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Title Rationale and background To describe a pharmacoepidemiological study using longitudinal data collected in 8 electronic health care databases from 6 EU countries to characterize the use of Direct Oral Anticoagulants (DOAC) as well as the risk of major bleeding in a real-world setting to help establish the effectiveness of existing and future risk minimization measures. Research question and objectives Objective 1. The risk of major bleeding associated with use of DOACs when compared to other oral anticoagulants (OACs) in patients with non-valvular atrial fibrillation (NVAF) overall and in relevant clinical and demographical subgroups in a real-life setting. Objective 2. The utilization of DOACs in the EU for treatment of NVAF, including the characterization of new DOAC users in NVAF patients. Objective 3. Prescribers’ compliance with recommendations included in sections 4.1, 4.3, 4.4, and 4.5 of the SmPC of each DOAC. Abstract objective 1 Aim: To characterize the risk of major bleeding in DOAC users in a real-world setting using longitudinal data collected in four electronic health care databases from different EU countries. Methods: A study cohort among consisted of 251,719 new users (≥18 years) of DOACs or VKAs with non-valvular atrial fibrillation from the UK, Spain, Germany and Denmark. We compared current use of DOACs with current use of VKAs with respect to the occurrence of major bleeding events. Results:Overall hazard ratios of major bleeding risk for DOACs versus VKAs ranged between 0.84 (Denmark) and 1.13 (UK CPRD). When stratifying according to the type of bleeding event, the risk of gastrointestinal bleeding was statistically significantly increased by 48-67% in users of dabigatran users and 30-50% for rivaroxaban users compared to VKA users in all data sources except for Denmark. Conclusion: Compared to VKAs, apixaban was not associated with an increased risk of GI bleeding in all data sources and seemed to be associated with the lowest risk of major bleeding events compared to dabigatran and rivaroxaban. Future exploration of reasons for non-adherence to DOAC treatment and its impact on bleeding risk are interesting to explore in more detail. Abstract objective 2 Aim: To estimate the incidence of Direct Oral Anticoagulant Drug (DOACs) use in nonvalvular atrial fibrillation (NVAF) and to describe user and treatment characteristics in 8 European health databases (Mondriaan, Bavarian CD, AOK Nordwest, BIFAP, SIDIAP, CPRD, EGB and NRD ) representing 6 European countries (Denmark, France, Germany, United Kingdom, The Netherlands and Spain) . Methods: Descriptive cohort study of new DOAC users with NVAF from January 2008 to December 2015. A common protocol approach was applied to each database. Annual period incidences and direct standardisation by age and sex were performed. A incidence percentage change in DOAC use was assessed from 2012-2013 (apixaban 2013-2014) to 2014-2015. Dose adjustment related to change in age and by renal function as well as concomitant use of potential interacting drugs were assessed. Results: A total of 186,405 new DOAC users (≥18 years) were identified. The standardized incidence increased for all DOACs over the study period, with the highest increase for apixaban (554.5%) followed by rivaroxaban (80.7%). The highest incidence for all DOACs was found in Denmark and Germany, with lower values and slight differences among the remaining databases. The incidence of DOAC use increased for both genders in most databases and especially in those older than 75 years. Concomitant use of contraindicated drugs varied between 16..4% (SIDIAP), and 70.5% (EGB) and dose adjustment ranged from 4.6% in the Spanish (BIFAP) to 15.6% in the French (EGB) study population. Conclusion: The overall incidence of new DOAC users increased, with the highest increase for apixaban. Cross national drug utilization studies with a standard protocol may help to compare drug use and identify sources of variation enabling health care decisions. Abstract objective 3 Aim: To analyse prescribers’ adherence to registered indications (IC), contraindications (CI), special warnings/precautions (SW/P), and potential drug-drug interactions (pDDIs). Methods: This retrospective cohort study was conducted in six databases covering regionally / nationally representative populations in 5 European countries. The study cohort consisted of patients (≥18 years) initiating dabigatran, rivaroxaban or apixaban between 2008 and 2015. ICs, CIs, SW/Ps, and pDDIs as registered in the Summary of Product Characteristics (SmPC) were mapped to respective coding systems. Results: Within the study period and the six included database, a DOAC was initiated in 407,576 patients (rivaroxaban: 240,985 (59.1%), dabigatran: 95,303 (23.4%), apixaban: 71,288 (17.5%)). In 2015, non-valvular atrial fibrillation was the most common IC registered, representing more than 60% of incident DOAC users in most databases. Between the databases, a substantial variety was found regarding the proportion of patients with at least one CI (inter-database range: 8.2% to 55.7%) with highest values for dabigatran in most databases. SW/Pc were present in a higher proportion of incident DOAC users (inter-database range: 35.8% – 75.2%) reaching highest values in incident apixaban users. Inter-database range for potential DDIs was 22.4% to 54.1% reaching highest values in dabigatran initiators. Conclusion: CIs, SW/Ps, and potential DDIs were present in a substantial number of new DOAC users. Differences found between the databases might be related to ‘true’ differences in prescription behaviour but also due to discrepancies in database characteristics. (EMA/2015/27/PH; EU PAS Register No: 16014)., The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network (led by Utrecht University). The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2015/27/PH. This report expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. The work in this report is based on: EU PAS Register No: EUPAS16014

