Real-world Evidence to Inform Decisions for Hypertension Treatment Escalation

项目摘要 超过1亿的美国成年人患有高血压，这是死亡和发病的主要原因，其中70%的人患有高血压。 单用单药治疗不能充分控制血压。尽管最近的临床实践 指南建议用两种药物开始治疗，超过50%的目前接受高血压治疗的人 从单一药物开始。对于这些患者，临床指南建议增加第二种降压药 治疗升级的药物。随机对照试验（RCT）中缺乏头对头比较 限制了临床指南提供关于增加哪种药物的循证建议的能力 其次是哪些病人。我们的长期目标是提供真实世界的证据，为RCT的决策提供信息， 高血压治疗升级，并提供最高质量的非随机证据来支持 指南建议。本申请的总体目标是确定与本发明的实施例的比较。 在单药治疗中添加第二种降压药的有效性和安全性 高血压中心假设是，第二种药物的有效性和安全性存在异质性。 抗高血压药物，最佳选择取决于患者特征和初始治疗。我们 初步数据表明在单一疗法中加入的第二种药物的选择有很大的变化， 提供了充分的机会来利用实践的变化来测试我们的假设。我们将首先确定 单药治疗中添加第二种降压药对主要心血管疾病的疗效比较 结果，如心肌梗死、卒中和因心力衰竭住院（目标1）。然后我们将 确定第二抗高血压药对潜在药物相关不良事件的比较风险， 如急性肾衰竭、血管性水肿、胃肠道出血和高钾血症（目的2）。最后我们将 评估按年龄、性别、人种和年龄定义的关键患者亚组之间有效性和安全性的异质性， 科摩罗（目标3）。我们召集了观察方法的专家来进行因果推理， 药物流行病学，临床信息学，高血压管理和实施科学，并将 使用五个电子健康记录（EHR）数据库中超过1亿美国成年人的真实世界数据（即，Optum， 退伍军人事务部、哥伦比亚、耶鲁和Sentara Healthcare EHR数据库）。我们会雇用国家- 最先进的观察性研究方法，包括活性对照药物新用户设计、大规模 倾向评分建模、阴性对照结局实验和经验校准，以模拟RCT 并比较药物组合。这项研究是创新的，因为它将是第一项研究， 应用大量真实世界的数据集和最先进的观察研究方法， 探讨单药治疗基础上加用第二种降压药的有效性和安全性。的 拟议的研究是重要的，因为它提供了关键的证据，为RCT的决策提供信息， 高血压治疗升级和支持指南建议。

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.