Heart failure is a leading global public health problem and clinical outcomes of patients with heart failure with reduced ejection fraction (HFrEF) remain poor (123). Guideline-directed medical therapy (GDMT) including beta-blockers, renin-angiotensin-system inhibitors, mineralocorticoid receptor antagonists, and sodium glucose co-transporter 2 inhibitors improve mortality and morbidity of HFrEF patients (4). Observational registries in India including the Trivandrum Heart Failure Registry and the National Heart Failure Registry of India demonstrate less than half of eligible HFrEF patients receive GDMT, revealing a key target for intervention to improve clinical outcomes. Increasing GDMT rates is one of the most cost-effective interventions and a global health system priority (5). Increasing GDMT rates also aligns with the national priorities of heart failure research in India outlined by leaders in medicine and science representing the Indian Council of Medical Research, National Centre for Advanced Research and Excellence in Heart Failure, International Academy of Cardiovascular Sciences, and the Heart Failure Association of India (6).

A HFrEF polypill-based implementation strategy has been proposed to increase GDMT rates and subsequent mortality and morbidity of undertreated HFrEF patients in India and globally (78). There are ongoing clinical trials in the United States (NCT06029712, NCT04633005) and planned clinical trials in South Asia (SLCTR/2024/003) to evaluate the efficacy and safety of HFrEF polypills. Successful implementation of novel innovations such as HFrEF polypills requires identification of key determinants including facilitators and barriers, contextually-relevant implementation strategies, and evaluation of the process of implementation (9). Mixed methods research leveraging insights from both qualitative and quantitative data is particularly useful in this context. As part of formative research for a National Heart, Lung, and Blood Institute funded randomized trial of a HFrEF polypill in South Asia, we aim to understand diverse perspectives on heart failure care and context of a HFrEF polypill-based implementation strategy using mixed methods to create an Implementation Research Logic Model to inform future research to improve heart failure trials and care in South Asia and beyond (8).

We conducted a convergent parallel mixed methods study integrating quantitative data from stakeholder surveys and qualitative data from key informant in-depth interviews to explore physician, nurse, pharmacist, and patient perspectives on a HFrEF polypill implementation strategy in India from January 2021 to April 2021. The study was approved by the institutional review board at Northwestern University (Chicago, United States), ethics committee at Cardiological Society of India-Kerala Chapter (Kochi, India), and ethics committee at Westfort Hi-Tech Hospital (Thrissur, Kerala). All participants provided consent prior to participation in the study, and their confidentiality was ensured throughout the research process. The study team includes members from India and the United States with diverse expertise including clinical cardiology, public health, qualitative research, and implementation science.

This convergent parallel mixed methods study provides insights into the facilitators, barriers, and context of heart failure care in India, and explores physician, nurse, pharmacist, and patient perspectives on a HFrEF polypill implementation strategy in India. Physicians and cardiologists representing most states and union territories in India noted moderate acceptability, appropriateness, and feasibility of the proposed HFrEF polypill implementation strategy. In-depth interview participants highlighted numerous relative advantages of the HFrEF polypill innovation including potential to simplify medication regimens and improve patient adherence. Key relative disadvantages elucidated include concerns about side effects and interruption of multiple GDMT medications due to polypill discontinuation for side effects or hospitalizations. The Implementation Research Logic Model integrates both quantitative and qualitative results to provide a theoretical framework for future HFrEF polypill research in South Asia.

The National Heart Failure Registry of India is a facility-based clinical registry of 10,851 consecutive patients hospitalized with acute decompensated heart failure in 53 hospitals across 21 different states. Of the eligible HFrEF patients in the registry, only 47.5% received GDMT (15). Importantly, those who did not receive GDMT experienced higher mortality compared to patients who received GDMT, revealing a key target for intervention with a HFrEF polypill-based implementation strategy. Previous qualitative research on heart failure care in Kerala, India identified patient non-adherence to GDMT as well as challenges with initiation and titration of GDMT by physicians due to busy clinical practices as important barriers to optimal heart failure care which aligns with our research findings (1617). An interrupted time series study evaluating a hospital-based quality improvement intervention including discharge checklists, audit-and-feedback mechanisms, and patient education demonstrated that patients had 70% higher odds of receiving GDMT at discharge in the intervention period compared to the control period (41% vs 28%, adjusted odds ratio [aOR] = 1.70, 95% CI 1.17, 2.46) (18). Despite this improvement, more than half of eligible patients with HFrEF remained sub-optimally treated suggesting additional implementation strategies are needed to improve care for this population. Future data from an ongoing trial evaluating collaborative care models delivering integrated heart failure care led by a trained nurse with support from physicians, dieticians, physiotherapists, and clinical psychologists to improve clinical outcomes of patients with HFrEF will inform outpatient and longitudinal heart failure care in India (19). A HFrEF polypill implementation strategy could be an important complement to existing and future strategies to improve GDMT use and HF care in South Asia.

Cost was, highlighted as a key characteristic of HFrEF polypills, identified by physicians as being important to their patients in considering acceptability, appropriateness, and feasibility of a HFrEF polypill-based implementation strategy in India. There is wide variability in availability, price, and affordability of GDMT in both public and private sectors of low- and middle-income countries (20). However, the robust generic drug market in India has led to greater accessibility and affordability of essential medicines including GDMT for patients with heart failure. A HFrEF polypill-based implementation strategy will need to be cost-effective to be implemented, adopted, scaled, and sustained. This study highlights the use of existing, but sub-optimal, fixed-dose combinations such as ACE-I and beta-blocker by physicians in India demonstrating acceptability of combination polypill therapy for the treatment of HFrEF patients, which has important policy implications and aligns with previous research on polypills for cardiovascular disease in India. Important considerations for future trials evaluating a HFrEF polypill implementation strategy include accompanying laboratory monitoring protocols to emphasize safety and initiation, titration, and maintenance protocols to guide physicians. Type I or Type II hybrid-effectiveness trial designs which emphasize a priori efficacy, effectiveness, and implementation process are ideally suited to study a HFrEF polypill-based implementation strategy in India and other undertreated populations globally (21).

This study has several strengths including the convergent parallel mixed methods data collection integrating both quantitative data from stakeholder surveys across India to members of the Cardiological Society of India (the largest professional association of cardiologists in the country) and qualitative data from key informant in-depth interviews to understand diverse perspectives on a HFrEF polypill-based implementation strategy to inform future clinical trial design (8). Furthermore, this is one of the few studies harnessing qualitative research methods to understand perspectives from patients with heart failure in South Asia, strengthening the applicability of our findings. Key limitations include limited sample size for the electronic stakeholder survey, greatest representation of private practice cardiologists in the survey, and selection of majority of participants for the key informant in-depth interviews from the state of Kerala in South India which could introduce selection bias. In addition, in-depth interview transcripts were not returned to participants for comments and/or corrections. Despite these limitations, our study is the first, to our knowledge, to understand diverse perspectives on a HFrEF polypill-based implementation strategy to directly assist future research in South Asia.

This convergent parallel mixed methods study demonstrates that a HFrEF polypill-based implementation strategy is considered moderately acceptable, feasible, and appropriate among healthcare providers in India. We identified facilitators and barriers to design contextually relevant implementation strategies including HFrEF polypills outlined in an Implementation Research Logic Model to inform future research to improve heart failure trials and care in South Asia and beyond.

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