ASPirin in Reducing Events in the Elderly - eXTension

总体研究报告-摘要/总结 在美国，低剂量阿司匹林（LDA）是最广泛使用的药物之一，因为它在 心血管疾病（CVD）的二级预防。近年来，一些专家机构，包括 美国预防服务工作组（USPSTF）建议将LDA常规用于主要 基于既往随机化研究的大量数据， 对照试验（RCT）主要在年轻人中进行。然而，对于70岁以上的成年人， USPSTF认为目前支持净效益的证据不足。此外，需要延长 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 人口老龄化日益严重的经济成本。为了弥补这些知识差距，国家信息评估/国家信息理事会- 赞助的阿司匹林减少老年人事件（ASPREE）研究是一项突破性的研究， RCT招募了19，114名最初健康的老年人，年龄在70岁以上（美国少数民族为65岁以上），从2010年开始， 2014年在美国和澳大利亚，研究是否开始5年的低剂量每日阿司匹林（LDA; 100 毫克/天）延长了老年人的健康寿命。2017年6月，随机治疗阶段 ASPREE在中位数为4.6年的治疗后暂停，因为LDA对 无残疾生存期（DFS）。对于次要结局，LDA意外地与 全因死亡风险增加（HR 1.14; 95% CI，1.01，1.28），原因是 癌症，尽管癌症发病率没有增加。此外，LDA显示出降低事件的趋势， 身体残疾的整体。这些挑衅性的初步发现要求继续研究和随访， ASPREE队列通过此U19提案。我们的总体目标是产生关于 阿司匹林在老年人中的作用，在老年人中阿司匹林对慢性疾病的一级预防的风险/益处 疾病被低估了。我们的首要假设是，ASPREE的长期随访 队列将证明LDA对癌症、痴呆和残疾的长期“遗留”益处。我们进一步 假设在随访期间收集的广泛的基因组、生化和成像相关信息将提供 对LDA对这些终点的影响的独特生物学见解，可能导致机械启发 生物标志物，以更“精确”的预防方法预防慢性病。因此，我们建议 建立ASPREE-XT，在未来5年内扩展ASPREE参与者的随访， 项目重点是癌症，痴呆症（包括阿尔茨海默氏症）和身体残疾，将得到支持， 6个核心，促进协同增效和协作。这个由多学科国际团队领导的U19 领先的研究人员，将提供一个前所未有的机会，以确定LDA的长期疗效， 指导临床建议，并提供对领先的生物学基础的基本见解。 老年人痴呆、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.