ASPirin in Reducing Events in the Elderly - eXTension

总体研究计划-摘要/摘要 在美国，小剂量阿司匹林(LDA)是使用最广泛的药物之一，因为它在 心血管疾病二级预防(CVD)。近年来，几个专家机构，包括 美国预防服务工作组(USPSTF)建议将LDA常规用于初级 心血管疾病和结直肠癌(CRC)的预防基于先前随机分组的大量数据 主要在年轻人中进行的对照试验(RCT)。然而，对于70岁以上的成年人来说， USPSTF认为目前支持净收益的证据不够充分。此外，有必要延长 健康的独立生活，没有痴呆症和严重残疾，是至关重要的，因为社会和 日益老龄化的人口造成的经济代价。为了解决这些知识差距，NIA/NCI- 阿司匹林减少老年人活动(ASPREE)研究是一项开创性的研究 RCT从2010年开始招募了19,114名年龄在70岁以上(美国少数民族为65岁以上)的初步健康的老年人- 2014年在美国和澳大利亚检查是否开始5年的低剂量每日阿司匹林(LDA；100 毫克/天)可延长老年人的健康寿命。2017年6月，红斑狼疮随机治疗阶段 ASPREE在治疗中位数4.6年后暂停，原因是LDA对 无残疾生存(DFS)的主要结果。对于次要结果，LDA出人意料地被关联 全因死亡风险增加(HR 1.14；95%CI，1.01，1.28) 癌症，尽管癌症发病率没有增加。此外，LDA呈现出事件发生率降低的趋势 总体上是身体残疾。这些具有挑衅性的初步发现要求继续研究和跟进 ASPREE队列通过这一U19提案。我们的总体目标是生成关于 阿司匹林在老年人中的作用，在老年人中，阿司匹林对慢性病一级预防的风险/益处 对疾病的研究还不够深入。我们的主要假设是ASPREE的延长后续行动 队列将展示LDA在癌症、痴呆症和残疾方面的长期“遗产”好处。我们进一步 假设在随访期间收集的广泛的基因组、生化和成像相关性将提供 对LDA对这些终点的影响的独特生物学见解，可能导致机械激发 生物标记物为慢性病预防采取更“精确”的预防方法。因此，我们建议 建立ASPREE-XT，以在未来5年内将ASPREE参与者的跟踪范围扩大到3年 重点关注癌症、痴呆症(包括阿尔茨海默氏症)和身体残疾的项目将得到 6个核心，促进协同和协作。一起，这架U19，由一个多学科的国际团队领导 将提供一个前所未有的机会来定义LDA的长期有效性 指导临床建议，并提供对领先的 老年人患痴呆症、残疾和死亡的原因。

OVERALL RESEARCH PLAN - ABSTRACT / SUMMARY In the U.S., low dose aspirin (LDA) is one of the most widely used medications given its established role in the secondary prevention of cardiovascular disease (CVD). In recent years, several expert bodies, including the U.S. Preventive Services Task Force (USPSTF), have recommended the routine use of LDA for the primary prevention of both CVD and colorectal cancer (CRC) based on substantial data from prior randomized controlled trials (RCTs) primarily conducted among younger adults. However, for adults aged 70+, the USPSTF deemed current evidence supporting a net benefit insufficient. Furthermore, the need to prolong healthy independent life, free of dementia and significant disability, is critical given the rising social and economic costs of the increasingly aging population. To address these knowledge gaps, the NIA/NCI- sponsored ASPirin in Reducing Events in the Elderly (ASPREE) study was developed as a ground-breaking RCT that recruited 19,114 initially healthy older individuals aged 70+ years (65+ for U.S. minorities) from 2010- 2014 in the U.S. and Australia to examine whether initiation of 5 years of low-dose daily aspirin (LDA; 100 mg/day) prolonged the healthy lifespan of older adults. In June 2017, the randomized treatment phase of ASPREE was suspended after a median of 4.6 years of treatment due to lack of an effect of LDA on the primary outcome of disability-free survival (DFS). For secondary outcomes, LDA unexpectedly was associated with an increased risk of all-cause mortality (HR 1.14; 95% CI, 1.01,1.28) driven by an excess of deaths due to cancer, despite no increase in incident cancer. Furthermore, LDA showed a trend toward lower incident physical disability overall. These provocative initial findings obligate continued study and follow-up of the ASPREE cohort through this U19 proposal. Our overall goal is to generate fundamental knowledge about the role of aspirin in older adults, a population in which aspirin's risk/benefit for primary prevention of chronic disease has been understudied. Our overarching hypothesis is that extended follow-up of the ASPREE cohort will demonstrate a long-term `legacy' benefit of LDA on cancer, dementia and disability. We further hypothesize that extensive genomic, biochemical, and imaging correlates collected during follow-up will offer unique biological insight into LDA's effects on these endpoints that may lead to mechanistically-inspired biomarkers for more `precision' prevention approaches to chronic disease prevention. Thus, we propose to establish ASPREE-XT to extend follow-up in ASPREE participants over the next 5 years to pursue three Projects focused on cancer, dementia (including Alzheimer's), and physical disability that will be supported by 6 Cores, facilitating synergy and collaboration. Together, this U19, led by a multidisciplinary, international team of leading investigators, will provide an unprecedented opportunity to define the long-term efficacy of LDA to guide clinical recommendations and offer fundamental insights into the biological underpinnings of the leading causes of dementia, disability and death among older adults.