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).

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.

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. 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. 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.

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.

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.

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. 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).

Effect of tramadol and DOACs with special attention to dabigatran on concomitant use, on the risk of mayor bleeding using BIFAP database in Spain.

Background: Tramadol, a weak opioid, inhibits the reuptake of serotonin, a key feature on vascular homeostasis. A suspected interaction exists between dabigatran and tramadol, which might trigger an excess on risk of bleeding however, there is a gap in knowledge on this topic.

Purpose: To estimate the effects of tramadol, dabigatran and concomitant use on the risk of hospitalized major bleeds (Gastrointestinal bleeding and intra-extracranial bleeds).

The role of prenatal exposure to antidepressants, anxiolytic, and hypnotics and its underlying illness on the risk of miscarriage using BIFAP database.

Purpose: Despite the notable increase on the prescription of antidepressants and anxiolytics during pregnancy, recommendation on maintaining the treatment during prenatal period is still controversial. We aimed to separately assess the role of effects of the antidepressants and anxiolytic and the underlying illness, controlled by potential confounding associated with miscarriage onset.

Methods: We used data from a validated pregnant cohort aged 15-49 years from 2002 to 2016 using BIFAP database.

A strategy for assessment and validation of major bleeding cases in a primary health care database in Spain.

Purpose: This study aims to validate major bleeding (MB) cases within a cohort of new users of direct oral anticoagulants (DOACs) in Electronic health records (EHRs) from primary care in Spain (BIFAP), introducing more efficient techniques and automating the process of validation in the pharmacoepidemiologic research with EHR data as much as possible.

Methods: Registered bleedings were identified in a cohort of new users of DOACs in BIFAP using ICPC 2 and ICD 9 codes; we ascertained these bleedings as MB through a validation strategy based on the MB definition from the International Society on Thrombosis and Hemostasis, which used hospitalization and critical localization as proxies. We assessed hospitalization with hospital discharge information (only available for some years and regions) and a free text-based algorithm created to identify hospitalization in EHR's clinical notes.

Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies.

Objective: To establish the risk of major bleeding in direct oral anticoagulant (DOAC) users (overall and by class) versus vitamin K antagonist (VKA) users, using health care databases from four European countries and six provinces in Canada.

Methods: A retrospective cohort study was performed according to a similar protocol. First-users of VKAs or DOACs with a diagnosis of non-valvular atrial fibrillation (NVAF) were included.

A Validation Study on the Frequency and Natural History of Miscarriages Using the Spanish Primary Care Database BIFAP.

(1) Background: There is a major gap of knowledge towards the natural history of miscarriages in electronic medical records. We aimed to calculate the frequency of miscarriages using data from BIFAP database. (2) Methods: We identified all pregnancy losses and carried out a multistep validation exercise.

Use of hydrochlorothiazide and risk of skin cancer in a large nested case-control study in Spain.

Purpose: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population.

Methods: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP.

Incidence Rates of Autoimmune Diseases in European Healthcare Databases: A Contribution of the ADVANCE Project.

Introduction: The public-private ADVANCE collaboration developed and tested a system to generate evidence on vaccine benefits and risks using European electronic healthcare databases. In the safety of vaccines, background incidence rates are key to allow proper monitoring and assessment. The goals of this study were to compute age-, sex-, and calendar-year stratified incidence rates of nine autoimmune diseases in seven European healthcare databases from four countries and to assess validity by comparing with published data.

Comparing risk of major bleeding between users of different oral anticoagulants in patients with nonvalvular atrial fibrillation.

Aims: The introduction of direct oral anticoagulants (DOACs) has broadened the treatment arsenal for nonvalvular atrial fibrillation, but observational studies on the benefit-risk balance of DOACs compared to vitamin K antagonists (VKAs) are needed. The aim of this study was to characterize the risk of major bleeding in DOAC users using longitudinal data collected from electronic health care databases from 4 different EU-countries analysed with a common study protocol.

Methods: A cohort study was conducted among new users (≥18 years) of DOACs or VKAs with nonvalvular atrial fibrillation using data from the UK, Spain, Germany and Denmark.

Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP): A data resource for pharmacoepidemiology in Spain.

Purpose: Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) is a population based database administered by the AEMPS (Spanish Agency for Medicines) of longitudinal electronic medical records (EMR) of patients attended in primary care. Its main purpose is to serve as source of information for independent studies on drug safety and support of medicines regulation activities. This article aim is to describe the characteristics of BIFAP, how to access the database and a summary of its potential for research.

Age-specific vaccination coverage estimates for influenza, human papillomavirus and measles containing vaccines from seven population-based healthcare databases from four EU countries - The ADVANCE project.

Background: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid benefit-risk monitoring of vaccines using existing healthcare databases in Europe. We estimated vaccine coverage from electronic healthcare databases as part of a fit-for-purpose assessment for vaccine benefit-risk studies.

Methods: A retrospective dynamic cohort study was conducted through a distributed network approach.

Impact of pre-exposure time bias in self-controlled case series when the event conditions the exposure: Hip/femur fracture and use of benzodiazepines as a case study.

