Primary Outcome:

Composite of cardiovascular death or recurrent heart failure hospitalization over study duration

Secondary Outcomes:

Cardiovascular death over study duration Recurrent heart failure hospitalizations over study duration All-cause mortality over study duration Change in left ventricular ejection fraction from baseline to 12 months by echocardiogram.

Change in natriuretic peptide levels from baseline to 12 months. Change in health-related quality of life from baseline to 12 months using the Kansas City Cardiomyopathy Questionnaire.

Change in New York Heart Association functional class from baseline to 12 months.

Adherence to heart failure medications assessed by pill count and questionnaire, medication persistence assessed as continuation of assigned therapy after initiation, and dose optimization assessed as proportion achieving final/target doses over study duration

Safety Outcomes:

Proportion of participants with serious adverse events or sudden unexpected serious adverse reaction over study duration Proportion with adverse events of special interest (symptomatic hypotension, diabetic ketoacidosis, severe hypoglycemia, lower limb amputation, hyperkalemia, or worsening kidney function) over study duration Proportion of participants who stop study drug because of adverse events over study duration Change in serum potassium over study duration Change in serum creatinine over study duration

Participants will be randomly assigned to one of two groups, intervention or usual care. The intervention group will be given four guideline-recommended medications for heart failure with reduced ejection fraction, combined in one over-encapsulated pill, with three dose strength options (at the discretion of their treating physician). Both groups will be observed over a minimum of 12-months of follow-up to assess their medication adherence, clinical symptoms, laboratory measures, health related quality of life, and need for medication adjustment amongst other measures.

The study intervention will be a heart failure with reduced ejection fraction (HFrEF) polypill consisting of bisoprolol (beta-blocker), losartan (ARB), eplerenone (MRA), and dapagliflozin (SGLT2i) manufactured using the over-encapsulation method and will undergo extensive stability testing to ensure quality. There will be 3 strengths of the HFrEF polypill available to facilitate initiation with low dose to prioritize clinical tolerability and laboratory safety and titration to higher doses of the HFrEF polypill. The dose of initiation and titration will be at the investigator's discretion. The HFrEF polypill will be delivered by licensed physicians responsible for managing heart failure at participating sites. Eligible providers must have formal medical qualifications in Sri Lanka and be actively involved in the care of patients with HFrEF. This includes cardiologists, internists, or general practitioners with experience in heart failure management. All participating physicians will receive standardized training on the study protocol including titration protocol, HFrEF polypill composition, and guidance for patient counseling prior to trial initiation to ensure consistent and accurate delivery of the intervention. Participants receiving the HFrEF polypill will also receive a "HFrEF polypill card" that delineates the drugs and doses included in the HFrEF polypill combination and contact information for the local study team in case of hospitalization at another facility.

HFrEF polypill combinations by strength:

HFrEF polypill strength 1: bisoprolol 2.5 mg + losartan 25 mg + eplerenone 25 mg + dapagliflozin 10 mg HFrEF polypill strength 2: bisoprolol 5 mg + losartan 50 mg + eplerenone 25 mg + dapagliflozin 10 mg HFrEF polypill strength 3: bisoprolol 10 mg + losartan 100 + eplerenone 50 mg + dapagliflozin 10 mg

Participants in the comparator control group will receive usual care from their healthcare providers. Providers will be encouraged to treat all participants according to international and local clinical practice guidelines. Participants in the intervention group will be provided with the HFrEF polypill by the study, and participants in the control group will be provided HFrEF medications through the pharmacy at the public hospital site(s) in Sri Lanka where they are generally free of cost.

Inclusion Criteria:

1. Adults (≥18 years old)
2. Diagnosis of heart failure with reduced ejection fraction (HFrEF) including clinical symptoms or clinical signs or natriuretic peptide elevation AND echocardiographic or other evidence of reduced ejection fraction (EF≤40%)
3. New York Heart Association Class II, III, or IV symptoms

Exclusion Criteria:

1. Known contraindication to any of the HFrEF polypill components (e.g., advanced renal disease, bradycardia, allergy, amongst others).
2. Significant renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2)
3. Raised serum potassium >5 mEq/L.
4. Symptomatic hypotension or systolic BP <100 mmHg as per the average of last 2 of the 3 measurements at visit 1.
5. Symptomatic bradycardia or second or third-degree heart block without a pacemaker on ECG review at visit 1.
6. History of type 1 diabetes mellitus.
7. Women who are pregnant, breastfeeding or of childbearing potential and are not using and do not plan to continue using medically acceptable form of contraception throughout the study (pharmacological or barrier methods).
8. Concomitant illness, physical impairment or mental condition which in the opinion of the study team/ primary physician could interfere with the conduct of the study including outcome assessment.
9. Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Patients in observational, natural history or epidemiological studies not involving an intervention are eligible.
10. Participant's responsible physician believes it is not appropriate for participant to participate in the study.
11. Inability or unwillingness to provide written informed consent.
12. Involvement in the planning and/or conduct of the study.
13. Unable to complete study procedures and/or plan to move out of the study site area in the next 2 months.

When the study is over, research findings will be available at www.ClinicalTrials.gov and Sri Lanka Clinical Trials Registry. Laboratory results will be shared with participants and their health care providers. The research findings will also be published in the form of research articles or presented at scientific meetings.