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.

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.

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). METHODS: Among a validated established cohort of new users of oral anticoagulants for non-valvular atrial fibrillation (NVAF) aged 18 years or older, we identified all hospitalized bleed episodes (GIB and extra/intracranial bleeds) within 2008-2015. A nested case-control analysis was conducted using conditional logistic regression. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated for dabigatran, tramadol, and concomitant use. Several sensitivity analyses were carried out. RESULTS: aORs (95%CIs) for current use of only dabigatran, only tramadol and concomitant users were 1.73 (1.37-2.18) and 1.38 (1.13-1.67) and 2.04 (0.74-5.67) compared with non-users of both drugs (>365 days). aORs for current continuers and non-continuer users of dabigatran were 1.36 (1.00-1.86) and 2.19 (1.61-2.98), respectively. For the latter, non-continuer users with a short duration of dabigatran cumulated the highest risk (3.36 [1.88-5.99]). There also was an increased risk with concomitant use of tramadol and rivaroxaban (2.24 [1.19-4.21]), or antagonist of vitamin K (1.30 [1.00-1.69]). CONCLUSION: There was a trend towards and increased risk of excess bleeds when using concomitantly with dabigatran. The effect decreases with a narrower definition of current use.

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.

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. All confirmed miscarriages were used to perform a nested control analysis using conditional logistic regression. Women were classified according to use of each drug of interest into four mutually exclusive groups: nonusers, users only during prepregnancy, continuers, and initiators during first trimester. Adjusted odds ratios (aORs) for major confounders during pregnancy such as number of visits to primary care practitioners visits, obesity, smoking, HTA, diabetes with 95% confidence intervals were calculated. RESULTS: Compared with nonusers, antidepressants continuers had the highest increased risk of miscarriage aOR (95%) of 1.29 (1.13-1.46), being continuers of paroxetine and fluoxetine the antidepressants with the strongest association. Likewise, continuers of anxiolytics and initiators showed an increased risk of 1.19 (1.04-1.37) and 1.30 (1.13-1.50). When separating the effect between the condition itself or the treatment, women exposed during first trimester, regardless treatment duration and/or the underlying illness, had the highest risk 1.27 (1.08-1.51) for antidepressants and 1.25 (1.13-1.39) for anxiolytics. CONCLUSIONS: Our analysis showed an association between prenatal exposure to antidepressants and anxiolytics and miscarriage onset after controlling by potential confounding adjusting for confounders and the underlying illness. This association was not supported for hypnotic medications. Further studies are warranted to evaluate the risk of miscarriage among subpopulation of pregnant women requiring these medications.

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. Incidence rates (IR) of MB were evaluated by bleeding type. RESULTS: The study cohort included 104 614 patients, with 274521.5 p-y of follow up. There were 6143 registered bleedings during the study period (519 intracranial bleeding - ICB, 4606 gastrointestinal bleeding - GIB, 1018 extracranial bleeding - ECB), from which 1679 were confirmed as MB (416 ICB, 1086 GIB, and 177 ECB). The free text-based semi-automatic algorithm had moderate recall (0.59), but high specificity (0.99), and precision (0.94). CONCLUSION: The combination of hospitalization and critical localization is a valid approach to validate MB in EHRs with incomplete information. The use of more automatic methods for case validation instead of manual review of clinical notes is favored.

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. Potential cases with positive predictive values (PPV) of miscarriage confirmation <85% or those confirming other pregnancy loss were excluded. Kaplan-Meier figures and incidence rates (IRs) of miscarriage with 95% confidence intervals (CIs) expressed by 1000 person-weeks were calculated. Stratifying analysis by age, specific high-risk groups, and drug exposure within the pre-pregnancy period were performed restricted to women with recording last menstrual period (LMP). (3) Results: Women with confirmed miscarriage (N = 18,070), tended to be older, with higher frequency of comorbidities and drug utilization. Restricting to women with LPM recorded, IR of miscarriage was 10.89 (CI 95% 10.68-11.10) per 1000 women-weeks, with a median follow-up of 10 weeks (IQR: 8-12). The IR according to age was: 2.71 (CI 95% 2.59-2.84) in those aged <30 years compared to 9.11 (CI 95% 8.55-9.70) in women aged ≥40 years. Advanced maternal age (Hazard Ratio (HR, 95% confidence interval) CI 95%: 3.34 (3.08-3.62)), use of antihypertensives (1.49 (1.21-1.84), and use of drugs classified as D or X during pregnancy (1.17 (1.07-1.29)) showed to be positive predictors associated with increased risk of miscarriages. (4) Conclusion: BIFAP database can be used to identify women suffering from miscarriages, which will serve to further study risk factors associated with miscarriages with special attention to drug utilization.

