Early Treatment With a Sodium-glucose Co-transporter 2 Inhibitor in High-risk Patients With Acute Heart Failure

Study Overview
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Brief Summary
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The EMPA-AHF trial is a multicentre, randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of early initiation of once-daily oral empagliflozin 10 mg in patients hospitalized for patients with acute heart failure (AHF) who are at a high risk of adverse events.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Empagliflozin in Patients With Acute Heart Failure

Conditions
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Acute Heart Failure

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet the below inclusion criteria will be randomized within 12 h after presentation to the hospital Age of ≥20 and <90 years Hospitalized with a diagnosis of acute heart failure, requiring intravenous loop diuretic therapy, and with all of the following characteristics: i. Dyspnoea at rest or induced by slight exertion ii. At least two of the following findings: jugular venous distention, pulmonary rales, lower leg edema, and pulmonary congestion on chest X-ray iii. If the patient has a sinus rhythm at the time of admission, BNP ≥350 pg/mL or NT-proBNP ≥1400 pg/mL; if the patient has atrial fibrillation at the time of admission, BNP ≥500 pg/mL or NT-proBNP ≥2000 pg/mL. For patients taking an angiotensin receptor neprilysin inhibitor, only the reference value for NT-proBNP will be applicable. At least one of the following characteristics: i. eGFR <60 mL/min/1.73m2, as calculated using the CKD Epidemiology Collaboration for JapaneseModification of Diet in Renal Disease formula ii. Already taking ≥40 mg of oral furosemide during the period before hospitalization. For patients on loop diuretics other than furosemide, the following conversion should be used: oral furosemide 20 mg = oral azosemide 30 mg = oral torasemide 5 mg. iii. Urine output of <300 mL during the 2 h following an appropriate dose of intravenous furosemide administered after hospitalization. An appropriate dose of intravenous furosemide is 20 mg for patients who have not been taking furosemide regularly before hospitalization and is the same as, or greater than, the daily oral dose for patients who have been taking furosemide regularly before hospitalization. Provided written consent to participate in the study Exclusion Criteria: eGFR <20 mL/min/1.73m2 at the time of admission Already taking an SGLT2i within 3 months prior to hospitalization Type 1 diabetes mellitus Systolic blood pressure <90 mmHg Expected to newly require treatment with thiazide, tolvaptan, or carperitide within 48 h after hospitalization Main cause of acute heart failure hospitalization is not fluid retention (e.g., persistent ventricular tachycardia, persistent atrial fibrillation/atrial flutter with a ventricular response rate of ≥130 bpm, persistent bradycardia with a ventricular response rate of <45 bpm, an infection, severe anemia, and an acute exacerbation of COPD) Acute coronary syndrome, pulmonary thromboembolism, or a cerebrovascular accident is the main cause of the present hospitalization. At risk of ketoacidosis or hyperosmolar hyperglycaemia On dialysis, including peritoneal dialysis, or the initiation of dialysis during hospitalization is planned Pregnant or lactating women Underwent the following therapeutic interventions within 30 days: cardiovascular surgery (e.g., coronary artery bypass grafting, surgery for valvular heart disease, transcatheter aortic valve implantation, percutaneous coronary intervention, percutaneous edge-to-edge mitral valve repair, and other types of surgery at the investigator's discretion) and implantation of an implantable defibrillator, cardiac resynchronization therapy defibrillator, or implantable ventricular-assist device A diagnosis of acute coronary syndrome, cerebral infarction, or transient ischemic attack made within 90 days Ventricular tachycardia with syncope within 90 days Heart transplant recipient or listed for heart transplantation and expected to undergo transplantation during the present treatment; implanted with an implantable ventricular-assist device or expected to require an implantable ventricular-assist device during the present treatment; or expected to switch to palliative care Intubated at the time of screening or expected to require intubation within 48 h after hospitalization Severe valvular heart disease expected to be treated with thoracostomy or catheterization (a reason to exclude secondary mitral or tricuspid regurgitation due to reduced cardiac function does not exist, except for the absence of a plan to perform cardiac surgery or therapeutic catheterization) A diagnosis of secondary cardiomyopathy such as amyloidosis, cardiac sarcoidosis, hemochromatosis, Fabry disease, and muscular dystrophy. Heart failure due to takotsubo cardiomyopathy, obstructive hypertrophic cardiomyopathy, complex congenital heart disease (as determined by the investigator), or pericardial constriction. A diagnosis of peripartum cardiomyopathy made within 6 months Active myocarditis Presence of uncontrolled thyroid disease Acute cardiac structural abnormalities (e.g., acute mitral regurgitation due to ruptured chordae tendineae) Symptomatic bradycardia or complete atrioventricular block, being treated with a temporary pacemaker implantation at the time of admission, or expected to require a temporary pacemaker implantation in the future. Patients who have already been treated with a permanent pacemaker implantation do not meet the exclusion criteria. Serious liver disorder (an increase in AST, ALT, or ALP level ≥3 times the upper limit of normal) or cirrhosis with varices or other findings suggestive of portal hypertension Alcohol use disorder of at least mild severity according to the DSM-V A diagnosis of active malignancy or suspected active malignancy made within 2 years Coexisting diseases other than heart failure with an expected survival prognosis of ≤1 year Participation in a clinical study of another drug 30 days before hospitalization Patients considered to require fasting at screening. Other conditions likely to interfere with the patient's safety or compliance with the protocol Other patients who are considered unsuitable by the principal investigator or other investigators

