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

项目总结 高血压(HTN)的患病率随着年龄的增长而增加，是几种慢性病的主要危险因素 包括阿尔茨海默病和相关痴呆症(ADRD)、心血管疾病(CVD)以及几种 癌症，以及死亡率。血管紧张素II受体阻滞剂与血管紧张素转换酶 抑制剂(ACEI)是最常用的两类抗HTN药物，约有4000万美国成年人使用。 ARBS和ACEI对HTN的生理异常有独特的有利下游作用， 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和多发病的长期风险。然而，目前的HTN指南 基于假定的同等益处和安全性，建议交替使用ARB和ACEI。我们的 目标是通过阐明最佳的首选RAS阻滞剂来优化最初的抗HTN药物处方 在ARB和ACEI之间。因为大约2300万美国成年人目前正在接受ACEI和生理学检查 有证据支持这些药物的下游效应存在差异，即使ARB只增加了15% 有效地，将一线RAS封锁从ACEI切换到ARB将对人口健康产生长期影响 变得巨大。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)评估ARBS与ACEIs对ADRD、多发病、 虚弱和健康调整的预期寿命(Hale；一个人的预期寿命占 一个人的累积发病率负担)。VHA和KP SoCal是执行这项研究的理想数据来源 因为它们包括1000万名患者的全面医疗信息，所以收集详细的 关于药物使用和健康结果的信息，并具有较高的患者保留率和10年的随访- 向上。具体目的是确定ARB-VS的长期比较效果，包括使用持续时间。 以ACEI为基础的抗HTN药物治疗方案(目的1)ADRD、CVD(卒中、心肌梗死)的发生率 梗死、冠状动脉血运重建或心力衰竭)和癌症，(目标2)患者- 以脆弱为中心的结果和以人口为中心的黑尔的结果。我们将使用一个有源比较器， 新用户设计说明服药依从性，以及自然语言处理以确定 ADRD在电子健康记录中比仅使用行政代码更准确。我们的团队很好- 具备分析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、心血管疾病发病率、癌症的评估 发病率和多发病；以及因果推理方法的应用。我们的项目可以支持 首选RAS的范式转变--封锁。目前的预测表明，ADRD将影响1.15亿英镑 到2050年人口增加，到2040年癌症发病率将达到每年2700万。对公众健康的潜在益处 解决这些知识差距，从而提高生命的质量和长度是巨大的。

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.