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.

COVID-19 and pregnancy: A European study on pre- and post-infection medication use.

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.

Building a Sustainable Learning Health Care System for Pregnant and Lactating People: Interview Study Among Data Access Providers.

BACKGROUND: In many areas of health care, learning health care systems (LHSs) are seen as promising ways to accelerate research and outcomes for patients by reusing health and research data. For example, considering pregnant and lactating people, for whom there is still a poor evidence base for medication safety and efficacy, an LHS presents an interesting way forward. Combining unique data sources across Europe in an LHS could help clarify how medications affect pregnancy outcomes and lactation exposures. In general, a remaining challenge of data-intensive health research, which is at the core of an LHS, has been obtaining meaningful access to data. These unique data sources, also called data access providers (DAPs), are both public and private organizations and are important stakeholders in the development of a sustainable and ethically responsible LHS. Sustainability is often discussed as a challenge in LHS development. Moreover, DAPs are increasingly expected to move beyond regulatory compliance and are seen as moral agents tasked with upholding ethical principles, such as transparency, trustworthiness, responsibility, and community engagement. OBJECTIVE: This study aims to explore the views of people working for DAPs who participate in a public-private partnership to build a sustainable and ethically responsible LHS. METHODS: Using a qualitative interview design, we interviewed 14 people involved in the Innovative Medicines Initiative (IMI) ConcePTION (Continuum of Evidence from Pregnancy Exposures, Reproductive Toxicology and Breastfeeding to Improve Outcomes Now) project, a public-private collaboration with the goal of building an LHS for pregnant and lactating people. The pseudonymized transcripts were analyzed thematically. RESULTS: A total of 3 themes were identified: opportunities and responsibilities, conditions for participation and commitment, and challenges for a knowledge-generating ecosystem. The respondents generally regarded the collaboration as an opportunity for various reasons beyond the primary goal of generating knowledge about medication safety during pregnancy and lactation. Respondents had different interpretations of responsibility in the context of data-intensive research in a public-private network. Respondents explained that resources (financial and other), scientific output, motivation, agreements collaboration with the pharmaceutical industry, trust, and transparency are important conditions for participating in and committing to the ConcePTION LHS. Respondents also discussed the challenges of an LHS, including the limitations to (real-world) data analyses and governance procedures. CONCLUSIONS: Our respondents were motivated by diverse opportunities to contribute to an LHS for pregnant and lactating people, primarily centered on advancing knowledge on medication safety. Although a shared responsibility for enabling real-world data analyses is acknowledged, their focus remains on their work and contribution to the project rather than on safeguarding ethical data handling. The results of our interviews underline the importance of a transparent governance structure, emphasizing the trust between DAPs and the public for the success and sustainability of an LHS.

Sex differences in the intensity of statin prescriptions at initiation in a primary care setting.

BACKGROUND: Current guidelines for the prevention and management of cardiovascular diseases (CVD) provide similar recommendations for the use of statins in both women and men. In this study, we assessed sex differences in the intensity of statin prescriptions at initiation and in the achievement of treatment targets, among individuals without and with CVD, in a primary care setting. METHODS: Electronic health record data from statin users were extracted from the PHARMO Data Network. Poisson regressions were used to investigate sex differences in statin intensity and in the achievement of treatment targets. Analyses were stratified by age group, disease status and/or CVD risk category. RESULTS: We included 82 714 individuals (46% women) aged 40-99 years old. In both sexes, the proportion of individuals with a dispensed prescription for high-intensity statin at initiation increased between 2011 and 2020. Women were less likely to be prescribed high-intensity statins as compared with men, both in the subgroups without a history of CVD (risk ratio (RR) 0.69 (95% CI: 0.63 to 0.75)) and with CVD (RR 0.77 (95% CI: 0.74 to 0.81)). Women were less likely than men to achieve target levels of low-density lipoprotein cholesterol following statin initiation in the subgroup without CVD (RR 0.98 (95% CI: 0.97 to 1.00)) and with a history of CVD (RR 0.94 (95% CI: 0.89 to 0.98)). CONCLUSION: Compared with men, women were less likely to be prescribed high-intensity statins at initiation and to achieve treatment targets, both in people without and with a history of CVD, and independent of differences in other individual and clinical characteristics.

Sex Differences in the Primary Prevention of Cardiovascular Diseases in a Dutch Primary Care Setting.

Background: Sex differences in the primary prevention of cardiovascular diseases (CVD) have been shown, but the evidence is mixed and fragmented. In this study, we assessed sex differences in cardiovascular risk factors assessment, risk factor levels, treatment, and meeting of treatment targets, within a Dutch primary care setting. Methods: Data were obtained from individuals aged 40 to 70 years old, without prior CVD, registered during the entire year in 2018 at one of the 51 general practices participating in the Julius General Practitioner's Network (JGPN). History of CVD was defined based on the International Classification of Primary Care (ICPC). Linear and Poisson regressions were used to investigate sex differences in risk factor assessment, risk factor levels, treatment, and meeting of treatment targets. Results: We included 83,903 individuals (50% women). With the exception of glycated hemoglobin (HbA1c), all risk factors for CVD were more often measured in women than in men. Lipid measurements and body mass index values were higher in women, while blood pressure (BP) and HbA1c levels were higher in men, along with estimated glomerular filtration rate (eGFR) levels. Among individuals with elevated BP or cholesterol levels, no sex difference was observed in the prescription of antihypertensive medications (RR 1.00, 95% CI: 0.94-1.06) but women were less likely than men to receive lipid-lowering medications (RR 0.87, 95% CI: 0.79-0.95). Among treated individuals, women were more likely than men to meet adequate levels of blood pressure (RR 1.17, 95% CI: 1.09-1.25) and less likely to meet target levels of cholesterol (RR 0.90, 95% CI: 0.83-0.98). Conclusion: While women were more likely to have their CVD risk factors measured, they were less likely to be prescribed lipid-lowering medications and to meet target levels. When treated, men were less likely to achieve adequate blood pressure control.

