School of Medicine and Public Health, The University of Newcastle, Callaghan, New South Wales, Australia
Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
BMJ Open. 2022 May 9;12(5):e058244. doi: 10.1136/bmjopen-2021-058244.
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.
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 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.
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.
一类抗血小板药物（P2Y12R 抑制剂）的作用靶点既存在于血小板上，也存在于大脑免疫细胞（小胶质细胞）上。本方案旨在描述一种因果分析方法（基于反事实模型），以使用真实世界的数据来分析用于中风二级预防的 P2Y12R 抑制剂是否通过其对小胶质细胞的作用而增加认知障碍或痴呆的风险。
这将是一项嵌套在瑞典国家健康和医疗登记处内的队列研究，包括 2006 年至 2016 年期间所有发生中风的患者。我们使用来自几位专家的输入信息，为操作性因果研究问题制定了有向无环图，考虑了潜在的时间独立和时间相关的混杂因素。我们遵循 Hernan 等人描述的目标试验方法的组成部分制定了研究方案，并描述了为进行因果推断所需的数据结构。我们还描述了为解决这个重要临床问题所需的统计方法；也就是说，基于竞争事件的方法来考虑全因死亡率的风险，对 1、2 和 5 年随访时认知障碍或痴呆的发展进行时间到事件分析。将量化因果效应估计值及其在这些估计值中的精度。
这项研究已获得哥德堡大学伦理委员会和瑞典统计局保密许可的批准（编号分别为 937-18 和 2019-0157）。分析和解释结果将严重依赖于所使用数据库的结构、质量和潜在偏差。在实施该方案时，我们将考虑并记录特定于数据集的任何偏差，并进行适当的敏感性分析。研究结果将通过会议向当地利益相关者传播，并在适当的科学期刊上发表。
