A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure

Phase 3

Completed

Conditions: Heart Failure

Interventions: Drug: Empagliflozin
Drug: Placebo to Empagliflozin

Registration Number: NCT04157751

Lead Sponsor: Boehringer Ingelheim

Brief Summary: This is a study in adults who are in hospital for acute heart failure. The purpose of this study is to find out whether starting to take a medicine called empagliflozin soon after first being treated in hospital helps people with acute heart failure.

Participants are in the study for about 3 months. At the beginning, participants are still in hospital. Later, they visit the hospital about 3 times and get 1 phone call. Participants are put into 2 groups by chance. One group takes 1 empagliflozin tablet a day. The other group takes

1 placebo tablet a day. Placebo tablets look like empagliflozin tablets but do not contain any medicine. Empagliflozin belongs to a class of medicines known as SGLT-2 inhibitors. It is used to treat type 2 diabetes.

During the study, the doctors check whether participants have additional heart failure events like needing to go to the hospital again because of heart failure. The participants answer questions about how their heart failure affects their life. We then compare the results between the empagliflozin and placebo groups. The doctors also regularly check the general health of the participants.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 530

Inclusion Criteria

Currently hospitalised for the primary diagnosis of acute heart failure (de novo or decompensated chronic HF), regardless of ejection fraction (EF). Patients with a diagnosis of hospitalized heart failure must have HF symptoms at the time of hospital admission
Evidence of left ventricular ejection fraction (LVEF, either reduced or preserved EF) as per local reading preferably measured during current hospitalisation or in the 12 months prior to randomisation
Patients must be randomised after at least 24 hours and no later than 5 days after admission, as early as possible after stabilization and while still in hospital
Patients must fulfil the following stabilisation criteria (while in the hospital):
- SBP ≥100mm Hg and no symptoms of hypotension in the preceding 6 hours,
- no increase in i.v. diuretic dose for 6 hours prior to randomisation,
- no i.v. vasodilators including nitrates within the last 6 hours prior to randomisation
- no i.v. inotropic drugs for 24 hours prior to randomisation.
Elevated NT-proBNP ≥ 1600pg/mL or BNP ≥400 pg/mL according to the local lab, for patients without atrial fibrillation (AF); or elevated NT-proBNP ≥ 2400pg/mL or BNP ≥600 pg/mL for patients with AF, measured during the current hospitalization or in the 72 hours prior to hospital admission,. For patients treated with an angiotensin receptor neprilysin inhibitor (ARNI) in the previous 4 weeks prior to randomisation, only NT-proBNP values should be used
HF episode leading to hospitalisation must have been treated with a minimum single dose of 40 mg of i.v. furosemide (or equivalent i.v. loop diuretic defined as 20 mg of torasemide or 1 mg of bumetanide)
Further Inclusion Criteria Apply

Exclusion Criteria

Cardiogenic shock
Current hospitalisation for acute heart failure primarily triggered by pulmonary embolism, cerebrovascular accident, or acute myocardial infarction (AMI)
Current hospitalisation for acute heart failure not caused primarily by intravascular volume overload;
Below interventions in the past 30 days prior to randomisation or planned during the study:
- Major cardiac surgery, or TAVI (Transcatheter Aortic Valve Implantation), or PCI, or Mitraclip
- All other surgeries that are considered major according to investigator judgement
- Implantation of cardiac resynchronisation therapy (CRT) device
- cardiac mechanical support implantation
- Carotid artery disease revascularisation (stent or surgery)
Acute coronary syndrome / myocardial infarction, stroke or transient ischemic attack (TIA) in the past 90 days prior to randomisation
Heart transplant recipient, or listed for heart transplant with expectation to receive a transplant during the course of this trial (according to investigator judgement), or planned for palliative care for HF, or currently using left ventricular assist device (LVAD) or intra-aortic balloon pump (IABP) or any other type of mechanical circulatory support, or patients on mechanical ventilation, or patients with planned inotropic support in an outpatient setting
Haemodynamically significant (severe) uncorrected primary cardiac valvular disease planned for surgery or intervention during the course of the study (note: secondary mitral regurgitation or tricuspid regurgitation due to dilated cardiomyopathy is not excluded unless planned for surgery or intervention during the course of the study)
Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 as measured during hospitalization (latest local lab measurement before randomisation) or requiring dialysis
Type 1 Diabetes Mellitus (T1DM)
History of ketoacidosis, including diabetic ketoacidosis (DKA)
Further Exclusion Criteria Apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Empagliflozin	Empagliflozin	-
Placebo	Placebo to Empagliflozin	-

