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使用直接口服抗凝剂(DOAC)，如达比卡特兰、利凡昔布- 阿班，阿普沙班优于华法林，用于预防高危房颤患者的中风。然而， 对于老年缺血性卒中患者来说，DOAC的选择可能是具有挑战性的。以秒为单位的风险收益比- 急性卒中预防与一级预防有很大的不同。不仅年长的中风幸存者 再次发生缺血性事件的风险增加、年龄较大和有缺血性中风病史也是主要危险因素 治疗出血并发症。虽然药物选择应该个体化是众所周知的，但这一点仍然未知。 如何根据药物的有效性/安全性和患者的独特特点量身定做抗凝治疗。 这是特征。长期目标是使用比较有效性研究来提高护理质量和出院- 适用于心血管疾病和中风患者。利用美国心脏协会(AHA) 使用指南-卒中登记(GWTG-Stroke)和Medicare住院患者和D部分数据库，Over- 这项应用的所有目标都是开发基于证据的策略，以改进适当的抗凝剂 老年缺血性卒中伴房颤患者二级预防的治疗。中心假设是不同的- 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，抗凝剂的选择就可以根据 患者风险档案，使治疗更安全、更有效。在强劲的初步数据指导下，这一点- 假体将通过追求两个具体目标进行测试：1)确定长期临床有效性和安全性 不同DOAC对老年缺血性卒中伴房颤患者的二级预防作用；2)研究DOAC 给药模式和评估剂量不足或过量对长期结果的潜在影响。这个 提出的研究在四个关键方面是创新的：1)使用以患者为中心的方法来解决现实生活中的 中风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的样本的重点 到全国有代表性的中风人群，包括社区中传统上代表性较低的亚群- 3)一种新的基于广义Boost模型的倾向性得分逆概率加权方法 (一种机器学习技术)将被用来模拟试验型多治疗设计，揭开治疗 异质性，最大限度地减少观测数据中的选择偏差；4)超越传统的科学机制 这项研究产生的证据将被传播给中风幸存者、临床医生和 相关利益攸关方通过AHA GWTG领导的国家质量倡议和患者主导的努力，确保 快速将开创性发现转化为临床实践。这项拟议的研究具有重要意义，因为它 有望帮助指导老年缺血性卒中幸存者的个性化抗凝治疗，最好的 满足他们的需求，并带来对患者最有意义的更好的结果。归根结底，这种知识具有 有可能为中风的循证治疗决策提供信息。中风目前困扰着超过720万美国人。

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.