Clinical trial NCT05392764: Early Treatment With a Sodium-glucose Co-transporter 2 Inhibitor in High-risk Patients With Acute Heart Failure
Official title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Empagliflozin in Patients With Acute Heart Failure
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Heart Failure
Lead sponsor: Juntendo University
Sponsor class: OTHER
Collaborators: name: Boehringer Ingelheim
First posted: 2022-05-26
Enrollment: 524
Sex: ALL
Minimum age (years): 20
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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 hours of study drug administration
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 within 48 hours of study drug administration
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

Primary outcomes:
measure: 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
timeFrame: Up to 90 days
Secondary outcomes:
measure: A hierarchical composite endpoint consisting of death within 90 days, heart failure readmission within 90 days, and WHF during hospitalization
timeFrame: Up to 90 days
measure: 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
timeFrame: Up to 90 days
measure: Change in NT-proBNP from randomization to 48 hours
timeFrame: Evaluated at 48 hours after randomization
measure: Diuretic response, calculated as urine output achieved by loop diuretics (40 mg intravenous furosemide-equivalent dose) at 48 h after treatment initiation
timeFrame: Evaluated at 48 hours after randomization
measure: Improvement in KCCQ-TSS of ≥5 points from randomization to 30 and 90 days after treatment initiation
timeFrame: Up to 90 days
measure: Time to hemodynamic stabilization during index hospitalization
timeFrame: During index hospitalization
measure: Re-worsening of heart failure during index hospitalization
timeFrame: During index hospitalization
measure: Heart failure rehospitalization
timeFrame: Up to 90 days
measure: Death
timeFrame: Up to 90 days
measure: Urine output during the 48 h after randomization
timeFrame: Evaluated at 48 hours after randomization
measure: Cardiovascular death
timeFrame: Up to 90 days
measure: Change in the visual analog scale score for dyspnea from after randomization to 24 and 48 h
timeFrame: Evaluated at 24 and 48 hours after randomization
measure: Change in high sensitivity cardiac troponin T
timeFrame: Evaluated at 48 hours after randomization
measure: Change in the KCCQ-TSS after randomization to 30 and 90 days
timeFrame: Up to 90 days
measure: 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
timeFrame: Up to 90 days
measure: Trend in eGFR after randomization to 24 h, 48 h, 30 days, and 90 days
timeFrame: Up to 90 days
Other outcomes:
Locations:
city: Anjo
country: Japan
facility: Anjo Kosei Hospital
state: Aichi
city: Nagakute
country: Japan
facility: Aichi Medical University Hospital
state: Aichi
city: Nagoya
country: Japan
facility: Nagoya University Hospital
state: Aichi
city: Hirosaki
country: Japan
facility: Hirosaki University Hospital
state: Aomori
city: Sumoto
country: Japan
facility: Hyogo Prefectural Awaji Medical Center
state: Awaji
city: Funabashi
country: Japan
facility: Funabashi Municipal Medical Center
state: Chiba
city: Kamogawa
country: Japan
facility: Kameda Medical Center
state: Chiba
city: Urayasu
country: Japan
facility: Juntendo University Urayasu Hospital
state: Chiba
city: Chikushino
country: Japan
facility: Fukuokaken Saiseikai Futsukaichi Hospital
state: Fukuoka
city: Kurume
country: Japan
facility: Kurume University Hospital
state: Fukuoka
city: Ogaki
country: Japan
facility: Ogaki Municipal Hospital
state: Gifu
city: Maebashi
country: Japan
facility: Gunma University Hospital
state: Gunma
city: Kushiro
country: Japan
facility: Kushiro-sanjikai Hospital
state: Hokkaido
city: Sapporo
country: Japan
facility: Medical Corporation Sapporo Heart Center
state: Hokkaido
city: Sapporo
country: Japan
facility: Sapporo Higashi Tokushukai Hospital
state: Hokkaido
city: Tsuchiura
country: Japan
facility: Tsuchiura Kyodo General Hospital
state: Ibaraki
city: Morioka
country: Japan
facility: Iwate Prefectural Cyuou Hospital
state: Iwate
city: Isehara
country: Japan
facility: Tokai University Hospital
state: Kanagawa
city: Kamakura
country: Japan
facility: Shonan Kamakura General Hospital
state: Kanagawa
city: Kawasaki
country: Japan
facility: St.Marianna University School of Medicine Hospital
state: Kanagawa
city: Nankoku
country: Japan
facility: Kochi Medical School Hospital
state: Kochi
city: Kashihara
country: Japan
facility: Nara Medical University Hospital
state: Nara
city: Urasoe
country: Japan
facility: Urasoe General Hospital
state: Okinawa
city: Osakasayama
country: Japan
facility: Kindai University Hospital
state: Osaka
city: Suita
country: Japan
facility: National Cerebral and Cardiovascular Center Hospital
state: Osaka
city: Kasukabe
country: Japan
facility: Kasukabe Chuo General Hospital
state: Saitama
city: Kawagoe
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Kawaguchi
country: Japan
facility: Kawaguchi Cardiovascular and Respiratory Hospital
state: Saitama
city: Soka
country: Japan
facility: Soka City Hospital
state: Saitama
city: Hamamatsu
country: Japan
facility: Seirei Mikatahara General Hospital
state: Shizuoka
city: Izunokuni
country: Japan
facility: Juntendo University Shizuoka Hospital
state: Shizuoka
city: Utsunomiya
country: Japan
facility: Saiseikai Utsunomiya Hospital
state: Tochigi
city: Adachi
country: Japan
facility: Nishiarai Hospital
state: Tokyo
city: Chiyoda
country: Japan
facility: Mitsui Memorial Hospital
state: Tokyo
city: Fuchū
country: Japan
facility: Sakakibara Heart Institute
state: Tokyo
city: Hachiōji
country: Japan
facility: Tokyo Medical University Hachioji Medical Center
state: Tokyo
city: Minato
country: Japan
facility: International University of Health and Welfare Mita Hospital
state: Tokyo
city: Minato
country: Japan
facility: Toranomon Hospital
state: Tokyo
city: Shinjuku
country: Japan
facility: Tokyo Women's Medical University Hospital
state: Tokyo
city: Tachikawa
country: Japan
facility: National Disaster Medical Center
state: Tokyo
city: Fukuoka
country: Japan
facility: Japanese Red Cross Fukuoka Hospital
city: Gifu
country: Japan
facility: Gifu University Graduate school of Medicine
city: Hiroshima
country: Japan
facility: Hiroshima City Hospital
city: Kanagawa
country: Japan
facility: Kitasato University Hospital
city: Kochi
country: Japan
facility: Chikamori Hospital
city: Nara
country: Japan
facility: Nara Prefecture General Medical Center
city: Okayama
country: Japan
facility: Sakakibara Heart Institute of Okayama
city: Okinawa
country: Japan
facility: Nakagami Hospital
city: Osaka
country: Japan
facility: Kitano Hospital
city: Osaka
country: Japan
facility: Osaka General Medical Center
city: Saitama
country: Japan
facility: Saitama Citizens Medical Center
city: Tokushima
country: Japan
facility: Tokushima University Hospital
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tokyo
country: Japan
facility: Juntendo University Nerima Hospital
city: Tokyo
country: Japan
facility: Nihon University Itabashi Hospital
city: Tokyo
country: Japan
facility: Nippon Medical School Hospital
city: Tokyo
country: Japan
facility: St. Luke's International Hospital
city: Tokyo
country: Japan
facility: Tokyo General Hospital
city: Tokyo
country: Japan
facility: Tokyo Medical University
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Bokutoh Hospital
city: Yokohama
country: Japan
facility: Yokohama City University Medical Center
Study officials:
affiliation: Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
name: Yuya Matsue, MD
role: PRINCIPAL_INVESTIGATOR
References: