Empagliflozin and Dapagliflozin in Patients Hospitalized for Acute Decompensated Heart Failure

Study Overview
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Brief Summary
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National, multicenter, randomized, double-blind, parallel-group, stratified by SGLT-2 inhibitor type, placebo-controlled trial, - a Phase III study. Primary objective of the study is to investigate the impact of SGLT-2 inhibitors (Empagliflozin and Dapagliflozin) on clinical endpoints in patients hospitalized with acute/decompensated HF.

Official Title
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Empagliflozin and Dapagliflozin in Patients Hospitalized for Acute Decompensated Heart Failure (EMPATHY) - a Phase III Trial.

Conditions
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Acute Decompensated Heart Failure

Intervention / Treatment
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* Drug: Empagliflozin 10 MG
* Drug: Dapagliflozin 10 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years of age with the capacity to provide written informed consent Currently hospitalized for a primary diagnosis of acute/decompensated HF (HFrEF, HFmrEF,HFpEF), including symptoms and signs of fluid overload regardless of ejection fraction or diabetes status In patients with HFpEF the diagnosis has to be confirmed according to the current HFpEF definition (by non-invasive testing: evidence of structural or functional changes in the heart as evidenced on echocardiography or by invasive testing as LVEDP assessment or right heart catheterisation). Randomized no earlier than 24 hours and up to 10 days after initial presentation while still hospitalized Stable as defined by: systolic blood pressure (SBP>100 mmHg for the preceding 6 hours) No intensification of IV diuretics within the last 6 hours, No use of IV vasodilators within the last 6 hours, No use of IV inotropes or levosimendan within the last 24 hours prior to randomization Elevated NT-proBNP >600 pg/mL during the current hospitalization in patients with HFrEF and >300 pg/mL in patients with HFmrEF or HFpEF (or above 900 pg/ml if atrial fibrillation is present at admission independently from EF). eGFR >20 ml/min/1,73m2 Exclusion Criteria: History of ketoacidosis Type 1 diabetes SGLT-2 Inhibitor at baseline or known allergy to SGLT-2 Inhibitors Current active cancer with less than 2 years of life expectancy Pulmonary embolism, cerebrovascular accident as the primary trigger for the current hospitalization Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy or known pericardial constriction Any severe (obstructive or regurgitant) valvular heart disease, expected to lead to surgery during the trial period Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant Blood pH<7.32 >1 episode of severe hypoglycaemia within the last 6 months under treatment with insulin or sulfonylurea Acute symptomatic urinary tract infection or genital infection

Ages Eligible for Study
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Minimum Age: 18 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: Two arms with a subsequent stratification based on the SGLT2 inhibitor type.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SGLT 2 Inhibitor<br>Empagliflozin (n=341) or Dapagliflozin (n=341): 9 months of treatment | Drug: Empagliflozin 10 MG<br>* once daily for 6 or 9 months<br>* Other names: Jardiance;Drug: Dapagliflozin 10 MG<br>* once daily for 6 or 9 months<br>* Other names: Forxiga;|
| Placebo Comparator: Placebo with a switch to SGLT 2 Inhibitor<br>Placebo (n=682) for 3 months of treatment with a subsequent switch to Empagliflozin (n=341) or Dapagliflozin (n=341): 6 months of treatment | Drug: Placebo<br>* once daily for 3 months<br>* Other names: Placebo with switch to SGLT2 inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first event of adjudicated cardiovascular (CV) death, or adjudicated hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) | combined endpoint | at 3 and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in the number of recurrent hospitalizations due to heart failure between the treatment groups | recurrent hospitalizations due to heart failure | at 3 and 9 months | 
| Difference in the number of hospitalizations for CV causes between the treatment groups | hospitalizations for CV causes | at 3 and 9 months | 
| Difference in the number of hospitalizations for other than CV causes between the treatment groups | hospitalizations for other than CV causes | at 3 and 9 months | 
| Time to adjudicated CV death | CV death | at 3 and 9 months | 
| Time to adjudicated all cause death | all cause death | at 3 and 9 months | 
| Time to adjudicated myocardial infarction | myocardial infarction | at 3 and 9 months | 
| eGFR (Estimated Glomerular Filtration Rate) (CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Equation)) creatine slope of change from baseline between the treatment groups | eGFR | at 3 and 9 months | 
| Difference in the number of hospital re-admissions due to heart failure between the treatment groups | hospital re-admissions due to heart failure | at 3 and 9 months | 
| Difference in the number of hospital re-admissions for any cause between the treatment groups | hospital re-admissions for any cause | at 3 and 9 months | 
| Difference in the duration of hospital stay between the treatment groups after initiation of the study treatment | duration of hospital stay | at 3 and 9 months | 
| Difference in the number of incidences of new onset AF and re-occurrence of AF between treatment groups | new onset AF | at 3 and 9 months | 
| Difference in the change of ejection fraction in echocardiography between treatment groups | ejection fraction | at 3 and 9 months | 
| Difference in the change of left ventricular diastolic function in echocardiography | left ventricular diastolic function | at 3 and 9 months | 
| Difference in the change of LV strain analysis in echocardiography | LV strain | at 3 and 9 months | 
| The time-averaged proportional change in NT-proBNP from | NT-proBNP | at 3 and 9 months | 
| The time-averaged proportional change in selected miRNA expression linked to hypertrophy, inflammation, fibrosis, apoptosis, electric stability between treatment groups and placebo group | miRNA expression | at 3 and 9 months | 
| The time-averaged proportional change in pre-specified biomarkers | biomarkers | at 3 and 9 months | 
| Change from baseline in clinical summary score (HF (Chronic Heart Failure) symptoms and physical limitations domains) of the Kansas City Cardiomyopathy Questionnaire (KCCQ) | HF score | at 3 and 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGLT-2 inhibitors, dapagliflozin, empagliflozin, acute heart failure, decompensated heart failure