Clinical trial NCT04157751: A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure
Official title: A Multicentre, Randomised, Double-blind, 90-day Superiority Trial to Evaluate the Effect on Clinical Benefit, Safety and Tolerability of Once Daily Oral EMPagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for acUte Heart faiLure (de Novo or Decompensated Chronic HF) Who Have Been StabilisEd (EMPULSE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
Collaborators: name: Eli Lilly and Company
First posted: 2019-11-08
Enrollment: 530
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Up to 90 days. For KCCQ-TSS: at baseline and at day 90.
Secondary outcomes:
measure: Number of Participants With Improvement of at Least 10 Points in KCCQ-TSS After 90 Days of Treatment
timeFrame: At baseline and at day 90.
measure: Change From Baseline in KCCQ-TSS After 90 Days of Treatment
timeFrame: At baseline, at day 15, 30 and at day 90.
measure: Change From Baseline in Log-transformed N-Terminal Pro-Brain Natriuretic Peptide (NTproBNP) Area Under the Curve (AUC) Over 30 Days of Treatment
timeFrame: From baseline to day 30.
measure: Percentage of Days Alive and Out of Hospital (DAOH) From Study Drug Initiation Until 30 Days After Initial Hospital Discharge
timeFrame: Up to 30 days after initial hospital discharge.
measure: Percentage of Days Alive and Out of Hospital (DAOH) From Study Drug Initiation Until 90 Days After Randomisation
timeFrame: Up to 90 days after randomisation.
measure: Incidence Rate of First Occurrence of Cardiovascular (CV) Death or Heart Failure Event (HFE) Until End of Trial Visit
timeFrame: Up to 127 days.
measure: Number of Participants With Hospitalization for Heart Failure (HHF) Until 30 Days After Initial Hospital Discharge
timeFrame: Up to 30 days after initial hospital discharge.
measure: Composite Renal Endpoint: Number of Participants With Chronic Dialysis, Renal Transplant, Sustained Reduction in eGFR(CKD-EPI)cr
timeFrame: Up to 90 days.
measure: Weight Change Per Mean Daily Loop Diuretic Dose After 15 Days of Treatment
timeFrame: At baseline and at day 15.
measure: Weight Change Per Mean Daily Loop Diuretic Dose After 30 Days of Treatment
timeFrame: At baseline and at day 30.
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: Torrance
country: United States
facility: The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
state: California
city: Daytona Beach
country: United States
facility: Cardiology Associates Research Co.
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Health Jacksonville
state: Florida
city: Atlanta
country: United States
facility: Grady Memorial Hospital
state: Georgia
city: Peoria
country: United States
facility: Methodist Medical Center
state: Illinois
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Jackson
country: United States
facility: University Of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Elmer
country: United States
facility: Cardiovascular Associates of the Delaware Valley
state: New Jersey
city: Washington Township
country: United States
facility: Jefferson Washington Township Hospital
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: Erie County Medical Center
state: New York
city: Greenvale
country: United States
facility: The DeMatteis Center for Cardiac Research and Education
state: New York
city: Stony Brook
country: United States
facility: Stony Brook Medicine
state: New York
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill
state: North Carolina
city: Raleigh
country: United States
facility: North Carolina Heart and Vascular
state: North Carolina
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Oklahoma City
country: United States
facility: South Oklahoma Heart Research Group
state: Oklahoma
city: Charleston
country: United States
