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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Heart Failure
• Intervention / Treatment: Drug: Empagliflozin 10 MG; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 500
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Yuya Matsue, MD; Phone Number: 81-3-3813-3111; Email: yuya8950@gmail.com

Study Locations

• Japan
  • Fukuoka, Japan
    • Recruiting
    • Japanese Red Cross Fukuoka Hospital
    • Contact: Ryuichi Matsukawa
  • Hiroshima, Japan
    • Recruiting
    • Hiroshima City Hospital
    • Contact: Tadanao Higaki
  • Kochi, Japan
    • Recruiting
    • Chikamori Hospital
    • Contact: Hayato Hosoda
  • Nara, Japan
    • Recruiting
    • Nara Prefecture General Medical Center
    • Contact: Hiroyuki Kawata
  • Okayama, Japan
    • Recruiting
    • Sakakibara Heart Institute of Okayama
    • Contact: Akihiro Hayashida
  • Okinawa, Japan
    • Recruiting
    • Nakagami Hospital
    • Contact: Satoshi Yamaguchi
  • Osaka, Japan
    • Recruiting
    • Kitano Hospital
    • Contact: Shinya Ito
  • Osaka, Japan
    • Recruiting
    • Osaka General Medical Center
    • Contact: Atsushi Kikuchi
  • Saitama, Japan
    • Recruiting
    • Saitama Citizens Medical Center
    • Contact: Tomohiro Nakamura
  • Tokushima, Japan
    • Recruiting
    • Tokushima University Hospital
    • Contact: Takayuki Ise
  • Tokyo, Japan
    • Recruiting
    • Juntendo University Hospital
    • Contact: Yuya Matsue
  • Tokyo, Japan
    • Recruiting
    • Juntendo University Nerima Hospital
    • Contact: Kikuo Isoda
  • Tokyo, Japan
    • Recruiting
    • Nihon University Itabashi Hospital
    • Contact: Yuki Saito
  • Tokyo, Japan
    • Recruiting
    • Tokyo Medical University
    • Contact: Masatake Kobayashi
  • Tokyo, Japan
    • Recruiting
    • Tokyo Metropolitan Bokutoh Hospital
    • Contact: Koichi Ohashi
  • Yokohama, Japan
    • Recruiting
    • Yokohama City University Medical Center
    • Contact: Yasushi Matsuzawa
  • Aichi
    • Anjo, Aichi, Japan
      • Not yet recruiting
      • Anjo Kosei Hospital
      • Contact: Yusuke Uemura
    • Nagoya, Aichi, Japan
      • Recruiting
      • Nagoya University Hospital
      • Contact: Takahiro Okumura
  • Aomori
    • Hirosaki, Aomori, Japan
      • Recruiting
      • Hirosaki University Hospital
      • Contact: Kimitaka Nishizaki
  • Awaji
    • Sumoto, Awaji, Japan
      • Recruiting
      • Hyogo Prefectural Awaji Medical Center
      • Contact: Koji Kuroda
  • Chiba
    • Funabashi, Chiba, Japan
      • Recruiting
      • Funabashi Municipal Medical Center
      • Contact: Shinichi Okino
    • Kamogawa, Chiba, Japan
      • Recruiting
      • Kameda Medical Center
      • Contact: Akira Mizukami
    • Urayasu, Chiba, Japan
      • Recruiting
      • Juntendo University Urayasu Hospital
      • Contact: Shohei Ouchi
  • Fukuoka
    • Chikushino, Fukuoka, Japan
      • Recruiting
      • Fukuokaken Saiseikai Futsukaichi Hospital
      • Contact: Ken Onitsuka
    • Kurume, Fukuoka, Japan
      • Recruiting
      • Kurume University Hospital
      • Contact: Tatsuhiro Shibata
  • Gunma
    • Maebashi, Gunma, Japan
      • Recruiting
      • Gunma University Hospital
      • Contact: Masaru Obokata
  • Hokkaido
    • Sapporo, Hokkaido, Japan
      • Recruiting
      • Sapporo Higashi Tokushukai Hospital
      • Contact: Yasunobu Goto
  • Hyogo
    • Himeji, Hyogo, Japan
      • Not yet recruiting
      • Hyogo Brain and Heart Center
      • Contact: Shogo Oishi
