EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced)

Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Completed
CT.gov ID
NCT03057977
Collaborator
Eli Lilly and Company (Industry)
3,730
520
2
38.7
7.2
0.2

Study Details

Study Description

Brief Summary

The aim of the study is to investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
3730 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase III Randomised, Double-blind Trial to Evaluate Efficacy and Safety of Once Daily Empagliflozin 10 mg Compared to Placebo, in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF)
Actual Study Start Date :
Mar 6, 2017
Actual Primary Completion Date :
May 1, 2020
Actual Study Completion Date :
May 28, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Empagliflozin

Drug: Empagliflozin
once daily
Other Names:
  • JARDIANCE, JARDIANZ, GIBTULIO
  • Placebo Comparator: Placebo

    Drug: Placebo
    once daily

    Outcome Measures

    Primary Outcome Measures

    1. Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF) [From randomisation until completion of the planned treatment period, up to 1040 days.]

      Time to the first event of adjudicated cardiovascular (CV) death or adjudicated hospitalisation for heart failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

    Secondary Outcome Measures

    1. Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent) [From randomisation until completion of the planned treatment phase, up to 1040 days.]

      Reported is the total number of HHF events (first and recurrent) which occurred. All data up to the end of the planned treatment period (including the data after the end of treatment for patients not completing the treatment period as planned) from all randomised patients was used.

    2. eGFR (CKD-EPI) cr Slope of Change From Baseline [Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days.]

      Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) [mL/min/1.73m2] slope of change from baseline. Available on-treatment change-from-baseline data were to be used. Patients without on-treatment data after randomisation were not to be included in this analysis. Slope represents the long term effect on eGFR. Timepoints after baseline were included in calculation of slope of change from baseline. Descriptive statistic (mean(standard error)) is reported.

    3. Time to First Event in Composite Renal Endpoint: Chronic Dialysis, Renal Transplant or Sustained Reduction of eGFR(CKD-EPI)cr [From randomisation until completion of the planned treatment period, up to 1040 days.]

      Time to the first event in the composite renal endpoint: chronic dialysis (with a frequency of twice per week or more for at least 90 days), 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). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

    4. Time to First Adjudicated Hospitalisation for Heart Failure (HHF) [From randomisation until completion of the planned treatment period, up to 1040 days.]

      Time to first adjudicated Hospitalisation for Heart Failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

    5. Time to Adjudicated Cardiovascular (CV) Death [From randomisation until completion of the planned treatment period, up to 1040 days.]

      Time to adjudicated CV (Cardiovascular) death. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

    6. Time to All-cause Mortality [From randomisation until completion of the planned treatment period, up to 1040 days.]

      Time to all-cause mortality. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

    7. Time to Onset of Diabetes Mellitus (DM) [From randomisation until completion of the planned treatment period, up to 1040 days.]

      Time to onset of DM (Glycated haemoglobin (HbA1c) ≥6.5% or as diagnosed by the investigator) in patients with pre-DM (no history of DM and no HbA1c ≥6.5% before treatment, and a pre-treatment HbA1c value of 5.7 to <6.5%). The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.

    8. Change From Baseline in KCCQ (Kansas City Cardiomyopathy Questionnaire) Clinical Summary Score at Week 52 [Assessed at baseline, week 12, week 32 and week 52.]

      Change from baseline in KCCQ (Kansas City cardiomyopathy questionnaire) clinical summary score at Week 52. The KCCQ is a 23-item self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, selfefficacy, and quality of life in patients with Heart Failure. The KCCQ-clinical summary score comprises the following domains: Symptom frequency, symptom burden and physical limitation. The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status. For patients who died, a worst score (score of 0) is imputed at all subsequent scheduled visits after the date of death. Standard error is adjusted standard error. Change from baseline in KCCQ-score at week 52 was modeled using a MMRM with visit (week 12, 32 and 52) as repeated measures, adjusted mean (standard error) at week 52 is reported.

    9. Number of All-cause Hospitalizations (First and Recurrent) [From randomisation until completion of the planned treatment phase, up to 1040 days.]

      Number of all-cause hospitalizations (first and recurrent).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria:
    • Male or female patient age >= 18 years at screening. For Japan only: Age >= 20 years at screening

    • Patients with chronic HF (Chronic Heart Failure) NYHA (New York Heart Association Classification) class II-IV and reduced EF (Ejection Fraction) (LVEF (Left Ventricular Ejection Fraction) <=40%) and elevated NT-proBNP (N-terminal of the prohormone brain natriuretic peptide)

    • If EF >= 36% to <= 40%: NT-proBNP >= 2500 pg/ml or patients without AF (atrial fibrillation/atrial flutter) and NT-proBNP >= 5000 pg/ml for patients with AF

    • If EF >= 31% to <= 35%: NT-proBNP >= 1000 pg/ml for patients without AF and NT-proBNP >=2000 pg/ml for patients with AF

    • If EF<= 30%: NT-proBNP >= 600 pg/ml for patients without AF and NT-proBNP >=1200 pg/ml for patients with AF

    • EF ≤ 40% and hospitalization for heart failure in the past 12 months: NTproBNP ≥ 600 pg/ml for patients without AF and NT-proBNP >= 1200 pg/ml for patients with AF

    • Appropriate dose of medical therapy for HF consistent with prevailing local and international CV (Cardiovascular) guidelines, stable for at least 1 week prior to Visit 1

    • Appropriate use of medical devices such as cardioverter defibrillator (ICD) or a cardiac resynchronization therapy (CRT) consistent with prevailing local or international CV guidelines

    • Signed and dated written ICF (Informed Consent Form)

    • Further inclusion criteria apply

    Exclusion criteria:
    • Myocardial infarction, coronary artery bypass graft surgery, or other major cardiovascular surgery, stroke or TIA (Transient Ischaemic Attack) in past 90 days prior to Visit 1

    • Heart transplant recipient, or listed for heart transplant

    • Acute decompensated HF

    • Systolic blood pressure (SBP) >= 180 mmHg at Visit 2.

    • Symptomatic hypotension and/or a SBP < 100 mmHg

    • Indication of liver disease

    • Impaired renal function, defined as eGFR (Estimated Glomerular Filtration Rate) < 20 mL/min/1.73 m2 (CKD-EPI (Chronic Kidney Disease - Epidemiology Collaboration Equation)) or requiring dialysis

    • History of ketoacidosis

    • Current use or prior use of a SGLT (Sodium-glucose co-transporter)-2 inhibitor or combined SGLT-1 and 2 inhibitor

    • Currently enrolled in another investigational device or drug study

    • Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors

    • Women who are pregnant, nursing, or who plan to become pregnant while in the trial

