Effect at 3 Months of Early Empagliflozin Initiation in Cardiogenic Shock Patients on Mortality, Rehospitalization, Left Ventricular Ejection Fraction and Renal Function.

Study Overview
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Brief Summary
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Long term prognosis of cardiogenic shock is related to the resolution of haemodynamic failure, associated visceral failure and the recovery of an adequate myocardial function. In the immediate aftermath of cardiogenic shock, after catecholamines weaning, there are no recommendations on cardiovascular treatments that would improve this long term prognosis. Indeed, the standard cardiovascular treatments such as inhibitors of the renin-angiotensin and aldosterone system and beta-blockers have hypotensive and negative inotropic effects and may worsen the renal function. In practice, given their side effects, they are not prescribed in the immediate aftermath of cardiogenic shock. Sodium-glucose co-transporter 2 (iSGLT2) inhibitors are now an integral part of the drug management of chronic heart failure and the EMPULSE-HF trial has just demonstrated a benefit in acute heart failure (PMID: 35228754). Several pivotal clinical trials have demonstrated a significant effect of iSGLT2 on the survival and the risk of re hospitalisation for heart failure (PMID: 32865377, 31535829, 33200892). Our hypothesis is that, in patients in cardiogenic shock, early treatment with Empaglifozin in addition to the standard management could reduce mortality and morbidity (death, transplantation/LVAD and rehospitalisation for heart failure) and improve myocardial function at 12 weeks, compared with standard management alone.

Official Title
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Effect at 3 Months of Early Empagliflozin Initiation in Cardiogenic Shock Patients on Mortality, Rehospitalization, Left Ventricular Ejection Fraction and Renal Function. A Randomized Multicentric Open Trial

Conditions
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Cardiogenic Shock

Intervention / Treatment
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* Drug: Empagliflozin 10 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients hospitalized in critical cardiac unit care or Intensive care unit for a cardiogenic shock Patient on catecholamine for more than 12 hours and less than 5 days. Exclusion Criteria: GFR< 20 ml/min/1.73m2. Chronic dialysis. Patient on SGLT2 inhibitors prior to admission to ICU or CCU. Known allergy to SGLT2 inhibitors or to any of its excipients (in particular, patients with hereditary disorders of galactose intolerance, total lactase deficiency or glucose or galactose malabsorption syndrome) Patients on lithium. Patient in shock for another cause or moribund (SAPS2> 90). Specific cardiogenic shock context: cardiac transplant patient or on transplant list. peripartum, adrenergic, valvular, restrictive, post embolic heart disease. caused by a conduction/rhythm disorder of non-ischemic etiology. related to cardiotropic drug intoxication. secondary to a cardiocirculatory arrest with more than 25 min of low flow or more than 5 min of no flow before recovery of a stable cardiac activity. Patient undergoing VA-ECMO at admission (before or in whom implantation is imminent (less than 3 hours)). Women of childbearing age without effective contraception. Person referred to in Articles 10, 31, 32, 33 and 34 of EU Regulation 536/2014 (Pregnant woman, parturient or breastfeeding mother, Minor (not emancipated), Adult person subject to a legal protection measure (guardianship, curatorship, safeguard of justice))

