Evaluation of Safety and Efficacy of Empagliflozin and Sacubitril/Valsartan for CHF With Reduced Ejection Fraction in ACHD 

Study Overview
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Brief Summary
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The treatment of adult patients with congenital heart disease (ACHD) and heart failure (HF) represents a great challenge since, to date, there is no standardized guideline for this specific population. Although new treatments for HF have been proposed, such as Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors and neprilisin and angiotensin receptor inhibitors, the benefit of these drugs in patients with HF associated with congenital heart disease in adults has not yet been demonstrated. For this reason, this study pretends to evaluate the efficacy of empagliflozin and sacubitril/valsartan in this population.

Detailed Description
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A 12-week randomized, open label, active-controlled trial to explore the effects of once-daily empagliflozin 10 mg and/or sacutril/valsartan 49 mg/51 mg in the reduction of systemic ventricular volumes (end-diastolic and end-systolic) in adult patients with HF associated with congenital heart disease.

Official Title
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An Open-label Clinical Trial to Evaluate the Safety and Efficacy of Empagliflozin and Sacubitril/Valsartan in Adult Patients With Chronic Heart Failure With Reduced Ejection Fraction Associated With Congenital Heart Disease

Conditions
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Congenital Heart Disease, Heart Failure, Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Sacubitril 49 MG / Valsartan 51 MG [Entresto] BID
* Drug: Empagliflozin 10 MG OD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: NYHA functional class II-IV Diagnosis of CHD: repaired, palliated or without previous treatment Systemic ventricular ejection fraction <40% Without unplanned hospital admissions within 3 months prior to randomization The participant is willing and able to give informed consent for participation in the study Exclusion Criteria: Pregnant and postpartum women Breastfeeding women during the study History of drug allergy to any SGLT-2 inhibitor and/or sacubitril/valsartan Previous administration of a drug regimen including an SGLT-2 inhibitor and/or sacubitril/valsartan Intellectual or physical disability that impedes the subject to perform the 6 minute walk-test Patients with any contraindication to SGLT-2 inhibitor and/or sacubitril/valsartan Medical history of myocardial infarction, cardiac surgery or fulminant myocarditis within the last three months Medical history of type 1 diabetes mellitus Medical history of hypertensive crisis in the previous 6-months Medical history of cardiogenic shock or heart failure decompensation in the previous 6-months Medical history of heart transplantation