    • Further exclusion criteria apply

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 La Mesa Cardiac Center La Mesa California United States 91942
    2 Long Beach Center for Clinical Research Long Beach California United States 90807
    3 VA Greater Los Angeles Healthcare System Los Angeles California United States 90073
    4 Merced Vein and Vascular Center Merced California United States 95340
    5 University of California Irvine Orange California United States 92865
    6 Covigilant Research, LLC Riverside California United States 92506
    7 University of California Torrance California United States 90502
    8 Orange County Research Center Tustin California United States 92780
    9 Blue Coast Cardiology Vista California United States 92083
    10 South Denver Cardiology Associates, PC Littleton Colorado United States 80120
    11 Integrated Heart Care Boca Raton Florida United States 33434
    12 Morton Plant Mease Health Care Clearwater Florida United States 33756
    13 Nature Coast Clinical Research Crystal River Florida United States 34429
    14 Avail Clinical Research, LLC DeLand Florida United States 32720
    15 Holy Cross Hospital Fort Lauderdale Florida United States 33308
    16 Integrative Research Associates Fort Lauderdale Florida United States 33312
    17 Nature Coast Clinical Research Inverness Florida United States 34452
    18 East Coast Institute for Research, LLC Jacksonville Florida United States 32216
    19 Jacksonville Center for Clinical Research Jacksonville Florida United States 32216
    20 Cardiovascular Research Center of South Florida Miami Florida United States 33173
    21 Peninsula Research, Inc. Ormond Beach Florida United States 32174
    22 Cardiology Consultants, Inc Pensacola Florida United States 32501
    23 Sarasota Memorial Hospital Sarasota Florida United States 34239
    24 Grady Clinical Research Center Atlanta Georgia United States 30303
    25 Augusta University Augusta Georgia United States 30912
    26 Columbus Regional Research Institute Columbus Georgia United States 31904
    27 Cardiovascular Group PC Lawrenceville Georgia United States 30046
    28 Meridian Clinical Research, LLC Savannah Georgia United States 31406
    29 Northwest Heart Clinical Research, LLC Arlington Heights Illinois United States 60005
    30 University of Chicago Chicago Illinois United States 60637
    31 Captain James A. Lovell Federal Health Care Center North Chicago Illinois United States 60064
    32 Rockford Cardiovascular Associates Rockford Illinois United States 61107
    33 Midwest Cardiovascular Research and Education Foundation Elkhart Indiana United States 46514
    34 St. Francis Medical Group-Indiana Heart Physicians, Inc Indianapolis Indiana United States 46237
    35 Reid Hospital Richmond Indiana United States 47374
    36 Beacon Medical Group Clinical Research South Bend Indiana United States 46601
    37 Research Integrity, LLC Owensboro Kentucky United States 42303
    38 Cambridge Medical Trials Alexandria Louisiana United States 71301
    39 Louisiana Heart Center Covington Louisiana United States 70433
    40 Clinical Trials of America, LLC Monroe Louisiana United States 71201
    41 Tulane University Hospital and Clinic New Orleans Louisiana United States 70112
    42 Anne Arundel Medical Center Annapolis Maryland United States 21401
    43 Johns Hopkins University Hospital School of Medicine Baltimore Maryland United States 21205
    44 MedStar Health Research Institute Baltimore Maryland United States 21237
    45 Metropolitan Cardiovascular Consultants Beltsville Maryland United States 20705
    46 Spectrum Clinical Research Towson Maryland United States 21204
    47 Tufts Medical Center Boston Massachusetts United States 02111
    48 East Mountain Medical Associates, PC Great Barrington Massachusetts United States 01230
    49 Alpena General Hospital Alpena Michigan United States 49707
    50 Regions Hospital Saint Paul Minnesota United States 55101
    51 Saint Louis University Saint Louis Missouri United States 63110
    52 SLHV Saint Louis Missouri United States 63136
    53 Palm Research Center Las Vegas Nevada United States 89148
    54 Advanced Heart Care, LLC Bridgewater New Jersey United States 08807
    55 Cardiac Care and Vascular Medicine, PLLC Bronx New York United States 10469
    56 Trinity Medical WNY, PC Cheektowaga New York United States 14227
    57 Northwell Health Great Neck New York United States 11021
    58 Mount Sinai School of Medicine Lake Success New York United States 11041
    59 St. Luke's Roosevelt Hospital New York New York United States 10025
    60 Harlem Cardiology New York New York United States 10035
    61 Stony Brook University Medical Center Stony Brook New York United States 11794
    62 Asheville Cardiology Associates Asheville North Carolina United States 28803
    63 Kernodle Clinic West Burlington North Carolina United States 27215
    64 The University of North Carolina at Chapel Hill Chapel Hill North Carolina United States 27599-5021
    65 Novant Health Heart and Vascular Institute Charlotte North Carolina United States 28204
    66 Duke University Medical Center Durham North Carolina United States 27609
    67 Clinical Research of Gastonia Gastonia North Carolina United States 28054
    68 Clinical Trials of America, Inc Lenoir North Carolina United States 28645
    69 Rama Research LLC Marion Ohio United States 43302
    70 University of Toledo Toledo Ohio United States 43614
    71 South Oklahoma Heart Research Group Oklahoma City Oklahoma United States 73135
    72 Doylestown Health Cardiology Doylestown Pennsylvania United States 18901
    73 York Hospital, WellSpan Health York Pennsylvania United States 17403
    74 AnMed Health Clinical Research Anderson South Carolina United States 29621
    75 Ralph H. Johnson VA Medical Center Charleston South Carolina United States 29401
    76 Palmetto Health Columbia South Carolina United States 29203
    77 William Jennings Bryan Dorn VA Medical Center Columbia South Carolina United States 29209
    78 Clinical Research of Rock Hill Rock Hill South Carolina United States 29732
    79 Palmetto Research Center, LLC Spartanburg South Carolina United States 29302
    80 Methodist University Hospital Memphis Tennessee United States 38104
    81 Baylor Heart and Vascular Hospital Dallas Texas United States 75226
    82 Soltero Cardiovascular Research Center Dallas Texas United States 75226
    83 University of Texas Southwestern Medical Center Dallas Texas United States 75390-8837
    84 University of North Texas Health Science Center Fort Worth Texas United States 76107
    85 The Methodist Hospital Houston Texas United States 77030
    86 The Heart Hospital Plano Texas United States 75093
    87 Alpine Research Organization Farmington Utah United States 84025
    88 Cardiac Health Management Network, P.C. Chester Virginia United States 23836
    89 Hunter Holmes McGuire VA Medical Center Richmond Virginia United States 23249
    90 Roanoke Heart Institute PLC Roanoke Virginia United States 24014
    91 Salem VA Medical Center Salem Virginia United States 24153
    92 Marshfield Clinic Marshfield Wisconsin United States 54449
    93 Hospital Interzonal General de Agudos Dr Jose Penna Bahia Blanca Argentina B8001DDU
    94 Hospital Italiano Regional del Sur, Bahia Blanca Bahia Blanca Argentina B8001HXM
    95 CIPREC Caba Argentina C1119ACN
    96 Hospital Italiano de Buenos Aires Caba Argentina C1199ABB
    97 Consultorios Asociados de Endocrinología e Invest Clínica Ciudad Autonoma Buenos Aires Argentina C1425AGC
    98 Instituto Cardiovascular de Buenos Aires Ciudad Autonoma Buenos Aires Argentina C1428ART
    99 CCBR - Buenos Aires - AR Ciudad Autonoma Buenos Aires Argentina C1430CKE
    100 Centro Médico Viamonte Ciudad Autonoma de Bs As Argentina C1120AAC
    101 Sanatorio Güemes Ciudad Autónoma de Bs As Argentina C1180AAX
    102 Instituto Medico Elsa Perez SRL (IMEP) Ciudadela Argentina 1702
    103 Clínica Colombo Cordoba Argentina X5002AOQ
    104 Instituto Médico DAMIC S.R.L. Cordoba Argentina X5003DCE
    105 Clinica Coronel Suarez SA Coronel Suarez Argentina B7540DOL
    106 Instituto de Cardiología de Corrientes Corrientes Argentina W3400AMZ
    107 Sanatorio Mayo Privado SA Córdoba Argentina 5000
    108 Centro de Investigaciones Clinicas Instituto del Corazon Córdoba Argentina X5000EVQ
    109 Sanatorio Allende S.A. Córdoba Argentina X5000JHQ
    110 Hospital Privado Córdoba Argentina X5016KEH
    111 Hospital Italiano de La Plata La Plata Argentina B1900AXI
    112 Centro de Investigaciones Médicas Mar del Plata Argentina B7600FYK
    113 Hospital Privado de Comunidad Mar del Plata Argentina B7602CBM
    114 Clínica Olivos Olivos Argentina 1602
    115 CER Instituto Médico Quilmes Argentina B1878DVB
    116 Instituto de Investigaciones Clínicas de Quilmes Quilmes Argentina B1878GEG
    117 Instituto de Investigaciones Clinicas de Rosario Rosario Argentina 2000
    118 Instituto Medico Fundación Grupo Colaborativo Rosario Rosario Argentina 2000
    119 Sanatorio Británico Rosario Argentina 2000
    120 Sanatorio Plaza Rosario Argentina 2000
    121 Sanatorio Parque Rosario Argentina S2000DSV
    122 Instituto CAICI Rosario Argentina S2000PBJ
    123 CORDIS S.A., Salta Salta Argentina A4400ANW
    124 Centro Cardiovascular Salta Salta Argentina A4406BFP
    125 Corporacion Medica de Gral. San Martin S.A. San Martin Argentina B1650CSQ
    126 Investigaciones Clinicas Tucuman San Miguel de Tucumán Argentina T4000ICL
    127 CCBR Tucuman San Miguel de Tucumán Argentina T4000
    128 Centro Medico Luquez San Vicente Argentina X5006CBI
    129 Centro de Investigaciones Clínicas del Litoral Santa Fe Argentina S3000FWO
    130 Hospital "Dr. José Maria Cullen " Santa Fé Argentina S3000EOZ
    131 Instituto de Cardiología Tucumán Argentina T4000JCU
    132 CEMEDIC - Centro de Especialidades Medicas Villa Luro Argentina C1440CFD
    133 John Hunter Hospital New Lambton Heights New South Wales Australia 2305
    134 CORE Research Group Milton Queensland Australia 4064
    135 Mater Hospital Brisbane South Brisbane Queensland Australia 4101
    136 SA-Heart Ashford Specialist Centre Ashford South Australia Australia 5035
    137 Heart and Vascular Research Fullarton South Australia Australia 5063
    138 The Northern Hospital Epping Victoria Australia 3076
    139 St Vincent's Hospital Melbourne Fitzroy Victoria Australia 3065
    140 University Hospital Geelong Geelong Victoria Australia 3220
    141 Royal Melbourne Hospital Parkville Victoria Australia 3050
    142 AZ Sint-Jan Brugge Brugge Belgium 3000
    143 C.H.U. de Charleroi Charleroi Belgium 6000
    144 AZ Sint-Blasius Dendermonde Belgium 9200
    145 Ziekenhuis Oost-Limburg - Campus Sint-Jan Genk Belgium 3600
    146 AZ Sint-Lucas - Campus Sint Lucas Gent Belgium 9000
    147 Grand Hôpital de Charleroi Gilly Belgium 6060
    148 Jessa Ziekenhuis - Campus Virga Jesse Hasselt Belgium 3500
    149 La Louvière - UNIV CHU Tivoli La Louvière Belgium 7100
    150 UZ Leuven Leuven Belgium 3000
    151 AZ Sint-Maarten Mechelen Belgium 2800
    152 Hospital Felicio Rocho Belo Horizonte Brazil 30110-060
    153 Hospital Vera Cruz Belo Horizonte Brazil 30140-062
    154 Cardresearch Cardiologia Assistencial e de Pesquisas Ltda Belo Horizonte Brazil 30150-240
    155 CCBR - Brasília Brasília Brazil 70200-730
    156 ICDF - Instituto de Cardiologia do Distrito Federal Brasília Brazil 70673-900
    157 CECAP - Centro de Cardiologia Clínica Brasília Brazil 70710-100
    158 Hospital Angelina Caron Campina Grande do Sul Brazil 83430-000
    159 Centro Especializado em Cardiol Loema Instituto de Pesq Clin Campinas Brazil 13010-001
    160 IPECC - Instituto de Pesquisa Clínica de Campinas Campinas Brazil 13060-080
    161 CAEP - Centro Avançado de Estudos e Pesquisas Ltda.,Campinas Campinas Brazil 13087-567
    162 Hospital Universitário Canoas Brazil 92425-900
    163 IPCEM - Instituto de Pesquisa Clínica para Estudos Multicêntricos - Universidade de Caxias do Sul Caxias do Sul Brazil 95070-560
    164 Irmandade da Santa Casa de Misericórdia de Curitiba Curitiba Brazil 80230-130
    165 Hospital de Messejana Dr. Carlos Alberto Studart Gomes Fortaleza Brazil 60846-190
    166 Barroso e Sebba Ltda Goiania Brazil 74223-130
    167 HC-UFG - Hospital das Clínicas da Universidade Federal de Goiás Goiânia Brazil 74605-020
    168 ICM - Instituto do Coracao de Marilia Marília Brazil 17515-000
    169 Hospital São Vicente de Paulo Passo Fundo Brazil 99010-080
    170 Santa Casa de Misericórdia de Porto Alegre Porto Alegre Brazil 90035-074
    171 Centro de Pesquisas em Diabetes Porto Alegre Brazil 90035-170
    172 Hospital de Clínicas de Porto Alegre Porto Alegre Brazil 90035-903
    173 Instituto de Cardiologia Rio Grande do Sul Porto Alegre Brazil 90620-001
    174 Hospital Agamenon Magalhaes Recife Brazil 52051-380
    175 H.C.da Fac. de Medicina de Ribeirao Preto Ribeirão Preto Brazil 14048-900
    176 Hospital Universitário Pedro Ernesto UERJ Rio De Janeiro - RJ Brazil CEP 20551
    177 CCBR - Rio de Janeiro - BR Rio de Janeiro Brazil 22271-100
    178 Pesquisare Santo André Brazil 09080-110
    179 Praxis Pesquisa Médica Santo André Brazil 09090-790
    180 Fundacao Faculdade Regional de Medicina, Sao Jose Sao Jose do Rio Preto Brazil 15090-000
    181 Centro de Pesquisa Clinica - CPCLIN Sao Paulo Brazil 01244-030
    182 FGM - Clínica Paulista de Doenças Cardiovasculares Sao Paulo Brazil 01323-000
    183 CEPIC - Centro Paulista de Investigacao Clinica Sao Paulo Brazil 04266-010
    184 INCOR e Hospital das Clínicas da Universidade de São Paulo Sao Paulo Brazil 05403-000
    185 CEMEC - Centro Multidisciplinar de Estudos Clínicos São Bernardo do Campo Brazil 09780-000
    186 CDEC BRASIL - Centro de Desenvolvimento em Estudos Clínicos Brasil São Paulo Brazil 04020-060
    187 Dr. Consulta São Paulo Brazil 04208-002
    188 CEDOES - Diagnóstico e Pesquisa,Vitória Vitória Brazil 29055-450
    189 Santa Casa de Votuporanga Votuporanga Brazil 15500-003
    190 Royal Alexandra Hospital Edmonton Alberta Canada T5H 3V9
    191 Vancouver General Hospital Vancouver British Columbia Canada V5Z 1M9
    192 St. Paul's Hospital Vancouver British Columbia Canada V6Z 1Y6
    193 Victoria Heart Institute Foundation Victoria British Columbia Canada V8R 4R2
    194 St. Boniface General Hospital Winnipeg Manitoba Canada R2H 2A6
    195 G.A. Research Associates Ltd Moncton New Brunswick Canada E1G 1A7
    196 QEII Health Sciences Centre Halifax Nova Scotia Canada B3H 2Y9
    197 Brampton Cardio Pulmonary Clinic Brampton Ontario Canada L6W 2X7
    198 JBN Medical Diagnostic Services Inc. Burlington Ontario Canada L7M 4Y1
    199 Cambridge Cardiac Care Inc. Cambridge Ontario Canada N1R 6V6
    200 Curnew Medicine Professional Corporation Hamilton Ontario Canada L8L 0A9
    201 Hamilton General Hospital Hamilton Ontario Canada L8L 2X2
    202 Southlake Regional Health Centre Newmarket Ontario Canada L3Y 2P6
    203 M Heffernan Medicine Professional Corp. Oakville Ontario Canada L6K 3W7
    204 Kawartha Cardiology Clinical Trials Peterborough Ontario Canada K9J 0B2
    205 Heart Health Institute Scarborough Ontario Canada M1B 4Z8
    206 Scarborough Cardiology Research Scarborough Ontario Canada M1E 5E9
    207 Health Sciences North Sudbury Ontario Canada P3E 5J1
    208 Canadian Phase Onward Inc. Toronto Ontario Canada M3J 2C5
    209 North York Diagnostic and Cardiac Centre Toronto Ontario Canada M6B 1N6
    210 Diabetes Heart Research Centre Toronto Ontario Canada M6G 1M2
    211 Mohan Babapulle Medicine Professional Medicine Waterloo Ontario Canada N2T 0C1
    212 Dr. Louis C.H. Yao York Ontario Canada M9N 1W4
    213 ViaCar Recherche Clinique Inc Greenfield Park Quebec Canada J4V 2G8
    214 Centre de Dépistage et Recherche Cardiovasculaire Rive-Sud Longeuil Quebec Canada J4M 2X1
    215 Clinique Santé Cardio MC Montreal Quebec Canada H1T 3Y7
    216 Montreal General Hospital - McGill University Health Centre Montreal Quebec Canada H3G 1A4
    217 McGill University Health Centre (MUHC) Montreal Quebec Canada H4A 3J1
    218 Centre de sante et de services sociaux de Beauce Saint George-de-Beauce Quebec Canada G5Y 4T8
    219 IUCPQ (Laval University) Quebec Canada G1V 4G5
    220 Cardiovascular Institute and Fu Wai Hospital Beijing China 100037
    221 Beijing Friendship Hospital Beijing China 100050
    222 First Hospital of Jilin University Changchun China 130021
    223 Hunan Provincial People's Hospital Changsha China 410005
    224 2nd Xiangya Hospital of Central South University Changsha China 410011
    225 The Third Hospital of Changsha Changsha China 410015
    226 Dongguan People's Hospital Dongguan China 523059
    227 The First Affiliated Hospital of Fujian Medical University Fuzhou China 350005
    228 The First Afiliated Hospital, Sun Yet-sen University Guangzhou China 510080
    229 Guangzhou First Municipal People's Hospital Guangzhou China 510180
    230 Haikou People's Hospital Haikou China 570208
    231 HaiNan Provincial People's Hospital Haikou China 570311
    232 The First Affiliated Hospital of Lanzhou University Lanzhou China 730000
    233 The Second Affiliated Hospital of Lanzhou Medical University Lanzhou China 730030
    234 The Affiliated Hospital of Southwest Medical University Luzhou China 646099
    235 Nanchang University Affiliated 3rd Hospital Nanchang China 330008
    236 First Hospital Affiliated with Nanjing Medical University Nanjing China 210029
    237 Huashan Hospital, Fudan University Shanghai China 200040
    238 General Hospital of Shenyang Military Region Shenyang China 110015
    239 Shengjing Hospital of China Medical University Shenyang China 110072
    240 Tianjin Union Medical Center Nankai University Affiliated Hospital Tianjin China 300121
    241 Tongji Hospital, Tongji University Wuhan China 430030
    242 Renmin Hospital of Wuhan University Wuhan China 430060
    243 First Affiliated Hospital of Xi'an JiaoTong University Xi'an China 710061
    244 Yanbian University Hospital Yanji China 133000
    245 the first people hospital of Yue Yang Yueyang China 414000
