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.

PROJECT NARRATIVE Heart failure is a leading public health problem, especially in low- and middle-income countries such as India, where clinical outcomes remain poor. Medications that reduce morbidity and mortality for patients with heart failure with reduced ejection fraction remain widely underutilized, despite decades-old evidence for their benefit. This proposal will develop, implement, and evaluate a novel late-stage implementation strategy of a polypill for patients with heart failure with reduced ejection fraction in India with the aim of changing the global paradigm of heart failure care.