Primary Outcome Measures

Name	Time	Method
Percentage of Pairwise Comparisons With Wins of Clinical Benefit, a Composite of Death, Number of Heart Failure Events (HFEs), Time to the First HFE and ≥5-point Difference in CfB in KCCQ-TSS After 90 Days of Treatment	Up to 90 days. For KCCQ-TSS: at baseline and at day 90.	Clinical benefit, a composite of death, number of HFEs, time to first HFE and change from baseline (CfB) in Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) after 90 days of treatment. All patients randomised to empagliflozin are compared to all patients randomised to placebo within strata. For any two patients, a patient will win, i.e. achieve a better clinical outcome, as determined by assessing the following criteria sequentially, stopping when an advantage for either patient is shown: 1. Death: death is worse than no death; earlier death is worse; tied if not possible to determine. 2. Number of HFEs: more HFEs is worse; tied, if same number of HFEs. 3. Time to first HFE: earlier HFE is worse; tied, if not possible to determine. 4. KCCQ-TSS CfB at Day 90: more positive CfB is better; the threshold for the difference is \>= 5 for a win; tied, if difference \< 5. The KCCQ-TSS ranges from 0 to 100, where a higher score reflects a better outcome. pct. = percentage

Secondary Outcome Measures

Name	Time	Method
Incidence Rate of First Occurrence of Cardiovascular (CV) Death or Heart Failure Event (HFE) Until End of Trial Visit	Up to 127 days.	Incidence rate of first occurrence of CV death or HFE until end of trial visit per 100 patient-year (pt-yrs) at risk is reported. Incidence rate per 100 pt-yrs = 100\* number of patients with event / time at risk \[years\].
Number of Participants With Improvement of at Least 10 Points in KCCQ-TSS After 90 Days of Treatment	At baseline and at day 90.	Number of participants with improvement of at least 10 points in Kansas City Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-TSS) from baseline after 90 days of treatment. The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire that includes 23 items that map to 7 domains: symptom frequency, symptom burden, symptom stability, physical limitations, social limitations, quality of life and self-efficacy. The symptom frequency and symptom burden domains are merged into the total symptom score. Scores are represented on a 0-to-100-point scale, where a higher score reflects a better health status.
Change From Baseline in KCCQ-TSS After 90 Days of Treatment	At baseline, at day 15, 30 and at day 90.	Change from baseline in Kansas City Cardiomyopathy Questionnaire - Total Symptom Score (KCCQ-TSS). The Kansas City Cardiomyopathy Questionnaire is a self-administered questionnaire that includes 23 items that map to 7 domains: symptom frequency, symptom burden, symptom stability, physical limitations, social limitations, quality of life and self-efficacy. The symptom frequency and symptom burden domains are merged into the total symptom score. The score is represented on a 0-to-100-point scale, where a higher score reflects a better health status. Change from baseline in KCCQ-TSS at day 90 was modeled using a MMRM with visit (day 15 and day 30) as repeated measures, adjusted mean (standard error) after 90 days of treatment is reported.
Change From Baseline in Log-transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) Area Under the Curve (AUC) Over 30 Days of Treatment	From baseline to day 30.	Change from baseline in log-transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) Area under the curve (AUC) over 30 days of treatment is reported.
Percentage of Days Alive and Out of Hospital (DAOH) From Study Drug Initiation Until 30 Days After Initial Hospital Discharge	Up to 30 days after initial hospital discharge.	The follow-up time for DAOH analyses was defined as 30 days after initial hospital discharge, or time between initial hospital discharge and date of censoring for non-fatal events except for patients who died within the first 30 days, where 30 days was considered as the DAOH follow-up time. DAOH for each patient was calculated as follow-up time subtracted by the number of days in hospital during the 30 days after initial hospital discharge as well as the number of days being dead within the 30 days. Percentage DAOH was defined as DAOH divided by the DAOH follow-up time of each patient multiplied by 100.
Percentage of Days Alive and Out of Hospital (DAOH) From Study Drug Initiation Until 90 Days After Randomisation	Up to 90 days after randomisation.	The follow-up time for DAOH analyses was defined as 90 days after randomisation, or time between randomisation and date of censoring for non-fatal events except for patients who died within the first 90 days, where 90 days was considered as the DAOH follow-up time. DAOH for each patient was calculated as follow-up time subtracted by the number of days in hospital during the 90 days after randomisation as well as the number of days being dead within the first 90 days. Percentage DAOH was defined as DAOH divided by the DAOH follow-up time of each patient multiplied by 100.
Number of Participants With Hospitalization for Heart Failure (HHF) Until 30 Days After Initial Hospital Discharge	Up to 30 days after initial hospital discharge.	Number of participants with hospitalization for heart failure (HHF) until 30 days after initial hospital discharge.
Composite Renal Endpoint: Number of Participants With Chronic Dialysis, Renal Transplant, Sustained Reduction in eGFR(CKD-EPI)cr	Up to 90 days.	The occurrence of the composite renal endpoint: * chronic dialysis (with a frequency of twice per week or more for at least 90 days), or * renal transplant, or * sustained reduction in Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) from baseline of ≥40%, or * sustained eGFR \[mL/min/1.73 m2\] \<15 and baseline value ≥30, or * sustained eGFR \<10 and baseline value \<30; is reported by number of participants with component events. (These events may have occurred after the endpoint was already met. Combinations may not have occurred on the same day). Sustained was determined by 2 or more consecutive post-baseline central laboratory measurements separated by at least 30 days.
Weight Change Per Mean Daily Loop Diuretic Dose After 15 Days of Treatment	At baseline and at day 15.	Diuretic effect as assessed by weight change per mean daily loop diuretic dose after 15 days of treatment. Diuretic dose = 40 mg intravenous furosemide or 80 mg oral furosemide. Abbreviation: Kg: Kilogram
Weight Change Per Mean Daily Loop Diuretic Dose After 30 Days of Treatment	At baseline and at day 30.	Diuretic effect as assessed by weight change per mean daily loop diuretic dose after 30 days of treatment. Diuretic dose = 40 mg intravenous furosemide or 80 mg oral furosemide Abbreviation: Kg: Kilogram