    246 Affiliated Hospital of Jiangsu University Zhenjiang China 212013
    247 Poliklinika Humanitas Bilovec Czechia 74301
    248 Medicus Services Ltd. Brandys Nad Czechia 250 01
    249 Internal and Cardiology Practice, MUDr. Karel Kamenik, Brno Brno Czechia 603 00
    250 MUDr. Alexandra Ludkova Brno Czechia 615 00
    251 Vojenska nemocnice Brno Brno Czechia 63600
    252 Nemocnice Milosrdnych bratri Brno Czechia 63900
    253 Edumed s.r.o Broumov Czechia 55001
    254 MUDr. Jan Hubac, s.r.o. Kardiologicka ambulance Chrudim Czechia 53702
    255 Nemocnice ve Frydku-Mistku, prispevkova organizace Frydek-Mistek Czechia 73818
    256 MUDr. Ladislav Busak Louny Czechia 440 01
    257 Zdenek Vomacka Olomouc Czechia 779 00
    258 PV-Kardiologie s.r.o. Pardubice Czechia 53002
    259 University Hospital Motol Prag 5 Czechia 15006
    260 General Faculty Hospital, Prague Prague 2 Czechia 128 08
    261 Thomayer Hospital Praha 4 - Krc Czechia 140 59
    262 Kardio Vaclavik s.r.o. Prerov Czechia 75000
    263 Clinic of Cardiology, Pribram Pribram Czechia 261 01
    264 Hospital Trebic, p.o. Trebic Czechia 67401
    265 Masaryk Hospital, Usti nad Labem Usti nad Labem Czechia 40113
    266 Angiocor s.r.o Zlin Czechia 76001
    267 KIGE s.r.o Znojmo Czechia 66902
    268 HOP de Bayonne Bayonne France 64100
    269 HOP Jean Minjoz Besançon France 25030
    270 HOP Louis Pradel Bron France 69500
    271 HOP Côte de Nacre Caen France 14033
    272 HOP Arnaud de Villeneuve Montpellier France 34295
    273 HOP La Pitié Salpêtrière Paris France 75651
    274 Centre Hospitalier de Pau Pau France 64046
    275 HOP Haut-Lévêque Pessac France 33600
    276 HOP Rangueil Toulouse France 31059
    277 INS Louis Mathieu Vandoeuvre-lès-Nancy France 54511
    278 Universitätsklinikum Aachen, AöR Aachen Germany 52074
    279 Praxis Dr. Rieker, Berlin Berlin Germany 10789
    280 Charité - Universitätsmedizin Berlin Berlin Germany 12200
    281 Vivantes Netzwerk für Gesundheit GmbH Berlin Germany 12351
    282 Charité - Universitätsmedizin Berlin Berlin Germany 13353
    283 Klinikum Bielefeld gGmbH Bielefeld Germany 33604
    284 Praxis Dr. Menzel Dessau-Roßlau Germany 06846
    285 St. Johannes Hospital Dortmund Dortmund Germany 44137
    286 Städtisches Klinikum Dresden Dresden Germany 01067
    287 GWT-TUD GmbH Dresden Germany 01307
    288 Helios Klinikum Erfurt Erfurt Germany 99089
    289 Studienzentrum Bocholderstraße Essen Germany 45355
    290 ClinPhenomics GmbH & Co KG, Frankfurt Frankfurt Germany 60594
    291 Universitätsmedizin Göttingen, Georg-August-Universität Göttingen Germany 37075
    292 Asklepios Klinik St. Georg Hamburg Germany 20099
    293 Medizinische Hochschule Hannover Hannover Germany 30625
    294 Universitätsklinikum Heidelberg Heidelberg Germany 69120
    295 Universitätsklinikum des Saarlandes Homburg Germany 66421
    296 Universitätsklinikum Jena Jena Germany 07740
    297 Universitätsklinikum Schleswig-Holstein, Campus Kiel Kiel Germany 24105
    298 Asklepios Klinik Langen-Seligenstadt GmbH Langen Germany 63225
    299 Märkische Gesundheitsholding GmbH & Co. KG, Klinikum Lüdenscheid Lüdenscheid Germany 58515
    300 Praxis Dr. Sarnighausen, Lüneburg Lüneburg Germany 21339
    301 Katholisches Klinikum St. Hildegardiskrankenhaus, Mainz Mainz Germany 55131
    302 Deutsches Herzzentrum München München Germany 80636
    303 Kardiologische Gemeinschaftspraxis Nienburg Nienburg Germany 31582
    304 Kardiologische Praxis Papenburg Papenburg Germany 26871
    305 Universitätsklinikum Regensburg Regensburg Germany 93053
    306 Praxis Dr. Stenzel, Riesa Riesa Germany 01587
    307 Zentrum für Klinische Forschung Wangen Germany 88239
    308 Josephs-Hospital Warendorf Warendorf Germany 48231
    309 Petrus-Krankenhaus Wuppertal Germany 42283
    310 Lausmed Kft. Outpatient Unit of Internal Medicine Baja Hungary 6500
    311 Belgyogyaszati es Kardiologiai Maganrendelo Bekescsaba Hungary 5600
    312 Clinexpert Kft. Budapest Hungary 1033
    313 Gottsegen Gyorgy Hungarian Instit.of Cardiology,Budapest Budapest Hungary 1096
    314 Bajcsy-Zsilinszky Hospital and Clinic Budapest Hungary 1106
    315 Semmelweis University Budapest Hungary 1122
    316 Milit.Hosp.-State Health Cent. Budapest Hungary 1134
    317 Uzsoki Street Hospital, Budapest Budapest Hungary 1145
    318 Nehezlegzes Ambulancia Debrecen Hungary 4027
    319 Bugat Pal Hospital, Gyongyos Gyongyos Hungary 3200
    320 Selye Janos Hospital Komarom Komarom Hungary 2900
    321 Dorottya Kanizsai Hospital Nagykanizsa Hungary 8800
    322 Dr. Nagy Laszlo Kardiologiai Maganrendeles Oroshaza Hungary 5900
    323 Da Vinci Maganklinika Pecs Hungary 7635
    324 Pecsi Tudomanyegyetem Pécs Hungary 7623
    325 Fejer County Saint George University Teaching Hospital Szekesfehervar Hungary 8000
    326 Veszpremi Sziv es Egeszseg Centrum Veszprem Hungary 8200
    327 Doctor Jivraj Mehta Smarak Health Foundation Ahmedabad India 380007
    328 Kamalnayan Bajaj Hospital Aurangabad India 431 005
    329 Narayana Institute of Cardiac Sciences Bangalore India 560099
    330 Rajarajeswari Medical College Bengaluru India 560074
    331 Madras Medical Mission, Chennai India 600 037
    332 Apollo Speciality Hospital Chennai India 600035
    333 Medanta-The Medicity Gurgaon India 122001
    334 B.M. Birla Heart research Centre Kolkatta India 700027
    335 Siddhi Hospital Nashik India 422007
    336 Vijan Cardiac and Critical Care Centre Nasik India 422005
    337 Batra Hospital and Medical Research Centre New Delhi India 110 062
    338 GB Pant Hospital New Delhi India 110002
    339 Fortis Escorts Heart Institute New Delhi India 110025
    340 Sir Gangaram Hospital New Delhi India 110060
    341 Azienda Ospedaliera G. Rummo Benevento Italy 82100
    342 ASST Papa Giovanni XXIII - A.O. Papa Giovanni XXIII Bergamo Italy 24127
    343 Azienda Ospedaliera Universitaria Arcispedale Sant'Anna Cona (FE) Italy 44124
    344 Ospedale della Val di Chiana Santa Margherita Cortona (AR) Italy 52040
    345 Centro Cardiologico Monzino-IRCCS Milano Italy 20138
    346 Azienda Ospedaliera Universitaria "Federico II" Napoli Italy 80131
    347 Azienda Ospedaliera Universitaria Pisana Pisa Italy 56126
    348 Umberto I Pol. di Roma-Università di Roma La Sapienza Roma Italy 00161
    349 Azienda Ospedaliera Sant'Andrea-Università di Roma La Sapienza Roma Italy 00189
    350 Azienda Servizi Sanitari 1 Triestina Trieste Italy 34128
    351 Kasugai Municipal Hospital Aichi, Kasugai Japan 486-8510
    352 Nagoya Kyoritsu Hospital Aichi, Nagoya Japan 454-0933
    353 Japanese Red Cross Nagoya Daini Hospital Aichi, Nagoya Japan 466-8650
    354 Toyota Memorial Hospital Aichi, Toyota Japan 471-8513
    355 Chiba Heart Clinic Chiba, Chiba Japan 263-0043
    356 Kimitsu Chuo Hospital Chiba, Kisarazu Japan 292-8535
    357 Seikeikai New Tokyo Heart Clinic Chiba, Matsudo Japan 271-0077
    358 Ehime Prefectural Central Hospital Ehime, Matsuyama Japan 790-0024
    359 Matsuyama Shimin Hospital Ehime, Matsuyama Japan 790-0067
    360 Uwajima City Hospital Ehime, Uwajima Japan 798-8510
    361 Fukuiken Saiseikai Hospital Fukui, Fukui Japan 918-8503
    362 Fukuoka University Chikushi Hospital Fukuoka, Chikushino Japan 818-8502
    363 Fukuokaken Saiseikai Futsukaichi Hospital Fukuoka, Chikushino Japan 818-8516
    364 Saiseikai Fukuoka General Hospital Fukuoka, Fukuoka Japan 810-0001
    365 National Hospital Organization Kyushu Medical Center Fukuoka, Fukuoka Japan 810-8563
    366 Kyushu University Hospital Fukuoka, Fukuoka Japan 812-8582
    367 Aso Co.,Ltd Iizuka Hospital Fukuoka, Iizuka Japan 820-8505
    368 Steel Memorial Yawata Hospital Fukuoka, Kitakyushu Japan 805-8508
    369 Japan Community Health Care Organization Kyushu Hospital Fukuoka, Kitakyushu Japan 806-8501
    370 Ogaki Municipal Hospital Gifu, Ogaki Japan 503-8502
    371 Chuno Kosei Hospital Gifu, Seki Japan 501-3802
    372 Fukuyama City Hospital Hiroshima, Fukuyama Japan 721-8511
    373 JA Hiroshima General Hospital Hiroshima, Hatsukaichi Japan 738-8503
    374 Shobara Red Cross Hospital Hiroshima, Shobara Japan 727-0013
    375 National Hospital Organization Hakodate Hospital Hokkaido, Hakodate Japan 041-8512
    376 Teine Keijinkai Clinic Hokkaido, Sapporo Japan 006-0811
    377 Tomakomai City Hospital Hokkaido, Tomakomai Japan 053-8567
    378 Hyogo Prefectural Amagasaki General Medical Center Hyogo, Amagasaki Japan 660-8550
    379 Hyogo Brain and Heart Center Hyogo, Himeji Japan 670-0981
    380 National Hospital Organization Kobe Medical Center Hyogo, Kobe Japan 654-0155
    381 Mito Medical Center Ibaraki, Higashiibaraki-gun Japan 311-3193
    382 National Hospital Organization Kanazawa Medical Center Ishikawa, Kanazawa Japan 920-8650
    383 Mitoyo General Hospital Kagawa, Kanonji Japan 769-1695
    384 Kagawa Prefectural Central Hospital Kagawa, Takamatsu Japan 760-8557
    385 Yamamoto Clinic Kanagawa, Sagamihara Japan 252-0311
    386 Kanagawa Cardiovascular and Respiratory Center Kanagawa, Yokohama Japan 236-0051
    387 Japanese Red Cross Kumamoto Hospital Kumamoto, Kumamoto Japan 861-8520
    388 Seiwakai Suizenji Touya Hospital Kumamoto, Kumamoto Japan 862-0950
    389 Kumamoto Rosai Hospital Kumamoto, Yatsushiro Japan 866-8533
    390 Uji-Tokushukai Medical Center Kyoto, Uji Japan 611-0041
    391 Sendai Kousei Hospital Miyagi, Sendai Japan 980-0873
    392 Sendai Tokushukai Hospital Miyagi, Sendai Japan 981-3131
    393 The Cardiovascular Center of Sendai Miyagi, Sendai Japan 981-3133
    394 National Hospital Organization Sendai Medical Center Miyagi, Sendai Japan 983-8520
    395 Miyazaki Medical Association Hospital Miyazaki, Miyazaki Japan 880-0834
    396 Hokushin General Hospital Nagano, Nakano Japan 383-8505
    397 Nagasaki Medical Center Nagasaki, Omura Japan 856-8562
    398 Okayama City General Medical Center Okayama, Okayama Japan 700-8557
    399 Naha City Hospital Okinawa, Naha Japan 902-8511
    400 Nanbu Tokushukai Hospital Okinawa, Shimajiri-gun Japan 901-0493
    401 Urasoe General Hospital Okinawa, Urasoe Japan 901-2132
    402 Higashiosaka City Medical Center Osaka, Higashiosaka Japan 578-8588
    403 Kitano Hospital Osaka, Osaka Japan 530-8480
    404 Yodogawa Christian Hospital Osaka, Osaka Japan 533-0024
    405 Seichokai Bell Land General Hospital Osaka, Sakai Japan 599-8247
    406 Hokusetsu General Hospital Osaka, Takatsuki Japan 569-8585
    407 San-Ai Hospital Saitama, Saitama Japan 338-0837
    408 Kosekai Iwatsuki-minami Hospital Saitama, Saitama Japan 339-0033
    409 Kusatsu General Hospital Shiga, Kusatsu Japan 525-8585
    410 Tokushima Prefectural Central Hospital Tokushima, Tokushima Japan 770-8539
    411 National Hospital Organization Tokyo Medical Center Tokyo, Meguro-ku Japan 152-8902
    412 Ome Municipal General Hospital Tokyo, Ome Japan 198-0042
    413 Tokyo Rosai Hospital Tokyo, Ota-ku Japan 143-0013
    414 Sekino Hospital Tokyo, Toshima-ku Japan 171-0014
    415 Minami Wakayama Medical Center Wakayama, Tanabe Japan 646-8558
    416 Kanmon Medical Center Yamaguchi, Shimonoseki Japan 752-8510
    417 Dong-A University Hospital Busan Korea, Republic of 602-715
    418 Inje University Busan Paik Hospital Busan Korea, Republic of 614-735
    419 Chungbuk National University Hospital Cheongju Korea, Republic of 361-771
    420 Chungnam National University Hospital Daejeon Korea, Republic of 35015
    421 Gachon University Gil Medical Center Incheon Korea, Republic of 21565
    422 Seoul National University Hospital Seoul Korea, Republic of 03080
    423 Severance Hospital Seoul Korea, Republic of 03722
    424 Asan Medical Center Seoul Korea, Republic of 05505
    425 Samsung Medical Center Seoul Korea, Republic of 06351
    426 Korea University Guro Hospital Seoul Korea, Republic of 08308
    427 Seoul National University Bundang Hospital Sungnam Korea, Republic of 463-707
    428 Wonju Severance Christian Hosp Wonju Korea, Republic of 26426
    429 Hospital Cardiologica Aguascalientes Aguascalientes Mexico 20230
    430 Instituto Nacional de Cardiologia Ignacio Chavez Ciudad de Mexico Mexico 14080
    431 Centro de Investigacion Biomedica y Farmaceutica, S.C. Distrito Federal Mexico 03100
    432 Unidad de Investigacion Clinica Cardiometabolica de Occident Guadalajara Mexico 44150
    433 Diseño y Planeación en Investigación Médica SC Guadalajara Mexico 44656
    434 Cardiologia Clinica e Intervencionista Guadalajara Mexico 44670
    435 Centro de Investigación Clinica Acelerada, S.C. Mexico Mexico 07020
    436 Instituto Cardiovascular de Monclova, S de RL de CV Monclova Mexico 25750
    437 CEDOPEC-Ctro Esp en Diab, Obesidad y Prev de Enf Cardiovasc México Mexico 11650
    438 Hospital Universitario Dr Jose Eleuterio Gonzalez Nuevo Leon Mexico 64460
    439 Centro Integral Medico SJR S.C. San Juan del Rio Mexico 76800
    440 Cardioarritmias e Investigación S.C San Luis Potosi Mexico 78213
    441 Centro de Investigacion Cardiovascular y Metabolica Tijuana Mexico 22500
    442 Centro de Investigacion Medica Alberto Bazzoni S.A. de C.V. Torreon Mexico 27000
    443 Hospital Dr Angel Leano Zapopan Mexico 45200
    444 Ziekenhuisgroep Twente locatie Almelo Almelo Netherlands 7609 PP
    445 BovenIJ Ziekenhuis Amsterdam Netherlands 1034 CS
    446 Onze Lieve Vrouwe Gasthuis, Locatie West Amsterdam Netherlands 1061 AE
    447 Amsterdam UMC Locatie VUMC Amsterdam Netherlands 1081HV
    448 Onze Lieve Vrouwe Gasthuis Amsterdam Netherlands 1091AC
    449 Amsterdam UMC, Locatie AMC Amsterdam Netherlands 1105 AZ
    450 Rode Kruis Ziekenhuis Beverwijk Beverwijk Netherlands 1942 LE
    451 Tergooiziekenhuizen locatie Blaricum Blaricum Netherlands 1261 AN
    452 Amphia Ziekenhuis Breda Netherlands 4818 CK
    453 HMC Bronovo Den Haag Netherlands 2597 AX
    454 Ziekenhuis Gelderse Vallei EDE Netherlands 6716 RP
    455 Catharina Ziekenhuis Eindhoven Netherlands 5623 EJ
    456 Universitair Medisch Centrum Groningen Groningen Netherlands 9713 GZ
    457 Zuyderland Medisch Centrum Heerlen Netherlands 6419 PC
    458 Vasculair Onderzoek Centrum Hoorn Netherlands 1624 NP
    459 Maastricht Universitair Medisch Centrum Maastricht Netherlands 6229 HX
    460 Diaconessenhuis Meppel Meppel Netherlands 7943 KA
    461 St. Antonius ziekenhuis, locatie Nieuwegein Nieuwegein Netherlands 3435 CM
    462 Radboud Universitair Medisch Centrum Nijmegen Netherlands 6525 GL
    463 Ziekenhuis Bernhoven Uden Uden Netherlands 5406 PT
    464 Vie Curi Medisch Centrum Venlo Netherlands 5912 BL
    465 De Heel - Zaans Medisch Centrum Zaandam Netherlands 1502 DV
    466 Gelre Ziekenhuis Zutphen Zutphen Netherlands 7207 AE
    467 KLIMED Marek Klimkiewicz Bialystok Poland 15-765
    468 Univ. Clinic Hosp, Bialystok Bialystok Poland 15276
    469 American Heart of Poland Sp. z o.o. Bielsko-Biala Poland 43-316
    470 NZOZ Centrum Medyczne KERmed Bydgoszcz Poland 85231
    471 Polsko-Amerykanskie Kliniki Serca Chorzow Poland 32-500
    472 American Heart of Poland Sp. z o.o. Dabrowa Gornicza Poland 41-300
    473 Poradnia Kardiologiczna Jaroslaw Jurowiecki Gdansk Poland 80-286
    474 University Clinical Center, Gdansk Gdansk Poland 80952
    475 Indywidualna Specjalistyczna Praktyka Lekarska Gdynia Poland 81-157
    476 Saint Wincenty a Paulo Hosp., Cardiology Dept., Gdynia Gdynia Poland 81348
    477 Szpital Zakonu Bonifratow Sp. z o.o. Katowice Poland 40-211
    478 Specialistic Cardiology&Hypertension Out-patient Clin,Kielce Kielce Poland 25525
    479 Leszek Bryniarski Specialized Medical Cabinet Krakow Poland 30-082
    480 Krakow Specialistic Hospital of John Paul II Krakow Poland 31-202
    481 SANTA FAMILIA Centrum Badan, Profilaktyki i Leczenia Lodz Poland 90-302
    482 Nzoz Salus Lodz Poland 91-302
    483 Individual Specialized Practice Lodz Poland 94-255
    484 Lowickie Cardiology Center Lowicz Poland 99-400
    485 American Heart of Poland Sp. z o.o. Nysa Poland 48-300
    486 Medicome Sp. z o.o. Oswiecim Poland 32-600
    487 Specialized Practice Dr. Janusz Spyra Ruda Slaska Poland 41-709
    488 Centrum Medyczne Medyk Rzeszow Poland 35-055
    489 Lukmed Lukasz Wozniak Siedlce Poland 08-110
    490 Clinmedica Research Omc sp. z o.o. sp.k., Skierniewice Skierniewice Poland 96-100
    491 KO-MED Centra Kliniczne Staszow Staszow Poland 28-200
    492 The Provincial Polyclinical Hospital in Torun Torun Poland 87-100
    493 American Heart of Poland Sp. z o.o. Tychy Poland 43-100
    494 American Heart of Poland Sp. z o.o. Ustron Poland 43-450
    495 Central Hospital of Medical Academy, Warsaw Warsaw Poland 02-097
    496 McM Polimedica Warszawa Poland 02-777
    497 4. Military Clinical Hospital with Polyclinic SP ZOZ Wroclaw Poland 50-981
    498 Zgierskie Center of Cardiology MED-PRO Zgierz Poland 95-100
    499 Specialist Hospital J. Dietla NZOZ Specialized Clinic "Gemini" Zychlin Poland 62-571
    500 Hospital Quiron. I.C.U. Barcelona Spain 08023
    501 Hospital Santa Creu i Sant Pau Barcelona Spain 08026
    502 Hospital Universitario Virgen de la Arrixaca El Palmar Spain 30120
    503 Hospital de Bellvitge L'Hospitalet de Llobregat Spain 08907
    504 Hospital Ramón y Cajal Madrid Spain 28034
    505 Hospital Clínico San Carlos Madrid Spain 28040
    506 Hospital Universitario 12 de Octubre Madrid Spain 28041
    507 Hospital La Paz Madrid Spain 28046
    508 Hospital Virgen de la Victoria Malaga Spain 29010
    509 Complejo Hospitalario Universitario de Orense Orense Spain 32005
    510 Hospital Clínico de Santiago Santiago de Compostela Spain 15706
    511 Hospital Clínico Universitario de Valladolid Valladolid Spain 47003
    512 Barnet General Hospital Barnet United Kingdom EN5 3DJ
    513 University Hospital of Wales Cardiff United Kingdom CF14 4XW
    514 Park & St Francis Surgery Eastleigh United Kingdom SO53 4ST
    515 Wycombe General Hospital High Wycombe United Kingdom HP11 2TT
    516 Glenfield Hospital Leicester United Kingdom LE3 9QP
    517 St Bartholomew's Hospital London United Kingdom EC1A 7BE
    518 Luton and Dunstable University Hospital Luton United Kingdom LU4 0DZ
    519 St Mary's Hospital Newport United Kingdom PO30 5TG
    520 Morriston Hospital Swansea United Kingdom SA6 6NL