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. The main outcome of interest was major bleeding and secondary outcomes included gastrointestinal (GI) bleeding and intracranial haemorrhage (ICH). Incidence rates of events per 1000 person years were calculated. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard regression model. Exposure and confounders were measured and analysed in a time-dependant way. Risk estimates were pooled using a random effect model. RESULTS: 421 523 patients were included. The risk of major bleeding for the group of DOACs compared to VKAs showed a pooled HR of 0.94 (95% CI: 0.87-1.02). Rivaroxaban showed a modestly increased risk (HR 1.11, 95% CI: 1.06-1.16). Apixaban and dabigatran showed a decreased risk of respectively HR 0.76 (95% CI: 0.69-0.84) and HR 0.85 (95% CI: 0.75-0.96). CONCLUSIONS: This study confirms that the risk of major bleeding of DOACs compared to VKAs is not increased when combining all DOACs. However, we observed a modest higher risk of major bleeding for rivaroxaban, whereas for apixaban and dabigatran lower risks of major bleeding were observed compared to VKAs.

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. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). RESULTS: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26-1.34) in SIDIAP and 1.20 (1.12-1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02-1.21]) than for SCC (1.71 [1.45-2.02]). A dose-response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09-1.43) in SIDIAP and 0.85 (0.64-1.13) in BIFAP. CONCLUSIONS: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose-response pattern.

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. METHODS: Event rates were calculated for the following outcomes: acute disseminated encephalomyelitis, Bell's palsy, Guillain-Barré syndrome, immune thrombocytopenia purpura, Kawasaki disease, optic neuritis, narcolepsy, systemic lupus erythematosus, and transverse myelitis. Cases were identified by diagnosis codes. Participating organizations/databases originated from Denmark, Italy, Spain, and the UK. The source population comprised all persons registered, with at least 1 year of data prior to the study start, or follow-up from birth. Stratified incidence rates were computed per database over the period 2003 to 2014. RESULTS: Between 2003 and 2014, 148,947 incident cases of nine autoimmune diseases were identified. Crude incidence rates were highest for Bell's palsy [23.8/100,000 person-years (PYs), 95% confidence interval (CI) 23.6-24.1] and lowest for Kawasaki disease (0.7/100,000 PYs, 95% CI 0.6-0.7). Specific patterns were observed by sex, age, calendar time, and data sources. Rates were comparable with published estimates. CONCLUSION: A range of autoimmune events could be identified in the ADVANCE system. Estimation of rates indicated consistency across selected European healthcare databases, as well as consistency with US published data.

Prescribers' compliance with summary of product characteristics of dabigatran, rivaroxaban and apixaban-A European comparative drug utilization study.

Despite a tremendous increase of direct oral anticoagulants (DOACs) prescriptions in recent years, only few data is available analysing prescribers' adherence to Summary of Product Characteristics (SmPC). We aimed to assess adherence to registered indications, contraindications, special warnings/precautions, and potential drug-drug interactions for three DOAC compounds (dabigatran, rivaroxaban, and apixaban) in six databases of five European countries (The Netherlands, United Kingdom, Spain, Denmark, and Germany). We included adult patients (≥18 years) initiating DOACs between 2008 and 2015. For several SmPC items, broad definitions were used due to ambiguous SmPC terms or lacking data in some databases. Within the study period, a DOAC was initiated in 407 576 patients (rivaroxaban: 240 985 (59.1%), dabigatran: 95 303 (23.4%), and apixaban: 71 288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common indication (>60% in most databases). For the whole study period, a substantial variation between the databases was found regarding the proportion of patients with at least one contraindication (inter-database range [IDR]: 8.2%-55.7%), with at least one special warning/precaution (IDR: 35.8%-75.2%) and with at least one potential drug-drug interaction (IDR: 22.4%-54.1%). In 2015, the most frequent contraindication was "malignant neoplasm" (IDR: 0.7%-21.3%) whereas the most frequent special warning/precaution was "prescribing to the elderly" (≥75 years; IDR: 25.0%-66.4%). The most common single compound class interaction was "concomitant use of non-steroidal anti-inflammatory drugs" (IDR: 3.0%-25.3%). Contraindications, special warnings/precautions, and potential drug-drug interactions were present in a relevant number of new DOAC users. Due to broad definitions used for some SmPC terms, overall proportions for contraindications are prone to overestimation. However, for unambiguous SmPC terms documented in the databases sufficiently, the respective estimates can be considered valid. Differences between databases might be related to "true" differences in prescription behaviour, but could also be partially due to differences in database characteristics.

