted Fine and Gray models. The risk modifying characteristics were applied to individual predictions with a flexible method using the population prevalence and the subdistribution hazard ratio (SHR) of the relevant predictor. Risk modifying characteristics that increased discrimination most were CAC percentile with 0.0198 [95% confidence interval (CI) 0.0115; 0.0281] and hs-Troponin-T with 0.0100 (95% CI 0.0063; 0.0137). External validation was performed in the Clinical Practice Research Datalink (CPRD) cohort (UK, n = 518 015, 12 675 CVD events). Adjustment of SCORE2-predicted risks with both single and multiple risk modifiers did not negatively affect calibration and led to a modest increase in discrimination [0.740 (95% CI 0.736-0.745) vs. unimproved SCORE2 risk C-index 0.737 (95% CI 0.732-0.741)]. CONCLUSION: The current paper presents a method on how to integrate possible risk modifying characteristics that are not included in existing CVD risk models for the prediction of CVD event risk in apparently healthy people. This flexible methodology improves the accuracy of predicted risks and increases applicability of prediction models for individuals with additional risk known modifiers.

Heart disease is a major health concern worldwide, and predicting an individual's risk for developing heart disease is an important tool for prevention. Current risk prediction models often use factors such as age, gender, smoking, and blood pressure, but other factors like education level, albuminuria (protein in the urine), and coronary artery calcium (CAC) may also affect an individual's risk. The aim of this study was to develop a new method for using these additional risk factors for predicting risk even more accurately. The researchers used data from several large studies that included over 400 000 apparently healthy individuals who were followed for 10 years. They examined the effect of various risk factors on cardiovascular disease (CVD) risk using a statistical model. They found that adding coronary scan ('CAC score'); NT-proBNP, a biomarker of heart strain; and hs-Troponin-T, a marker of heart damage, to the existing risk prediction model (SCORE2) improved the accuracy of predicted CVD risk. The key findings are: The methods presented in the current study can help to add additional risk factors to predictions of existing models, such as SCORE2. This flexible method may help identify individuals who are at higher risk for CVD and guide prevention strategies.

Cohort Event Monitoring of Adverse Reactions to COVID-19 Vaccines in Seven European Countries: Pooled Results on First Dose.

INTRODUCTION: COVID-19 vaccines were rapidly authorised, thus requiring intense post-marketing re-evaluation of their benefit-risk profile. A multi-national European collaboration was established with the aim to prospectively monitor safety of the COVID-19 vaccines through web-based survey of vaccinees. METHODS: A prospective cohort event monitoring study was conducted with primary consented data collection in seven European countries. Through the web applications, participants received and completed baseline and up to six follow-up questionnaires on self-reported adverse reactions for at least 6 months following the first dose of COVID-19 vaccine (Netherlands, France, Belgium, UK, Italy) and baseline and up to ten follow-up questionnaires for one year in Germany and Croatia. Rates of adverse reactions have been described by type (solicited, non-solicited; serious/non-serious; and adverse events of special interest) and stratified by vaccine brand. We calculated the frequency of adverse reaction after dose 1 and prior to dose 2 among all vaccinees who completed at least one follow-up questionnaire. RESULTS: Overall, 117,791 participants were included and completed the first questionnaire in addition to the baseline: 88,196 (74.9%) from Germany, 27,588 (23.4%) from Netherlands, 984 (0.8%) from France, 570 (0.5%) from Italy, 326 (0.3%) from Croatia, 89 (0.1%) from the UK and 38 (0.03%) from Belgium. There were 89,377 (75.9%) respondents who had received AstraZeneca vaccines, 14,658 (12.4%) BioNTech/Pfizer, 11,266 (9.6%) Moderna and 2490 (2.1%) Janssen vaccines as a first dose. Median age category was 40-49 years for all vaccines except for Pfizer where median age was 70-79 years. Most vaccinees were female with a female-to-male ratio of 1.34, 1.96 and 2.50 for AstraZeneca, Moderna and Janssen, respectively. BioNtech/Pfizer had slightly more men with a ratio of 0.82. Fatigue and headache were the most commonly reported solicited systemic adverse reactions and injection-site pain was the most common solicited local reaction. The rates of adverse events of special interest (AESIs) were 0.1-0.2% across all vaccine brands. CONCLUSION: This large-scale prospective study of COVID-19 vaccine recipients showed, for all the studied vaccines, a high frequency of systemic reactions, related to the immunogenic response, and local reactions at the injection site, while serious reactions or AESIs were uncommon, consistent with those reported on product labels. This study demonstrated the feasibility of setting up and conducting cohort event monitoring across multiple European countries to collect safety data on novel vaccines that are rolled out at scale in populations which may not have been included in pivotal trials.

Bias in observational studies on the effectiveness of in hospital use of hydroxychloroquine in COVID-19.

PURPOSE: During the first waves of the coronavirus pandemic, evidence on potential effective treatments was urgently needed. Results from observational studies on the effectiveness of hydroxychloroquine (HCQ) were conflicting, potentially due to biases. We aimed to assess the quality of observational studies on HCQ and its relation to effect sizes. METHODS: PubMed was searched on 15 March 2021 for observational studies on the effectiveness of in-hospital use of HCQ in COVID-19 patients, published between 01/01/2020 and 01/03/2021 on. Study quality was assessed using the ROBINS-I tool. Association between study quality and study characteristics (journal ranking, publication date, and time between submission and publication) and differences between effects sizes found in observational studies compared to those found in RCTs, were assessed using Spearman's correlation. RESULTS: Eighteen of the 33 (55%) included observational studies were scored as critical risk of bias, eleven (33%) as serious risk and only four (12%) as moderate risk of bias. Biases were most often scored as critical in the domains related to selection of participants (n = 13, 39%) and bias due to confounding (n = 8, 24%). There were no significant associations found between the study quality and the characteristics nor between the study quality and the effect estimates. DISCUSSION: Overall, the quality of observational HCQ studies was heterogeneous. Synthesis of evidence of effectiveness of HCQ in COVID-19 should focus on RCTs and carefully consider the added value and quality of observational evidence.