Safety Monitoring of COVID-19 Vaccines in Persons with Prior SARS-CoV-2 Infection: A European Multi-Country Study.

In all pivotal trials of COVID-19 vaccines, the history of previous SARS-CoV-2 infection was mentioned as one of the main exclusion criteria. In the absence of clinical trials, observational studies are the primary source for evidence generation. This study aims to describe the patient-reported adverse drug reactions (ADRs) following the first COVID-19 vaccination cycle, as well as the administration of booster doses of different vaccine brands, in people with prior SARS-CoV-2 infection, as compared to prior infection-free matched cohorts of vaccinees. A web-based prospective study was conducted collecting vaccinee-reported outcomes through electronic questionnaires from eleven European countries in the period February 2021-February 2023. A baseline questionnaire and up to six follow-up questionnaires collected data on the vaccinee's characteristics, as well as solicited and unsolicited adverse reactions. Overall, 3886 and 902 vaccinees with prior SARS-CoV-2 infection and having received the first dose or a booster dose, respectively, were included in the analysis. After the first dose or booster dose, vaccinees with prior SARS-CoV-2 infection reported at least one ADR at a higher frequency than those matched without prior infection (3470 [89.6%] vs. 2916 [75.3%], and 614 [68.2%] vs. 546 [60.6%], respectively). On the contrary side, after the second dose, vaccinees with a history of SARS-CoV-2 infection reported at least one ADR at a lower frequency, compared to matched controls (1443 [85.0%] vs. 1543 [90.9%]). The median time to onset and the median time to recovery were similar across all doses and cohorts. The frequency of adverse reactions was higher in individuals with prior SARS-CoV-2 infection who received Vaxzevria as the first dose and Spikevax as the second and booster doses. The frequency of serious ADRs was low for all doses and cohorts. Data from this large-scale prospective study of COVID-19 vaccinees could be used to inform people as to the likelihood of adverse effects based on their history of SARS-CoV-2 infection, age, sex, and the type of vaccine administered. In line with pivotal trials, the safety profile of COVID-19 vaccines was also confirmed in people with prior SARS-CoV-2 infection.

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.

What is the Safety of COVID-19 Vaccines in Immunocompromised Patients? Results from the European "Covid Vaccine Monitor" Active Surveillance Study.

BACKGROUND: The safety profile of COVID-19 vaccines in immunocompromised patients has not been comprehensively evaluated. AIM: To measure the frequency of patient-reported adverse drug reactions (ADRs) related to the first/second/booster dose of COVID-19 vaccine in immunocompromised subject versus matched cohort. As a secondary objective, the time course, evaluated as time to onset (TTO) and time to recovery (TTR), of COVID-19 vaccine-related ADRs was explored. METHODS: A prospective cohort study, based on electronic questionnaires filled by vaccinees from 11 European countries in the period February 2021 to February 2023 was conducted. All immunocompromised vaccinees who provided informed consent and registered to the project's web-app within 48 h after first/booster vaccine dose administration of any EMA-authorised COVID-19 vaccine were recruited. Participants filled baseline and up to six follow-up questionnaires (FU-Qs) over 6 months from vaccination, collecting information on suspected COVID-19 vaccine-related ADRs. As a control group, non-immunocompromised vaccinees from the same source population were 1:4 matched by sex, age, vaccine dose, and brand. A descriptive analysis of demographic/clinical characteristics of vaccinees was conducted. Heatmaps of the frequency of solicited ADRs, stratified by gender and vaccine brand, were generated. Median TTO/TTR of reported ADRs were visualised using violin/box-plots. RESULTS: A total of 773 immunocompromised vaccines were included in the analyses. Most participants were females (F/M ratio: 2.1 and 1.6) with a median age of 56 (43-74) and 51 (41-60) years, at the first vaccination cycle and booster dose, respectively. Injection-site pain and fatigue were the most frequently reported ADRs in immunocompromised vaccinees with higher frequency than matched control, especially after the first dose (41.2% vs 37.8% and 38.2% vs 32.9%, respectively). For both cohorts, all solicited ADRs were more frequently reported in females than males, and in those who had received a first dose of the Vaxzevria vaccine. Dizziness was the most frequently reported unsolicited ADR after the first dose in both groups (immunocompromised subjects: 2.5% and matched controls: 2.1%). At the booster dose, lymphadenopathy (3.9%) and lymphadenitis (1.8%) were the most reported unsolicited ADRs for immunocompromised subjects and matched controls, respectively. A very low number of subjects reported adverse event of special interest (AESI) (2 immunocompromised, 3 matched controls) and serious ADRs (5 immunocompromised, 5 matched controls). A statistically significant difference among study cohorts was observed for median TTO after the booster dose, and for median TTR after the first vaccination cycle and booster dose (p < 0.001). CONCLUSION: The overall safety profile of COVID-19 vaccines in immunocompromised people was favourable, with minor differences as compared to non-immunocompromised vaccinees. Participants mostly experienced mild ADRs, mainly reported after the first dose of Vaxzevria and Jcovden vaccines. Serious ADRs and AESI were rare.