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. The incidence of major bleeding events (overall and by bleeding site) was compared between current use of DOACs and VKAs. Cox regression analysis was used to calculate hazard ratios and 95% confidence intervals (CI) and adjust for confounders. RESULTS/CONCLUSION: Overall, 251 719 patients were included across the 4 study cohorts (mean age ~75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACs vs VKAs ranging between 0.84 (95% CI: 0.79-0.90) in Denmark and 1.13 (95% CI 1.02-1.25) in the UK. When stratifying according to the bleeding site, risk of gastrointestinal bleeding was increased by 48-67% in dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except Denmark. Compared to VKAs, apixaban was not associated with an increased risk of gastrointestinal bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban.

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. METHODS: Health problems are registered by primary care physicians as episodes of care and include socio-demographic data, results of diagnostic procedures, lifestyle data, general data, and interventions. A proportion of data on hospitalizations and specialist care are currently available through linkage with other data sources. EMRs of the Spanish healthcare system are provided by the regional administrations. Specific data extraction and standardization processes are performed. RESULTS: BIFAP includes data from 12 million patients starting in 2001 and updated annually. Validation of drug and diagnosis definitions has been ascertained. Participation in international collaborative projects and a number of articles in peer reviewed journals reflect its contribution to the knowledge of the risks associated with medicines and drug utilization patterns. CONCLUSIONS: BIFAP is a useful tool for generating scientific evidence on medicines related issues, helping regulatory decision making in Europe. The main strengths of BIFAP are related to large sample size, population-based, longitudinal nature and annual update of data. BIFAP shares common challenges with similar data sources including accurate and efficient identification of health outcomes and of treatment exposure.

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. Coverage with measles-vaccine for birth year 2006, human papillomavirus (HPV)-vaccine for birth years 1990-2000 and influenza-vaccine for birth years 1920-1950 was estimated using period-prevalence and inverse probability weighting methods. Seven databases from four countries participated: Italy (Pedianet, Val Padana), Spain (BIFAP, SIDIAP), UK (RCGP-RSC, THIN), Denmark (SSI/AUH). Database access providers extracted the data, transformed it into a common structure and ran an R-script locally. The created output tables were shared and pooled at a central server. RESULTS: The total study population comprised 274,616 persons for measles-vaccine, 2,011,666 persons for HPV-vaccine and 14,904,033 persons for influenza-vaccine. Measles-vaccine coverage varied from 84.3% (Denmark) to 96.5% (Italy, Val Padana) for the first dose and from 82.8% (Italy, Val Padana) to 90.9% (UK) for the second dose at the age of 7 years. The HPV-vaccine coverage, aggregated over birth years 1997-2000, ranged from 60% (UK) to 88.3% (Denmark) at the age of 15 years. The influenza-vaccine coverage for the influenza seasons from 2009 to 2015 for persons aged 65 years and more was roughly stable around 43% in Denmark and around 68% in the UK while a decrease from 58 to 50% was observed in Catalonia (Spain). CONCLUSIONS: We obtained detailed, age-specific coverage estimates though a common procedure. We discussed between database comparability and comparability to published national estimates.

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. OBJECTIVES: To assess the magnitude of bias introduced in a SCCS when HFF conditions the posterior exposure to BDZ and explore ways to correct it. METHODS: Four thousand four hundred fifty cases of HFF who had at least one BZD prescription were selected from the primary care health record database BIFAP. Exposure to BZD was divided into non-use, current, recent, and past use. Conditional Poisson regression was used to estimate incidence rate ratios (IRRs) of HFF among current vs non-use/past, adjusted for age. To investigate possible event-exposure dependence, a pre-exposure time of different lengths (15, 30, and 60 days) was excluded from the reference category to evaluate the IRR. RESULTS: IRR of HHF for current use was 0.79 (0.72-0.86); removing 30 days, IRR was 1.43 (1.31-1.57). Removing 15 days, IRR was 1.29 (1.18-1.41), and removing 60 days, IRR was 1.56 (1.42-1.72). A pre-exposure period up to 182 days was necessary to remove such effect giving an IRR of 1.64 (1.48-1.81). CONCLUSIONS: HFF remarkably conditioned the use of BDZs resulting in seriously biased IRRs when this association was studied through a SCCS design. The use of pre-exposure periods of different lengths helped to correct this error.

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. The algorithm applied sequential cycles that searched in hierarchical order for indicators of conception, delivery or pregnancy loss, and other codes suggestive of pregnancy. Length of pregnancy was assessed by searching for last menstrual period (LMP) date, gestational age, and outcomes of pregnancy. Prescription of specific drugs during the pre-pregnancy period and first trimester and time trends during pregnancy were evaluated. RESULTS: We identified a total of 155 419 pregnancies during the study period (77.5% completed pregnancies, 21.5% pregnancies losses, 0.8% ectopic pregnancies, and 0.2% stillbirths). Excluding vitamins and supplements, 43.8% of women received at least one prescription during the pre-pregnancy period and 68.4% during the first trimester. During the first trimester, the most commonly drugs prescribed were analgesics (16.3%) followed by antibiotics (11.8%). From 2002/2003 to 2014/2015, there was an increase of prescriptions for thyroid hormones (1.0% vs 4.7%), H2 blockers (1.0% vs 2.2%), and PPIs (1.4% vs 2.2%). While antidepressants (2.0% vs 1.5%) and benzodiazepines (3.1% vs 2.4%) decreased in the last period. CONCLUSION: Having in mind the challenges of identifying pregnancies in health care databases, this study demonstrates the usefulness of BIFAP database for studies on drug utilization during pregnancy.

