Heart Failure With Reduced Ejection Fraction Polypill in Sri Lanka: A Multi-Center Type I Hybrid Randomized Controlled Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 1,672
- 试验地点
- 21
- 主要终点
- Composite rate of cardiovascular disease mortality and recurrent HF hospitalizations
研究概览
简要总结
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:
- Rate of cardiovascular disease mortality over study duration
- Rate of recurrent heart failure hospitalizations over the study duration
- Rate of all-cause mortality over the study duration
- Change in left ventricular ejection fraction at 12-months and end of study assessed by transthoracic echocardiogram
- Change in BNP levels at 12 months and end of study
- 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)
- Change in physician-reported New York Heart Association class at 12-months and end of study
- 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:
- Proportion of participants with serious adverse events according to Good Clinical Practice guidelines over study duration
- Proportion of participants with adverse events of special interest over study duration
- Proportion of participants with adverse events leading to HF drug discontinuation over study duration
- Mean change from baseline to 12-months and end of study in serum potassium (mEq/L)
- 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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adults (≥18 years old)
- •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 left ventricular ejection fraction (EF ≤40%)
- •New York Heart Association Class II, III, or IV symptoms
排除标准
- •Known contraindication to any of the HFrEF polypill components (e.g., advanced renal disease, bradycardia, allergy, amongst others).
- •Significant renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2).
- •Raised serum potassium >5 mEq/L.
- •Symptomatic hypotension or systolic BP <100 mmHg as per the average of last 2 of the 3 measurements at visit
- •Symptomatic bradycardia or second or third-degree heart block without a pacemaker on ECG review at visit
- •History of type 1 diabetes mellitus.
- •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).
- •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.
- •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.
- •Participant's responsible physician believes it is not appropriate for participant to participate in the study.
- •Inability or unwillingness to provide written informed consent.
- •Involvement in the planning and/or conduct of the study.
- •Unable to complete study procedures and/or plan to move out of the study site area in the next 12 months.
研究组 & 干预措施
HFrEF Polypill
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
Every intervention participant will be established on the highest tolerated strength of the HFrEF polypill, with Strength 3 as the target dose. Following initiation at the strength matched to the participant's background guideline-directed medical therapy, the polypill strength will be advanced by one level at each scheduled study visit aligned with the initiation and titration protocol.
干预措施: HFrEF Polypill (Drug)
Usual Care
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.
干预措施: Usual Care (Other)
结局指标
主要结局
Composite rate of cardiovascular disease mortality and recurrent HF hospitalizations
时间窗: 1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.
Cardiovascular disease mortality is defined as death due to acute myocardial infarction, worsening heart failure, stroke, sudden cardiac death, arrhythmia, pulmonary embolism, cardiovascular procedures, vascular causes, or any death of unknown cause unless a non-cardiovascular etiology is clearly established. Recurrent HF hospitalizations is defined as any hospitalization in which the primary cause is worsening 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.
Composite rate of cardiovascular disease mortality and recurrent heart failure hospitalizations over study duration
时间窗: 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.
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.
次要结局
- Rate of cardiovascular disease mortality(1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.)
- Rate of recurrent heart failure hospitalizations(1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.)
- Rate of all-cause mortality(1 month, 3 months, 6 months, 9 months, 12 months, through study completion, an average of 18 months.)
- Change in left ventricular ejection fraction(Baseline, 12 months)
- Natriuretic peptide levels change(Baseline, 12 months)
- Change in overall and domain specific health-related quality of life(Baseline, 12 months)
- Physician-reported New York Heart Association class change(Baseline, 12 months)
- Adherence to guideline-directed medical therapy(Baseline, 1 month, 3 months, 6 months, 9 months, 12 months)
- Adherence to Guideline-Directed Medical Therapy(Baseline, 1 month, 3 month, 6 month, 9 month, 12 month)
- Persistence to Guideline-Directed Medical Therapy(Baseline, 1 month, 3 month, 6 month, 9 month, 12 month)
- Optimization of Guideline-Directed Medical Therapy(6 and 12 months)
- Change in BNP levels at 12 months and end of study(Baseline, 12 months, and at study completion, an average of 18 months.)
- Rate of cardiovascular disease mortality over study duration(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(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(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(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(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(Baseline, 12 months, and at study completion, an average of 18 months.)
- Adherence to guideline-directed medical therapy, persistence and dose optimization(Baseline, 1, 6, 12 months, and at study completion, an average of 18 months)
研究者
Anubha Agarwal
Assistant Professor of Medicine
Washington University School of Medicine