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: Multicentre, interregional, randomised, controlled, open-label clinical trial evaluating the effect of early initiation of a SGLT2 inhibitor i.e Empaglifozin, in cardiogenic shock.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empaglifozin in addition to standard management<br>Patients in cardiogenic shock receiving empagliflozin in addition to standard management at a dose of 10 mg per day per os (or through nasogastric tube in intubated patients) for a duration of 12 weeks | Drug: Empagliflozin 10 MG<br>* Patients in cardiogenic shock receiving empagliflozin in addition to standard management at a dose of 10 mg per day per os (or through nasogastric tube in intubated patients) for a duration of 12 weeks.<br>|
| No Intervention: Standard management<br>Patients in cardiogenic shock receiving a standard management. SGLT2 inhibitor, which are now standard of care in chronic heart failure, in the strict respect of their indications, could be prescribed in the standard management group after hospitalization discharge. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to all-cause death | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on composite endpoint components: All-cause mortality or heart transplantation or ventricular assist, Rehospitalization for heart failure, Left ventricular ejection fraction. Hierarchical composite endpoint, assessed at 12 weeks from randomization (win-ratio method): Rank 1: Time to all-cause death or cardiac transplantation or mechanical ventricular assist, Rank 2: Time to rehospitalization for heart failure, Rank 3: Left ventricular ejection fraction assessed during a research cardiac ultrasound. | 12-week after randomisation | 
| Time to cardiac transplantation | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on composite endpoint components: All-cause mortality or heart transplantation or ventricular assist, Rehospitalization for heart failure, Left ventricular ejection fraction. Hierarchical composite endpoint, assessed at 12 weeks from randomization (win-ratio method): Rank 1: Time to all-cause death or cardiac transplantation or mechanical ventricular assist, Rank 2: Time to rehospitalization for heart failure, Rank 3: Left ventricular ejection fraction assessed during a research cardiac ultrasound. | 12-week after randomisation | 
| Time to mechanical ventricular assist | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on composite endpoint components: All-cause mortality or heart transplantation or ventricular assist, Rehospitalization for heart failure, Left ventricular ejection fraction. Hierarchical composite endpoint, assessed at 12 weeks from randomization (win-ratio method): Rank 1: Time to all-cause death or cardiac transplantation or mechanical ventricular assist, Rank 2: Time to rehospitalization for heart failure, Rank 3: Left ventricular ejection fraction assessed during a research cardiac ultrasound. | 12-week after randomisation | 
| Time to rehospitalization for heart failure. | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on composite endpoint components: All-cause mortality or heart transplantation or ventricular assist, Rehospitalization for heart failure, Left ventricular ejection fraction. Hierarchical composite endpoint, assessed at 12 weeks from randomization (win-ratio method): Rank 1: Time to all-cause death or cardiac transplantation or mechanical ventricular assist, Rank 2: Time to rehospitalization for heart failure, Rank 3: Left ventricular ejection fraction assessed during a research cardiac ultrasound. | 12-week after randomisation | 
| Left ventricular ejection fraction assessed by cardiac ultrasound. | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on composite endpoint components: All-cause mortality or heart transplantation or ventricular assist, Rehospitalization for heart failure, Left ventricular ejection fraction. Hierarchical composite endpoint, assessed at 12 weeks from randomization (win-ratio method): Rank 1: Time to all-cause death or cardiac transplantation or mechanical ventricular assist, Rank 2: Time to rehospitalization for heart failure, Rank 3: Left ventricular ejection fraction assessed during a research cardiac ultrasound. | 12-week after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on all-cause mortality at 12 weeks from randomization | 12-week after randomisation | 
| Heart transplantation or long-term ventricular assistance | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on heart transplantation or long-term ventricular assistance, at 12 weeks from randomization | 12-week after randomisation | 
| Rehospitalization for heart failure | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on rehospitalization for heart failure, at 12 weeks from randomization | from hospital discharge to 12-week after randomisation | 
| Left ventricular ejection fraction assessed by cardiac ultrasound. | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on left ventricular ejection fraction, at 12 weeks from randomization. | 12-week after randomisation | 
| E' wave assessed by cardiac ultrasound | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the left ventricular diastolic function and filling pressures, at 12 weeks from randomization. | 12-week after randomisation | 
| E/e' ratio assessed by cardiac ultrasound | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the left ventricular diastolic function and filling pressures, at 12 weeks from randomization. | 12-week after randomisation | 
| TAPSE assessed by cardiac ultrasound | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the right ventricular function, at 12 weeks from randomization | 12-week after randomisation | 
| S wave at the annular tricuspid level assessed by cardiac ultrasound | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the right ventricular function, at 12 weeks from randomization | 12-week after randomisation | 
| Renal replacement therapy | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the renal function, at 12 weeks from randomization | Randomisation and 12-week after randomisation | 
| Renal function | The number of patients requiring renal replacement therapy between randomization and 12 weeks, and change in renal function assessed at baseline and 12 weeks: glomerular filtration rate calculated by the CKD-EPI method | Randomisation and 12-week after randomisation | 
| Bilirubin | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the hepatic function, at 12 weeks from randomization | Randomisation and 12-week after randomisation | 
| Prothrombin Ratio (PT) | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the hepatic function, at 12 weeks from randomization | Randomisation and 12-week after randomisation | 
| SGOT | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the hepatic function, at 12 weeks from randomization | Randomisation and 12-week after randomisation | 
| SGPT | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the hepatic function, at 12 weeks from randomization | Randomisation and 12-week after randomisation | 
| NT-Pro-BNP | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the evolution of the hydro-sodic overload, at 12 weeks from randomization. The measure of NT-Pro-BNP will be measured at 12 weeks and delta from randomisation will be calculated | Randomisation and 12-week after randomisation | 
| Weight | To compare the effect of early introduction of empagliflozin in addition to standard management versus standard management alone on the evolution of the hydro-sodic overload, at 12 weeks from randomization. The weight will be measured at 12 weeks and delta from randomisation will be calculated | Randomisation and 12-week after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart failure, Acute heart failure, Cardiogenic shock, SGLT2 inhibitor, Mortality