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). METHODS: We created simulation scenarios with different proportions of completeness of follow-up. Both completeness independent and dependent from vaccination date and status were considered. The root mean squared error (RMSE) and relative difference between the estimated and true coverage were used to assess the performance of the different methods for each of the scenarios. We included data examples on the vaccination coverage of human papilloma virus and pertussis component containing vaccines from the Spanish BIFAP database. RESULTS: Under completeness independent from vaccination date or status, several methods provided estimates with bias close to zero. However, when dependence between completeness of follow-up and vaccination date or status was present, all methods generated biased estimates. The IPW/CDF methods were generally the least biased. Preference for a specific method should be based on the type of censoring and type of dependence between completeness of follow-up and vaccination. Additional insights into these aspects, might be gained by applying several methods.

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. Annual period incidences and direct standardisation by age and sex were performed. Dose adjustment related to change in age and by renal function as well as concomitant use of potentially interacting drugs were assessed. RESULTS: A total of 186 405 new DOAC users (age ≥18 years) were identified. Standardized incidences varied from 1.93-2.60 and 0.11-8.71 users/10 000 (2011-2015) for dabigatran and rivaroxaban, respectively, and from 0.01-8.12 users/10 000 (2012-2015) for apixaban. In 2015, the DOAC incidence ranged from 9 to 28/10 000 inhabitants in SIDIAP (Spain) and DNR (Denmark) respectively. There were differences in population coverage among the databases. Only 1 database includes the total reference population (DNR) while others are considered a population representative sample (CPRD, BIFAP, SIDIAP, EGB, Mondriaan). They also varied in the type of drug data source (administrative, clinical). Dose adjustment ranged from 4.6% in BIFAP (Spain) to 15.6% in EGB (France). Concomitant use of interacting drugs varied between 16.4% (SIDIAP) and 70.5% (EGB). Cardiovascular comorbidities ranged from 25.4% in Mondriaan (The Netherlands) to 82.9% in AOK Nordwest (Germany). CONCLUSION: Overall, apixaban and rivaroxaban increased its use during the study period while dabigatran decreased. There was variability in patient characteristics such as comorbidities, potentially interacting drugs and dose adjustment. (EMA/2015/27/PH).

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. METHODS: BIFAP includes a Vaccination File filled by PC practitionners and pediatricians. Information on women with HPV vaccinations recorded at any age was identified and validated according to whether (1) doses adhered to the following standard intervals: 27 to 269 days between first and second doses, >55 days between second and third doses, and <366 between first and third doses, and (2) additional information recorded in clinical records confirmed (through recording the brand, batch, expiring date, administration site, or vaccination comment) or refuted the vaccination and date. The latter was retrieved through manual review of anonymous records randomly selected. RESULTS: One hundred seventeen thousand seventy-three women with HPV vaccination records were identified (mean age 14.7 years); 82.5% had three jabs, 87.3% in recommended intervals. A sample of 978 patients' records, including 2245 jabs, was reviewed. Of the 363 jabs with additional information, 91% confirmed the vaccination. Confirmatory data was more frequent when doses strictly adhered to recommendations (96.8%-100%) than not (60.0%-85.7%). CONCLUSIONS: In BIFAP, a cohort of women vaccinated against HPV, mostly with three doses in recommended intervals, was identified. Although additional information about the vaccination was scarce, when present, it highly confirmed it, making BIFAP a potential data source for HPV vaccine research.

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. Interrater and intrarater reliability were determined using 20 randomly selected studies, assessed by three other independent reviewers including one performing a 3-week retest. RESULTS: The developed checklist examines eight domains: study design and objectives, selection bias, attrition, adverse events information bias, other information bias, statistical methods to control confounding, other statistical methods, and conflicts of interest. The total number of questions varied from 10 to 32 depending on the study design. Interrater and intrarater agreements were fair with Kendall's W of 0.70 and 0.74, respectively. Median time to complete the checklist was 8.5 minutes. CONCLUSION: The developed checklist showed face and content validity and acceptable reliability to assess the risk of bias for studies analyzing drug adverse events. Hence, it might be considered as a novel useful tool for systematic reviews and meta-analyses focusing on drug safety.