Acute Myocardial Infarction
Conditions
Keywords
Biomarker, Heart failure, SGLT-2 inhibitor, Empagliflozin, Randomized controlled trial
Brief summary
This study is planned to investigate the impact of Empagliflozin on biomarkers of heart failure in patients with myocardial infarction with and without type 2 diabetes mellitus within 6 months after the event.
Detailed description
Type 2 diabetes mellitus (T2DM) is associated with an about two to three-fold increased risk for cardiovascular events as compared to subjects without diabetes. Sodium-dependent glucose cotransporter 2 (SGLT-2) is mainly expressed in human kidneys and small intestinal cells. In the proximal tubule of the nephron SGLT-2 is responsible for the reabsorption of approximately 90% of the filtrated glucose. Inhibition of SGLT-2 was shown to increase renal glucose excretion and to lower glucose. Subsequently, a number of SGLT-2 inhibitors were developed and are currently approved for the treatment of type 2 diabetes. Recently, Zinman et al published the results of the Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patient trial (EMPA REG OUTCOME TRIAL) where the cardiovascular impact of a glucose lowering regimen including Empagliflozin as compared to usual glucose control without an SGLT-2 inhibitor was investigated. The trial demonstrated an unexpected reduction in the primary composite endpoint, comprising cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The reduction was mainly driven by a 38% relative risk reduction in cardiovascular deaths; moreover they demonstrated an impressive 35% relative risk reduction in the secondary endpoint hospitalization for heart failure. Of note, the beneficial effects observed in the Empagliflozin group seem to occur very rapidly after commencing the treatment, as suggested by the early separation of the Kaplan-Meier curves. However, the mechanisms responsible for this finding remain unclear. Diuretic effects with subsequent impact on hemodynamics or potential cardioprotective effects of glucagon, which levels rise under the treatment with SGLT-2 inhibitors and the resulting rise in ketone bodies or a small increase in hematocrit have been suggested. The aim of our trial is to investigate whether Empagliflozin treatment commenced within 72-h after acute myocardial infarction has an impact on heart failure in subjects with and without diabetes mellitus type 2.
Interventions
DRUGEmpagliflozin 10 mg
The subject will receive Empagliflozin 10 mg orally once daily for 26 weeks.
DRUGPlacebo Oral Tablet
The subject will receive Placebo orally once daily for 26 weeks.
Sponsors
United Arab Emirates University
Medical University of Vienna
Landeskrankenhaus Feldkirch
Paracelsus Medical University
Hospital Rudolfstiftung
Klinikum Klagenfurt am Wörthersee
Barmherzige Brüder Eisenstadt
Cardinal Schwarzenberg Hospital
Johannes Kepler University of Linz
Landesklinikum Sankt Polten
Landeskrankenhaus II Graz West
Medical University of Graz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Myocardial infarction with evidence of significant myocardial necrosis defined as a rise in creatinine kinase \>800 U/l and a troponin T-level (or troponin I-level) \>10x upper limit of normal (ULN). In addition at least 1 of the following criteria must be the met: * Symptoms of ischemia * ECG (electrocardiogram) changes indicative of new ischemia (new ST-T changes or new LBBB) * Imaging evidence of new regional wall motion abnormality 2. 18 - 80 years of age 3. Informed consent has to be given in written form 4. estimated glomerular filtration rate (eGFR) \> 45 ml/min/1.73m2 5. Blood pressure before first drug dosing: Riva Rocci (RR) systolic \>110 mmHg 6. Blood pressure before first drug dosing: Riva Rocci (RR) diastolic \>70 mmHg 7. ≤72h after myocardial infarction (after the performance of a coronary angiography)
Exclusion criteria
