Efficacy and Safety of Sacubitril/Valsartan in Maintenance Hemodialysis Patients With Heart Failure

Study Overview
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Brief Summary
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Sacubitril/valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction, and has been recently indicated as a new treatment option with a strong level of recommendation (class I, level of evidence B) in the main international guidelines. Cardiovascular disease (CVD) is the most common cause of death in end stage renal disease (ESRD) patients undergoing hemodialysis (HD). Hence, treatments to improve mortality and specifically cardiovascular outcomes in this population are greatly needed. So far, no data available about the efficacy and safety of sacubitril/valsartan in ESRD patients undergoing hemodialysis, although this medication was noted to be effective and comparably well tolerable in those with estimated glomerular filtration rate(eGFR) 20 to 60 mL/min/1.73 m2 in the United Kingdom Heart and Renal Protection-III trial. The purpose of this open label, randomized controlled study with prospective data collection is to assess the efficacy and safety of sacubitril/valsartan in maintenance hemodialysis patients with heart failure.

Official Title
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A Multi-center, Randomized, Open-label, Active-controlled, 12-week Study to Evaluate the Efficacy and Safety of Sacubitril/Valsartan in Maintenance Hemodialysis Patients With Heart Failure

Conditions
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Hemodialysis Complication, Heart Failure

Intervention / Treatment
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* Drug: Sacubitril / Valsartan Oral Tablet [Entresto]
* Drug: Valsartan 80mg Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent obtained before any study assessment is performed. End stage renal disease (ESRD) patients (eGFR<15ml/min/1.73m² as measured by the Chronic Kidney Disease Epidemiology Collaboration formula at screening) who have been receiving hemodialysis 3 times a week for at least 12 weeks before registration. Chronic heart failure (NYHA class ≥ II) with reduced ejection fraction, defined as known LVEF ≤ 50%. Mean sitting systolic blood pressure(msSBP)≥110 mmHg. Use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker for at least 2 weeks. Good compliance. Exclusion Criteria: Acute renal failure with hemodialysis. Isolated right heart failure owing to pulmonary disease, primary cause of dyspnea due to noncardiac, non-HF causes such as acute or chronic respiratory disorders. Systolic blood pressure lower than 100 mmHg at screening (<95 mmHg at the randomization visit). Previous history of intolerance to recommended target doses of angiotensin receptor blockers. Significant laboratory abnormalities at screening interfering with assessment of study drug safety or efficacy (such as serum potassium>5.5 or <3.5mmol/L, serum sodium<130mmol/L or alanine aminotransferase or aspartate aminotransferase>2 times the upper limit of the normal range) History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar chemical classes. History of angioedema. Any medications that have potential for drug-drug interaction with LCZ696 will not be allowed during the study. Pregnant female. Use of sacubitril/valsartan prior to week-2.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacubitril/valsartan<br>Patients in experimental group will receive sacubitril/valsartan with the recommended starting dose: 50mg twice daily (if previous angiotensin converting enzyme inhibitor(ACEI), ensure 36-hour washout period), after 2-4 weeks, the dose will be doubled to the target maintenance dose of 100mg twice daily(if tolerated) for 12 weeks. | Drug: Sacubitril / Valsartan Oral Tablet [Entresto]<br>* Patients in experimental group will receive sacubitril/valsartan with the recommended starting dose: 50mg twice daily (if previous ACEI, ensure 36-hour washout period), after 2-4 weeks, the dose will be doubled to the target maintenance dose of 100mg twice daily(if tolerated) for 12 weeks.<br>* Other names: LCZ696 100 mg tablet;|
| Active Comparator: Valsartan<br>Patients in active comparator group will receive Valsartan with an dose of 80 mg once daily. | Drug: Valsartan 80mg Tablet<br>* Patients in active comparator group will receive Valsartan with an dose of 80 mg once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular ejection fraction (LVEF) | Change from baseline in left ventricular ejection fraction (LVEF) between baseline and end of study | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| N terminal pro B type natriuretic peptide (NT-prpBNP) | Blood samples will be collected for analysis of concentration of N terminal pro B type natriuretic peptide (NT-proBNP) every 2 weeks. | 12 weeks | 
| Left ventricular end diastolic volume (LVEDV) | LVEDV is measured as baseline and after 12 weeks follow-up. | 12 weeks | 
| Left atrial volume (LAV) | LAV is measured as baseline and after 12 weeks follow-up. | 12 weeks | 
| The ratio of mitral early diastolic blood flow peak and mitral annulus velocity (E/E') | E/E' is measured as baseline and after 12 weeks follow-up. | 12 weeks | 
| Pulmonary Artery Pressure | Pulmonary Artery Pressure is measured as baseline and after 12 weeks follow-up. | 12 weeks | 
| Concentration of high-sensitivity serum troponin T | Blood samples will be collected for analysis of concentration of serum troponin every 4 weeks. | 12 weeks | 
| NYHA functional classification | NYHA functional classification is assessed from baseline and 12 weeks follow-up. | 12 weeks | 
| Minnesota Heart Failure Quality of Life Questionnaire (LiHFe) | Change in health status is assessed using the disease-specific Minnesota Heart Failure Quality of Life Questionnaire. | 12 weeks | 
| Systolic and diastolic blood pressure | Systolic and diastolic blood pressure will be measured every 2 weeks. | 12 weeks | 
| Concentration of postassium | Blood samples will be collected for analysis of concentration of postassium every 2 weeks. | 12 weeks | 
| Electrocardiogram(ECG) | ECG QT Interval analysis was performed at baseline and 12 weeks follow-up. | 12 weeks | 
| Estimated glomerular filtration rate(eGFR) | Change in estimated glomerular filtration rate(eGFR) | 12 weeks | 
| Incidence of Angioedema | Incidence of Angioedema during the study period 12 weeks. | 12 weeks | 
| Concentration of alanine aminotransferase or aspartate aminotransferase | Blood samples will be collected for analysis of concentration of alanine aminotransferase or aspartate aminotransferase every 2 weeks. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sacubitril/valsartan, valsartan, Hemodialysis, Heart failure