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

Abstract

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.

Keywords: Dementia; EPIDEMIOLOGY; STATISTICS & RESEARCH METHODS; Stroke.

Figure 1

A casual directed acyclic graph (DAG) representing the assumed relationships (edges) between variables of interest (nodes) at baseline. This DAG represents variables that may affect the relationship between treatment (P2Y12R inhibitors) and outcome (mild cognitive disorder/dementia), and the competing event (death). Green with arrow denotes exposure; blue with I denotes outcome; other blue denotes ancestors of outcome; white denotes adjusted; dark grey denotes other variable; pale grey denotes unobserved (latent) variable; red denotes ancestors of exposure and outcome. CNS, central nervous system; P2Y12R, P2Y12 receptor.

Figure 2

A causal directed acyclic graph (DAG) representing the assumed relationships (edges) between time-varying variables of interest (nodes) to be taken into account in the per-protocol analysis. This DAG represents variables that may affect the likelihood of receiving treatment (P2Y12 receptor (P2Y12R) inhibitors) over time, including treatment allocation (Z), time-varying covariates (L) and treatment (A), to follow-up time (t) and incorporates the possible influence of unmeasured confounding bias (U). In this analysis, prior treatment adherence to P2Y12R inhibitors may affect measured covariates (such the occurrence of acute coronary syndromes, including recurrent stroke), and the probability of future treatment. This treatment-confounder feedback will require the use of g-methods such as inverse probability weighting, to calculate the per-protocol effect of treatment with P2Y12R inhibitors over time on the outcome of dementia/mild cognitive disorder.

Figure 3

A graphical depiction of the study design for the main analysis, depicting baseline confounders. Based on the recommendations of the article by Schneeweiss et al. ACS, acute coronary syndrome; MCD, mild cognitive disorder; NOAC, non-vitamin K antagonist oral anticoagulants; P2Y12R, P2Y12 receptor; SVD, small-vessel disease; TIA, transient ischaemic attack.