Open Label RCT for Chronic Severe AR : Entresto vs. CCB/ARB

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy of sacubitril-valsartan compared to the combination of ARB/CCB on left ventricular remodeling in patients with chronic aortic valve regurgitation.

Detailed Description
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After being informed consent about the study and potential risk, all patients giving written informed consent will undergo a 1 month screening period to determine eligibility for study entry. At week 0, patients who meet the eligibility requirements will be randomized in an open-label manner in a 1:1 ratio to sacubitril-valsartan or amlodipine/losartan.

Official Title
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Multicenter, Randomized, Open-label Trial to Assess the Efficacy of Sacubitril/Valsartan vs. Amlodipine/Losartan on Left Ventricular Remodeling in Patients With Chronic Severe Aortic Regurgitation

Conditions
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Aortic Valve Insufficiency

Intervention / Treatment
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* Drug: Sacubitril-valsartan
* Drug: Amlodipine-losartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant over 20 years of age who has not been hospitalized for heart failure Participant with hypertension or systolic blood pressure 125 mmHg or higher NYHA I Participant with chronic severe aortic regurgitation (VCW >0.6cm) Participant with AV regurgitant volume ≥ 60mL or effective regurgitant orifice area ≥ 0.3 cm2 Participant with left ventricular ejection fraction ≥ 55% Exclusion Criteria: A history of hypersensitivity or allergy to clinical trial drugs or similar compounds or ARB/NEP inhibitors History of angioedema Patients with an ascending aorta dilated by more than 55 mm Patients with aortic valve insufficiency due to hereditary aortic disease (Marfan syndrome, Ehlers-Danlos syndrome) Patients with moderate to severe aortic stenosis Patients with claustrophobia or with metallic implants unsuitable for magnetic resonance imaging History of acute heart failure within 6 weeks and dyspnea of NYHA II or higher Symptomatic hypotension or SBP < 100 mmHg at screening Patients with renal failure (Estimated GFR < 30 mL/min/1.73 m2) or on dialysis Significant increase in blood potassium level (Potassium > 5 mmol/L) Blood AST or ALT value is more than twice the upper limit of normal or symptoms and signs of cirrhosis (history of hepatic coma, history of esophageal varices, history of symptomatic ascites) In case of acute coronary syndrome, stroke, thoracic surgery, and percutaneous coronary angioplasty within 3 months If aortic valve surgery is scheduled within the next 6 months In case of severe mitral valve disease Patients with primary hyperaldosteronism If a woman of childbearing potential has not used double contraception Women who are currently pregnant or lactating When it is judged that there are clinically significant abnormalities in physical examination, diagnostic examination, electrocardiogram, etc. at the time of the screening visit

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 90 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 |
| --- | --- |
| Active Comparator: Sacubitril-Valsartan Group<br>Participant start Sacubitril/Valsartan tablet 50mg twice a day and uptitrate to 100mg twice a day. Participants take the maximum dose considering blood pressure for a total of 48 weeks. | Drug: Sacubitril-valsartan<br>* 50mg 100mg twice daily<br>* Other names: Entresto;|
| Placebo Comparator: Amlodipine-Losartan group<br>Participant start amlodipine/losartan 25/2.5mg once a day and uptitrate to 5/100mg once a day. Participants take the maximum dose considering blood pressure for a total of 48 weeks. | Drug: Amlodipine-losartan<br>* amlodipine/losartan 2.5/25mg   5/100mg once daily<br>* Other names: Amosartan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of left ventricular end-diastolic volume index from baseline to 12 months follow-up | Change = [LVEDV on CMR at 12 months]-[LVEDV on CMR at baseline] | Baseline and month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of regurgitant volume of aortic valve regurgitation from baseline to 12 months follow-up. | Change = [regurgitant volume at 12 months]-[regurgitant volume at baseline] | Baseline and month 12 | 
| Change of EROA of aortic valve regurgitation from baseline to 12 months follow-up. | Measurement of regurgitant volume of AR is derived from Doppler imaging on echocardiography. Change = [regurgitant volume at 12 months]-[regurgitant volume at baseline] | Baseline and month 12 | 
| Change of LV end-systolic volume from baseline to 12 months follow-up. | Change = [LVEDV at 12 months]-[LVEDV at baseline] | Baseline and month 12 | 
| Holodiastolic flow reversal in the proximal abdominal aorta and descending thoracic aorta from baseline to 12 months follow-up | presence or absence of holodiastolic flow reversal in the proximal abdominal and descending thoracic aorta on echocardiography | Baseline and month 12 | 
| Change of NT-proBNP level from baseline to 12 months follow-up. | Change =[NT-proBNP at 12 months]-[NTproBNP at baseline] | Baseline and month 12 | 
| Aortic valve replacement or repair operation | Any surgical event for correction of AR | During 12 months after enrollment |