Trial Locations

Locations (118): University of Southern California
🇺🇸
Los Angeles, California, United States
Grady Memorial Hospital
🇺🇸
Atlanta, Georgia, United States
Toronto General Hospital
🇨🇦
Toronto, Ontario, Canada
Alrijne Leiderdorp
🇳🇱
Leiderdorp, Netherlands
Bravis ziekenhuis, locatie Roosendaal
🇳🇱
Roosendaal, Netherlands
Diakonessenhuis Utrecht
🇳🇱
Utrecht, Netherlands
Beth Israel Deaconess Medical Center
🇺🇸
Boston, Massachusetts, United States
UNIV Ambroise Paré
🇧🇪
Mons, Belgium
Brussels - UNIV UZ Brussel
🇧🇪
Brussel, Belgium
North Carolina Heart and Vascular
🇺🇸
Raleigh, North Carolina, United States
Inova Fairfax Medical Campus
🇺🇸
Falls Church, Virginia, United States
Bremer Institut für Herz- und Kreislaufforschung (BIHKF) am Klinikum Links der Weser
🇩🇪
Bremen, Germany
Klinikum Leverkusen gGmbH, Leverkusen
🇩🇪
Leverkusen, Germany
District Hospital, Tabor
🇨🇿
Tabor, Czechia
Ziekenhuis Oost-Limburg - Campus Sint-Jan
🇧🇪
Genk, Belgium
University of Florida Health Jacksonville
🇺🇸
Jacksonville, Florida, United States
Jefferson Washington Township Hospital
🇺🇸
Washington Township, New Jersey, United States
The DeMatteis Center for Cardiac Research and Education
🇺🇸
Greenvale, New York, United States
University of Pecs
🇭🇺
Pecs, Hungary
AZ Sint-Blasius
🇧🇪
Dendermonde, Belgium
Erie County Medical Center
🇺🇸
Buffalo, New York, United States
Pharmatex Research
🇺🇸
Amarillo, Texas, United States
Sentara Norfolk General Hospital
🇺🇸
Norfolk, Virginia, United States
Charité - Universitätsmedizin Berlin
🇩🇪
Berlin, Germany
Universitetssykehuset Nord-Norge, Tromsø
🇳🇴
Tromsø, Norway
Gelre Ziekenhuizen Apeldoorn
🇳🇱
Apeldoorn, Netherlands
Ospedale della Val di Chiana Santa Margherita
🇮🇹
Cortona, Italy
Az.Osp. Universitaria "Ospedali Riuniti"
🇮🇹
Foggia, Italy
Japan Community Health Care Organization Kyushu Hospital
🇯🇵
Fukuoka, Kitakyushu, Japan
Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH
🇩🇪
Freiburg, Germany
Asklepios Klinik Langen-Seligenstadt GmbH
🇩🇪
Langen, Germany
Klinikum der Stadt Ludwigshafen am Rhein gGmbH
🇩🇪
Ludwigshafen, Germany
Herzzentrum Dresden GmbH Universitätsklinik
🇩🇪
Dresden, Germany
Akershus Universitetssykehus HF
🇳🇴
Lørenskog, Norway
Hospital Nuestra Señora de Valme
🇪🇸
Sevilla, Spain
Hospital de Bellvitge
🇪🇸
L'Hospitalet de Llobregat, Spain
Universitätsklinikum Würzburg AÖR
🇩🇪
Würzburg, Germany
Kanagawa Cardiovascular and Respiratory Center
