Heart Failure Polypill in India: A Late-Stage Implementation Strategy

项目总结/摘要 心力衰竭（HF）是一个主要的全球性公共卫生问题。HF的负担在低和中等水平增加， 收入国家和临床结果仍然很差。指南指导的药物治疗（结合 不同药物类别的不同药物）改善了HF患者的发病率和死亡率， 射血分数降低（HFrEF）。尽管有这些高质量的证据，指南指导的药物治疗 在全球范围内，特别是在印度，仍然普遍未得到充分利用。这一差距是干预的一个关键目标 拯救生命Agarwal博士的K99/R 00提案旨在通过改变 序贯启动的多药治疗中治疗不足的HFrEF患者的治疗模式， 一种新的晚期实施策略的滴定指南导向的药物治疗HFrEF复方制剂 包括β-阻断剂、血管紧张素受体阻断剂和盐皮质激素受体拮抗剂。首先，博士。 Agarwal将进行形成性混合方法研究，包括HF治疗共识会议， 焦点小组讨论，以指导印度基于HFrEF息肉的战略的制定。第二，她会 评估与常规治疗相比，HFrEF复方制剂实施策略是否会减少心血管疾病 使用多中心I型研究，在印度成人HFrEF患者中，12个月时的疾病死亡率和HF住院率 混合随机临床试验设计。她还将评估HFrEF复方制剂实施的效果 重要次要结局的策略，包括药物依从性、HF疾病严重程度标志物， 健康相关的生活质量和通过不良事件测量的安全性。最后，Agarwal博士将应用以下方法： 过程评价，以评估HFrEF复方制剂在印度的实施成果，这是转化的关键一步 在全球范围内得到更广泛的使用。K99阶段还将提供必要的方法 培训Agarwal博士在R 00阶段过渡到独立研究。Agarwal博士建议培训 1）实施科学方法，2）临床试验方法，包括创新平台试验设计，以及 3)全球药理学临床试验的监管科学。这次K99培训将使她成为一名领导者 全球心力衰竭实施科学的临床试验员。Agarwal博士的全球导师团队由Dr. Mark霍夫曼（美国西北大学），心血管专家提供关键的共同指导 Dorairaj Prabhakaran博士（慢性病中心 Control，印度）和Anushka Patel（乔治全球健康研究所，澳大利亚）。这个导师团队 在主要合作者（赫什霍恩博士、莫哈南博士、乔利诺博士）和顾问（扬西博士、埃尔德-琼斯博士）的支持下， 将确保科学上的成功，并监督候选人在其相关专业领域的高级培训。 这个K99/R 00提案支持Agarwal博士的过渡，以启动一个独立的职业生涯，作为未来的领导者， 全球性的后期转化心血管研究。重要的是，该提案有可能 通过简化印度和其他环境（包括美国）的护理来改变HF护理。

PROJECT SUMMARY/ABSTRACT Heart failure (HF) is a leading global public health problem. The burden of HF is increasing in low- and middle- income countries and clinical outcomes remain poor. Guideline-directed medical therapy (a combination of distinct medications from disparate drug classes) improves morbidity and mortality in patients with HF with reduced ejection fraction (HFrEF). Despite this high-quality evidence, guideline-directed medical therapy remains widely underutilized globally and specifically in India. This gap represents a key target for intervention to save lives. Dr. Agarwal’s K99/R00 proposal aims to substantially simplify HF management by shifting the treatment paradigm for undertreated patients with HFrEF from multi-drug therapy with sequential initiation and titration to a novel late-stage implementation strategy of a HFrEF polypill of guideline-directed medical therapy including a beta-blocker, angiotensin receptor blocker, and mineralocorticoid receptor antagonist. First, Dr. Agarwal will conduct formative mixed methods research including a HF treatment consensus meeting and focus group discussions to guide development of the HFrEF polypill-based strategy in India. Second, she will evaluate whether, compared to usual care, a HFrEF polypill implementation strategy will reduce cardiovascular disease mortality and HF hospitalizations at 12 months in adults with HFrEF in India using a multi-center, type I hybrid randomized clinical trial design. She will also assess the effect of the HFrEF polypill implementation strategy on important secondary outcomes including medication adherence, markers of HF disease severity, health-related quality of life, and safety measured by adverse events. Finally, Dr. Agarwal will apply methods of process evaluation to assess implementation outcomes of the HFrEF polypill in India, a key step in translating evidence generated into broader use globally. The K99 phase will also provide essential methodological training for Dr. Agarwal to transition to research independence in the R00 phase. Dr. Agarwal proposes training in 1) implementation science methods, 2) clinical trial methods including innovative platform trial designs, and 3) regulatory science for global pharmacological clinical trials. This K99 training will prepare her to be a leading clinical trialist in global heart failure implementation science. Dr. Agarwal’s global mentorship team is led by Dr. Mark Huffman (Northwestern University, US), with key co-mentorship provided by experts in cardiovascular clinical trials in low- and middle-income countries, Drs. Dorairaj Prabhakaran (Centre for Chronic Disease Control, India) and Anushka Patel (The George Institute for Global Health, Australia). This mentorship team, supported by key collaborators (Drs. Hirschhorn, Mohanan, Ciolino) and advisors (Drs. Yancy, Lloyd-Jones), will ensure scientific success and oversee the candidate’s advanced training in their relative areas of expertise. This K99/R00 proposal supports Dr. Agarwal’s transition to launch an independent career as a future leader in global, late-stage translational cardiovascular research. Importantly, this proposal has the potential to transform HF care through simplified care in India and other settings, including in the United States.