Background: In self-controlled case series (SCCS), the event should not condition the probability of subsequent exposure. If this assumption is not met, an important bias could take place. The association of hip/femur fracture (HFF) and use of benzodiazepines (BDZ) has a bidirectional causal relationship and can serve as case study to investigate the impact of this methodological issue.

An algorithm to identify pregnancies in BIFAP Primary Care database in Spain: Results from a cohort of 155 419 pregnancies.

Purpose: There has been a notable progress on the development of methods for identification of pregnancies using primary care databases. We aimed to evaluate the prescription of medications during pregnancy applying a novel algorithm.

Methods: We identified pregnancies in women aged 15 to 49 years registered in the Database for Pharmacoepidemiological Research in Primary Care (BIFAP) between 2002 and 2015.

Estimation of vaccination coverage from electronic healthcare records; methods performance evaluation - A contribution of the ADVANCE-project.

Introduction: The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public private collaboration aiming to develop and test a system for rapid benefit-risk (B/R) monitoring of vaccines, using existing electronic healthcare record (eHR) databases in Europe. Part of the data in such sources is missing due to incomplete follow-up hampering the accurate estimation of vaccination coverage. We compared different methods for coverage estimation from eHR databases; naïve period prevalence, complete case period prevalence, period prevalence adjusted for follow-up time, Kaplan-Meier (KM) analysis and (adjusted) inverse probability weighing (IPW).

Incidence of direct oral anticoagulant use in patients with nonvalvular atrial fibrillation and characteristics of users in 6 European countries (2008-2015): A cross-national drug utilization study.

Aims: To estimate the incidence of direct oral anticoagulant drug (DOAC) use in patients with nonvalvular atrial fibrillation and to describe user and treatment characteristics in 8 European healthcare databases representing 6 European countries.

Methods: Longitudinal drug utilization study from January 2008 to December 2015. A common protocol approach was applied.

The recording of human papillomavirus (HPV) vaccination in BIFAP primary care database: A validation study.

Purpose: In Spain, a human papillomavirus (HPV) vaccine was firstly marketed in 2006 and mainly administered in primary care (PC) practices for girls/women or schools. As for all vaccines, a valid data source is required for research on observational effectiveness or safety. The objective of this study is to identify and validate HPV vaccinations recorded among women in The Primary Care Database For Pharmacoepidemiological Research (BIFAP) from 2007.

A new risk of bias checklist applicable to randomized trials, observational studies, and systematic reviews was developed and validated to be used for systematic reviews focusing on drug adverse events.

Objectives: The objective of the study was to develop and validate an adequate tool to evaluate the risk of bias of randomized controlled trials, observational studies, and systematic reviews assessing drug adverse events.

Study Design And Setting: We developed a structured risk of bias checklist applicable to randomized trials, cohort, case-control and nested case-control studies, and systematic reviews focusing on drug safety. Face and content validity was judged by three experienced reviewers.

Methodological comparison of marginal structural model, time-varying Cox regression, and propensity score methods: the example of antidepressant use and the risk of hip fracture.

Background: Observational studies including time-varying treatments are prone to confounding. We compared time-varying Cox regression analysis, propensity score (PS) methods, and marginal structural models (MSMs) in a study of antidepressant [selective serotonin reuptake inhibitors (SSRIs)] use and the risk of hip fracture.

Methods: A cohort of patients with a first prescription for antidepressants (SSRI or tricyclic antidepressants) was extracted from the Dutch Mondriaan and Spanish Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP) general practice databases for the period 2001-2009.

Case-only designs for studying the association of antidepressants and hip or femur fracture.

Purpose: The purpose of this study is to evaluate the performance and validity of the case-crossover (CCO) and self-controlled case-series (SCCS) designs when studying the association between hip/femur fracture (HF) and antidepressant (AD) use in general practitioner databases. In addition, comparability with cohort and case-control designs is discussed.

Methods: Adult patients with HF and who received an AD prescription during 2001-2009 were identified from UK's The Health Improvement Network (THIN) and the Dutch Mondriaan databases.

Understanding inconsistency in the results from observational pharmacoepidemiological studies: the case of antidepressant use and risk of hip/femur fractures.

Purpose: Results from observational studies on the same exposure-outcome association may be inconsistent because of variations in methodological factors, clinical factors or health care systems. We evaluated the consistency of results assessing the association between antidepressant use and the risk of hip/femur fractures in three European primary care databases using two different study designs.

Methods: Cohort and nested case control studies were conducted in three European primary care databases (Spanish BIFAP, Dutch Mondriaan and UK THIN) to assess the association between use of antidepressants and hip/femur fracture.

Risk of acute liver injury associated with use of antibiotics. Comparative cohort and nested case-control studies using two primary care databases in Europe.

Purpose: To assess the impact of varying study designs, exposure and outcome definitions on the risk of acute liver injury (ALI) associated with antibiotic use.

Methods: The source population comprised of patients registered in two primary care databases, in the UK and in Spain. We identified a cohort consisting of new users of antibiotics during the study period (2004-2009) and non-users during the study period or in the previous year.