Real-world Evidence to Inform Decisions for Hypertension Treatment Escalation

项目摘要 超过1亿美国成年人患有高血压，高血压是导致死亡和发病的主要原因，其中70% 仅靠单一疗法不能达到足够的血压控制。尽管最近的临床实践 指南建议使用两种药物开始治疗，目前接受治疗的高血压患者中有50%以上 从单一的药物开始。对于这些患者，临床指南建议增加第二种降压药 用于治疗升级的药物。随机对照试验(RCT)中缺乏面对面比较 限制了临床指南提供关于添加哪种药物的循证建议的能力 下一位是哪些病人。我们的长期目标是产生真实世界的证据，为关于RCT的决策提供信息 为高血压治疗升级提供最高质量的非随机证据支持 指南建议。此应用程序的总体目标是确定比较 高血压患者单药治疗中加用二次降压药的有效性和安全性 高血压。核心假设是，第二种方案的有效性和安全性存在异质性。 抗高血压药物，最优选择取决于患者的特点和最初的治疗。我们的 初步数据显示，添加到单一疗法中的第二种药物的选择存在很大差异， 提供了充分的机会来利用实践差异来测试我们的假设。我们将首先确定 二联抗高血压药与单药联用治疗主要心血管疾病的疗效比较 结果，如心肌梗死、中风和心力衰竭住院(目标1)。到时候我们会的 确定第二种降压药对潜在药物相关不良事件的比较风险， 例如急性肾功能衰竭、血管水肿、胃肠道出血和高血钾(目标2)。最后，我们会 评估按年龄、性别、种族和性别定义的关键患者亚组之间的有效性和安全性的异质性 共病(目标3)。我们召集了观察方法方面的专家进行因果推理， 药物流行病学、临床信息学、高血压管理、实施科学和意志 在五个电子健康记录(EHR)数据库中使用来自超过1亿美国成年人的真实世界数据(即， 退伍军人事务部、哥伦比亚、耶鲁和Sentara Healthcare EHR数据库)。我们将雇佣州政府- 最先进的观测研究方法，包括主动比较器新用户设计，大规模 倾向评分建模、阴性对照结果实验和经验校准，以模拟随机对照试验 并比较药物组合。这项拟议的研究具有创新性，因为这将是第一项 应用海量真实世界数据集和最先进的观测研究方法，全面 观察在单一治疗的基础上加用第二种降压药的有效性和安全性。这个 拟议的研究具有重要意义，因为它提供了关键证据，为有关RCT的决策提供信息 高血压治疗升级并支持指南建议。

Project Summary Over 100 million US adults have hypertension, a leading cause of mortality and morbidity, and 70% of them cannot achieve adequate blood pressure control with monotherapy alone. Although recent clinical practice guidelines suggest initiating therapy with two drugs, more than 50% of people currently treated for hypertension start with a single medication. For these patients, clinical guidelines propose adding a second antihypertensive drug for treatment escalation. The absence of head-to-head comparison in randomized controlled trials (RCTs) has limited the ability of clinical guidelines to provide evidence-based recommendations about which drug to add next for which patients. Our long-term goal is to produce real-world evidence to inform decisions about RCTs for hypertension treatment escalation and to provide the highest quality non-randomized evidence to support guideline recommendations. The overall objective in this application is to determine the comparative effectiveness and safety of the second antihypertensive agents added to monotherapy in patients with hypertension. The central hypothesis is that there is heterogeneity in the effectiveness and safety of the second antihypertensive agents, and the optimal choice depends on patient characteristics and the initial therapy. Our preliminary data demonstrate a large variation in the choice of the second agents added to monotherapy, providing ample opportunity to leverage practice variation to test our hypothesis. We will first determine the comparative effectiveness of the second antihypertensive agents added to monotherapy on major cardiovascular outcomes, such as myocardial infarction, stroke, and hospitalization for heart failure (Aim 1). We will then determine the comparative risk of the second antihypertensive agents on potential drug-related adverse events, such as acute renal failure, angioedema, gastrointestinal bleeding, and hyperkalemia (Aim 2). Finally, we will assess heterogeneity in effectiveness and safety among key patient subgroups defined by age, sex, race, and comorbidity (Aim 3). We have assembled experts in observational methods for causal inference, pharmacoepidemiology, clinical informatics, hypertension management, and implementation science, and will use real-world data from over 100 million US adults in five electronic health record (EHR) databases (i.e., Optum, Department of Veterans Affairs, Columbia, Yale, and Sentara Healthcare EHR databases). We will employ state- of-the-art observational research methods, including an active comparator new-user design, large-scale propensity score modeling, negative control outcome experiments, and empirical calibration, to emulate RCTs and to compare drug combinations. The proposed research is innovative because it will be the first study that applies massive real-world datasets and state-of-the-art observational research methods to comprehensively investigate the effectiveness and safety of the second antihypertensive agents added to monotherapy. The proposed research is significant because it provides critical evidence to inform decisions about RCTs for hypertension treatment escalation and to support guideline recommendations.