EU PV & PE Research Network under the Framework service contract (nr. EMA/2015/27/PH) Study Protocol “Characterising the risk of major bleeding in patients with Non-Valvular Atrial Fibrillation: non-interventional study of patients taking Direct Oral Anticoagulants in the EU” Version: 01 November 2016 For EMA review Name Role Dr. Helga Gardarsdottir1,2 Protocol 1 lead Dr. Christiane Gasse3 Protocol 1 co-lead/AU Danish National Registers lead Dr. Rianne van den Ham1 Protocol 1 co-lead/CPRD Database lead Marietta Rottenkolber4 Protocol 2 co-lead/Bavarian Claims Database lead Dr. Consuelo Huerta5 Protocol 2 co-lead/BIFAP Database lead Dr. Elisa Martín Merino5 BIFAP Database co-lead Dr. Luisa Ibanez6 Protocol 2 lead/SIDIAP Database lead Dr. Mónica Sabaté6 Protocol 2 co-lead/SIDIAP Database co-lead Dr. Xavier Vidal6 Protocol 2 co-lead/SIDIAP database co-lead Dr. Patrick Souverein1 CPRD&Mondriaan Database lead Prof. Dr. Nicholas Moore7 French Claims Database lead Dr. HenrietteThisted Horsdal3 Co-investigator/Danish National Registers Dr. Dolores Montero5 Co-investigator/BIFAP database Dr. Rolf Groenwold1,2 Co-investigator/CPRD&Mondriaan Dr. Sven Schmiedl8 AOK NORDWEST lead Prof. Dr. Katrin Janhsen8 AOK NORDWEST co-lead Prof. dr. Olaf Klungel1,2 PI/coordinator of EU PV & PE Research Network Ms. Satu J Siiskonen1 Project manager of EU PV & PE Research Network 1. Universiteit Utrecht, Utrecht, The Netherlands (UU) 2. University Medical Center Utrecht, Utrecht, The Netherlands (UMCU) 3. Aarhus University, Aarhus, Denmark (AU) 4 Klinikum der Universität München, München, Germany (KUM) 5 Agencia Espanola de Medicamentos y Productos Sanitarios, Madrid, Spain (AEMPS) 6. Fundació Institut Català de Farmacologia (FICF), Barcelona, Spain. 7. Bordeaux Pharmacoepi, Université de Bordeaux, Bordeaux, France (UB) 8. Witten/Herdecke University, Witten, Germany (UW/H) Any amendments to and/or deviations from this protocol will be documented by the PI/coordinator of EU PV & PE Research Network. EMA/2015/27/PH Version 01 Nov 2016 2 TABLE OF CONTENTS 1 Context of the proposal ........................................................................................................................................ 5 2 Objectives ............................................................................................................................................................. 5 3 Methods ............................................................................................................................................................... 5 3.1 Data sources ................................................................................................................................................. 5 3.1.1 Mondriaan ............................................................................................................................................ 5 3.1.2 Danish National Registries .................................................................................................................... 6 3.1.3 Bavarian claims database ..................................................................................................................... 6 3.1.4 AOK NORDWEST ................................................................................................................................... 6 3.1.5 BIFAP ..................................................................................................................................................... 6 3.1.6 System for the Development of Research in Primary Care (SIDIAP) ..................................................... 7 3.1.7 Clinical Practice Research Datalink (UK) ............................................................................................... 7 3.1.8 French Claims database: EGB ............................................................................................................... 7 3.2 Period of valid data collection ...................................................................................................................... 8 3.2.1 CPRD/Mondriaan/BIFAP/SIDIAP ........................................................................................................... 8 3.2.2 Danish registers .................................................................................................................................... 8 3.2.3 Bavarian claims ..................................................................................................................................... 8 3.2.4 AOK NORDWEST ................................................................................................................................... 8 3.2.5 EGB ....................................................................................................................................................... 8 3.3 Ethical issues ................................................................................................................................................. 8 4 Feasibility .............................................................................................................................................................. 9 5 Study Designs ..................................................................................................................................................... 11 5.1 Descriptive studies ..................................................................................................................................... 11 5.1.1 Data Sources ....................................................................................................................................... 11 5.1.2 Descriptive study investigating the utilization of DOACs in NVAF patients (objective 2) ................... 11 5.1.3 Descriptive study investigating prescriber compliance with SmPC recommendations (objective 3) . 14 5.2 Cohort study ............................................................................................................................................... 17 5.2.1 Population and study period .............................................................................................................. 17 5.2.2 Outcome ............................................................................................................................................. 17 5.2.3 Exposure definition ............................................................................................................................. 17 5.2.4 Potential confounders ........................................................................................................................ 19 5.2.5 Effect modifiers (subgroups) ............................................................................................................... 19 5.2.6 Analysis ............................................................................................................................................... 19 6 Limitations .......................................................................................................................................................... 20 6.1 Limitations related to the data source. ...................................................................................................... 20 6.2 Limitations related to methodology. .......................................................................................................... 20 6.3 Methodological study on exposure misclassification. ................................................................................ 20 6.3.1 Study design ........................................................................................................................................ 20 6.3.2 Analysis ............................................................................................................................................... 21 7 References .......................................................................................................................................................... 22 8 Annexes .............................................................................................................................................................. 24 8.1 Annex I: Information about the study drugs, dosing and indication. ......................................................... 24 Table 8.1.1. Oral anticoagulants, ATC codes and DDD ................................................................................ 24 Table 8.1.2. CPRD product codes ................................................................................................................ 24 Table 8.1.3. Indications and product recommended dose according to SmPCs for dabigatran, rivaroxaban and apixaban (SmPC item 4.1) ..................................................................................................................... 27 Table 8.1.4. Codes for indication according to the SmPC section 4.1. ........................................................ 28 Table 8.1.5. Posology and method of administration (SmPC item 4.2) ....................................................... 29 8.2 Annex II: Information about contraindications (SmPC item 4.3), special warnings and precautions (SmPC item 4.4) and interactions (SmPC item 4.5). ..................................................................................................... 32 Table 8.2.1. Registered contraindications (SmPC item 4.3) ........................................................................ 32 Table