    Sponsors and Collaborators

    • Boehringer Ingelheim
    • Eli Lilly and Company

    Investigators

    • Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Boehringer Ingelheim
    ClinicalTrials.gov Identifier:
    NCT03057977
    Other Study ID Numbers:
    • 1245.121
    • 2016-002280-34
    First Posted:
    Feb 20, 2017
    Last Update Posted:
    May 18, 2021
    Last Verified:
    Apr 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details A randomised, double-blind trial to demonstrate superiority of empagliflozin versus placebo, in patients with chronic Heart Failure with reduced Ejection Fraction (HFrEF).
    Pre-assignment Detail Patients were included in the trial after they had signed the informed consent form (ICF). All patients who met the all inclusion and none of the exclusion criteria during screening and at the randomisation approximately 1 to 4 weeks later were randomised to empagliflozin or placebo in a 1:1 ratio.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Period Title: Discontinuation From Treatment
    STARTED 1867 1863
    Treated 1863 1863
    COMPLETED 1352 1381
    NOT COMPLETED 515 482
    Period Title: Discontinuation From Treatment
    STARTED 1867 1863
    Treated 1863 1863
    COMPLETED 1847 1841
    NOT COMPLETED 20 22

    Baseline Characteristics

    Arm/Group Title Placebo 10 mg Empagliflozin Total
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily. Total of all reporting groups
    Overall Participants 1867 1863 3730
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    66.5
    (11.2)
    67.2
    (10.8)
    66.8
    (11.0)
    Sex: Female, Male (Count of Participants)
    Female
    456
    24.4%
    437
    23.5%
    893
    23.9%
    Male
    1411
    75.6%
    1426
    76.5%
    2837
    76.1%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    613
    32.8%
    616
    33.1%
    1229
    32.9%
    Not Hispanic or Latino
    1178
    63.1%
    1164
    62.5%
    2342
    62.8%
    Unknown or Not Reported
    76
    4.1%
    83
    4.5%
    159
    4.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    24
    1.3%
    15
    0.8%
    39
    1%
    Asian
    335
    17.9%
    337
    18.1%
    672
    18%
    Native Hawaiian or Other Pacific Islander
    6
    0.3%
    8
    0.4%
    14
    0.4%
    Black or African American
    134
    7.2%
    123
    6.6%
    257
    6.9%
    White
    1304
    69.8%
    1325
    71.1%
    2629
    70.5%
    More than one race
    33
    1.8%
    28
    1.5%
    61
    1.6%
    Unknown or Not Reported
    31
    1.7%
    27
    1.4%
    58
    1.6%

