Balancing Risks and Benefits of Direct Oral Anticoagulants in Older Ischemic Stroke Patients with Atrial Fibrillation

2019年美国实践指南建议直接口服抗凝剂（DOAC），如达比加群、利伐洛- 阿哌沙班与华法林相比，在高危房颤患者中预防卒中。然而，在这方面， DOAC的选择对于老年缺血性中风患者是具有挑战性的。第二阶段的风险收益比- 预防性卒中与一级预防有很大不同。不仅老年中风幸存者 缺血性事件复发的风险增加、年龄较大和缺血性卒中病史也是主要的风险因素 治疗出血并发症虽然人们知道药物的选择应该是个性化的， 如何根据抗凝剂的有效性/安全性和患者的独特特点定制抗凝治疗- 特征长期目标是利用比较有效性研究来提高护理质量， 心血管疾病和中风的患者。美国心脏协会（AHA） 了解指南-卒中登记（GWTG-卒中）和医疗保险住院患者和D部分数据库， 本申请的所有目的是开发基于证据的策略，以改善适当的抗凝剂 老年缺血性卒中房颤患者的二级预防治疗。中心假设是， DOAC之间在有效性和安全性方面存在差异，这对治疗有直接影响。 选择.一旦知道了相对有效性/安全性，就可以根据 对患者的风险状况进行评估，使治疗更安全、更有效。在强有力的初步数据的指导下，这一hy- 将通过两个具体目标对假设进行检验：1）确定长期临床有效性和安全性 在老年缺血性卒中伴AF患者中进行二级预防的不同DOAC; 2）研究DOAC 给药模式，并评估用药不足或用药过量对长期结局的潜在影响。的 拟议的研究在四个关键方面具有创新性：1）以患者为中心的方法用于解决现实生活中的 脑卒中幸存者和临床医生面临的决策困境; 2）它转移了临床试验中选定样本的焦点 一个全国性的代表性中风人群，包括传统上代表性不足的亚组， 基于广义Boosted模型的倾向得分逆概率加权方法 （一种机器学习技术）将用于模拟试验型多治疗设计， 异质性，并最大限度地减少观察数据中的选择偏差; 4）超越传统的科学机制 出版物，本研究产生的证据将传播给中风幸存者，临床医生， 通过AHA GWTG领导的国家质量倡议和患者主导的努力， 将开创性的发现快速转化为临床实践。这项研究之所以重要，是因为 有望帮助指导老年缺血性卒中幸存者的个性化抗凝治疗， 满足他们的需求，并带来对患者最有意义的更好结果。最终，这些知识 有可能为中风的循证治疗决策提供信息，目前有超过720万美国人受到中风的折磨。

The 2019 U.S. practice guidelines recommend direct oral anticoagulants (DOACs) such as dabigatran, rivarox- aban, and apixaban over warfarin for stroke prevention in high-risk patients with atrial fibrillation (AF). However, the selection of a DOAC can be challenging for older ischemic stroke patients. The risk-benefit ratios in second- ary stroke prevention differ substantially from those in primary prevention. Not only are older stroke survivors at increased risk for recurrent ischemic events, older age and history of ischemic stroke are also major risk factors for bleeding complications. While it is known that drug selection should be individualized, it remains unknown how to tailor anticoagulant therapy according to the effectiveness/safety of the agents and patient unique char- acteristics. The long-term goal is to use comparative effectiveness research to improve quality of care and out- comes in patients with cardiovascular disease and stroke. Leveraging the American Heart Association (AHA) Get With The Guidelines-Stroke Registry (GWTG-Stroke) and Medicare inpatient and Part D database, the over- all objective of this application is to develop evidence-based strategies to improve appropriate anticoagulant therapy for secondary prevention in older ischemic stroke patients with AF. The central hypothesis is that differ- ences exist between DOACs in terms of effectiveness and safety, which have direct implications for therapeutic selection. Once the relative effectiveness/safety is known, the selection of an anticoagulant can be made based on patient risk profiles, making treatment safer and more effective. Guided by strong preliminary data, this hy- pothesis will be tested by pursuing two specific aims: 1) Determine the long-term clinical effectiveness and safety of different DOACs for secondary prevention in older ischemic stroke patients with AF; 2) Investigate DOACs dosing patterns and evaluate the potential impact of underdosing or overdosing on long-term outcomes. The proposed research is innovative in four key ways: 1) A patient-centered approach is used to address a real-life decisional dilemma facing stroke survivors and clinicians; 2) It shifts focus from selected samples in clinical trials to a nationwide representative stroke population, including traditionally underrepresented subgroups in commu- nity practice; 3) A novel propensity score inverse probability weighting method using generalized boosted models (a machine learning technique) will be employed to mimic a trial-type multi-treatment design, uncover treatment heterogeneity, and minimize selection bias in observational data; 4) Beyond traditional mechanisms of scientific publications, the evidence generated from this study will be disseminated to stroke survivors, clinicians, and relevant stakeholders through the AHA GWTG-led national quality initiatives and patient-led efforts to ensure a rapid translation of seminal findings into clinical practice. The proposed research is significant because it is expected to help guide personalized anticoagulant therapy in older ischemic stroke survivors that could best meet their needs and lead to better outcomes most meaningful to patients. Ultimately, such knowledge has the potential to inform evidence-based treatment decisions in stroke that now afflicts more than 7.2 million Americans.