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
Interventional Model Description: Open-label randomized clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional treatment of Heart failure and Sacubitril/Valsartan<br>Patients will receive conventional treatment consisting of spironolactone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours) or eplerenone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours); beta-blockers: bisoprolol 1.5 mg orally every 24 hours (maximum dose 10 mg every 24 hours) or metoprolol succinate 12.5 mg every 24 hours orally (maximum dose 200 mg every 24 hours) or carvedilol 3125 mg every 24 hours (maximum dose 25 mg every 24 hours) or ivabradine 5 mg every 12 hours (maximum dose 7.5 mg every 12 hours); diuretics: furosemide 20 to 400 mg orally every 24 hours or bumetanide 1 to 15 mg orally every 24 hours and/or chlorthalidone 25 mg orally every 24 hours. Additionally, patients will receive Sacubitril/Valsartan, with the intention to titrate up to 49 mg/51 mg orally every 12 hours. | Drug: Sacubitril 49 MG / Valsartan 51 MG [Entresto] BID<br>* This group of patients will receive the conventional treatment of heart failure according to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and Sacubitril/Valsartan as an active comparator.<br>* Other names: Entresto;|
| Experimental: Conventional treatment plus Empagliflozin and Sacubitril/valsartan<br>Patients will receive conventional treatment consisting of spironolactone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours) or eplerenone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours); beta-blockers: bisoprolol 1.5 mg orally every 24 hours (maximum dose 10 mg every 24 hours) or metoprolol succinate 12.5 mg every 24 hours orally (maximum dose 200 mg every 24 hours) or carvedilol 3125 mg every 24 hours (maximum dose 25 mg every 24 hours) or ivabradine 5 mg every 12 hours (maximum dose 7.5 mg every 12 hours); diuretics: furosemide 20 to 400 mg orally every 24 hours or bumetanide 1 to 15 mg orally every 24 hours and/or chlorthalidone 25 mg orally every 24 hours. Additionally, patients will use Sacubitril/Valsartan, with the intention to titrate up to 49 mg/51 mg orally every 12 hours and Empagliflozin 10 mg orally every 24 hours. | Drug: Sacubitril 49 MG / Valsartan 51 MG [Entresto] BID<br>* This group of patients will receive the conventional treatment of heart failure according to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and Sacubitril/Valsartan as an active comparator.<br>* Other names: Entresto;Drug: Empagliflozin 10 MG OD<br>* This group of patients will receive the conventional treatment of heart failure according to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and Empagliflozin as an experimental drug.<br>* Other names: Jardiance;|
| Experimental: Conventional treatment plus Empagliflozin<br>Patients will receive conventional treatment consisting of spironolactone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours) or eplerenone 25 mg orally every 24 hours (maximum dose 50 mg every 24 hours); beta-blockers: bisoprolol 1.5 mg orally every 24 hours (maximum dose 10 mg every 24 hours) or metoprolol succinate 12.5 mg every 24 hours orally (maximum dose 200 mg every 24 hours) or carvedilol 3125 mg every 24 hours (maximum dose 25 mg every 24 hours) or ivabradine 5 mg every 12 hours (maximum dose 7.5 mg every 12 hours); diuretics: furosemide 20 to 400 mg orally every 24 hours or bumetanide 1 to 15 mg orally every 24 hours and/or chlorthalidone 25 mg orally every 24 hours. Additionally, patients will use Empagliflozin 10 mg orally every 24 hours. | Drug: Empagliflozin 10 MG OD<br>* This group of patients will receive the conventional treatment of heart failure according to the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and Empagliflozin as an experimental drug.<br>* Other names: Jardiance;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3D echocardiographic systemic ventricular end-diastolic volume index | Change of 8.2 ml or greater in systemic ventricular end-diastolic volume index measured by 3D echocardiogram. | Twelve weeks | 
| 3D echocardiographic systemic ventricular end-systolic volume index | Change of 6.0 ml or greater in end-systolic volume index measured by 3D echocardiogram. | Twelve weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional class | A clinically relevant change of greater than or equal to 5 points from baseline score in the functional class measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). This questionnaire evaluates 23 elements and is divided into 7 different domains. The score will interpreted as follows: 0-24 points: very poor to poor 25-49 points: poor to fair 50-74 points: fair to good 75-100 points: good to excellent | Twelve weeks | 
| Pulmonary congestion | Change in pulmonary B score measured by the quantification and characteristics of B-lines seen with pulmonary ultrasound assessing 8 regions total using the following scoring system: 0 points: less than 3 B-lines per zone 1 point: greater than or equal to 3 B-lines per zone | Twelve weeks | 
| 6-minute walking test | Difference in meters walked in the 6-minute walking test. | Twelve weeks | 
| Echocardiographic ejection fraction from the systemic ventricle | A change in the percentage of ejection fraction from the systemic ventricle measured by echocardiogram. | Twelve weeks | 
| Echocardiographic longitudinal overall strain | A change in the percentage of longitudinal overall strain measured by echocardiogram at baseline and after treatment. | Twelve weeks | 
| NT-proBNP | Change in NT-proBNP values. | Twelve weeks | 
| Systemic venous congestion | Change in VExUS grading system measured by the diameter of the inferior vena cava in cm and Doppler pattern abnormalities on hepatic, portal and intra-renal veins using the following scoring system: No congestion (0): IVC less than 2 cm Mild (1): IVC greater than or equal to 2cm and any normal or mildly abnormal patterns Moderate (2): IVC greater than or equal to 2cm and ONE severely abnormal pattern Severe (3): IVC greater than or equal to 2 cm and more than or equal to TWO severely abnormal patterns | Twelve weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adult congenital heart disease, Heart Failure with Reduced Ejection Fraction, Empagliflozin, Sacubitril-valsartan