Rationale and background In March 2018, the European risk minimisation measures (RMMs) with a Pregnancy Prevention Program (PPP) for valproate-containing medicines was updated. A pharmacoepidemiological study was conducted using longitudinal data collected in five electronic health care databases from four EU countries and the UK to investigate the use of valproates authorised in the EU before and after implementation of the 2018 revised measures for pregnancy prevention in clinical practice, and effectiveness of the 2018 intervention. Objectives Objective 1: To determine drug utilisation and prescription patterns of valproate-containing medicinal products in females of childbearing potential, and to investigate whether significant changes in prescribing patterns occurred (pre-/post-intervention). Objective 2: To determine prescribers’ compliance with the recommendations in the Summary of Products Characteristics (SmPC) for valproate-containing medicinal products, by indication, age group, duration of use, and database. Objective 3: To determine patients’ use of effective contraception in compliance with recommendations in the SmPC for valproate-containing medicinal products, by indication, age group, method of contraception, and database. Objective 4: To determine drug utilisation and prescription patterns over time for alternative medicines prescribed in women who became pregnant, where valproate-containing medicinal products had previously been prescribed or discontinued, by indication, by age group and by database. Objective 5: Based on the results of the above, to estimate the effectiveness of the 2018 RMMs for valproates. Methods We performed an observational times series study including all female subjects of childbearing age (aged 12 to 55 years) from the corresponding databases in Denmark (Danish National Registers, DNR), Italy (ARS Tuscany), the Netherlands (PHARMO Database Network), Spain (Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria, BIFAP), and UK (Clinical Practice Research Datalink, CPRD) between 01 January 2010 to 31 December 2020. In Objective 1, the incident use, prevalent use and rate of discontinuation thereof was estimated per month in each data source, in addition to the change in level and trend in use after the implementation of the 2018 EU RMMs, using an interrupted time series (ITS) analysis design. In Objective 2, first, we separately estimated the proportion of valproate users with a record of a pregnancy test within the 90 days i) before and ii) after the date of valproate prescribing or dispensing per month. We estimated the change in level and trend in these proportions after the implementation of the 2018 EU RMMs. Second, we estimated the proportion of valproate users with a record of contraceptive (prescribed or dispensed with a prescription, or identified through medical events or procedures records) in 90-days before the prescription, or prescribed/dispensed during a contraceptive episode. We then estimated the change in level and trend in this proportion after the implementation of the 2018 EU intervention, using an ITS analysis design. In Objective 3, we estimated the incidence of new pregnancies during a period of valproate use per month and the change in level and trend in this rate after the implementation of the 2018 EU intervention, using an ITS analysis design. In Objective 4, we estimated the rates of alternative medication prescriptions/dispensings for the indications epilepsy, bipolar disorder, and migraine among valproate users and the rate of switching from valproate to an alternative medicine per month. Then, the change in trend of switches from valproate to alternative medications before and after the implementation of the 2018 EU intervention was estimated, using an ITS analysis design. In Objective 5, evidence generated from Objectives 1-4, weighed by the strengths and limitations of the analyses, was used to draw conclusions on the effectiveness of the RMMs, per country and across European countries included in the study. Results Objective 1: There were 69,533 valproate users out of a total of 9,699,371 female subjects of childbearing age from the five participating centres during the study period. The median follow-up time of the study population ranged between 3.5-10.0 years and the mean age at the start of follow-up was always ≥30 years in different centres. The monthly incidence rate of valproate use ranged between 0.01-0.47 per 1000 persons months across databases and the prevalence rate ranged between 1.2-7.7 per 1000 female subjects. While the observed rates were similar for DNR, PHARMO, BIFAP and CPRD, the rates of prevalent use were much higher in ARS Tuscany. We observed a statistically significant declining trend in prevalent use of valproates in all countries/regions, for which an ITS analysis could be performed, but no significant decreasing trend in incidence rates after the 2018 RMMs compared to the period before. The monthly rate of valproate discontinuers ranged between 1-8% across all databases, and in no database we observed a significant increase in trend or level of valproate discontinuation after the 2018 intervention compared to time prior. Objective 2: We included 69,533 female valproate users from the five participating centres during the study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. Due to the limited data on pregnancy tests from all databases, modelling