Major bleeding in users of direct oral anticoagulants in atrial fibrillation: A pooled analysis of results from multiple population-based cohort studies
van den Ham, Hendrika A.; Souverein, Patrick C.; Klungel, Olaf H.; Platt, Robert W.; Ernst, Pierre; Dell'Aniello, Sophie; Schmiedl, Sven; Grave, Birgit; Rottenkolber, Marietta; Huerta, Consuelo; Martín Merino, Elisa; León-Muñoz, Luz M.; Montero, Dolores; Andersen, Morten; Aakjær, Mia; De Bruin, Marie L.; Gardarsdottir, Helga
(2021) Pharmacoepidemiology and Drug Safety, volume 30, issue 10, pp. 1339 - 1352
(Article)
Abstract
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
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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.
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Keywords: atrial fibrillation, cohort studies, directoral anticoagulants, major bleeding, oral anticoagulants, vitamin K antagonists, Epidemiology, Pharmacology (medical)
ISSN: 1053-8569
Publisher: John Wiley and Sons Ltd
Note: Funding Information: The research leading to these results was conducted as part of the activities of the PE & PV (Pharmacoepidemiology and Pharmacovigilance) Research Network which is a public academic partnership coordinated by the University of Utrecht, The Netherlands. The project has received support from the European Medicines Agency under the Framework service contract nr EMA/2015/27/PH. The authors of the BIFAP database would like to acknowledge the excellent collaboration of the primary care general practitioners and paediatricians, and also the support of the regional governments to the database. This study is based in part on data from the “Base de datos para la investigación Farmacoepidemiológica en Atención Primaria” (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 AEMPS. The Canadian Network for Observational Drug Effect Studies (CNODES), a collaborating centre of the Drug Safety and Effectiveness Network (DSEN), is funded by the Canadian Institutes of Health Research (Grant Numbers DSE‐111845 and DSE‐146021). This study was made possible through data sharing agreements between CNODES member research centres and the respective provincial governments of Alberta, British Columbia, Manitoba (HIPC # 2017/2018–07), Nova Scotia, Ontario, and Saskatchewan. The BC Ministry of Health and the BC Vital Statistics Agency approved access to and use of BC data facilitated by Population Data BC for this study. British Columbia data sources were as follows ( http://www.popdata.bc.ca/data ): British Columbia Ministry of Health [creator] (2017): Medical Services Plan (MSP) Payment Information File. BC Ministry of Health [publisher]. MOH (2017); British Columbia Ministry of Health [creator] (2017): PharmaNet. BC Ministry of Health [publisher]. Data Stewardship Committee (2017); Canadian Institute for Health Information [creator] (2017): National Ambulatory Care Reporting System. BC Ministry of Health [publisher]. MOH (2017); Canadian Institute for Health Information [creator] (2017): Discharge Abstract Database (Hospital Separations). BC Ministry of Health [publisher]. MOH (2017); British Columbia Ministry of Health [creator] (2017): Consolidation File (MSP Registration & Premium Billing). BC Ministry of Health [publisher]. MOH (2017); BC Vital Statistics Agency [creator] (2017): Vital Statistics Deaths. BC Ministry of Health [publisher]. Vital Statistics Agency (2017). This manuscript is under concurrent review by the Saskatchewan Ministry of Health and, based on their recommendations, may be subject to change within 30 days from the date of submission to a journal. The opinions, results, and conclusions reported in this paper are those of the authors. No endorsement by the provinces or data stewards is intended or should be inferred. We acknowledge the programming support of Jianguo Zhang (Alberta), Greg Carney (British Columbia), Matthew Dahl (Manitoba), Yan Wang (Nova Scotia), Anjie Huang (Ontario), and Nianping Hu (Saskatchewan). We also acknowledge the important contributions of all of the CNODES collaborators and assistants at each site. This work was supported by the European Medicines Agency (EMA) under the Framework service contract [nr. EMA/2015/27/PH] with regard to the re‐opening of competition no.3 and the Canadian Institutes of Health Research [Grant Number DSE‐146021]. The Canadian Network for Observational Drug Effect Studies (CNODES) Investigators are: Samy Suissa (Principal Investigator); Colin R. Dormuth (British Columbia); Brenda R. Hemmelgarn (Alberta); Jacqueline Quail and Gary F. Teare (Saskatchewan); Patricia Caetano and Dan Chateau (Manitoba); David A. Henry and J. Michael Paterson (Ontario); Jacques LeLorier (Québec); Adrian R. Levy (Atlantic: NS, NL, NB, PEI); Pierre Ernst and Kristian B. Filion (UK Clinical Practice Research Datalink (CPRD)); Robert W. Platt (Methods); and Ingrid S. Sketris (Knowledge Translation). CNODES, a collaborating centre of the Drug Safety and Effectiveness Network (DSEN), is funded by the Canadian Institutes of Health Research (Grant Number DSE‐146021). This document expresses the opinion of the authors of the paper, 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. Funding Information: Other than de direct funders of the study (European Medicines Agency and Canadian Institutes of Health Research), authors Hendrika A. van den Ham, Patrick C. Souverein, Olaf H. Klungel, Pierre Ernst, Sophie Dell'’Aniello, Birgit Grave, Marietta Rottenkolber, Consuelo Huerta, Elisa Martín Merino, Luz M León‐Muñoz, Dolores Montero and Helga Gardarsdottir had nothing to disclose. Marie L. De Bruin reports grants from Novo Nordisk, grants from Ferring Pharmaceuticals, grants from LEO Pharma, grants from Lundbeck, outside the submitted work. Sven Schmiedl reports a lecture fee from Daiichi Sankyo Deutschland GmbH. Robert W. Platt reports personal fees from Biogen, personal fees from Eli Lilly, personal fees from Pfizer, personal fees from Merck, personal fees from Amgen, outside the submitted work. Morten Andersen reports research grants from AstraZeneca, H. Lundbesenck & Mertz, Janssen, Merck Sharp & Dohme, Novartis and Pfizer, received by the institutions at which he has been employed. Morten Andersen has received fees for organising and teaching pharmacoepidemiology courses at Medicademy, the Danish Association for the Pharmaceutical Industry. Morten Andersen's professorship is supported by a grant from the Novo Nordisk Foundation to the University of Copenhagen (NNF15SA0018404). Mia Aakjær received support for her PhD study from Novo Nordisk Foundation (NNF15SA0018404). Publisher Copyright: © 2021 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.
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