The aim of this study is to evaluate, in adults with HFrEF in Sri Lanka, the effects of an HFrEF polypill implementation strategy on the composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations, compared with usual care over a minimum of 12-months of follow-up. Primary outcome of the study: 1\) Composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations over study duration Secondary outcomes of the study: 1. Rate of cardiovascular disease mortality over study duration 2. Rate of recurrent heart failure hospitalizations over the study duration 3. Rate of all-cause mortality over the study duration 4. Change in left ventricular ejection fraction at 12-months and end of study assessed by transthoracic echocardiogram 5. Change in BNP levels at 12 months and end of study 6. Change in overall and domain specific health-related quality of life at 12-months and end of study assessed by a translated validated version of the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) 7. Change in physician-reported New York Heart Association class at 12-months and end of study 8. Adherence to guideline-directed medical therapy assessed by pill count and MARS-5 questionnaire at baseline, 1-, 6-, 12-months, and end of study. Persistence assessed as continuation of assigned therapy at each follow-up visit. Dose optimization assessed as proportion achieving target doses (Strength 3 of the polypill, or comparable individual GDMT doses in the comparator arm) at 6-, 12-months, and end of study. Safety outcomes: 1. Proportion of participants with serious adverse events according to Good Clinical Practice guidelines over study duration 2. Proportion of participants with adverse events of special interest over study duration 3. Proportion of participants with adverse events leading to HF drug discontinuation over study duration 4. Mean change from baseline to 12-months and end of study in serum potassium (mEq/L) 5. Mean change from baseline to 12-months and end of study in serum creatinine (mg/dL) Participants will be randomly assigned 1:1 stratified by sex and site to one of two groups, intervention (experimental arm) or usual care (control arm). 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. Both groups will be observed over a minimum of 12-months of follow-up to assess key outcomes.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
1,672
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 will receive their HFrEF medications through the pharmacy at the sites, where guideline-directed medical therapy are dispensed without charge to participants when available on the public hospital formulary.
The study intervention is a HFrEF polypill consisting of bisoprolol (beta-blocker), losartan (ARB), eplerenone (MRA), and dapagliflozin (SGLT2i) manufactured using the over-encapsulation method. There will be 3 strengths of the HFrEF polypill available: 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 mg + eplerenone 50 mg + dapagliflozin 10 mg.
National Hospital Kandy
Kandy, Central Province, Sri Lanka
RECRUITINGTeaching Hospital Kurunegala
Kurunegala, North Western Province, Sri Lanka
NOT_YET_RECRUITINGTeaching Hospital Jaffna
Jaffna, Northern Province, Sri Lanka
RECRUITINGRathnapura Teaching Hospital
Colombo, Ratnapura, Sri Lanka
NOT_YET_RECRUITINGNational Hospital Galle
Galle, Southern Province, Sri Lanka
RECRUITINGNational Hospital of Sri Lanka
Colombo, Western Province, Sri Lanka
NOT_YET_RECRUITINGUniversity Hospital - General Sir John Kotelawala Defence University
Colombo, Western Province, Sri Lanka
NOT_YET_RECRUITINGColombo South Teaching Hospital
Dehiwala, Western Province, Sri Lanka
RECRUITINGGampaha District General Hospital
Gampaha, Western Province, Sri Lanka
NOT_YET_RECRUITINGDistrict General Hospital Negombo
Negombo, Western Province, Sri Lanka
NOT_YET_RECRUITING...and 1 more locations
Composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations over study duration
Cardiovascular disease mortality is defined as death due to acute myocardial infarction, worsening heart failure, stroke, sudden cardiac death, arrhythmia, pulmonary embolism, cardiovascular procedures or their complications, other vascular causes, or any death of unknown cause unless a non-cardiovascular etiology is clearly established. HF hospitalization is defined as any unplanned hospitalization for at least 24 hours, for which the primary cause is heart failure, accompanied by objective evidence of decompensation and requiring initiation or intensification of HF-specific therapy, occurring after a documented period of clinical stability of at least 12 hours since the prior HF event. Adjudicated by the blinded Outcome Adjudication Committee.
Time frame: 1 month, 3 month, 6 month, 9 month, 12 month study visits, and every 3 months thereafter through study completion, an average of 18 months.
Rate of cardiovascular disease mortality over study duration
Cardiovascular disease mortality is defined as death due to acute myocardial infarction, worsening heart failure, stroke, sudden cardiac death, arrhythmia, pulmonary embolism, cardiovascular procedures or their complications, other vascular causes, or any death of unknown cause unless a non-cardiovascular etiology is clearly established. Adjudicated by the blinded Outcome Adjudication Committee.
Time frame: 1 month, 3 month, 6 month, 9 month, 12 month study visits, and every 3 months thereafter, through study completion, an average of 18 months.
Rate of recurrent heart failure hospitalizations over the study duration
HF hospitalization is defined as any unplanned hospitalization for at least 24 hours, for which the primary cause is heart failure, accompanied by objective evidence of decompensation and requiring initiation or intensification of HF-specific therapy, occurring after a documented period of clinical stability of at least 12 hours since the prior HF event. Adjudicated by the blinded Outcome Adjudication Committee.
Time frame: 1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
Rate of all-cause mortality over the study duration
All-cause mortality is defined as death due to any cause.
Time frame: 1 month, 3 month, 6 month, 9 month, 12 month visit, and thereafter every 3 months, through study completion, an average of 18 months.
Change in left ventricular ejection fraction at 12-months and end of study assessed by transthoracic echocardiogram
Time frame: Baseline, 12 months, and at study completion, an average of 18 months.
Change in BNP levels at 12 months and end of study
Time frame: Baseline, 12 months, and at study completion, an average of 18 months.
Change in overall and domain specific health-related quality of life at 12-months and end of study
Health-related quality of life (HRQoL) will be assessed by a translated validated Kansas City Cardiomyopathy Questionnaire-23 (KCCQ-23)
Time frame: Baseline, 12 months, and at study completion, an average of 18 months.
Change in physician-reported New York Heart Association class at 12-months and end of study
Time frame: Baseline, 12 months, and at study completion, an average of 18 months.
Adherence to guideline-directed medical therapy, persistence and dose optimization
Adherence to guideline-directed medical therapy assessed by pill count and MARS-5 questionnaire. Persistence assessed as continuation of assigned therapy at each follow-up visit. Dose optimization assessed as proportion achieving target doses (Strength 3 of the polypill, or comparable individual GDMT doses in the comparator arm) at 6-, 12-months, and end of study.
Time frame: Baseline, 1, 6, 12 months, and at study completion, an average of 18 months
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