Guiding next steps for SPRINT-MIND implementation: Identifying high-benefit subgroups and comparative effects of ARB- vs. ACEI-based regimens

项目摘要 阿尔茨海默氏病和相关痴呆症（ADRD）是老年人依赖和残疾的主要原因。 全球老年人口，每年花费美国医疗保健系统超过2000亿美元。因为ADRD 代表着持续的不可逆转的身体和认知能力下降，确定有效的方法， 预防势在必行。高血压，特别是中年高血压，与认知功能障碍的风险增加有关。 下降和ADRD。随机收缩压（SBP）干预试验的最新数据 （SPRINT）记忆和认知降低高血压（SPRINT MIND）表明， SBP控制（<120 mmHg）降低了判定的轻度认知功能障碍（MCI）的综合发生率 和可能的痴呆，以及与标准BP相比的异常白色病变（WML）体积 对照组（<140 mmHg）5年随访。为了最大限度地发挥公共卫生影响，关键是要确定 患者从强化SBP治疗中获得最大的认知和净（总体）获益， 受益是由于特定抗高血压药物对认知的直接影响， 除此之外，还有降血压的作用。之前的动物和人类研究以及我们的初步数据表明， 血管紧张素II受体阻滞剂（ARB）对认知的影响大于血管紧张素转换酶， 酶抑制剂（ACEI）。如果得到证实，这一发现将是重要的，因为ARB和ACEI目前 在老年人最常开的药物中， 和安全性我们的目标是回答剩余的问题，如何安全地实施SPRINT在旧的 最有可能从强化SBP治疗中获得认知益处的患者。由于样本量大，5 年随访，以及严格判定的认知结果的高质量重复测量，脑 成像和抗高血压药物的使用，SPRINT MIND提供了一个独特的，具有成本效益的，理想的 来回答这些问题。我们的目标是：（1）开发和验证一个预测工具， 患者的预期认知获益和净（总体）获益， SBP强化治疗下SAE的心血管获益和风险，以及（2）确定比较 ARB与ACEI为基础的降压药物治疗方案对 认知和脑结构结果独立于降低SBP的作用。虽然SPRINT MIND是 在第一批证明对认知有益的预防作用的随机试验中， SPRINT-MIND应在哪些患者中实施。该项目的成功完成将 指导下一步的实施，确定：（1）哪些患者获得最大的认知和 强化SBP治疗的净（总体）获益，以及（2）如果ARB对认知功能有更大的有益作用， 结果和WML体积比ACEI，独立于其相似的SBP降低作用。

PROJECT SUMMARY Alzheimer’s disease and related dementias (ADRD) are the leading cause of dependence and disability in the elderly population worldwide, costing the US healthcare system over $200 billion annually. Because ADRD represents a continuous irreversible physical and cognitive decline, identifying effective approaches for its prevention is imperative. Hypertension, particularly in midlife, is associated with an increased risk of cognitive decline and ADRD. Recent data from the randomized Systolic Blood Pressure (SBP) Intervention Trial (SPRINT) Memory and cognition IN Decreased hypertension (SPRINT MIND) demonstrated that intensive SBP control (<120 mmHg) reduced the combined incidence of adjudicated mild cognitive impairment (MCI) and probable dementia, as well as abnormal white matter lesion (WML) volume compared to standard BP control (<140 mmHg) over five years follow up. To maximize public health impact, it is critical to identify which patients derive the greatest cognitive and net (overall) benefit from intensive SBP treatment and if cognitive benefits were due to direct effects of specific antihypertensive medications on cognition independent of, or in addition to, their BP-lowering effect. Prior animal and human studies, as well as our preliminary data, suggest that angiotensin II receptor blockers (ARB) have greater effects on cognition than angiotensin-converting- enzyme inhibitors (ACEI). If verified, this finding would be significant since ARBs and ACEIs are currently among the medications most commonly prescribed to older adults and are thought to be equivalent in benefit and safety. Our objective is to answer remaining questions of how to safely implement SPRINT in older patients most likely to derive cognitive benefits from intensive SBP treatment. With its large sample size, 5 years follow-up, and high-quality repeated measures of rigorously adjudicated cognitive outcomes, brain imaging, and antihypertensive medication use, SPRINT MIND provides a unique, cost-efficient, and ideal setting to answer these questions. We aim to: (1) develop and validate a prediction tool that quantifies patients’ expected cognitive benefits and net (overall) benefit incorporating cognitive and cardiovascular benefit and risk of SAEs under intensive SBP treatment, and (2) determine comparative effects, including dose-response, of ARB- vs. ACEI-based antihypertensive medication regimens on cognitive and brain structure outcomes independent of SBP-lowering effects. Though SPRINT MIND is among the first randomized trials to demonstrate a beneficial preventive effect on cognition, it is uncertain how SPRINT-MIND should be implemented and in which patients. Successful completion of this project will guide next steps for implementation by determining: (1) which patients derive the greatest cognitive and net (overall) benefit from intensive SBP treatment and (2) if ARBs have greater beneficial effects on cognitive outcomes and WML volume than ACEIs, independent of their similar SBP lowering effects.