Prescribing of low-dose rivaroxaban in patients with atherosclerotic cardiovascular disease in the United Kingdom and the Netherlands.

AIMS: Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users. METHODS: In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2.5 mg, twice daily) was measured in Clinical Practice Research Datalink Aurum (United Kingdom [UK]) and the PHARMO Database Network (the Netherlands) from 1 January 2015 to 28 February 2022 in patients with an ASCVD diagnosis. Incidence rates (IRs) and incidence rate ratios (IRRs) of new use (within 182 days) compared to the reference period, 2015-2018, were calculated. Age, sex and comorbidities of users were compared to those of nonusers. RESULTS: In the UK, from 721 271 eligible subjects the IR of new use of low-dose rivaroxaban in the period 2015-2018, before guideline changes, was 12.4 per 100 000 person-years and after guideline changes in 2020-2022 was 124.0 (IRR 10.0, 95% confidence interval [CI] 8.5, 11.8). In the Netherlands from 394 851 subjects, the IR in 2015-2018 was 2.4 per 100 000 person-years and in 2020 was 16.3 (IRR 6.7, 95% CI 4.0, 11.4). Users were younger (UK mean difference [MD] -6.1 years, Netherlands -2.4 years; P < .05) and more likely to be male (UK difference 11.5%, Netherlands 13.4%; P < .001) than nonusers. CONCLUSIONS: There was a statistically significant increase in the use of low-dose rivaroxaban for the management of ASCVD after guideline changes in the UK and the Netherlands. There were international differences, but low-dose rivaroxaban has not been put into widespread practice.

Primary nonadherence to drugs prescribed by general practitioners: A Dutch database study.

AIM: Primary nonadherence (PNA) is defined as not filling the first prescription for a drug treatment. PNA can lead not only to poor patient outcomes but also to exposure misclassification in written prescription databases. This study aims to estimate PNA in primary care in the Netherlands and to investigate associated factors. METHODS: Patients from the Nivel Primary Care Database (Nivel-PCD) who received a new prescription (>1 year not prescribed) from a general practitioner in 2012 were linked to pharmacy dispensing information of consenting pharmacies based on sex, year of birth, four-digit postal code and at least 50% matching Anatomical Therapeutic Classification codes. PNA was defined as not having a prescription dispensed within 30 days from the prescribing date. PNA was assessed overall and per drug class. The associations between PNA and several patient- and prescription-related characteristics were assessed using mixed-effects logistic regression models. RESULTS: After matching 86 361 of 396 251 subjects (21.8%) in the Nivel-PCD records to the pharmacy records, this study included 65 877 subjects who received 181 939 new drug prescriptions. Overall, PNA was 11.5%. PNA was lowest for thyroid hormones (5.5%) and highest for proton pump inhibitors (12.8%). Several factors were associated with PNA, such as having comorbidities (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.37-1.56 for >3 active diagnoses, compared to no active diagnoses) or reimbursement status (OR 2.78, 95% CI 2.65-2.92 for not reimbursed drugs compared to fully reimbursed drugs). CONCLUSIONS: A total of 11.5% of newly prescribed drugs were not dispensed. This can lead to overestimation of the actual drug exposure status when using written prescription databases.

Myocarditis and pericarditis associated with SARS-CoV-2 vaccines: A population-based descriptive cohort and a nested self-controlled risk interval study using electronic health care data from four European countries.

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.

Use of sodium-glucose co-transporter 2 inhibitors, changes in body mass index and risk of fracture: A population-based cohort study.

AIMS: Sodium-glucose co-transporter-2 (SGLT-2) inhibitor-induced weight loss might play a role in the debated elevated fracture risk with these agents. The aim of the current study was to investigate the association between SGLT-2 inhibitor use, changes in body mass index (BMI) and fracture risk. METHODS: A retrospective cohort study was conducted using data from the UK Clinical Practice Research Datalink (CPRD) GOLD (2013-2018). The study population (N = 34,960) consisted of adults with diabetes initiating a sulphonylurea or SGLT-2 inhibitor. Cox proportional hazards models estimated hazard ratios (HRs) for major osteoporotic fracture with SGLT-2 inhibitor use versus sulphonylurea use, stratified by change in BMI, average daily dose and cumulative dose. Analyses were adjusted for age, sex, lifestyle variables, comorbidities, and concomitant drug use. RESULTS: SGLT-2 inhibitor use was not associated with an increased fracture risk compared to sulphonylurea use (adjusted HR 1.19; 95% confidence interval (CI): 0.80-1.79). This finding remained consistent after stratification by BMI change. However, the highest cumulative dose category was associated with an increased fracture risk (adjusted HR: 2.10, 95 %CI: 1.11-3.99). CONCLUSION: SGLT-2 inhibitor use was not associated with increased osteoporotic fracture risk, irrespective of change in BMI. However, a high cumulative dose could be an important risk factor.