    Outcome Measures

    1. Primary Outcome
    Title Time to the First Event of Adjudicated Cardiovascular (CV) Death or Adjudicated Hospitalisation for Heart Failure (HHF)
    Description Time to the first event of adjudicated cardiovascular (CV) death or adjudicated hospitalisation for heart failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.
    Time Frame From randomisation until completion of the planned treatment period, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Randomised Set: All randomised patients.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1867 1863
    Number (95% Confidence Interval) [Patients with events/ 100 pt-yrs at risk]
    21.00
    15.77
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments Model with terms for age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment. alpha = 0.0496 (resulting from interim analysis) eGFR (CKP-EPI)cr: Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement LVEF: Left ventricular ejection fraction.
    Type of Statistical Test Superiority
    Comments H0: There is no difference between the effect of placebo and the effect of empagliflozin.
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.75
    Confidence Interval (2-Sided) 95.04%
    0.65 to 0.86
    Parameter Dispersion Type:
    Value:
    Estimation Comments Comparison vs. Placebo [T/P]
    2. Secondary Outcome
    Title Occurrence of Adjudicated Hospitalisation for Heart Failure (HHF) (First and Recurrent)
    Description Reported is the total number of HHF events (first and recurrent) which occurred. All data up to the end of the planned treatment period (including the data after the end of treatment for patients not completing the treatment period as planned) from all randomised patients was used.
    Time Frame From randomisation until completion of the planned treatment phase, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Randomised Set (RS): All randomised patients.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1867 1863
    Number [HHF events]
    553
    388
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments Model accounts for dependence between recurrent HHF and cardiovascular death, with terms for age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment. eGFR (CKP-EPI)cr: Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement LVEF: Left ventricular ejection fraction.
    Type of Statistical Test Superiority
    Comments H0: There is no difference between the effect of placebo and the effect of empagliflozin.
    Statistical Test of Hypothesis p-Value 0.0003
    Comments
    Method Joint frailty model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.70
    Confidence Interval (2-Sided) 95.04%
    0.58 to 0.85
    Parameter Dispersion Type:
    Value:
    Estimation Comments HR vs placebo of recurrent HFF
    3. Secondary Outcome
    Title eGFR (CKD-EPI) cr Slope of Change From Baseline
    Description Glomerular filtration rate estimated by the chronic kidney disease epidemiology collaboration formula with serum creatinine measurement (eGFR (CKD-EPI)cr) [mL/min/1.73m2] slope of change from baseline. Available on-treatment change-from-baseline data were to be used. Patients without on-treatment data after randomisation were not to be included in this analysis. Slope represents the long term effect on eGFR. Timepoints after baseline were included in calculation of slope of change from baseline. Descriptive statistic (mean(standard error)) is reported.
    Time Frame Assessed at baseline, week 4, 12, 32, 52, 76, 100, 124, 148 and at end of treatment (EOT), up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Treated Set (TS): All patients treated with at least one dose of the study medication and at least one on-treatment measurement of eGFR.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1792 1799
    Mean (Standard Error) [Milliliter/minute/1.73 meters squared]
    -2.278
    (0.229)
    -0.546
    (0.227)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments Random coefficient model allowing for random intercept and random slope per patient, with the same factors used for the primary endpoint (age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment) and additional factors "time", "treatment-by-time interaction", and "baseline eGFR (CKD-EPI)cr-by-time interaction". Only "on-treatment" data from treated patients were used. alpha=0.001
    Type of Statistical Test Superiority
    Comments H0: There is no difference between the effect of placebo and the effect of empagliflozin.
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Random intercept random coef. model
    Comments
    Method of Estimation Estimation Parameter Treatment by time interaction
    Estimated Value 1.733
    Confidence Interval (2-Sided) 99.9%
    0.669 to 2.796
    Parameter Dispersion Type:
    Value:
    Estimation Comments Empa vs Placebo slope [/year]
    4. Secondary Outcome
    Title Time to First Event in Composite Renal Endpoint: Chronic Dialysis, Renal Transplant or Sustained Reduction of eGFR(CKD-EPI)cr
    Description Time to the first event in the composite renal endpoint: chronic dialysis (with a frequency of twice per week or more for at least 90 days), 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). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.
    Time Frame From randomisation until completion of the planned treatment period, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Randomised Set: All randomised patients.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1867 1863
    Number (95% Confidence Interval) [Patients with events/ 100 pt-yrs at risk]
    3.07
    1.56
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0019
    Comments
    Method Regression, Cox
    Comments Cox regression model with terms for age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.50
    Confidence Interval (2-Sided) 95%
    0.32 to 0.77
    Parameter Dispersion Type:
    Value:
    Estimation Comments Comparison vs. Placebo
    5. Secondary Outcome
    Title Time to First Adjudicated Hospitalisation for Heart Failure (HHF)
    Description Time to first adjudicated Hospitalisation for Heart Failure (HHF). The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.
    Time Frame From randomisation until completion of the planned treatment period, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Randomised Set (RS): All randomised patients.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1867 1863
    Number (95% Confidence Interval) [Patients with events/ 100 pt-yrs at risk]
    15.55
    10.75
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Regression, Cox
    Comments Cox regression model with terms for age, baseline eGFR (CKD-EPK)cr, region, baseline diabetes status, sex, baseline LVEF, and treatment.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.69
    Confidence Interval (2-Sided) 95%
    0.59 to 0.81
    Parameter Dispersion Type:
    Value:
    Estimation Comments Comparison vs Placebo
    6. Secondary Outcome
    Title Time to Adjudicated Cardiovascular (CV) Death
    Description Time to adjudicated CV (Cardiovascular) death. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.
    Time Frame From randomisation until completion of the planned treatment period, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Randomised Set: All randomised patients.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1867 1863
    Number (95% Confidence Interval) [Patients with events/ 100 pt-yrs at risk]
    8.13
    7.55
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.4133
    Comments
    Method Regression, Cox
    Comments Model with terms for age, baseline eGFR (CKD-EPI), region, baseline diabetes status, sex, baseline LVEF and treatment.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.92
    Confidence Interval (2-Sided) 95%
    0.75 to 1.12
    Parameter Dispersion Type:
    Value:
    Estimation Comments Comparison vs. Placebo
    7. Secondary Outcome
    Title Time to All-cause Mortality
    Description Time to all-cause mortality. The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.
    Time Frame From randomisation until completion of the planned treatment period, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Randomised Set: All randomised patients.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1867 1863
    Number (95% Confidence Interval) [Patients with events/ 100 pt-yrs at risk]
    10.71
    10.06
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3536
    Comments
    Method Regression, Cox
    Comments Cox regression model with terms for age, baseline eGFR (CKD-EPI), region, baseline diabetes status, sex, baseline LVEF and treatment.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.92
    Confidence Interval (2-Sided) 95%
    0.77 to 1.10
    Parameter Dispersion Type:
    Value:
    Estimation Comments Comparison vs. placebo
    8. Secondary Outcome
    Title Time to Onset of Diabetes Mellitus (DM)
    Description Time to onset of DM (Glycated haemoglobin (HbA1c) ≥6.5% or as diagnosed by the investigator) in patients with pre-DM (no history of DM and no HbA1c ≥6.5% before treatment, and a pre-treatment HbA1c value of 5.7 to <6.5%). The incidence rate (patients with events per 100 person years at risk) is reported. The incidence rate per 100 patient years (100 * number of patients with event /time at risk [years]) is presented. With time at risk [year] calculated as: Sum of time at risk [days] over all patients in a treatment group / 365.25. Patients without a specific endpoint event were censored at the last date the patient was known to be free of the event or at the end of the planned treatment period, whichever was earlier. Unit of Measure: Patients with events per 100 patient-years (pt-yrs) at risk.
    Time Frame From randomisation until completion of the planned treatment period, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Patients in the randomised set with pre-DM.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 636 632
    Number (95% Confidence Interval) [Patients with events/ 100 pt-yrs at risk]
    10.62
    9.31
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.3576
    Comments
    Method Regression, Cox
    Comments Cox regression model with terms for age, baseline eGFR (CDK-EPI), region, sex, baseline LVEF and treatment.
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.86
    Confidence Interval (2-Sided) 95%
    0.62 to 1.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments Comparison vs. placebo
    9. Secondary Outcome
    Title Change From Baseline in KCCQ (Kansas City Cardiomyopathy Questionnaire) Clinical Summary Score at Week 52
    Description Change from baseline in KCCQ (Kansas City cardiomyopathy questionnaire) clinical summary score at Week 52. The KCCQ is a 23-item self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, selfefficacy, and quality of life in patients with Heart Failure. The KCCQ-clinical summary score comprises the following domains: Symptom frequency, symptom burden and physical limitation. The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status. For patients who died, a worst score (score of 0) is imputed at all subsequent scheduled visits after the date of death. Standard error is adjusted standard error. Change from baseline in KCCQ-score at week 52 was modeled using a MMRM with visit (week 12, 32 and 52) as repeated measures, adjusted mean (standard error) at week 52 is reported.
    Time Frame Assessed at baseline, week 12, week 32 and week 52.

    Outcome Measure Data

    Analysis Population Description
    Patients in the randomized set (RS) with available data for this endpoint, including values obtained on treatment or post-treatment.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1395 1401
    Least Squares Mean (Standard Error) [Score on a scale]
    -3.36
    (0.69)
    -1.30
    (0.69)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments Mixed model with age, baseline eGFR (CKD-EPI) as linear covariate(s) and region, baseline diabetes status, sex, baseline LVEF, week reachable, treatment by visit interaction, baseline KCCQ - Clinical Summary Score by Visit interaction as fixed effects. An unstructured covariance structure has been used.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0340
    Comments
    Method Mixed Model
    Comments Mixed model for repeated measures (MMRM)
    Method of Estimation Estimation Parameter Difference of adjusted means
    Estimated Value 2.06
    Confidence Interval (2-Sided) 95%
    0.16 to 3.96
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.97
    Estimation Comments Comparison vs. placebo
    10. Secondary Outcome
    Title Number of All-cause Hospitalizations (First and Recurrent)
    Description Number of all-cause hospitalizations (first and recurrent).
    Time Frame From randomisation until completion of the planned treatment phase, up to 1040 days.

    Outcome Measure Data

    Analysis Population Description
    Randomised Set: All randomised patients.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    Measure Participants 1867 1863
    Number [Hospitalizations for any cause]
    1570
    1364
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, 10 mg Empagliflozin
    Comments Joint frailty model with terms for age, baseline eGFR (CDK-EPI), region, sex, baseline diabetes status and baseline LVEF. Model accounts for dependence between recurrent all-cause hospitalizations and all-cause mortality.
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0065
    Comments
    Method Joint frailty model
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.85
    Confidence Interval (2-Sided) 95%
    0.75 to 0.95
    Parameter Dispersion Type:
    Value:
    Estimation Comments Comparison vs. placebo