🇯🇵
Kanagawa, Yokohama, Japan
Universitair Medisch Centrum Groningen
🇳🇱
Groningen, Netherlands
IRCCS San Raffaele
🇮🇹
Roma, Italy
Hospital Clínico de Valencia
🇪🇸
Valencia, Spain
Mito Medical Center
🇯🇵
Ibaraki, Higashiibaraki-gun, Japan
Groene Hart ziekenhuis
🇳🇱
Gouda, Netherlands
Sahlgrenska Universitetssjukhuset, Östra
🇸🇪
Göteborg, Sweden
Centro Cardiologico Monzino-IRCCS
🇮🇹
Milano, Italy
Saitama Sekishikai Hospital
🇯🇵
Saitama, Sayama, Japan
Hospital Universitario Virgen de la Arrixaca
🇪🇸
El Palmar, Spain
Hospital Moises Broggi
🇪🇸
Sant Joan Despi, Spain
The Sakakibara Heart Institute of Okayama
🇯🇵
Okayama, Okayama, Japan
Hospital Puerta de Hierro
🇪🇸
Majadahonda, Spain
Jeroen Bosch Ziekenhuis-Hertogenbosch
🇳🇱
's HERTOGENBOSCH, Netherlands
TREANT Zorggroep
🇳🇱
Emmen, Netherlands
Sahlgrenska US, Göteborg
🇸🇪
Göteborg, Sweden
Nihon University Itabashi Hospital
🇯🇵
Tokyo, Itabashi-ku, Japan
Hospital Virgen de la Victoria
🇪🇸
Malaga, Spain
The First Hospital of Jilin University
🇨🇳
Changchun, China
Aalborg Universitetsshospital
🇩🇰
Aalborg, Denmark
Frederiksberg Hospital
🇩🇰
Frederiksberg, Denmark
Viborg Regionhospital
🇩🇰
Viborg, Denmark
ASST degli Spedali Civili di Brescia
🇮🇹
Brescia, Italy
Università degli Studi "Magna Grecia" - Campus "S. Venuta"
🇮🇹
Catanzaro, Italy
ASST Grande Ospedale Metropolitano Niguarda
🇮🇹
Milano, Italy
Osp. Guglielmo da Saliceto AUSL di Piacenza
🇮🇹
Piacenza, Italy
AO Città della Salute e della
🇮🇹
Torino, Italy
Shinshu University Hospital
🇯🇵
Nagano, Matsumoto, Japan
Kawaguchi Cardiovascular and Respiratory Hospital
🇯🇵
Saitama, Kawaguchi, Japan
Osaka University Hospital
🇯🇵
Osaka, Suita, Japan
University Of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Sykehuset Innlandet HF, Avd. Lillehammer
🇳🇴
Lillehammer, Norway
Card.Cli.Mil.Med.Ac.Uni.Cli.Hosp. Cent.Vetera.Hosp.Lodz
🇵🇱
Lodz, Poland
Csongrad Country Dr Bugyi Istvan Hosp.
🇭🇺
Szentes, Hungary
Helse Stavanger, Stavanger Universitetssykehus
🇳🇴
Stavanger, Norway
Cent.Clin.Hosp.Med.Univ.Lodz,Electrocard
🇵🇱
Lodz, Poland
Royal Jubilee Hospital
🇨🇦
Victoria, British Columbia, Canada
Semmelweis University
🇭🇺
Budapest, Hungary
University Debrecen Hospital
🇭🇺
Debrecen, Hungary
Provincial Specialist M. Kopernik Hospital
🇵🇱
Lodz, Poland
Universitätsklinikum Gießen und Marburg GmbH
🇩🇪
Gießen, Germany
Stony Brook Medicine
🇺🇸
Stony Brook, New York, United States
UZ Leuven
🇧🇪
Leuven, Belgium
