Sacubitril-Valsartan in Heart Failure With Preserved Ejection Fraction and Secondary Mitral Valve Regurgitation

Study Overview
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Brief Summary
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The main objective of this study is to assess the hemodynamic effects of sacubitril-valsartan in patients with heart failure with preserved ejection fraction and at least moderate atrial functional mitral regurgitation (AFMR), using a combination of cardiopulmonary exercise testing and stress echocardiography (referred to as CPETecho) at baseline and after six months of therapy. The patients included in this study will be randomly assigned to receive sacubitril-valsartan as an adjunct to standard medical care, as opposed to adhering solely to the standard of care which involves sodium-glucose cotransporter-2 (SGLT-2) inhibitor and mineralocorticoid receptor antagonist (MRA).

Official Title
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Sacubitril-Valsartan in Heart Failure With Preserved Ejection Fraction and Secondary Mitral Valve Regurgitation

Conditions
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Heart Failure With Preserved Ejection Fraction, Functional Mitral Regurgitation

Intervention / Treatment
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* Drug: Sacubitril-valsartan
* Drug: Standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years. New York Heart Association class II to IV. Written informed consent. Left ventricular (LV) ejection fraction ≥ 50%. Objective evidence of cardiac structural and/or functional abnormalities consistent with the presence of LV diastolic dysfunction/raised LV filling pressures, including raised natriuretic peptides. ≥ moderate functional MR assessed by transthoracic echocardiography within the previous year. Exclusion Criteria: Systolic blood pressure < 100 mmHg. Potassium ≥ 5.2 mmol/L. Estimated Glomerular Filtration Rate ≤ 25 ml/min/1.73m². History of angioedema or unacceptable side effects during receipt of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). Structural mitral valve disease and previous or planned mitral valve intervention. Already receiving angiotensin receptor neprilysin inhibitor (ARNI, sacubitril-valsartan) therapy. Severe comorbid condition limiting life expectancy < 24 months or inability to perform a maximal CPETecho. Myocardial infarction, unstable angina, coronary revascularization within 12 weeks prior enrolment. Severe aortic, tricuspid or pulmonary valve disease. Pregnancy, lactation, or use of any method of contraception that is not highly effective.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 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
Interventional Model Description: Multicenter, Investigator-initiated, Prospective, Randomized trial with Open Blinded Endpoint
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Intervention arm<br>Sacubitril-Valsartan (target dose 97/103 mg twice daily) on top of standard of care (including SGLT-2 inhibitor and MRA) | Drug: Sacubitril-valsartan<br>* sacubitril-valsartan (target dose 97/103 mg twice daily)<br>Drug: Standard of care<br>* including SGLT-2 inhibitor and MRA<br>|
| Placebo Comparator: Control arm<br>Standard of care (including SGLT-2 inhibitor and MRA) | Drug: Standard of care<br>* including SGLT-2 inhibitor and MRA<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean pulmonary arterial pressure over cardiac output slope assessed by CPETecho |  | Six months of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in peak oxygen uptake |  | Six months of treatment | 
| Change in mitral effective regurgitant orifice area (EROA) |  | Six months of treatment | 
| Change in natriuretic peptide levels |  | Six months of treatment | 
| Change in left atrial volume (LAVI) |  | Six months of treatment | 
| Change the minute ventilation over carbon dioxide production slope |  | Six months of treatment | 
| Change in patient reported outcomes (Kansas City Cardiomyopathy Questionnaire, KCCQ-12) |  | Six months of treatment | 
| Change in left atrial function (peak atrial longitudinal strain, PALS) |  | Six months of treatment |