facility: Ralph H. Johnson VA Medical Center
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Amarillo
country: United States
facility: Pharmatex Research
state: Texas
city: Plano
country: United States
facility: Center for Advanced Cardiac Care - Heart Failure Clinic
state: Texas
city: Falls Church
country: United States
facility: Inova Fairfax Medical Campus
state: Virginia
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Aalst
country: Belgium
facility: Aalst - HOSP Onze-Lieve-Vrouw
city: Brussel
country: Belgium
facility: Brussels - UNIV UZ Brussel
city: Dendermonde
country: Belgium
facility: AZ Sint-Blasius
city: Genk
country: Belgium
facility: Ziekenhuis Oost-Limburg - Campus Sint-Jan
city: Leuven
country: Belgium
facility: UZ Leuven
city: Liège
country: Belgium
facility: Liège - HOSP CHR de la Citadelle
city: Mons
country: Belgium
facility: UNIV Ambroise Paré
city: Victoria
country: Canada
facility: Royal Jubilee Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Beijing
country: China
facility: Beijing Chao-Yang Hospital
city: Beijing
country: China
facility: Beijing AnZhen Hospital
city: Changchun
country: China
facility: The First Hospital of Jilin University
city: Chengdu
country: China
facility: West China Hospital
city: Xiamen
country: China
facility: Xiamen Cardiovascular Hospital Xiamen University
city: Xian
country: China
facility: First Affiliated Hospital of Xi'an JiaoTong University
city: Brno
country: Czechia
facility: University Hospital Brno
city: Brno
country: Czechia
facility: Univ.Hosp U Svate Anny, I.Internal Clinic-Cardiology,Brno
city: Prag
country: Czechia
facility: University Hospital Motol
city: Tabor
country: Czechia
facility: District Hospital, Tabor
city: Aalborg
country: Denmark
facility: Aalborg Universitetsshospital
city: Frederiksberg
country: Denmark
facility: Frederiksberg Hospital
city: Herlev
country: Denmark
facility: Herlev and Gentofte Hospital
city: Hvidovre
country: Denmark
facility: Hvidovre Hospital
city: Viborg
country: Denmark
facility: Viborg Regionhospital
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Bremen
country: Germany
facility: Bremer Institut für Herz- und Kreislaufforschung (BIHKF) am Klinikum Links der Weser
city: Dresden
country: Germany
facility: Herzzentrum Dresden GmbH Universitätsklinik
city: Freiburg
country: Germany
facility: Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen und Marburg GmbH
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Langen
country: Germany
facility: Asklepios Klinik Langen-Seligenstadt GmbH
city: Leverkusen
country: Germany
facility: Klinikum Leverkusen gGmbH, Leverkusen
city: Ludwigshafen
country: Germany
facility: Klinikum der Stadt Ludwigshafen am Rhein gGmbH
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein, Campus Lübeck
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg AÖR
city: Budapest
country: Hungary
facility: Semmelweis University
city: Debrecen
country: Hungary
facility: University Debrecen Hospital
city: Pecs
country: Hungary
facility: University of Pecs
city: Szekesfehervar
country: Hungary
facility: Fejer County Saint George University Teaching Hospital
city: Szentes
country: Hungary
facility: Csongrad Country Dr Bugyi Istvan Hosp.
city: Brescia
country: Italy
facility: ASST degli Spedali Civili di Brescia
city: Catanzaro
country: Italy
facility: Università degli Studi "Magna Grecia" - Campus "S. Venuta"
city: Cortona
country: Italy
facility: Ospedale della Val di Chiana Santa Margherita
city: Foggia
country: Italy
facility: Az.Osp. Universitaria "Ospedali Riuniti"
city: Milano
country: Italy
facility: Centro Cardiologico Monzino-IRCCS
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
city: Piacenza
country: Italy
facility: Osp. Guglielmo da Saliceto AUSL di Piacenza
city: Roma
country: Italy
facility: IRCCS San Raffaele
city: Torino
country: Italy
facility: AO Città della Salute e della
city: Trieste
country: Italy
facility: Azienda Sanitaria Universitaria Giuliano Isontina
city: Fukuoka, Kitakyushu
country: Japan
facility: Japan Community Health Care Organization Kyushu Hospital
city: Ibaraki, Higashiibaraki-gun
country: Japan
facility: Mito Medical Center
city: Kanagawa, Yokohama
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
city: Nagano, Matsumoto
country: Japan
facility: Shinshu University Hospital
city: Okayama, Okayama
country: Japan
facility: The Sakakibara Heart Institute of Okayama
city: Osaka, Suita
country: Japan
facility: Osaka University Hospital
city: Saitama, Kawaguchi
country: Japan
facility: Kawaguchi Cardiovascular and Respiratory Hospital
city: Saitama, Sayama
country: Japan
facility: Saitama Sekishikai Hospital
city: Tokyo, Itabashi-ku
country: Japan
facility: Nihon University Itabashi Hospital
city: 's HERTOGENBOSCH
country: Netherlands
facility: Jeroen Bosch Ziekenhuis-Hertogenbosch
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen Apeldoorn
city: Den Haag
country: Netherlands
facility: HagaZiekenhuis
city: Emmen
country: Netherlands
facility: TREANT Zorggroep
city: Gouda
country: Netherlands
facility: Groene Hart ziekenhuis
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Harderwijk
country: Netherlands
facility: Sint Jansdal Ziekenhuis
city: Leiderdorp
country: Netherlands
facility: Alrijne Leiderdorp
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis, locatie Roosendaal
city: Utrecht
country: Netherlands
facility: Diakonessenhuis Utrecht
city: Førde
country: Norway
facility: Helse Førde HF, Førde Sentralsjukehus
city: Lillehammer
country: Norway
facility: Sykehuset Innlandet HF, Avd. Lillehammer
city: Lørenskog
country: Norway
facility: Akershus Universitetssykehus HF
city: Stavanger
country: Norway
facility: Helse Stavanger, Stavanger Universitetssykehus
city: Tromsø
country: Norway
facility: Universitetssykehuset Nord-Norge, Tromsø
city: Gdynia
country: Poland
facility: Saint Wincenty a Paulo Hosp., Cardiology Dept., Gdynia
city: Lodz
country: Poland
facility: Card.Cli.Mil.Med.Ac.Uni.Cli.Hosp. Cent.Vetera.Hosp.Lodz
city: Lodz
country: Poland
facility: Cent.Clin.Hosp.Med.Univ.Lodz,Electrocard
city: Lodz
country: Poland
facility: Provincial Specialist M. Kopernik Hospital
city: El Palmar
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: L'Hospitalet de Llobregat
country: Spain
facility: Hospital de Bellvitge
city: Majadahonda
country: Spain
facility: Hospital Puerta de Hierro
city: Malaga
country: Spain
facility: Hospital Virgen de la Victoria
city: Sant Joan Despi
country: Spain
facility: Hospital Moises Broggi
city: Sevilla
country: Spain
facility: Hospital Nuestra Señora de Valme
city: Valencia
country: Spain
facility: Hospital Clínico de Valencia
city: Göteborg
country: Sweden
facility: Sahlgrenska US, Göteborg
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset, Östra
Study officials:
References:
citation: Kosiborod MN, Angermann CE, Collins SP, Teerlink JR, Ponikowski P, Biegus J, Comin-Colet J, Ferreira JP, Mentz RJ, Nassif ME, Psotka MA, Tromp J, Brueckmann M, Blatchford JP, Salsali A, Voors AA. Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial. Circulation. 2022 Jul 26;146(4):279-288. doi: 10.1161/CIRCULATIONAHA.122.059725. Epub 2022 Apr 4.
citation: Voors AA, Angermann CE, Teerlink JR, Collins SP, Kosiborod M, Biegus J, Ferreira JP, Nassif ME, Psotka MA, Tromp J, Borleffs CJW, Ma C, Comin-Colet J, Fu M, Janssens SP, Kiss RG, Mentz RJ, Sakata Y, Schirmer H, Schou M, Schulze PC, Spinarova L, Volterrani M, Wranicz JK, Zeymer U, Zieroth S, Brueckmann M, Blatchford JP, Salsali A, Ponikowski P. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022 Mar;28(3):568-574. doi: 10.1038/s41591-021-01659-1. Epub 2022 Feb 28.