  • Ibaraki
    • Tsuchiura, Ibaraki, Japan
      • Recruiting
      • Tsuchiura Kyodo General Hospital
      • Contact: Tsunekazu Kakuta
  • Iwate
    • Morioka, Iwate, Japan
      • Recruiting
      • Iwate Prefectural Cyuou Hospital
      • Contact: Masanobu Miura
  • Kanagawa
    • Isehara, Kanagawa, Japan
      • Recruiting
      • Tokai University Hospital
      • Contact: Takeshi Ijichi
    • Kawasaki, Kanagawa, Japan
      • Recruiting
      • St.Marianna University School of Medicine Hospital
      • Contact: Keisuke Kida
  • Kochi
    • Nankoku, Kochi, Japan
      • Recruiting
      • Kochi Medical School Hospital
      • Contact: Toru Kubo
  • Nara
    • Kashihara, Nara, Japan
      • Recruiting
      • Nara Medical University Hospital
      • Contact: Kazutaka Nogi
  • Okinawa
    • Urasoe, Okinawa, Japan
      • Recruiting
      • Urasoe General Hospital
      • Contact: Masami Abe
  • Osaka
    • Osakasayama, Osaka, Japan
      • Recruiting
      • Kindai University Hospital
      • Contact: Koichiro Matsumura
    • Suita, Osaka, Japan
      • Recruiting
      • National Cerebral and Cardiovascular Center Hospital
      • Contact: Takeshi Kitai
  • Saitama
    • Kasukabe, Saitama, Japan
      • Recruiting
      • Kasukabe Chuo General Hospital
      • Contact: Keisuke Nakabayashi
    • Kawagoe, Saitama, Japan
      • Recruiting
      • Saitama Medical Center
      • Contact: Kentaro Jujo
    • Kawaguchi, Saitama, Japan
      • Recruiting
      • Kawaguchi Cardiovascular and Respiratory Hospital
      • Contact: Eiichi Akiyama
    • Soka, Saitama, Japan
      • Recruiting
      • Soka City Hospital
      • Contact: Hiroshi Inagaki
  • Shizuoka
    • Izunokuni, Shizuoka, Japan
      • Recruiting
      • Juntendo University Shizuoka Hospital
      • Contact: Satoru Suwa
  • Tochigi
    • Utsunomiya, Tochigi, Japan
      • Recruiting
      • Saiseikai Utsunomiya Hospital
      • Contact: Kayo Misumi
  • Tokyo
    • Adachi, Tokyo, Japan
      • Recruiting
      • Nishiarai Hospital
      • Contact: Jujo Kentaro
    • Chiyoda, Tokyo, Japan
      • Recruiting
      • Mitsui Memorial Hospital
      • Contact: Yu Horiuchi
    • Fuchū, Tokyo, Japan
      • Recruiting
      • Sakakibara Heart Institute
      • Contact: Mamoru Nanasato
    • Hachiōji, Tokyo, Japan
      • Recruiting
      • Tokyo Medical University Hachioji Medical Center
      • Contact: Nobuhiro Tanaka
    • Minato, Tokyo, Japan
      • Not yet recruiting
      • International University of Health and Welfare MITA Hospital
      • Contact: Yuichi Tamura
    • Minato, Tokyo, Japan
      • Not yet recruiting
      • Toranomon Hospital
      • Contact: Tetsuo Yamaguchi
    • Shinjuku, Tokyo, Japan
      • Recruiting
      • Tokyo Women's Medical University Hospital
      • Contact: Nobuhisa Hagiwara
    • Tachikawa, Tokyo, Japan
      • Recruiting
      • National Disaster Medical Center
      • Contact: Kazuto Hayasaka

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Juntendo University
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Yuya Matsue, MD, Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2022
• Primary Completion (Estimated): March 31, 2025
• Study Completion (Estimated): June 30, 2025

Study Registration Dates

• First Submitted: May 14, 2022
• First Submitted That Met QC Criteria: May 20, 2022
• First Posted (Actual): May 26, 2022

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: jRCTs031210682

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No