    Adverse Events

    Time Frame From first intake of study medication until end of planned treatment period + 7 days (Residual Effect Period), up to 1047 days.
    Adverse Event Reporting Description [All-Cause Mortality]: Randomised Set: All randomised patients. [Serious Adverse Events and Other Adverse Events]: Treated Set: All patients treated with at least one dose of study drug.
    Arm/Group Title Placebo 10 mg Empagliflozin
    Arm/Group Description 1 film-coated tablet of matching placebo was administered orally once daily. Film-coated tablet of 10 milligram (mg) Empagliflozin was administered orally once daily.
    All Cause Mortality
    Placebo 10 mg Empagliflozin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 266/1867 (14.2%) 249/1863 (13.4%)
    Serious Adverse Events
    Placebo 10 mg Empagliflozin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 896/1863 (48.1%) 772/1863 (41.4%)
    Blood and lymphatic system disorders
    Anaemia 6/1863 (0.3%) 10/1863 (0.5%)
    Blood loss anaemia 1/1863 (0.1%) 0/1863 (0%)
    Disseminated intravascular coagulation 0/1863 (0%) 1/1863 (0.1%)
    Iron deficiency anaemia 0/1863 (0%) 1/1863 (0.1%)
    Leukocytosis 1/1863 (0.1%) 0/1863 (0%)
    Pancytopenia 1/1863 (0.1%) 1/1863 (0.1%)
    Splenic haematoma 1/1863 (0.1%) 0/1863 (0%)
    Splenic infarction 1/1863 (0.1%) 0/1863 (0%)
    Thrombocytopenia 0/1863 (0%) 1/1863 (0.1%)
    Cardiac disorders
    Acute coronary syndrome 3/1863 (0.2%) 0/1863 (0%)
    Acute left ventricular failure 5/1863 (0.3%) 7/1863 (0.4%)
    Acute myocardial infarction 18/1863 (1%) 24/1863 (1.3%)
    Angina pectoris 10/1863 (0.5%) 6/1863 (0.3%)
    Angina unstable 9/1863 (0.5%) 11/1863 (0.6%)
    Aortic valve stenosis 1/1863 (0.1%) 0/1863 (0%)
    Arrhythmia 1/1863 (0.1%) 1/1863 (0.1%)
    Arrhythmia supraventricular 0/1863 (0%) 1/1863 (0.1%)
    Arteriosclerosis coronary artery 2/1863 (0.1%) 0/1863 (0%)
    Atrial fibrillation 44/1863 (2.4%) 24/1863 (1.3%)
    Atrial flutter 11/1863 (0.6%) 3/1863 (0.2%)
    Atrial tachycardia 2/1863 (0.1%) 4/1863 (0.2%)
    Atrial thrombosis 2/1863 (0.1%) 2/1863 (0.1%)
    Atrioventricular block complete 1/1863 (0.1%) 4/1863 (0.2%)
    Atrioventricular block second degree 0/1863 (0%) 1/1863 (0.1%)
    Bradyarrhythmia 0/1863 (0%) 2/1863 (0.1%)
    Bradycardia 4/1863 (0.2%) 0/1863 (0%)
    Bundle branch block left 1/1863 (0.1%) 1/1863 (0.1%)
    Cardiac aneurysm 1/1863 (0.1%) 0/1863 (0%)
    Cardiac arrest 10/1863 (0.5%) 9/1863 (0.5%)
    Cardiac asthma 0/1863 (0%) 2/1863 (0.1%)
    Cardiac disorder 0/1863 (0%) 1/1863 (0.1%)
    Cardiac dysfunction 1/1863 (0.1%) 0/1863 (0%)
    Cardiac failure 444/1863 (23.8%) 332/1863 (17.8%)
    Cardiac failure acute 29/1863 (1.6%) 19/1863 (1%)
    Cardiac failure chronic 32/1863 (1.7%) 18/1863 (1%)
    Cardiac failure congestive 41/1863 (2.2%) 26/1863 (1.4%)
    Cardiac tamponade 0/1863 (0%) 1/1863 (0.1%)
    Cardiac ventricular thrombosis 2/1863 (0.1%) 5/1863 (0.3%)
    Cardio-respiratory arrest 4/1863 (0.2%) 1/1863 (0.1%)
    Cardiogenic shock 11/1863 (0.6%) 8/1863 (0.4%)
    Cardiomegaly 1/1863 (0.1%) 0/1863 (0%)
    Cardiomyopathy 1/1863 (0.1%) 0/1863 (0%)
    Cardiopulmonary failure 1/1863 (0.1%) 1/1863 (0.1%)
    Cardiorenal syndrome 1/1863 (0.1%) 0/1863 (0%)
    Cardiovascular disorder 0/1863 (0%) 1/1863 (0.1%)
    Chronic left ventricular failure 0/1863 (0%) 1/1863 (0.1%)
    Congestive cardiomyopathy 6/1863 (0.3%) 1/1863 (0.1%)
    Coronary artery disease 16/1863 (0.9%) 2/1863 (0.1%)
    Coronary artery occlusion 3/1863 (0.2%) 3/1863 (0.2%)
    Coronary artery stenosis 2/1863 (0.1%) 3/1863 (0.2%)
    Coronary ostial stenosis 0/1863 (0%) 1/1863 (0.1%)
    Intracardiac thrombus 2/1863 (0.1%) 2/1863 (0.1%)
    Ischaemic cardiomyopathy 1/1863 (0.1%) 1/1863 (0.1%)
    Left ventricular dysfunction 1/1863 (0.1%) 1/1863 (0.1%)
    Left ventricular failure 3/1863 (0.2%) 3/1863 (0.2%)
    Low cardiac output syndrome 1/1863 (0.1%) 2/1863 (0.1%)
    Mitral valve incompetence 5/1863 (0.3%) 4/1863 (0.2%)
    Myocardial infarction 16/1863 (0.9%) 16/1863 (0.9%)
    Myocardial ischaemia 1/1863 (0.1%) 3/1863 (0.2%)
    Palpitations 1/1863 (0.1%) 0/1863 (0%)
    Paroxysmal atrioventricular block 0/1863 (0%) 1/1863 (0.1%)
    Pericardial effusion 0/1863 (0%) 1/1863 (0.1%)
    Prinzmetal angina 1/1863 (0.1%) 1/1863 (0.1%)
    Pulseless electrical activity 1/1863 (0.1%) 0/1863 (0%)
    Right ventricular failure 1/1863 (0.1%) 1/1863 (0.1%)
    Supraventricular tachycardia 6/1863 (0.3%) 2/1863 (0.1%)
    Torsade de pointes 0/1863 (0%) 1/1863 (0.1%)
    Trifascicular block 1/1863 (0.1%) 0/1863 (0%)
    Ventricular arrhythmia 5/1863 (0.3%) 1/1863 (0.1%)
    Ventricular extrasystoles 2/1863 (0.1%) 2/1863 (0.1%)
    Ventricular fibrillation 8/1863 (0.4%) 10/1863 (0.5%)
    Ventricular flutter 1/1863 (0.1%) 1/1863 (0.1%)
    Ventricular tachyarrhythmia 1/1863 (0.1%) 0/1863 (0%)
    Ventricular tachycardia 37/1863 (2%) 55/1863 (3%)
    Congenital, familial and genetic disorders
    Dermoid cyst 2/1863 (0.1%) 0/1863 (0%)
    Gastrointestinal arteriovenous malformation 0/1863 (0%) 1/1863 (0.1%)
    Phimosis 1/1863 (0.1%) 1/1863 (0.1%)
    Type IV hyperlipidaemia 1/1863 (0.1%) 0/1863 (0%)
    Ear and labyrinth disorders
    Deafness 1/1863 (0.1%) 0/1863 (0%)
    Deafness neurosensory 1/1863 (0.1%) 0/1863 (0%)
    Deafness unilateral 0/1863 (0%) 1/1863 (0.1%)
    Mixed deafness 0/1863 (0%) 1/1863 (0.1%)
    Sudden hearing loss 1/1863 (0.1%) 0/1863 (0%)
    Vertigo 0/1863 (0%) 1/1863 (0.1%)
    Vertigo positional 0/1863 (0%) 1/1863 (0.1%)
    Endocrine disorders
    Cushing's syndrome 0/1863 (0%) 1/1863 (0.1%)
    Hyperthyroidism 2/1863 (0.1%) 3/1863 (0.2%)
    Hypothyroidism 2/1863 (0.1%) 0/1863 (0%)
    Eye disorders
    Cataract 3/1863 (0.2%) 5/1863 (0.3%)
    Cataract cortical 0/1863 (0%) 1/1863 (0.1%)
    Diabetic retinopathy 1/1863 (0.1%) 0/1863 (0%)
    Glaucoma 5/1863 (0.3%) 3/1863 (0.2%)
    Macular degeneration 1/1863 (0.1%) 0/1863 (0%)
    Open angle glaucoma 0/1863 (0%) 1/1863 (0.1%)
    Retinal detachment 0/1863 (0%) 3/1863 (0.2%)
    Retinal tear 1/1863 (0.1%) 1/1863 (0.1%)
    Vitreous haemorrhage 1/1863 (0.1%) 0/1863 (0%)
    Gastrointestinal disorders
    Abdominal pain 3/1863 (0.2%) 3/1863 (0.2%)
    Abdominal pain upper 0/1863 (0%) 2/1863 (0.1%)
    Abdominal wall haematoma 0/1863 (0%) 1/1863 (0.1%)
    Acute abdomen 1/1863 (0.1%) 1/1863 (0.1%)
    Chronic gastritis 0/1863 (0%) 1/1863 (0.1%)
    Coeliac disease 0/1863 (0%) 1/1863 (0.1%)
    Colitis 0/1863 (0%) 1/1863 (0.1%)
    Colitis ischaemic 1/1863 (0.1%) 1/1863 (0.1%)
    Constipation 1/1863 (0.1%) 3/1863 (0.2%)
    Diarrhoea 2/1863 (0.1%) 2/1863 (0.1%)
    Duodenal ulcer 0/1863 (0%) 2/1863 (0.1%)
    Enteritis 1/1863 (0.1%) 0/1863 (0%)
    Erosive oesophagitis 0/1863 (0%) 1/1863 (0.1%)
    Gastric haemorrhage 1/1863 (0.1%) 0/1863 (0%)
    Gastric mucosa erythema 1/1863 (0.1%) 0/1863 (0%)
    Gastric perforation 1/1863 (0.1%) 0/1863 (0%)
    Gastric ulcer 0/1863 (0%) 1/1863 (0.1%)
    Gastritis 1/1863 (0.1%) 2/1863 (0.1%)
    Gastritis erosive 1/1863 (0.1%) 1/1863 (0.1%)
    Gastrointestinal haemorrhage 4/1863 (0.2%) 8/1863 (0.4%)
    Gastrointestinal necrosis 1/1863 (0.1%) 0/1863 (0%)
    Gastrointestinal ulcer haemorrhage 0/1863 (0%) 1/1863 (0.1%)
    Gastrointestinal vascular malformation haemorrhagic 1/1863 (0.1%) 0/1863 (0%)
    Gingival bleeding 1/1863 (0.1%) 0/1863 (0%)
    Haematochezia 1/1863 (0.1%) 0/1863 (0%)
    Haemorrhoids 0/1863 (0%) 2/1863 (0.1%)
    Ileus 0/1863 (0%) 1/1863 (0.1%)
    Ileus paralytic 1/1863 (0.1%) 0/1863 (0%)
    Incarcerated inguinal hernia 0/1863 (0%) 1/1863 (0.1%)
    Inguinal hernia 0/1863 (0%) 7/1863 (0.4%)
    Intestinal ischaemia 2/1863 (0.1%) 0/1863 (0%)
    Intestinal obstruction 2/1863 (0.1%) 2/1863 (0.1%)
    Intussusception 1/1863 (0.1%) 0/1863 (0%)
    Large intestine polyp 2/1863 (0.1%) 1/1863 (0.1%)
    Mallory-Weiss syndrome 0/1863 (0%) 1/1863 (0.1%)
    Mechanical ileus 0/1863 (0%) 1/1863 (0.1%)
    Mesenteric artery stenosis 0/1863 (0%) 1/1863 (0.1%)
    Nausea 1/1863 (0.1%) 1/1863 (0.1%)
    Obstructive pancreatitis 2/1863 (0.1%) 0/1863 (0%)
    Oesophageal obstruction 1/1863 (0.1%) 0/1863 (0%)
    Pancreatitis 1/1863 (0.1%) 1/1863 (0.1%)
    Pancreatitis acute 2/1863 (0.1%) 1/1863 (0.1%)
    Pancreatitis chronic 1/1863 (0.1%) 0/1863 (0%)
    Periodontal disease 1/1863 (0.1%) 0/1863 (0%)
    Pharyngo-oesophageal diverticulum 0/1863 (0%) 1/1863 (0.1%)
    Rectal haemorrhage 3/1863 (0.2%) 3/1863 (0.2%)
    Small intestinal obstruction 1/1863 (0.1%) 0/1863 (0%)
    Upper gastrointestinal haemorrhage 7/1863 (0.4%) 5/1863 (0.3%)
    Vomiting 1/1863 (0.1%) 0/1863 (0%)
    General disorders
    Cardiac death 8/1863 (0.4%) 4/1863 (0.2%)
    Chest pain 2/1863 (0.1%) 2/1863 (0.1%)
    Death 27/1863 (1.4%) 20/1863 (1.1%)
    Discomfort 1/1863 (0.1%) 0/1863 (0%)
    Euthanasia 0/1863 (0%) 1/1863 (0.1%)
    Foreign body reaction 1/1863 (0.1%) 0/1863 (0%)
    Gait disturbance 0/1863 (0%) 1/1863 (0.1%)
    Implant site haematoma 1/1863 (0.1%) 0/1863 (0%)
    Medical device site haematoma 2/1863 (0.1%) 0/1863 (0%)
    Multiple organ dysfunction syndrome 1/1863 (0.1%) 1/1863 (0.1%)
    Non-cardiac chest pain 7/1863 (0.4%) 5/1863 (0.3%)
    Oedema due to cardiac disease 0/1863 (0%) 1/1863 (0.1%)
    Oedema peripheral 2/1863 (0.1%) 3/1863 (0.2%)
    Pyrexia 1/1863 (0.1%) 1/1863 (0.1%)
    Stent-graft endoleak 2/1863 (0.1%) 0/1863 (0%)
    Sudden cardiac death 10/1863 (0.5%) 8/1863 (0.4%)
    Sudden death 5/1863 (0.3%) 5/1863 (0.3%)
    Systemic inflammatory response syndrome 0/1863 (0%) 1/1863 (0.1%)
    Vascular device occlusion 1/1863 (0.1%) 0/1863 (0%)
    Vessel puncture site phlebitis 0/1863 (0%) 1/1863 (0.1%)
    Hepatobiliary disorders
    Acute hepatic failure 0/1863 (0%) 1/1863 (0.1%)
    Bile duct obstruction 1/1863 (0.1%) 0/1863 (0%)
    Bile duct stone 1/1863 (0.1%) 1/1863 (0.1%)
    Cardiac cirrhosis 1/1863 (0.1%) 0/1863 (0%)
    Cholangitis 1/1863 (0.1%) 0/1863 (0%)
    Cholangitis acute 1/1863 (0.1%) 1/1863 (0.1%)
    Cholecystitis 3/1863 (0.2%) 2/1863 (0.1%)
    Cholecystitis acute 5/1863 (0.3%) 2/1863 (0.1%)
    Cholecystitis chronic 1/1863 (0.1%) 0/1863 (0%)
    Cholelithiasis 2/1863 (0.1%) 1/1863 (0.1%)
    Drug-induced liver injury 1/1863 (0.1%) 1/1863 (0.1%)
    Hepatic cirrhosis 1/1863 (0.1%) 1/1863 (0.1%)
    Hepatic failure 2/1863 (0.1%) 1/1863 (0.1%)
    Hepatic function abnormal 4/1863 (0.2%) 1/1863 (0.1%)
    Hepatic steatosis 0/1863 (0%) 1/1863 (0.1%)
    Hepatitis 2/1863 (0.1%) 0/1863 (0%)
    Liver disorder 0/1863 (0%) 1/1863 (0.1%)
    Liver injury 5/1863 (0.3%) 3/1863 (0.2%)
    Non-alcoholic steatohepatitis 1/1863 (0.1%) 0/1863 (0%)