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 89 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin<br>Patients will be randomized 1:1 to either empagliflozin or placebo. | Drug: Empagliflozin 10 MG<br>* once-daily oral empagliflozin 10 mg<br>|
| Placebo Comparator: Placebo<br>Placebo matching empagliflozin | Drug: Placebo<br>* Placebo matching empagliflozin 10 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A hierarchical composite endpoint consisting of death within 90 days, heart failure rehospitalization within 90 days, WHF during hospitalization, and urine output up to 48 hours after treatment initiation, assessed by the win ratio | WHF, worsening heart failure | Up to 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A hierarchical composite endpoint consisting of death within 90 days, heart failure readmission within 90 days, and WHF during hospitalization | WHF, worsening heart failure | Up to 90 days | 
| A composite endpoint consisting of WHF during hospitalization, death, heart failure rehospitalization, urgent visit for WHF, intensification of diuretic therapy, and worsening NYHA class within 90 days | WHF, worsening heart failure | Up to 90 days | 
| Change in NT-proBNP from randomization to 48 hours |  | Evaluated at 48 hours after randomization | 
| Diuretic response, calculated as urine output achieved by loop diuretics (40 mg intravenous furosemide-equivalent dose) at 48 h after treatment initiation |  | Evaluated at 48 hours after randomization | 
| Improvement in KCCQ-TSS of ≥5 points from randomization to 30 and 90 days after treatment initiation | KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire - Total Symptom Score. The scores range from 0 to 100, with 100 being the best possible score. | Up to 90 days | 
| Time to hemodynamic stabilization during index hospitalization |  | During index hospitalization | 
| Re-worsening of heart failure during index hospitalization |  | During index hospitalization | 
| Heart failure rehospitalization |  | Up to 90 days | 
| Death |  | Up to 90 days | 
| Urine output during the 48 h after randomization |  | Evaluated at 48 hours after randomization | 
| Cardiovascular death |  | Up to 90 days | 
| Change in the visual analog scale score for dyspnea from after randomization to 24 and 48 h | The scores range from 0 to 100, with 100 being the best possible score. | Evaluated at 24 and 48 hours after randomization | 
| Change in high sensitivity cardiac troponin T |  | Evaluated at 48 hours after randomization | 
| Change in the KCCQ-TSS after randomization to 30 and 90 days | KCCQ-TSS, Kansas City Cardiomyopathy Questionnaire - Total Symptom Score. The scores range from 0 to 100, with 100 being the best possible score. | Up to 90 days | 
| Composite of renal replacement therapy, renal transplantation, eGFR <15 mL/min/1.73m2, ≥50% decrease in eGFR compared to the first sample or a ≥2-fold increase in creatinine level compared to the first sample within 90 days of randomization |  | Up to 90 days | 
| Trend in eGFR after randomization to 24 h, 48 h, 30 days, and 90 days |  | Up to 90 days |