The efficacy and safety of empagliflozin in patients with acute heart failure

JRCT ID: jRCTs031210682

Registered date:22/03/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Acute Heart Failure
• Date of first enrollment: 20/09/2022
• Target sample size: 500
• Study type: Interventional
• Intervention(s): Among patients with acute heart failure, those who (1) have an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.72m2, (2) have already been treated with furosemide at a dose of 40 mg or more prior to admission, or (3) have a reaction urine volume of less than 300 ml up to 2 hours after intravenous injection of furosemide after admission (2) Patients who have already been treated with furosemide at a dose of 40 mg or higher prior to hospitalization (3) Patients who have a urine output of less than 300 ml by 2 hours after intravenous injection of furosemide after hospitalization will receive empagliflozin 10 mg in addition to the usual treatment.

Outcome(s)

• Primary Outcome: Win ratio for a hierarchical composite endpoint consisting of death within 90 days of randomization, heart failure readmission within 90 days of randomization, heart failure re-exacerbation during hospitalization, and urine output up to 48 hours after starting treatment.

Secondary Outcome

Key Secondary Endpoints
1) Win ratio for a hierarchical composite endpoint consisting of death within 90 days of randomization, heart failure readmission within 90 days of randomization, and heart failure re-exacerbation during hospitalization
2) A composite endpoint consisting of in-hospital re-worsening heart failure, death within 90 days after randomization, heart failure rehospitalization, urgent visit for worsening heart failure, intensification of diuretic therapy after discharge, and worsening NYHA class after discharge
3) Group differences in NT-proBNP in geometric mean rate of changes after randomization and up to 48 hours
4) Diuretic response to per 40 mg furosemide by urine excretion up to 48 h after the start of treatment
5) Improvement of 5 points or more after randomization of Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) 30 and 90 days after randomization

Secondary Endpoints
1) Time to hemodynamic stabilization
2) Re-exacerbation of heart failure during hospitalization
3) Heart failure rehospitalization within 90 days of randomization
4) Death within 90 days of randomization
5) Urine output up to 48 hours after initiation of therapy
6) Cardiovascular death within 90 days of randomization
7) Change in visual analog scale (VAS) for dyspnea from randomization to 24, 48 hours after randomization
8) Between-group difference in geometric mean change in high-sensitivity troponin T from randomization to 48 hours
9) Change in KCCQ-TSS from post-randomization to 30 and 90 days after randomization
10) Renal replacement therapy (ultrafiltration, hemofiltration, hemodialysis) within 90 days after randomization, renal transplantation, estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73m^2, >50% decrease in eGFR compared to the initial sample, and Composite endpoint of >2-fold increase in creatinine level compared to the initial sample
11) eGFR at 24, 48 hours, 30 days, and 90 days after randomization

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: < 90age old
• Gender: Both

Include criteria

1. Age >=20 and <90 years
2. Patients who have been hospitalized with a diagnosis of acute heart failure and require intravenous loop diuretic therapy, and meet all the following:
i) Dyspnea at rest or induced by slight exertion
ii) Have at least two of the following findings: jugular venous distention, pulmonary rales, lower leg edema, and pulmonary congestion on a plain film
iii) If the patient has a sinus rhythm at the time of admission, brain natriuretic peptide (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.
3. Patients who meet at least one of the following:
i) Estimated glomerular filtration rate (eGFR) <60 mL/min/1.72m^2
ii) Patients who have been taking loop diuretics >=40 mg of furosemide daily prior to hospitalization
iii) Urine output of <300 mL during 2 h following an adequate dose of intravenous furosemide
4. Patients who have given written consent to participate in the study

Exclude criteria

1. eGFR <20 mL/min/1.73m^2 at the time of admission
2. Patients who have taken SGLT2 inhibitors within 3 months prior to admission
3. Type 1 diabetes mellitus
4. Systolic blood pressure < 90 mmHg
5. Are expected to newly require treatment with thiazide, tolvaptan, or carperitide from time of admission to within 48 hours of study drug administration
6. Acute heart failure hospitalization, the main cause of which is not fluid retention (e.g., persistent ventricular tachycardia, persistent atrial fibrillation / atrial flutter with a ventricular response rate of >=130, persistent bradycardia with a ventricular response rate of <45, an infection, severe anemia, and an acute exacerbation of chronic obstructive pulmonary disease - COPD)
7. Acute coronary syndrome, pulmonary thromboembolism, or a cerebrovascular accident is the main cause of the present hospitalization.
8. Have a risk of ketoacidosis or hyperosmolar hyperglycemia
9. Patients who are on dialysis including peritoneal dialysis or in whom the initiation of dialysis during hospitalization is planned
10. Pregnant or lactating women
11. Have undergone the following therapeutic intervention 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, a cardiac resynchronization therapy defibrillator, or an implantable ventricular assist device
12. A diagnosis of acute coronary syndrome, cerebral infarction, or transient ischemic attack made within 90 days
13. Findings of ventricular tachycardia with syncope revealed within 90 days
14. Heart transplant recipients or patients listed for heart transplantation who are expected to undergo transplantation during the present treatment, patients implanted with an implantable ventricular assist device, patients expected to require an implantable ventricular assist device during the present treatment, and patients expected to switch to palliative care
15. Patients intubated at the time of screening or patients expected to require intubation within 48 h after study drug administration
16. Severe valvular heart disease expected to be treated with thoracotomy or catheterization (there is no reason to exclude secondary mitral or tricuspid regurgitation due to reduced cardiac function, except for the absence of a plan to perform cardiac surgery or therapeutic catheterization)
17. Patients with a diagnosis of secondary cardiomyopathy such as amyloidosis, cardiac sarcoidosis, hemochromatosis, Fabry's 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
18. A diagnosis of peripartum cardiomyopathy made within 6 months
19. Active myocarditis
20. Presence of uncontrolled thyroid disease
21. Acute cardiac structural abnormalities (e.g., acute mitral regurgitation due to ruptured chordae tendineae)
22. Patients with symptomatic bradycardia or complete atrioventricular block who are being treated with temporary pacemaker implantation at the time of admission, or who are expected to require temporary pacemaker implantation in the future. Patients who have already been treated with permanent pacemaker implantation do not meet the exclusion criteria
23. Serious liver disorder (an increase in AST, ALT, or ALP >= 3 times the upper limit of normal) or cirrhosis with varices or other findings suggestive of portal hypertension
24. Patients judged to be at least mildly affected by the DSM-V alcohol use disorder diagnostic criteria
25. A diagnosis of active malignancy or suspected active malignancy made within 2 years
26. Coexisting diseases other than heart failure with an expected survival prognosis of <=1 year
27. Participation in a clinical study of another drug 30 days before the hospitalization
28. Patients considered to require fasting management at screening period
29. Other conditions likely to interfere with the patient's safety or compliance with the protocol
30. Patients who are judged to be unsuitable by the principal investigator or the investigator.

Related Information

• Primary Sponsor: Matsue Yuya
• Source(s) of Monetary Support: Nippon Boehringer Ingelheim Co., Ltd.