Empagliflozin for New On-set Heart Failure Study Regardless of Ejection Fraction

Phase 3

Recruiting

Brief Summary: Heart failure (HF) is one of the most important reasons for hospital admission and is associated with high mortality and morbidity. After discharge, up to 40% of patients are readmitted within 6 months and 1-year post-discharge mortality is high. The cost burden of treating patients with HF is high and \~80% of healthcare costs are related to hospital admissions.

Sodium-glucose cotransporter-2 (SGLT2) inhibitor is considered one of the four foundational therapies (ACE-I or ARNI, beta-blockers, MRA, and SGLT2 inhibitors) for HFrEF. In particular, empagliflozin has been shown in randomized controlled trials to reduce the combined risk of cardiovascular death or HF hospitalization in HF patients with both reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). However, guidelines do not specify the sequence and the timing of which therapy to be commenced. The timing of SGLT inhibitors initiation in the treatment of acute HF is not established. In particular, new-onset acute HF is a group which is understudied in the major trials to date. This study aims to evaluate the efficacy and safety of in-hospital initiation of empagliflozin in patients hospitalized for new onset acute HF, regardless of LVEF for up to 90 days of follow-up.

Recruitment & Eligibility

Inclusion Criteria

Subject age >18 hospitalized for primary diagnosis of acute HF
Dyspnoea (exertional or at rest) and 2 of the following signs: Congestion on chest X-ray; Rales on chest auscultation; Clinically relevant oedema (e.g. ≥1+ on a 0 to 3+ scale); Elevated jugular venous pressure
Stabilization criteria (while in the hospital): systolic blood pressure ≥100mmHg and no symptoms of hypotension in the preceding 24 hours; No increase in i.v. diuretic dose for 24 h prior; No i.v. vasodilators including nitrates within the last 24 h prior; No i.v. inotropic drugs for 24 h prior
NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL. (Patients with atrial fibrillation: NT-proBNP ≥2400 pg/mL or BNP

≥600 pg/mL. Measured during index hospitalization
Heart failure hospitalization that requires the treatment of a minimum single dose of 40 mg of i.v.

furosemide( or Equivalent i.v loop diuretics defined as 20 mg of torsemide or 1mg of bumetanide)

Exclusion Criteria

Cardiogenic shock
Documented history of HF with previous HF admission
Current hospitalization for acute HF primarily triggered by pulmonary embolism, cerebrovascular accident, or acute myocardial infraction
Interventions in the past 30 days prior or planned during the study: Major cardiac surgery, or Transcatheter aortic valve implantation (TAVI), or percutaneous coronary intervention (PCI), or MitraClip; Implantation of cardiac resynchronization therapy device; Cardiac mechanical support implantation
Current or expected heart transplant, left ventricular assist device (LVAD), intraaortic balloon pumping (IABP), or patients with planned inotropic support in an outpatient setting
Haemodynamically severe uncorrected primary cardiac valvular disease planned for surgery or intervention during the course of the study
eGFR <20 mL/min/1.73m2 as measured during index hospitalization (latest measurement before randomization) or patients requiring dialysis
Type 1 diabetes mellitus (DM)
History of ketoacidosis, including diabetic ketoacidosis
Current or prior treatment with SGLT2 inhibitors in the 90 days prior to enrolment.

Arm && Interventions

Group	Intervention	Description
Empagliflozin 10 MG	Empagliflozin 10 MG	-

Primary Outcome Measures

Name	Time	Method
All-cause mortality	90 days	All-cause mortality after 90 days of treatment
Heart failure (HF) events	90 days	Number of heart failure events (including hospitalization for HFs, urgent heart failure visits and unplanned outpatient visits), time to first heart failure event.

Secondary Outcome Measures

Name	Time	Method
Change in Kansas City Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-TSS)	90 days	Change from baseline in KCCQ-TSS. Scores are transformed to a range of 0-100, where higher scores reflect better health status.
NT-proBNP level	90 days	Change from baseline in log-transformed NT-proBNP level
New York Heart Association (NYHA) class	90 days	Change in NYHA class (I-IV), Class IV is most severe; Class I least severe
Change in 6 minute hall walk (6MHW)	90 days	Change from baseline in 6MHW result
Major Adverse Cardiovascular Event (MACE)	90 days	Measure the occurrence of MACE, including Days alive and out of hospital, occurrence of hypertensive Heart failure from study drug initiation until 90 days after initial hospital discharge and randomization; Time to first occurrence of cardiovascular death or heart failure event until end of trial visit
Occurrence of kidney damage	90 days	Occurrence of chronic dialysis or renal transplant or sustained reduction of ≥40% estimated glomerular filtration rate (eGFR), or * Sustained eGFR \<15mL/min/1.73m2 for patients with baseline eGFR ≥30 mL/min/1.73m2 * Sustained eGFR \<10mL/min/1.73m2 for patients with baseline eGFR \<30 mL/min/1.73m2.
Weight loss	90 days	Weight loss per mean daily loop diuretic dose after 15, 30, 60 and 90 days of treatment.
Quality-adjusted life years (QALY) gained	90 days	Quality-adjusted life years (QALY) gained due to early initiation of empagliflozin