    Immune system disorders
    Heart transplant rejection 1/1863 (0.1%) 0/1863 (0%)
    Infections and infestations
    Abdominal sepsis 0/1863 (0%) 2/1863 (0.1%)
    Appendicitis 3/1863 (0.2%) 3/1863 (0.2%)
    Appendicitis perforated 0/1863 (0%) 2/1863 (0.1%)
    Atypical pneumonia 1/1863 (0.1%) 0/1863 (0%)
    Bacteraemia 0/1863 (0%) 1/1863 (0.1%)
    Bacterial sepsis 0/1863 (0%) 2/1863 (0.1%)
    Bronchitis 5/1863 (0.3%) 5/1863 (0.3%)
    Bullous erysipelas 1/1863 (0.1%) 0/1863 (0%)
    COVID-19 3/1863 (0.2%) 1/1863 (0.1%)
    COVID-19 pneumonia 1/1863 (0.1%) 0/1863 (0%)
    Cellulitis 3/1863 (0.2%) 8/1863 (0.4%)
    Clostridium difficile infection 1/1863 (0.1%) 0/1863 (0%)
    Cystitis 1/1863 (0.1%) 0/1863 (0%)
    Dengue fever 1/1863 (0.1%) 0/1863 (0%)
    Device related infection 0/1863 (0%) 2/1863 (0.1%)
    Diabetic foot infection 0/1863 (0%) 3/1863 (0.2%)
    Disseminated tuberculosis 0/1863 (0%) 1/1863 (0.1%)
    Diverticulitis 0/1863 (0%) 1/1863 (0.1%)
    Encephalitis viral 1/1863 (0.1%) 0/1863 (0%)
    Endocarditis 3/1863 (0.2%) 2/1863 (0.1%)
    Erysipelas 3/1863 (0.2%) 1/1863 (0.1%)
    Escherichia bacteraemia 0/1863 (0%) 1/1863 (0.1%)
    Eye abscess 1/1863 (0.1%) 0/1863 (0%)
    Fournier's gangrene 0/1863 (0%) 1/1863 (0.1%)
    Gangrene 1/1863 (0.1%) 4/1863 (0.2%)
    Gastritis viral 0/1863 (0%) 1/1863 (0.1%)
    Gastroenteritis 9/1863 (0.5%) 4/1863 (0.2%)
    Gastrointestinal infection 2/1863 (0.1%) 1/1863 (0.1%)
    Haemorrhagic fever 1/1863 (0.1%) 0/1863 (0%)
    Herpes zoster 2/1863 (0.1%) 0/1863 (0%)
    Human anaplasmosis 0/1863 (0%) 1/1863 (0.1%)
    Implant site infection 0/1863 (0%) 1/1863 (0.1%)
    Infected skin ulcer 0/1863 (0%) 1/1863 (0.1%)
    Infection 2/1863 (0.1%) 0/1863 (0%)
    Infective spondylitis 0/1863 (0%) 1/1863 (0.1%)
    Influenza 5/1863 (0.3%) 4/1863 (0.2%)
    Intervertebral discitis 0/1863 (0%) 1/1863 (0.1%)
    Labyrinthitis 1/1863 (0.1%) 0/1863 (0%)
    Localised infection 2/1863 (0.1%) 0/1863 (0%)
    Lower respiratory tract infection 2/1863 (0.1%) 2/1863 (0.1%)
    Medical device site infection 0/1863 (0%) 1/1863 (0.1%)
    Nail infection 1/1863 (0.1%) 0/1863 (0%)
    Nocardiosis 0/1863 (0%) 1/1863 (0.1%)
    Osteomyelitis 2/1863 (0.1%) 2/1863 (0.1%)
    Osteomyelitis chronic 0/1863 (0%) 1/1863 (0.1%)
    Pelvic abscess 1/1863 (0.1%) 0/1863 (0%)
    Perineal abscess 1/1863 (0.1%) 0/1863 (0%)
    Peritonitis 1/1863 (0.1%) 2/1863 (0.1%)
    Peritonitis bacterial 0/1863 (0%) 1/1863 (0.1%)
    Pharyngitis 0/1863 (0%) 1/1863 (0.1%)
    Pneumonia 62/1863 (3.3%) 53/1863 (2.8%)
    Pneumonia bacterial 3/1863 (0.2%) 1/1863 (0.1%)
    Pneumonia chlamydial 1/1863 (0.1%) 0/1863 (0%)
    Pneumonia influenzal 0/1863 (0%) 1/1863 (0.1%)
    Postoperative wound infection 2/1863 (0.1%) 0/1863 (0%)
    Pulmonary sepsis 0/1863 (0%) 2/1863 (0.1%)
    Pulmonary tuberculosis 1/1863 (0.1%) 0/1863 (0%)
    Pyelitis 1/1863 (0.1%) 0/1863 (0%)
    Pyelonephritis 0/1863 (0%) 1/1863 (0.1%)
    Pyelonephritis acute 2/1863 (0.1%) 0/1863 (0%)
    Respiratory syncytial virus bronchitis 0/1863 (0%) 1/1863 (0.1%)
    Respiratory tract infection 0/1863 (0%) 1/1863 (0.1%)
    Sepsis 8/1863 (0.4%) 8/1863 (0.4%)
    Septic encephalopathy 1/1863 (0.1%) 0/1863 (0%)
    Septic shock 5/1863 (0.3%) 9/1863 (0.5%)
    Sinobronchitis 1/1863 (0.1%) 0/1863 (0%)
    Spinal cord abscess 0/1863 (0%) 2/1863 (0.1%)
    Staphylococcal bacteraemia 0/1863 (0%) 1/1863 (0.1%)
    Staphylococcal sepsis 1/1863 (0.1%) 0/1863 (0%)
    Streptococcal sepsis 1/1863 (0.1%) 1/1863 (0.1%)
    Upper respiratory tract infection 1/1863 (0.1%) 2/1863 (0.1%)
    Urinary tract infection 10/1863 (0.5%) 14/1863 (0.8%)
    Urosepsis 0/1863 (0%) 4/1863 (0.2%)
    Vessel puncture site cellulitis 1/1863 (0.1%) 0/1863 (0%)
    Viral diarrhoea 1/1863 (0.1%) 0/1863 (0%)
    Injury, poisoning and procedural complications
    Ankle fracture 3/1863 (0.2%) 2/1863 (0.1%)
    Avulsion fracture 0/1863 (0%) 2/1863 (0.1%)
    Bladder injury 0/1863 (0%) 1/1863 (0.1%)
    Carbon monoxide poisoning 1/1863 (0.1%) 0/1863 (0%)
    Concussion 1/1863 (0.1%) 0/1863 (0%)
    Contusion 1/1863 (0.1%) 1/1863 (0.1%)
    Coronary artery restenosis 1/1863 (0.1%) 0/1863 (0%)
    Costal cartilage fracture 0/1863 (0%) 1/1863 (0.1%)
    Craniocerebral injury 1/1863 (0.1%) 1/1863 (0.1%)
    Fall 4/1863 (0.2%) 15/1863 (0.8%)
    Femoral neck fracture 2/1863 (0.1%) 1/1863 (0.1%)
    Femur fracture 3/1863 (0.2%) 5/1863 (0.3%)
    Fibula fracture 1/1863 (0.1%) 0/1863 (0%)
    Fracture 0/1863 (0%) 1/1863 (0.1%)
    Head injury 0/1863 (0%) 3/1863 (0.2%)
    Heat stroke 0/1863 (0%) 1/1863 (0.1%)
    Hip fracture 3/1863 (0.2%) 2/1863 (0.1%)
    Humerus fracture 1/1863 (0.1%) 2/1863 (0.1%)
    Jaw fracture 0/1863 (0%) 1/1863 (0.1%)
    Joint dislocation 1/1863 (0.1%) 0/1863 (0%)
    Limb crushing injury 0/1863 (0%) 1/1863 (0.1%)
    Limb injury 1/1863 (0.1%) 1/1863 (0.1%)
    Lumbar vertebral fracture 1/1863 (0.1%) 2/1863 (0.1%)
    Multiple injuries 2/1863 (0.1%) 0/1863 (0%)
    Open globe injury 1/1863 (0.1%) 0/1863 (0%)
    Overdose 0/1863 (0%) 1/1863 (0.1%)
    Pelvic fracture 3/1863 (0.2%) 1/1863 (0.1%)
    Post procedural haemorrhage 1/1863 (0.1%) 0/1863 (0%)
    Post procedural swelling 1/1863 (0.1%) 0/1863 (0%)
    Post-traumatic pain 1/1863 (0.1%) 0/1863 (0%)
    Postoperative respiratory failure 0/1863 (0%) 1/1863 (0.1%)
    Procedural shock 0/1863 (0%) 2/1863 (0.1%)
    Rib fracture 2/1863 (0.1%) 0/1863 (0%)
    Road traffic accident 2/1863 (0.1%) 4/1863 (0.2%)
    Skin laceration 0/1863 (0%) 2/1863 (0.1%)
    Spinal compression fracture 0/1863 (0%) 1/1863 (0.1%)
    Splenic rupture 0/1863 (0%) 1/1863 (0.1%)
    Subdural haematoma 0/1863 (0%) 2/1863 (0.1%)
    Subdural haemorrhage 0/1863 (0%) 1/1863 (0.1%)
    Thermal burn 0/1863 (0%) 1/1863 (0.1%)
    Tibia fracture 1/1863 (0.1%) 0/1863 (0%)
    Tooth fracture 1/1863 (0.1%) 0/1863 (0%)
    Toxicity to various agents 1/1863 (0.1%) 0/1863 (0%)
    Traumatic fracture 0/1863 (0%) 6/1863 (0.3%)
    Traumatic haematoma 0/1863 (0%) 1/1863 (0.1%)
    Traumatic intracranial haemorrhage 0/1863 (0%) 1/1863 (0.1%)
    Upper limb fracture 1/1863 (0.1%) 0/1863 (0%)
    Vascular pseudoaneurysm 2/1863 (0.1%) 1/1863 (0.1%)
    Wound dehiscence 1/1863 (0.1%) 1/1863 (0.1%)
    Wrist fracture 1/1863 (0.1%) 0/1863 (0%)
    Investigations
    Aspartate aminotransferase increased 0/1863 (0%) 1/1863 (0.1%)
    Blood creatinine increased 1/1863 (0.1%) 0/1863 (0%)
    Cardiac electrophysiologic study 1/1863 (0.1%) 0/1863 (0%)
    Ejection fraction decreased 1/1863 (0.1%) 0/1863 (0%)
    Endoscopic retrograde cholangiopancreatography 1/1863 (0.1%) 0/1863 (0%)
    Hepatic enzyme abnormal 0/1863 (0%) 1/1863 (0.1%)
    Hepatic enzyme increased 1/1863 (0.1%) 0/1863 (0%)
    Weight increased 1/1863 (0.1%) 0/1863 (0%)
    Metabolism and nutrition disorders
    Acidosis 2/1863 (0.1%) 0/1863 (0%)
    Cachexia 1/1863 (0.1%) 1/1863 (0.1%)
    Decreased appetite 1/1863 (0.1%) 0/1863 (0%)
    Dehydration 4/1863 (0.2%) 8/1863 (0.4%)
    Diabetes mellitus 5/1863 (0.3%) 4/1863 (0.2%)
    Diabetes mellitus inadequate control 2/1863 (0.1%) 0/1863 (0%)
    Diabetic complication 1/1863 (0.1%) 0/1863 (0%)
    Diabetic metabolic decompensation 7/1863 (0.4%) 2/1863 (0.1%)
    Gout 3/1863 (0.2%) 1/1863 (0.1%)
    Hyperglycaemia 2/1863 (0.1%) 0/1863 (0%)
    Hyperglycaemic hyperosmolar nonketotic syndrome 0/1863 (0%) 1/1863 (0.1%)
    Hyperkalaemia 9/1863 (0.5%) 2/1863 (0.1%)
    Hypernatraemia 0/1863 (0%) 1/1863 (0.1%)
    Hypoglycaemia 5/1863 (0.3%) 6/1863 (0.3%)
    Hypokalaemia 2/1863 (0.1%) 3/1863 (0.2%)
    Hyponatraemia 2/1863 (0.1%) 1/1863 (0.1%)
    Hypophagia 1/1863 (0.1%) 0/1863 (0%)
    Hypovolaemia 1/1863 (0.1%) 0/1863 (0%)
    Lactic acidosis 0/1863 (0%) 2/1863 (0.1%)
    Metabolic acidosis 3/1863 (0.2%) 4/1863 (0.2%)
    Type 2 diabetes mellitus 0/1863 (0%) 1/1863 (0.1%)
    Musculoskeletal and connective tissue disorders
    Ankylosing spondylitis 2/1863 (0.1%) 0/1863 (0%)
    Arthralgia 1/1863 (0.1%) 1/1863 (0.1%)
    Arthropathy 1/1863 (0.1%) 0/1863 (0%)
    Back pain 1/1863 (0.1%) 2/1863 (0.1%)
    Cervical spinal stenosis 0/1863 (0%) 1/1863 (0.1%)
    Crystal arthropathy 1/1863 (0.1%) 0/1863 (0%)
    Gouty arthritis 1/1863 (0.1%) 0/1863 (0%)
    Intervertebral disc disorder 0/1863 (0%) 1/1863 (0.1%)
    Joint destruction 1/1863 (0.1%) 0/1863 (0%)
    Lumbar spinal stenosis 1/1863 (0.1%) 0/1863 (0%)
    Muscular weakness 1/1863 (0.1%) 1/1863 (0.1%)
    Musculoskeletal chest pain 1/1863 (0.1%) 2/1863 (0.1%)
    Osteoarthritis 7/1863 (0.4%) 3/1863 (0.2%)
    Osteochondrosis 1/1863 (0.1%) 0/1863 (0%)
    Pathological fracture 1/1863 (0.1%) 0/1863 (0%)
    Polymyalgia rheumatica 1/1863 (0.1%) 0/1863 (0%)
    Rhabdomyolysis 2/1863 (0.1%) 2/1863 (0.1%)
    Rotator cuff syndrome 1/1863 (0.1%) 1/1863 (0.1%)
    Spondylitis 0/1863 (0%) 1/1863 (0.1%)
    Systemic lupus erythematosus 1/1863 (0.1%) 0/1863 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal neoplasm 0/1863 (0%) 1/1863 (0.1%)
    Adenocarcinoma gastric 1/1863 (0.1%) 0/1863 (0%)
    Adenocarcinoma of colon 2/1863 (0.1%) 2/1863 (0.1%)
    Adenocarcinoma of the cervix 0/1863 (0%) 1/1863 (0.1%)
    Adenocarcinoma pancreas 2/1863 (0.1%) 0/1863 (0%)
    Adrenal adenoma 1/1863 (0.1%) 0/1863 (0%)
    Basal cell carcinoma 4/1863 (0.2%) 4/1863 (0.2%)
    Bile duct adenocarcinoma 1/1863 (0.1%) 0/1863 (0%)
    Bladder cancer 3/1863 (0.2%) 1/1863 (0.1%)
    Bladder cancer stage IV 1/1863 (0.1%) 0/1863 (0%)
    Bladder neoplasm 1/1863 (0.1%) 1/1863 (0.1%)
    Bladder transitional cell carcinoma 1/1863 (0.1%) 1/1863 (0.1%)
    Bowen's disease 1/1863 (0.1%) 0/1863 (0%)
    Chronic lymphocytic leukaemia 0/1863 (0%) 1/1863 (0.1%)
    Chronic myelomonocytic leukaemia 1/1863 (0.1%) 0/1863 (0%)
    Clear cell renal cell carcinoma 0/1863 (0%) 1/1863 (0.1%)
    Colon adenoma 1/1863 (0.1%) 1/1863 (0.1%)
    Colon cancer 3/1863 (0.2%) 0/1863 (0%)
    Cutaneous T-cell lymphoma 0/1863 (0%) 1/1863 (0.1%)
    Diffuse large B-cell lymphoma 0/1863 (0%) 1/1863 (0.1%)
    Diffuse large B-cell lymphoma recurrent 0/1863 (0%) 1/1863 (0.1%)
    Gastric cancer 2/1863 (0.1%) 0/1863 (0%)
    Gastrointestinal neoplasm 0/1863 (0%) 1/1863 (0.1%)
    Hepatic cancer 1/1863 (0.1%) 0/1863 (0%)
    Hypergammaglobulinaemia benign monoclonal 1/1863 (0.1%) 0/1863 (0%)
    Invasive ductal breast carcinoma 1/1863 (0.1%) 1/1863 (0.1%)
    Lung neoplasm 0/1863 (0%) 1/1863 (0.1%)
    Lung neoplasm malignant 2/1863 (0.1%) 0/1863 (0%)
    Malignant melanoma 1/1863 (0.1%) 0/1863 (0%)
    Metastases to spine 0/1863 (0%) 1/1863 (0.1%)
    Metastatic carcinoma of the bladder 1/1863 (0.1%) 0/1863 (0%)
    Metastatic neoplasm 0/1863 (0%) 1/1863 (0.1%)
    Myelodysplastic syndrome 2/1863 (0.1%) 0/1863 (0%)
    Non-Hodgkin's lymphoma 1/1863 (0.1%) 0/1863 (0%)
    Oesophageal carcinoma 2/1863 (0.1%) 0/1863 (0%)
    Ovarian adenoma 0/1863 (0%) 1/1863 (0.1%)
    Pancreatic carcinoma 3/1863 (0.2%) 0/1863 (0%)
    Pancreatic carcinoma metastatic 0/1863 (0%) 1/1863 (0.1%)
    Plasma cell myeloma 1/1863 (0.1%) 0/1863 (0%)
    Prostate cancer 7/1863 (0.4%) 6/1863 (0.3%)
    Prostate cancer metastatic 0/1863 (0%) 1/1863 (0.1%)
    Rectal adenocarcinoma 0/1863 (0%) 1/1863 (0.1%)
    Renal cancer 0/1863 (0%) 1/1863 (0.1%)
    Renal cancer metastatic 0/1863 (0%) 1/1863 (0.1%)
    Renal neoplasm 0/1863 (0%) 1/1863 (0.1%)
    Squamous cell carcinoma 0/1863 (0%) 1/1863 (0.1%)
    Squamous cell carcinoma of lung 2/1863 (0.1%) 0/1863 (0%)
    Squamous cell carcinoma of skin 1/1863 (0.1%) 6/1863 (0.3%)
    Transitional cell carcinoma 0/1863 (0%) 1/1863 (0.1%)
    Ureteric cancer 0/1863 (0%) 1/1863 (0.1%)
    Nervous system disorders
    Brain injury 0/1863 (0%) 1/1863 (0.1%)
    Carotid arteriosclerosis 0/1863 (0%) 1/1863 (0.1%)
    Carotid artery occlusion 1/1863 (0.1%) 1/1863 (0.1%)
    Carotid artery stenosis 0/1863 (0%) 1/1863 (0.1%)
    Cerebellar haemorrhage 0/1863 (0%) 1/1863 (0.1%)
    Cerebellar infarction 1/1863 (0.1%) 0/1863 (0%)
    Cerebellar stroke 1/1863 (0.1%) 0/1863 (0%)
    Cerebral haematoma 0/1863 (0%) 1/1863 (0.1%)
    Cerebral haemorrhage 1/1863 (0.1%) 2/1863 (0.1%)
    Cerebral hypoperfusion 0/1863 (0%) 1/1863 (0.1%)
    Cerebral infarction 2/1863 (0.1%) 4/1863 (0.2%)
    Cerebral ischaemia 0/1863 (0%) 1/1863 (0.1%)
    Cerebrovascular accident 12/1863 (0.6%) 17/1863 (0.9%)
    Cerebrovascular insufficiency 0/1863 (0%) 1/1863 (0.1%)
    Dementia 3/1863 (0.2%) 0/1863 (0%)
    Dizziness 0/1863 (0%) 1/1863 (0.1%)
    Dysarthria 0/1863 (0%) 1/1863 (0.1%)
    Embolic stroke 0/1863 (0%) 1/1863 (0.1%)
    Epilepsy 3/1863 (0.2%) 2/1863 (0.1%)
    Guillain-Barre syndrome 1/1863 (0.1%) 0/1863 (0%)
    Haemorrhagic stroke 1/1863 (0.1%) 2/1863 (0.1%)
    Headache 0/1863 (0%) 1/1863 (0.1%)
    Hemiparesis 1/1863 (0.1%) 1/1863 (0.1%)
    Hemiplegia 1/1863 (0.1%) 0/1863 (0%)
    Hepatic encephalopathy 0/1863 (0%) 1/1863 (0.1%)
    Hyperglycaemic seizure 0/1863 (0%) 1/1863 (0.1%)
    Hypoxic-ischaemic encephalopathy 1/1863 (0.1%) 0/1863 (0%)
    Intracranial aneurysm 0/1863 (0%) 1/1863 (0.1%)
    Ischaemic stroke 20/1863 (1.1%) 19/1863 (1%)
    Lacunar infarction 0/1863 (0%) 1/1863 (0.1%)
    Loss of consciousness 0/1863 (0%) 2/1863 (0.1%)
    Lumbar radiculopathy 1/1863 (0.1%) 0/1863 (0%)
    Lumbosacral radiculopathy 1/1863 (0.1%) 0/1863 (0%)
    Migraine 0/1863 (0%) 1/1863 (0.1%)
    Myoclonus 1/1863 (0.1%) 0/1863 (0%)
    Paraplegia 0/1863 (0%) 1/1863 (0.1%)
    Peroneal nerve palsy 1/1863 (0.1%) 1/1863 (0.1%)
    Postresuscitation encephalopathy 1/1863 (0.1%) 0/1863 (0%)
    Presyncope 0/1863 (0%) 4/1863 (0.2%)
    Seizure 3/1863 (0.2%) 2/1863 (0.1%)
    Spinal cord compression 0/1863 (0%) 1/1863 (0.1%)
    Subarachnoid haemorrhage 0/1863 (0%) 1/1863 (0.1%)
    Syncope 8/1863 (0.4%) 17/1863 (0.9%)
    Transient ischaemic attack 9/1863 (0.5%) 5/1863 (0.3%)
    Uraemic encephalopathy 1/1863 (0.1%) 0/1863 (0%)
    Vascular dementia 1/1863 (0.1%) 0/1863 (0%)
    Vascular encephalopathy 1/1863 (0.1%) 0/1863 (0%)
    Vertebrobasilar insufficiency 1/1863 (0.1%) 0/1863 (0%)
    Product Issues
    Device breakage 0/1863 (0%) 1/1863 (0.1%)
    Device dislocation 0/1863 (0%) 1/1863 (0.1%)
    Device failure 0/1863 (0%) 1/1863 (0.1%)
    Device inappropriate shock delivery 0/1863 (0%) 1/1863 (0.1%)
    Device lead damage 1/1863 (0.1%) 0/1863 (0%)
    Device lead issue 0/1863 (0%) 2/1863 (0.1%)
    Device malfunction 4/1863 (0.2%) 3/1863 (0.2%)
    Device physical property issue 1/1863 (0.1%) 0/1863 (0%)
    Psychiatric disorders
    Anxiety 1/1863 (0.1%) 0/1863 (0%)
    Bipolar disorder 0/1863 (0%) 1/1863 (0.1%)
    Completed suicide 0/1863 (0%) 1/1863 (0.1%)
    Delirium 4/1863 (0.2%) 8/1863 (0.4%)
    Delirium tremens 1/1863 (0.1%) 0/1863 (0%)
    Depression 1/1863 (0.1%) 0/1863 (0%)
    Drug abuse 1/1863 (0.1%) 0/1863 (0%)
    Hallucination 0/1863 (0%) 1/1863 (0.1%)
    Renal and urinary disorders
    Acute kidney injury 55/1863 (3%) 35/1863 (1.9%)
    Azotaemia 2/1863 (0.1%) 0/1863 (0%)
    Chronic kidney disease 6/1863 (0.3%) 3/1863 (0.2%)
    Diabetic nephropathy 0/1863 (0%) 1/1863 (0.1%)
    Dysuria 1/1863 (0.1%) 1/1863 (0.1%)
    End stage renal disease 1/1863 (0.1%) 0/1863 (0%)
    Haematuria 2/1863 (0.1%) 1/1863 (0.1%)
    Hydronephrosis 2/1863 (0.1%) 0/1863 (0%)
    Nephrolithiasis 0/1863 (0%) 1/1863 (0.1%)
    Nephropathy 1/1863 (0.1%) 2/1863 (0.1%)
    Nephropathy toxic 1/1863 (0.1%) 0/1863 (0%)
    Prerenal failure 0/1863 (0%) 1/1863 (0.1%)
    Renal failure 14/1863 (0.8%) 9/1863 (0.5%)
    Renal impairment 27/1863 (1.4%) 17/1863 (0.9%)
    Renal infarct 1/1863 (0.1%) 0/1863 (0%)
    Renal tubular necrosis 0/1863 (0%) 1/1863 (0.1%)
    Ureterolithiasis 0/1863 (0%) 3/1863 (0.2%)
    Urethral stenosis 0/1863 (0%) 2/1863 (0.1%)
    Urinary retention 1/1863 (0.1%) 1/1863 (0.1%)
    Reproductive system and breast disorders
    Acquired hydrocele 1/1863 (0.1%) 0/1863 (0%)
    Balanoposthitis 0/1863 (0%) 1/1863 (0.1%)
    Benign prostatic hyperplasia 1/1863 (0.1%) 1/1863 (0.1%)
    Fibrocystic breast disease 0/1863 (0%) 1/1863 (0.1%)
    Uterovaginal prolapse 0/1863 (0%) 1/1863 (0.1%)
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema 2/1863 (0.1%) 3/1863 (0.2%)
    Acute respiratory failure 5/1863 (0.3%) 3/1863 (0.2%)
    Aspiration 1/1863 (0.1%) 0/1863 (0%)
    Asthma 1/1863 (0.1%) 0/1863 (0%)
    Asthmatic crisis 1/1863 (0.1%) 0/1863 (0%)
    Bronchiectasis 2/1863 (0.1%) 0/1863 (0%)
    Bronchitis chronic 1/1863 (0.1%) 1/1863 (0.1%)
    Chronic obstructive pulmonary disease 13/1863 (0.7%) 11/1863 (0.6%)
    Dyspnoea 4/1863 (0.2%) 7/1863 (0.4%)
    Dyspnoea exertional 2/1863 (0.1%) 0/1863 (0%)
    Epistaxis 3/1863 (0.2%) 2/1863 (0.1%)
    Haemoptysis 0/1863 (0%) 1/1863 (0.1%)
    Haemothorax 1/1863 (0.1%) 0/1863 (0%)
    Idiopathic pulmonary fibrosis 1/1863 (0.1%) 0/1863 (0%)
    Lung disorder 0/1863 (0%) 2/1863 (0.1%)
    Organising pneumonia 0/1863 (0%) 1/1863 (0.1%)
    Paranasal cyst 1/1863 (0.1%) 0/1863 (0%)
    Pleural effusion 5/1863 (0.3%) 2/1863 (0.1%)
    Pleuritic pain 0/1863 (0%) 1/1863 (0.1%)
    Pneumonia aspiration 3/1863 (0.2%) 2/1863 (0.1%)
    Pneumonitis 1/1863 (0.1%) 0/1863 (0%)
    Pneumothorax 3/1863 (0.2%) 3/1863 (0.2%)
    Pulmonary arterial hypertension 1/1863 (0.1%) 0/1863 (0%)
    Pulmonary congestion 1/1863 (0.1%) 0/1863 (0%)
    Pulmonary embolism 4/1863 (0.2%) 5/1863 (0.3%)
    Pulmonary fibrosis 1/1863 (0.1%) 0/1863 (0%)
    Pulmonary hypertension 3/1863 (0.2%) 2/1863 (0.1%)
    Pulmonary oedema 1/1863 (0.1%) 1/1863 (0.1%)
    Respiratory acidosis 0/1863 (0%) 1/1863 (0.1%)
    Respiratory failure 5/1863 (0.3%) 2/1863 (0.1%)
    Sleep apnoea syndrome 2/1863 (0.1%) 0/1863 (0%)
    Vocal cord thickening 1/1863 (0.1%) 0/1863 (0%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 0/1863 (0%) 1/1863 (0.1%)
    Angioedema 3/1863 (0.2%) 0/1863 (0%)
    Dermatitis bullous 0/1863 (0%) 1/1863 (0.1%)
    Diabetic foot 2/1863 (0.1%) 6/1863 (0.3%)
    Eczema 0/1863 (0%) 1/1863 (0.1%)
    Pemphigoid 0/1863 (0%) 1/1863 (0.1%)
    Skin ulcer 3/1863 (0.2%) 4/1863 (0.2%)
    Stasis dermatitis 2/1863 (0.1%) 0/1863 (0%)
    Surgical and medical procedures
    Cardiac resynchronisation therapy 0/1863 (0%) 1/1863 (0.1%)
    Cardioversion 1/1863 (0.1%) 0/1863 (0%)
    Coronary arterial stent insertion 0/1863 (0%) 1/1863 (0.1%)
    Hip arthroplasty 2/1863 (0.1%) 0/1863 (0%)
    Implantable defibrillator insertion 1/1863 (0.1%) 0/1863 (0%)
    Percutaneous coronary intervention 0/1863 (0%) 1/1863 (0.1%)
    Vascular disorders
    Aortic aneurysm 0/1863 (0%) 1/1863 (0.1%)
    Aortic dissection 1/1863 (0.1%) 0/1863 (0%)
    Aortic intramural haematoma 1/1863 (0.1%) 0/1863 (0%)
    Aortic stenosis 1/1863 (0.1%) 0/1863 (0%)
    Arterial thrombosis 1/1863 (0.1%) 0/1863 (0%)
    Arteriosclerosis 2/1863 (0.1%) 0/1863 (0%)
    Bleeding varicose vein 1/1863 (0.1%) 0/1863 (0%)
    Circulatory collapse 5/1863 (0.3%) 0/1863 (0%)
    Deep vein thrombosis 5/1863 (0.3%) 4/1863 (0.2%)
    Diabetic vascular disorder 1/1863 (0.1%) 0/1863 (0%)
    Dry gangrene 0/1863 (0%) 1/1863 (0.1%)
    Embolism 0/1863 (0%) 1/1863 (0.1%)
    Extremity necrosis 1/1863 (0.1%) 2/1863 (0.1%)
    Femoral artery embolism 0/1863 (0%) 1/1863 (0.1%)
    Hypertension 1/1863 (0.1%) 0/1863 (0%)
    Hypertensive crisis 4/1863 (0.2%) 6/1863 (0.3%)
    Hypertensive emergency 1/1863 (0.1%) 0/1863 (0%)
    Hypertensive urgency 1/1863 (0.1%) 1/1863 (0.1%)
    Hypotension 13/1863 (0.7%) 14/1863 (0.8%)
    Hypovolaemic shock 1/1863 (0.1%) 0/1863 (0%)
    Intermittent claudication 0/1863 (0%) 1/1863 (0.1%)
    Leriche syndrome 0/1863 (0%) 2/1863 (0.1%)
    Lymphocele 1/1863 (0.1%) 0/1863 (0%)
    Orthostatic hypotension 1/1863 (0.1%) 4/1863 (0.2%)
    Peripheral arterial occlusive disease 4/1863 (0.2%) 7/1863 (0.4%)
    Peripheral artery aneurysm 0/1863 (0%) 1/1863 (0.1%)
    Peripheral artery stenosis 1/1863 (0.1%) 1/1863 (0.1%)
    Peripheral artery thrombosis 0/1863 (0%) 1/1863 (0.1%)
    Peripheral embolism 2/1863 (0.1%) 0/1863 (0%)
    Peripheral ischaemia 4/1863 (0.2%) 5/1863 (0.3%)
    Peripheral vascular disorder 0/1863 (0%) 1/1863 (0.1%)
    Shock haemorrhagic 0/1863 (0%) 1/1863 (0.1%)
    Subclavian artery occlusion 1/1863 (0.1%) 1/1863 (0.1%)
    Subclavian vein occlusion 1/1863 (0.1%) 0/1863 (0%)
    Subgaleal haemorrhage 0/1863 (0%) 1/1863 (0.1%)
    Thrombosis 1/1863 (0.1%) 0/1863 (0%)
    Vascular insufficiency 0/1863 (0%) 1/1863 (0.1%)
    Other (Not Including Serious) Adverse Events
    Placebo 10 mg Empagliflozin
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 369/1863 (19.8%) 328/1863 (17.6%)
    Infections and infestations
    Nasopharyngitis 94/1863 (5%) 89/1863 (4.8%)
    Metabolism and nutrition disorders
    Hyperkalaemia 109/1863 (5.9%) 99/1863 (5.3%)
    Hyperuricaemia 115/1863 (6.2%) 63/1863 (3.4%)
    Vascular disorders
    Hypotension 109/1863 (5.9%) 120/1863 (6.4%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

    Results Point of Contact

    Name/Title Boehringer Ingelheim, Call Centre
    Organization Boehringer Ingelheim
    Phone 1-800-243-0127
    Email clintriage.rdg@boehringer-ingelheim.com
    Responsible Party:
    Boehringer Ingelheim
    ClinicalTrials.gov Identifier:
    NCT03057977
    Other Study ID Numbers:
    • 1245.121
    • 2016-002280-34
    First Posted:
    Feb 20, 2017
    Last Update Posted:
    May 18, 2021
    Last Verified:
    Apr 1, 2021