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Do P2Y12 receptor inhibitors prescribed poststroke modify the risk of cognitive disorder or dementia? Protocol for a target trial using multiple national Swedish registries

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posted on 07.06.2022, 04:53 authored by M Hinwood, J Nyberg, L Leigh, S Gustavsson, J Attia, C Oldmeadow, M Ilicic, T Linden, ND Åberg, C Levi, N Spratt, Leeanne CareyLeeanne Carey, M Pollack, SJ Johnson, GH Kuhn, FR Walker, M Nilsson
INTRODUCTION: The target of a class of antiplatelet medicines, P2Y12R inhibitors, exists both on platelets and on brain immune cells (microglia). This protocol aims to describe a causal (based on a counterfactual model) approach for analysing whether P2Y12R inhibitors prescribed for secondary prevention poststroke may increase the risk of cognitive disorder or dementia via their actions on microglia, using real-world evidence. METHODS AND ANALYSIS: This will be a cohort study nested within the Swedish National Health and Medical Registers, including all people with incident stroke from 2006 to 2016. We developed directed acyclic graphs to operationalise the causal research question considering potential time-independent and time-dependent confounding, using input from several experts. We developed a study protocol following the components of the target trial approach described by Hernan et al and describe the data structure that would be required in order to make a causal inference. We also describe the statistical approach required to derive the causal estimand associated with this important clinical question; that is, a time-to-event analysis for the development of cognitive disorder or dementia at 1, 2 and 5-year follow-up, based on approaches for competing events to account for the risk of all-cause mortality. Causal effect estimates and the precision in these estimates will be quantified. ETHICS AND DISSEMINATION: This study has been approved by the Ethics Committee of the University of Gothenburg and Confidentiality Clearance at Statistics Sweden with Dnr 937-18, and an approved addendum with Dnr 2019-0157. The analysis and interpretation of the results will be heavily reliant on the structure, quality and potential for bias of the databases used. When we implement the protocol, we will consider and document any biases specific to the dataset and conduct appropriate sensitivity analyses. Findings will be disseminated to local stakeholders via conferences, and published in appropriate scientific journals.


Research Council (G2000554) and the Hunter Medical Research Institute (G2100140).


Publication Date



BMJ open





Article Number

ARTN e058244


(p. e058244)





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© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: