Does a HFrEF polypill-based care strategy for HFrEF reduce the composite outcome of cardiovascular mortality and heart failure hospitalizations compared with usual care over at least 12 months of follow-up among adults with HFrEF in Sri Lanka?

Study sites: The National Hospital of Sri Lanka, Colombo North Teaching Hospital, Teaching Hospital Jaffna, Colombo South Teaching Hospital, National Hospital Kandy, University Hospital General Sir John Kotelawala Defence University, National Hospital Galle, Teaching Hospital Kurunegala, Negombo District General Hospital

Randomization: Randomization will be done through a randomization list for equal allocation (1:1) to intervention arm and comparator arm through the electronic data capturing system REDCap. Neither the participant nor the study team will know beforehand to which treatment group the participant will be allocated, as it will be determined by a computer generated random sequence.

Intervention Experimental arm: The study intervention will be a HFrEF polypill consisting of bisoprolol (beta-blocker), losartan (ARB), eplerenone (MRA), and dapagliflozin (SGLT2i) manufactured using the over-encapsulation method and will undergo 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. HFrEF polypill strengths: Strength 1: bisoprolol 2.5 mg + losartan 25 mg + eplerenone 25 mg + dapagliflozin 10 mg Strength 2: bisoprolol 5 mg + losartan 50 mg + eplerenone 25 mg + dapagliflozin 10 mg Strength 3: bisoprolol 10 mg + losartan 100 + eplerenone 50 mg + dapagliflozin 10 mg

Comparator group: Participants in the control arm will receive the standard of care by their healthcare providers. Healthcare providers will be encouraged to treat all participants according to international and local clinical practice guidelines.

Participants with HFrEF will be recruited from in-patient departments prior to hospital discharge or from outpatient departments. Once enrolled and after a baseline visit, participants will complete 1-month, 3-month, 6-month, 9-month and 12-month study visits and thereafter, every 3 months by telephone or in-person until study end to assess outcomes

1. Both male and female adults ( 18 years or older)
2. Diagnosis of heart failure with reduced ejection fraction (HFrEF) including a) clinical symptoms or clinical signs or natriuretic peptide elevation AND b) echocardiographic or other evidence of reduced left ventricular ejection fraction (EF less than or equal to 40%)
3. New York Heart Association Class II, III, or IV symptoms

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 5 mEq/L.
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 a highly 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 12 months