Informing optimal first-line antihypertensive therapy: A rigorous comparative effectiveness analysis of ARBs vs. ACEIs on long-term risk of dementia, cancer, heart disease, and quality of life

项目摘要 高血压（HTN）患病率随着年龄的增长而增加，是几种慢性疾病的主要危险因素 包括阿尔茨海默病和相关痴呆（ADRD）、心血管疾病（CVD）和几种 癌症和死亡率。血管紧张素II受体阻滞剂（ARB）和血管紧张素转换酶 ACEI是两种最常用的抗HTN药物，约有4000万美国成年人使用。 ARB和ACEI对HTN的生理异常具有独特的有益下游效应， 包括血管收缩、炎症、纤维化和氧化应激，这反过来可能导致不同的 与衰老相关的ADRD和多发性硬化症的长期风险。然而，目前的HTN指南 由于假定的等效获益和安全性，建议交替使用ARB和ACEI。我们 目的是通过阐明最佳首选RAS阻滞剂来优化初始抗HTN药物处方 ARB与ACEI之间的差异。因为大约2300万美国成年人目前正在服用ACEI和生理药物， 有证据支持这些药物下游效应的差异，即使ARB仅多15%， 有效，从ACEI转换为ARB的一线RAS阻断对人群健康的长期影响将 是巨大的。我们将利用退伍军人健康管理局（VHA）和Kaiser Permanente的数据， 南加州（KP SoCal），评价ARB与ACEI对ADRD、多药耐药风险的影响， 健康调整预期寿命（health adjusted life expectancy，黑尔）：一个人可以预期生活的时间， 一个人的累积发病率负担）。VHA和KP SoCal是执行此研究的理想数据源 因为它们包含超过1000万患者的全面医疗保健信息， 关于药物使用和健康结果的信息，并且患者保留率高，随访时间>10年- 起来具体目的是确定ARB-vs. 基于ACEI的抗HTN药物治疗方案对（目的1）ADRD、CVD（卒中、心肌梗死）发生率的影响 梗死、冠状动脉血运重建或心力衰竭）和癌症，以及（目标2）患者- 以虚弱为中心的结局和以人群为中心的黑尔结局。我们将使用活性对照药物， 新用户设计考虑药物依从性，以及自然语言处理，以确定 ADRD在电子健康记录中比单独使用行政代码更准确。我们的团队很好- 考虑到之前分析VHA和KP数据的丰富经验，适合进行研究，包括 抗HTN药物使用的药物流行病学分析; ADRD、CVD发生率、癌症 发病率和多发病率;因果推理方法的应用。我们的项目可以支持 首选RAS阻断的范式转变。目前的预测表明，ADRD将影响超过1.15亿人 到2040年癌症发病率将达到每年2700万。潜在的公共卫生效益 解决这些知识差距，从而提高生活质量和寿命是巨大的。

PROJECT SUMMARY Hypertension (HTN) prevalence increases with aging and is a leading risk factor for several chronic illnesses including Alzheimer's disease and related dementias (ADRD), cardiovascular disease (CVD), and several cancers, as well as mortality. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are two of the most commonly prescribed anti-HTN classes, used by ~40 million US adults. ARBs and ACEIs and have distinctive beneficial downstream effects on physiologic abnormalities in HTN, including vasoconstriction, inflammation, fibrosis, and oxidative stress, which in turn may result in different long-term risks of ADRD and multimorbidity associated with aging. However, current HTN guidelines recommend prescribing ARBs and ACEIs interchangeably due to presumed equivalent benefit and safety. Our goal is to optimize initial anti-HTN medication prescribing by clarifying the optimal first choice RAS-blocker between ARBs vs. ACEIs. Because ~23 million US adults are currently taking an ACEI and physiologic evidence supports differences in downstream effects of these medications, even if ARBs are only 15% more effective, the long-term population health impact of switching first-line RAS-blockade from ACEI to ARB would be enormous. We will leverage data from the Veterans Health Administration (VHA) and Kaiser Permanente Southern California (KP SoCal) to evaluate the effects of ARBs vs. ACEIs on the risk of ADRD, multimorbidity, frailty, and health-adjusted life expectancy (HALE; the amount of time one can expect to live accounting for one's cumulative morbidity burden). The VHA and KP SoCal are ideal data sources to perform this research because they include comprehensive healthcare information for >10 million patients, collect detailed information on medication use and health outcomes, and have high patient retention with >10 years of follow- up. The specific aims are to determine long-term comparative effects, including duration of use, of ARB- vs. ACEI-based anti-HTN medication regimens on (Aim 1) the incidence of ADRD, CVD (stroke, myocardial infarction, coronary revascularization, or heart failure), and cancers, separately and (Aim 2) the patient- centered outcome of frailty and the population-centered outcome of HALE. We will use an active comparator, new-user design accounting for medication adherence, as well as natural language processing to ascertain ADRD more accurately in the electronic health record over using administrative codes alone. Our team is well- suited to perform the study given considerable prior experience analyzing VHA and KP data, including pharmacoepidemiologic analyses of anti-HTN medication use; assessment of ADRD, CVD incidence, cancer incidence, and multimorbidity; and application of causal inference methods. Our project could support a paradigm shift of first-choice RAS-blockade. Current projections indicate that ADRD will affect >115 million people by 2050 and cancer incidence will be 27 million per year by 2040. The potential public health benefit of addressing these knowledge gaps and, thereby, improving the quality and length of life is enormous.