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

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.

Grant Number: 5R00HL157687-04
NIH Institute/Center: NIH
Principal Investigator: ANUBHA AGARWAL