EMPA Acute Heart Failure

Study Overview
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Brief Summary
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In this study the investigators are aiming to treat patients with acute heart failure with or without diabetes with Empagliflozin or placebo. Given the beneficial effects of Empagliflozin on heart failure hospitalization in the EMPA-REG OUTCOME trial, the investigators do expect a similar beneficial effect to be present in patients with acute heart failure. Acute heart failure is a state of hydropic decompensation resulting in dyspnea and congestions, caused by different etiologies of cardiac disease. Recompensation is reached by application of diuretic drugs and fluid restriction.

Detailed Description
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In the present study patients will be randomized into 2 groups (standard of care + Empagliflozin 10 mg/d or standard of care + placebo). Cardiac output will be assessed by a medical device for noninvasive monitoring of hemodynamic parameters (cardiac output, systemic vascular resistance, stroke volume and blood pressure) using finger cuff technology for pulse contour analysis. These investigations will inform about Empagliflozin dependent effects on hemodynamic and cardiac function in patients with acute heart failure. The investigation will further assess the therapeutic efficacy of Empagliflozin on heart failure symptoms using objective (respiratory rate, oxygen requirement, peak expiratory flow rate, urinary volume, body weight, diuretic requirement, length of hospital stay) and well accepted, patient orientated secondary endpoints. In addition, metabolic regulators and parameters relevant for cardiac function and substrate metabolism will be assessed to further investigate possible mechanisms of Empagliflozin-dependent actions on cardiac function.

Official Title
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Effect of Empagliflozin on Cardiac Output in Patients With Acute Heart Failure (EMPA Acute Heart Failure)

Conditions
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Diabetes Mellitus, Type 2, Acute Heart Failure

Intervention / Treatment
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* Drug: Empagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Patients with acute heart failure with associated signs or symptoms (dyspnea on exertion, orthopnea, paroxysmal dyspnea, peripheral oedema, chest x-ray with pulmonary congestion) Serum levels of NT-proBNP ≥ 1000 pg/ml within 48 hours of Informed Consent Written informed consent prior to study participation Exclusion Criteria: Type 1 diabetes Participants of child-bearing age without adequate contraception Pregnancy or lactating females Cardiogenic shock Acute coronary syndrome within 30 days prior to randomization Planned or recent percutaneous or surgical coronary intervention within 30 days prior to randomization Signs of ketoacidosis and/or hyperosmolar hyperglycemic syndrome (pH ≤ 7.30 and glucose >14 mmol/l and HCO3- ≤ 18 mmol/l) Signs of uncontrolled active infection Dyspnea due to non-cardiac causes (severe pulmonary disease, anemia, severe obesity), non-HF causes such as acute or chronic respiratory disorders Coronary artery disease with requirement for revascularization within the study period Renal impairment (GFR < 20 ml/min/1,73 m2) Known hepatic impairment (as evidenced by total bilirubin >3 mg/dL) or history of cirrhosis with evidence of portal hypertension (e.g., presence of esophageal varices) Uncontrolled thyroid disease Endocrinopathies like Graves' disease, acromegaly, Cushings' disease Hypertensive retinopathy or encephalopathy Bariatric surgery in last 2 years prior to randomization Patients in whom study participation is not deemed appropriate under consideration of clinical wellbeing by the principal investigator The subject is mentally or legally incapacitated The subject received an investigational drug within 30 days prior to inclusion into this study Urinary tract infections or significant formation of residual urine in medical history Patients with particular risk for ketoacidosis (alcohol abuse, pancreatitis, pancreatic insulin deficiency from any cause, caloric restriction etc.) or ketoacidosis in the past Frequent hypoglycaemic events (in the opinion of the investigator) Intolerance to Empagliflozin and excipients in Empagliflozin or rather placebo Patients with severe stenosis or regurgitation of the aortic, pulmonary or mitral valve

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: Single center, prospective, placebo-controlled, double blind, randomized, 2-arm parallel, interventional, exploratory pilot study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Patients will receive empagliflozin 10 mg qd for a period of 30 days. | Drug: Empagliflozin<br>* Standard of Care + Empagliflozin: 10 mg (tablets) once daily<br>* Other names: Jardiance;|
| Placebo Comparator: Placebo<br>Patients of the placebo arm will receive placebo tablets qd for a period of 30 days. | Drug: Placebo<br>* Standard of Care + Placebo: Matching Placebo (tablets) once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| effect of Empagliflozin 10mg qd versus placebo on cardiac output in patients with acute heart failure | by ClearSight System | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamics | Systemic vascular resistance (mmHg⋅min⋅mL-1) | 30 days | 
| Hemodynamics | Stroke volume (ml/beat) | 30 days | 
| Exercise Capacity | Hand grip | 30 days | 
| Cardio vascular | blood pressure (mmHg) | 30 days | 
| Effect of Empagliflozin on systemic quality of life | Quality of life questionnaire | 30 days | 
| Effect of Empagliflozin on hospitalization due to cardiovascular causes or readmission for heart failure or renal failure | length of initial hospital stay | 30 days | 
| Effect of Empagliflozin on death due to cardiovascular causes | days alive and out of hospital | 30 days | 
| Urine | 24 h sodium excretion (mmol/day) | 30 days | 
| Body weight | body weight (kg) | 30 days | 
| Cardio vascular | 24 h heart rate (bpm) | 30 days | 
| Blood | NT-proBNP (ng/l) | 30 days | 
| Blood | cystatin C(mg/dl) | 30 days | 
| Blood | serum levels of Glucose, Glucagon, Insulin, Total-Ketone bodies, Hydroxybutyrate, Aldosterone, Free fatty acidy (mg/dl) | 30 days | 
| Blood | Hemoglobin, Haematocrit, Erythropoietin | 30 days | 
| Respiratory rate | breaths/min | 30 days | 
| Diuretic response | Δ weight kg/[(total i.v. dose)/40mg]+[(total oral dose)/80mg)] furosemide | 30 days | 
| Kidney injury risk score | by NephroCheck® (defined by TIMP-2 x IGFBP7 in urine) | 30 days | 
| change of microbiome | stool sample | 30 days | 
| Patient-reported dyspnea | visual analogue scale (VAS), 7 point categorical Likert scale | 30 days | 
| Peak expiratory flow rate |  | 30 days | 
| Oxygen | Saturation (%) | 30 days | 
| Oxygen | delivered (l/min) | 30 days | 
| Clinical judged diuretic requirement |  | 30 days | 
| Blood | eGFR | 30 days | 
| Blood | Lactate, pH, HCO3- | 30 days | 
| Blood | Serum osmolarity, Potassium, Chloride | 30 days | 
| Effect of Empagliflozin 10 mg daily on Left ventricular systolic function | ejection fraction | 30 days | 
| Effect of Empagliflozin 10 mg daily on Left ventricular diastolic function | 2D and 3D parameter global strain rate E by echocardiography and by standardized parameter E/E' and left atrial (LA) volume | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Empagliflozin, acute heart failure, cardiac output, left ventricular systolic and diastolic function, exercise capacity