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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

Hintergrund: Mit zunehmendem Lebensalter und Gebrechlichkeit steigt oftmals die Anzahl der täglich einzunehmenden Medikamente. Polypharmazie erhöht das Risiko von unerwünschten Arzneimittelwirkungen und Krankenhausaufenthalten. Ein möglicher Ansatz, diese negativen Auswirkungen zu [zum vollständigen Text gelangen Sie über die oben angegebene URL]

Supplemental material, sj-docx-1-taw-10.1177_20420986221122684 for Development of a deprescribing manual for frail older people for use in the COFRAIL study and in primary care by Nina-Kristin Mann, Sven Schmiedl, Achim Mortsiefer, Veronika Bencheva, Susanne Löscher, Manuela Ritzke, Eva Drewelow, Gregor Feldmeier, Sara Santos, Stefan Wilm and Petra A. Thürmann in Therapeutic Advances in Drug Safety

Background: The COVID-19 pandemic declared by the World Health Organization (WHO) in March 2020 continues, not least due to the now dominant, highly infectious delta variant. A ray of hope in the fight against the pandemic are the m-RNA and vector-based COVID-19 vaccines, which have also been successively [for full text, please go to the a.m. URL]

Background: Polypharmacy affects multimorbid and frail older people, increasing the risk of adverse drug events and hospitalisations [ref:1]. A structured deprescribing process using a newly developed deprescribing manual was implemented in the COFRAIL study (funded by the GB-A innovation [for full text, please go to the a.m. URL]

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.

Publisher's version (útgefin grein)., 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 research leading to these results was conducted as part of the activities of the PE‐PV Consortium (Pharmacoepidemiology and Pharmacovigilance Consortium), which is a public academic partnership coordinated by the University of Utrecht. The project has received support from the European Medicines Agency under the Framework service contract (nr EMA/2015/27/PH) with regard to the reopening of competition no3. K. Janhsen (Witten/Herdecke University, Alfred‐Herrhausen‐ Straße 50, 58448 Witten, Germany (UW/H)) and B. Grave (AOK NORDWEST, Kopenhagener Straße 1, 44269 Dortmund, Germany). R. Gerlach and M. Tauscher (National Association of Statutory Health Insurance Physicians of Bavaria, Elsenheimerstr. 39, D‐80687 Munich, Germany). The authors of the BIFAP database would like to acknowledge the excellent collaboration of the primary care general practitioners and pediatricians, and also the support of the regional governments to the database. This study is based in part on data from the BIFAP fully financed by the Spanish Agency on Medicines and Medical Devices (AEMPS). The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the EMA (European Medicines Agency) or one of its committees or working parties, or AEMPS (Agencia Española de Medicamentos y Productos Sanitarios).