Cardiology Associates Research Co.
🇺🇸
Daytona Beach, Florida, United States
The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
🇺🇸
Torrance, California, United States
University of California Irvine
🇺🇸
Orange, California, United States
Methodist Medical Center
🇺🇸
Peoria, Illinois, United States
United Hospital
🇺🇸
Saint Paul, Minnesota, United States
Cardiovascular Associates of the Delaware Valley
🇺🇸
Elmer, New Jersey, United States
West China Hospital
🇨🇳
Chengdu, China
Beijing Chao-Yang Hospital
🇨🇳
Beijing, China
Xiamen Cardiovascular Hospital Xiamen University
🇨🇳
Xiamen, China
St. Boniface General Hospital
🇨🇦
Winnipeg, Manitoba, Canada
Beijing AnZhen Hospital
🇨🇳
Beijing, China
University Hospital Brno
🇨🇿
Brno, Czechia
First Affiliated Hospital of Xi'an JiaoTong University
🇨🇳
Xian, China
University Hospital Motol
🇨🇿
Prag, Czechia
Univ.Hosp U Svate Anny, I.Internal Clinic-Cardiology,Brno
🇨🇿
Brno, Czechia
Hvidovre Hospital
🇩🇰
Hvidovre, Denmark
Herlev and Gentofte Hospital
🇩🇰
Herlev, Denmark
Universitätsklinikum Schleswig-Holstein, Campus Lübeck
🇩🇪
Lübeck, Germany
Universitätsklinikum Jena
🇩🇪
Jena, Germany
Fejer County Saint George University Teaching Hospital
🇭🇺
Szekesfehervar, Hungary
Azienda Sanitaria Universitaria Giuliano Isontina
🇮🇹
Trieste, Italy
HagaZiekenhuis
🇳🇱
Den Haag, Netherlands
Helse Førde HF, Førde Sentralsjukehus
🇳🇴
Førde, Norway
Sint Jansdal Ziekenhuis
🇳🇱
Harderwijk, Netherlands
Saint Wincenty a Paulo Hosp., Cardiology Dept., Gdynia
🇵🇱
Gdynia, Poland
Cedars-Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Aalst - HOSP Onze-Lieve-Vrouw
🇧🇪
Aalst, Belgium
Liège - HOSP CHR de la Citadelle
🇧🇪
Liège, Belgium
Saint Luke's Hospital of Kansas City
🇺🇸
Kansas City, Missouri, United States
University of Nebraska Medical Center
🇺🇸
Omaha, Nebraska, United States
The University of North Carolina at Chapel Hill
🇺🇸
Chapel Hill, North Carolina, United States
University of Oklahoma
🇺🇸
Oklahoma City, Oklahoma, United States
South Oklahoma Heart Research Group
🇺🇸
Oklahoma City, Oklahoma, United States
Ralph H. Johnson VA Medical Center
🇺🇸
Charleston, South Carolina, United States
Vanderbilt University Medical Center
🇺🇸
Nashville, Tennessee, United States
University of Wisconsin
🇺🇸
Madison, Wisconsin, United States
Center for Advanced Cardiac Care - Heart Failure Clinic
🇺🇸
Plano, Texas, United States
Montefiore Medical Center
🇺🇸
Bronx, New York, United States