Coronary Artery Calcium in the PRagmatic EValuation of evENTs And Benefits of Lipid lowering in the Elderly: CAC PREVENTABLE Ancillary Study

摘要 预测风险对于动脉粥样硬化性心血管疾病的有效一级预防至关重要 疾病（ASCVD），但在≥75岁的成人中分类风险仍然非常高 挑战性冠状动脉钙（CAC）评分和高敏肌钙蛋白（hs-Tn）是 老年人风险分层的有前途的工具，因为它们提供了单一和持久的 直接量化累积风险因素暴露和个人风险的组合的快照 弹性或脆弱性。联合使用，我们已经表明，CAC和hs-Tn的低值可能 对老年人“降低风险”是有用的， 预防性治疗可能无益的预后。然而，尽管有希望 观察数据显示，CAC和hs-Tn在老年人中的真正临床价值仍不确定 由于缺乏专门的、有充分把握度的随机试验。NIA/NHLBI资助 老年人降脂事件和益处的评价 成人）的实用临床试验，目前正在随机选择20，000名年龄≥75岁的成人， 阿托伐他汀40 mg或安慰剂和以下ASCVD事件，提供了理想的测试环境 CAC和hs-Tn联合确定老年人受益最大的关键假设， 最少的是他汀类药物。在本提案中，我们寻求执行基线CAC扫描 和hs-Tn测量10，000名可预防参与者。审判结束后，我们将 进行CAC分层分析，以及CAC和hs-Tn联合分析，把握度>85%， 通过生物标志物状态确定他汀类药物效应的异质性。在审判结束时，我们将 使用传统风险因素开发全面的ASCVD风险分类模型，CAC， 和hs-Tn，并在梅萨和ARIC中验证。然后，我们将构建一个类似于 用于计算年龄≥75岁原发性高血压患者中他汀类药物治疗估计获益的LIFE-CVD模型 预防人群中，在详细考虑了 可预防。总之，我们认为CAC扫描和hs-Tn测量在 预防是最迅速和最有指导意义的方式，以填补关键的知识差距， 在老年一级预防人群中的亚临床ASCVD，并确定 生物标志物引导的精准医学方法，用于告知预防性治疗的个人益处 他汀类药物治疗

ABSTRACT Predicting risk is critical for effective primary prevention of atherosclerotic cardiovascular disease (ASCVD), however classifying risk in adults ≥75 years of age remains extremely challenging. Coronary artery calcium (CAC) scoring and high-sensitivity troponin (hs-Tn) are promising tools for risk stratification in older adults because they provide singular and enduring snapshots that directly quantify a composite of cumulative risk factor exposure and individual resiliency or vulnerability. Used jointly, we have shown that low values of CAC and hs-Tn may be useful for “de-risking” older populations, identifying individuals with highly favorable prognosis in whom preventive therapy may not be beneficial. However, despite promising observational data, the true clinical value of CAC and hs-Tn in older adults remains uncertain due to lack of a dedicated, adequately powered randomized trial. The NIA/NHLBI-funded PREVENTABLE (PRagmatic EValuation of evENTs And Benefits of Lipid-lowering in oldEr adults) pragmatic clinical trial, which is currently randomizing 20,000 adults ≥75 years of age to atorvastatin 40mg or placebo and following for ASCVD events, provides the ideal setting to test the critical hypothesis that CAC and hs-Tn jointly identify older adults who will benefit the most, and the least, from statin therapy. In this proposal, we seek to perform baseline CAC scanning and hs-Tn measurement in 10,000 PREVENTABLE participants. At trial conclusion, we will conduct analyses stratified by CAC, and jointly by CAC and hs-Tn, with >85% power to determine heterogeneity of statin effect by biomarker status. At the end of the trial, we will develop a comprehensive ASCVD risk classification model using traditional risk factors, CAC, and hs-Tn and validate this in MESA and ARIC. We will then construct an online tool similar to the LIFE-CVD model for calculating estimated benefit of statin therapy in the age ≥75 primary prevention population, after detailed accounting for non-CVD competing risks observed in PREVENTABLE. In summary, we believe that CAC scanning and hs-Tn measurement in PREVENTABLE is the most expeditious and instructive way to fill critical knowledge gaps about subclinical ASCVD in an older primary prevention population and to determine the value of a biomarker-guided precision medicine approach for informing individual benefit of preventive statin therapy.