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

Acute Heart Failure Clinical Trial

— EMPA-AHF  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05392764
• Other study ID #: jRCTs031210682
• Status: Recruiting
• Phase: Phase 3
• Start date: September 10, 2022
• Est. completion date: June 30, 2025

Study information

• Verified date: March 2024
• Source: Juntendo University
• Contact: Yuya Matsue, MD
• Phone: 81-3-3813-3111
• Email: yuya8950[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: June 30, 2025
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 89 Years

Eligibility

Inclusion Criteria:

Patients who meet the below inclusion criteria will be randomized within 12 h after presentation to the hospital

1. Age of =20 and <90 years

2. 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.

3. 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.

4. Provided written consent to participate in the study

Exclusion Criteria:

1. eGFR <20 mL/min/1.73m2 at the time of admission

2. Already taking an SGLT2i within 3 months prior to hospitalization

3. Type 1 diabetes mellitus

4. Systolic blood pressure <90 mmHg

5. Expected to newly require treatment with thiazide, tolvaptan, or carperitide within 48 h after hospitalization

6. 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)

7. Acute coronary syndrome, pulmonary thromboembolism, or a cerebrovascular accident is the main cause of the present hospitalization.

8. At risk of ketoacidosis or hyperosmolar hyperglycaemia

9. On dialysis, including peritoneal dialysis, or the initiation of dialysis during hospitalization is planned

10. Pregnant or lactating women

11. 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

12. A diagnosis of acute coronary syndrome, cerebral infarction, or transient ischemic attack made within 90 days

13. Ventricular tachycardia with syncope within 90 days

14. 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

15. Intubated at the time of screening or expected to require intubation within 48 h after hospitalization

16. 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)

17. 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.

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. 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.

23. 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

24. Alcohol use disorder of at least mild severity according to the DSM-V

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 hospitalization

28. Patients considered to require fasting at screening.

29. Other conditions likely to interfere with the patient's safety or compliance with the protocol

30. Other patients who are considered unsuitable by the principal investigator or other investigators

Related Conditions & MeSH terms

• Acute Heart Failure
• Heart Failure

Intervention

Drug:
• Empagliflozin 10 MG
once-daily oral empagliflozin 10 mg
• Placebo
Placebo matching empagliflozin 10 mg

Locations

Country	Name	City	State
Japan	Nishiarai Hospital	Adachi	Tokyo
Japan	Anjo Kosei Hospital	Anjo	Aichi
Japan	Fukuokaken Saiseikai Futsukaichi Hospital	Chikushino	Fukuoka
Japan	Mitsui Memorial Hospital	Chiyoda	Tokyo
Japan	Sakakibara Heart Institute	Fuchu	Tokyo
Japan	Japanese Red Cross Fukuoka Hospital	Fukuoka
Japan	Funabashi Municipal Medical Center	Funabashi	Chiba
Japan	Tokyo Medical University Hachioji Medical Center	Hachioji	Tokyo
Japan	Hyogo Brain and Heart Center	Himeji	Hyogo
Japan	Hirosaki University Hospital	Hirosaki	Aomori
Japan	Hiroshima City Hospital	Hiroshima
Japan	Tokai University Hospital	Isehara	Kanagawa
Japan	Juntendo University Shizuoka Hospital	Izunokuni	Shizuoka
Japan	Kameda Medical Center	Kamogawa	Chiba
Japan	Nara Medical University Hospital	Kashihara	Nara
Japan	Kasukabe Chuo General Hospital	Kasukabe	Saitama
Japan	Saitama Medical Center	Kawagoe	Saitama
Japan	Kawaguchi Cardiovascular and Respiratory Hospital	Kawaguchi	Saitama
Japan	St.Marianna University School of Medicine Hospital	Kawasaki	Kanagawa
Japan	Chikamori Hospital	Kochi
Japan	Kurume University Hospital	Kurume	Fukuoka
Japan	Gunma University Hospital	Maebashi	Gunma
Japan	International University of Health and Welfare Mita Hospital	Minato	Tokyo
Japan	Toranomon Hospital	Minato	Tokyo
Japan	Iwate Prefectural Cyuou Hospital	Morioka	Iwate
Japan	Nagoya University Hospital	Nagoya	Aichi
Japan	Kochi Medical School Hospital	Nankoku	Kochi
Japan	Nara Prefecture General Medical Center	Nara
Japan	Sakakibara Heart Institute of Okayama	Okayama
Japan	Nakagami Hospital	Okinawa
Japan	Kitano Hospital	Osaka
Japan	Osaka General Medical Center	Osaka
Japan	Kindai University Hospital	Osakasayama	Osaka
Japan	Saitama Citizens Medical Center	Saitama
Japan	Sapporo Higashi Tokushukai Hospital	Sapporo	Hokkaido
Japan	Tokyo Women's Medical University Hospital	Shinjuku	Tokyo
Japan	Soka City Hospital	Soka	Saitama
Japan	National Cerebral and Cardiovascular Center Hospital	Suita	Osaka
Japan	Hyogo Prefectural Awaji Medical Center	Sumoto	Awaji
Japan	National Disaster Medical Center	Tachikawa	Tokyo
Japan	Tokushima University Hospital	Tokushima
Japan	Juntendo University Hospital	Tokyo
Japan	Juntendo University Nerima Hospital	Tokyo
Japan	Nihon University Itabashi Hospital	Tokyo
Japan	Tokyo Medical University	Tokyo
Japan	Tokyo Metropolitan Bokutoh Hospital	Tokyo
Japan	Tsuchiura Kyodo General Hospital	Tsuchiura	Ibaraki
Japan	Urasoe General Hospital	Urasoe	Okinawa
Japan	Juntendo University Urayasu Hospital	Urayasu	Chiba
Japan	Saiseikai Utsunomiya Hospital	Utsunomiya	Tochigi
Japan	Yokohama City University Medical Center	Yokohama

Sponsors (2)

Lead Sponsor	Collaborator
Juntendo University	Boehringer Ingelheim

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	Change in NT-proBNP from randomization to 48 hours		Evaluated at 48 hours after randomization
Secondary	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
Secondary	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
Secondary	Time to hemodynamic stabilization during index hospitalization		During index hospitalization
Secondary	Re-worsening of heart failure during index hospitalization		During index hospitalization
Secondary	Heart failure rehospitalization		Up to 90 days
Secondary	Death		Up to 90 days
Secondary	Urine output during the 48 h after randomization		Evaluated at 48 hours after randomization
Secondary	Cardiovascular death		Up to 90 days
Secondary	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
Secondary	Change in high sensitivity cardiac troponin T		Evaluated at 48 hours after randomization
Secondary	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
Secondary	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
Secondary	Trend in eGFR after randomization to 24 h, 48 h, 30 days, and 90 days		Up to 90 days