of any trend change in proportion of valproate prescriptions or dispensings with an adherent pregnancy test before versus after 2018 RMMs was not possible. The rate of recorded contraceptive coverage at the start of valproate treatment was low across all centres, as only 0.5-23% of valproate prescriptions/dispensings each month were accompanied by a contraceptive prescription in 90-days before, and only between 0.5-25% of new valproate treatment episode had started during contraceptive use. There was no increasing trend in compliant valproate prescriptions/ dispensings with a contraceptive coverage after the 2018 RMMs across the studied databases, and the only increase in level was observed in PHARMO. Objective 3: We included 69,533 female valproate users from the five participating centres during study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. In general, we observed a substantial number of concurrent new valproate prescriptions/dispensings during a pregnancy time window in ARS Tuscany (386 pre- and 40 post 2018 intervention), BIFAP (330 pre and 20 post) and CPRD (204 pre and 56 post), while there were fewer concurrent events in PHARMO (27 pre and 0 post). However, the rates of concurrent events declined for most databases after the 2018 intervention. There was no data on pregnancy counts available from DNR. Objective 4: We included 69,533 female valproate users from the five participating centres during study period, with a median follow-up time between 4.4-11.0 years and the mean age at the start of follow-up ≥34 years. We found an increasing trend in rates of alternative medicine use for epilepsy and bipolar diseases indications of valproates across the study period in most databases (i.e., DNR, ARS Tuscany, PHARMO and CPRD), while the rates for migraine were mostly steady. The monthly rate of switch from a valproate to an alternative medication was similar across all DAPs and ranged between 1-8%. Running an ITS analysis was not possible for most of the included databases due to the low frequency of switching, but there was a significant increase in trend in switching rates from valproates to alternative medicine after the 2018 RMMs in ARS Tuscany. Objective 5: We found a generally declining trend in prevalence rate of valproate use after the 2018 RMMs in almost all databases (Objective 1), but also no increasing trend in compliant valproate prescriptions/dispensings with a contraceptive coverage (Objective 2). There was a substantial number of occurrences of pregnancy events (as the final endpoint) concurrently with valproate exposure across most included databases, but the rates declined after 2018 (Objective 3). Furthermore, we observed a significant increase in switching rates from valproates to alternative medications only in few regions (such as ARS Tuscany) (Objective 4). Noteworthy, these findings should be interpreted in context of the limitations that we faced, such as an inability to investigate some objectives due to limited data availability on pregnancy test or over-the-counter use of some contraceptives, and the occurrence of COVID-19 pandemic, which has shortened and impacted our post-intervention period and limited our ability to run ITS analyses for some objectives and some databases. Conclusions Objective 1: We observed declining trends in prevalent use of valproates after the 2018 RMMs across all databases. However, there were no declining trends in incidence rate of valproates in none of databases. The rate of discontinuation of valproates was not affected by the 2018 RMMs. Objective 2: We found in general low rates of recorded adherent contraceptive coverage with valproate use across all studied regions/countries, and there was no increased trend in compliant valproate prescriptions/dispensings with a contraceptive coverage after the 2018 RMMs compared to time prior. Due to limited data availability, rates of adherent pregnancy tests and the trend change after the intervention could not be studied. Objective 3: Despite the declining rates after the 2018 intervention, high counts and rates of concurrent pregnancy events with a valproate prescription/dispensing were observed across most studied countries/regions. Objective 4: Although the trend in alternative medication use for most indications of valproates (epilepsy and bipolar disorder) was increasing during the study period, the only significant increase in trend in switching rates from valproates to alternative medications after the 2018 RMMs was observed in ARS Tuscany. Objective 5: Based on the findings on various objectives in this study, we can conclude that there was a small impact of the 2018 RMMs on valproate use and prescribing in the studied European countries/regions. Considering the limitations of this study (such as not studying all PPP elements, the included databases had important limitations, and the study period after 2018 intervention was rather short), the results of other currently ongoing studies are needed to have a clearer picture of the appropriate implementation of 2018 RMMs on valproate use in Europe., The research leading to these results was conducted as part of the activities of the EU PE&PV (Pharmacoepidemiology and Pharmacovigilance) Research Network which is a public academic partnership coordinated by the Utrecht University, the Netherlands. The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2018/28/PE. The content of this paper expresses the opinion of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

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 similar to 75 years, % females between 41.3 and 54.3%), with overall hazard ratios of major bleeding risk for DOACsvsVKAs 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.