1. Any other form of diabetes mellitus than type 2 diabetes mellitus, history of diabetic ketoacidosis 2. Blood potential hydrogen (pH) \< 7,32 3. Known allergy to SGLT-2 inhibitors 4. Hemodynamic instability as defined by intravenous administration of catecholamine, calcium sensitizers or phosphodiesterase inhibitors 5. \>1 episode of severe hypoglycemia within the last 6 months and treatment with insulin or sulfonylurea 6. Females of childbearing potential without adequate contraceptive methods (i.e. sterilization, intrauterine device, vasectomized partner; or medical history of hysterectomy) 7. Acute symptomatic urinary tract infection (UTI) or genital infection 8. Patients currently being treated with any SGLT-2 inhibitor or having received treatment with any SGLT-2 inhibitor within the 4 weeks prior to the screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes of Nt-proBNP (N-terminales Pro Brain Natriuretic Peptide) Levels | 26 weeks | Difference in the change of nt-proBNP (N terminales pro brain natriuretic peptide) levels between treatment groups from randomization to week 26 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Ejection Fraction | 26 weeks | Difference in the change of ejection fraction between treatment groups from randomization to week 26 Ejection fraction was measured by ultrasound. |
| Changes in Left Ventricular End-diastolic Volume | 26 weeks | Difference in the change of left ventricular end-diastolic volume from randomization to week 26 (measured by ultrasound) |
| Duration of Hospital Stay | 30 weeks | Difference in the duration of hospital stay between the treatment groups after initiation of the study treatment. This outcome measure includes all days of an inpatient stay in a hospital after the initial discharge. |
| Changes in E/è Ratio From Baseline to Week 26 | From Baseline to Week 26 | E/E' ratio is a measure of left ventricular filling pressure. The E/e' ratio is a parameter for diastolic function assessment that is frequently used for Heart failure with preserved ejection fraction evaluation. To derive the E/e´ ratio one must divide the maximum velocity of the E-wave of mitral valve inflow by the maximal velocity of E. In normal individuals the E/e´ ratio is \<8. In the presence of diastolic dysfunction / impaired relaxation, e´ will be rather low. In contrast, the E-wave increases with elevated filling pressures. Thus the E/e´ ratio will increase in the presence of diastolic dysfunction. An E/e´ratio \>14 is highly suggestive of elevated filling pressures. |
| Changes in Left Ventricular End-systolic Volume (LVESV) From Baselin to Week 26 | Baseline to Week 26 | End-systolic volume (ESV) is the volume of blood in a ventricle at the end of contraction, or systole, and the beginning of filling, or diastole. Left ventricular end-systolic volume (LVESV) was measured at baseline and after 26 weeks by echocardiography. |
Countries
Austria
Participant flow
Recruitment details
Recruitment between May 2017 (FPFV) and Oct 2021 (LPFV), at 11 sites: 1) University Hospital Graz; 2) Hospital Klagenfurt 3) Brothers of Saint John of God Eisenstadt; 4) Paracelsus Medical Private University Salzburg; 5) Vorarlberg Institute for Vascular Investigation and Treatment; 6) Kardinal Schwarzenberg Hospital Schwarzach; 7) J. Kepler University Hospital Linz; 8) University Hospital St. Pölten; 9) Allgemeines Krankenhaus Vienna; 10) Hospital Graz II: 11) Hospital Landstrasse Vienna
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin The subjects will receive Empagliflozin 10mg.
Empagliflozin 10 mg: The subject will receive Empagliflozin 10 mg orally once daily for 26 weeks. | 237 |
| Placebo Oral Tablet The subjects will receive placebo.
Placebo Oral Tablet: The subject will receive Placebo orally once daily for 26 weeks. | 239 |
| Total | 476 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 12 | 8 |
| Overall Study | Withdrawal by Subject | 8 | 4 |
Baseline characteristics
| Characteristic | Placebo Oral Tablet | Total | Empagliflozin |
|---|---|---|---|
| Age, Continuous | 57 years | 57 years | 57 years |
| Alanine aminotransferase | 50 U/L | 50 U/L | 50 U/L |
| Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker | 97 Participants | 193 Participants | 96 Participants |
| Angiotensin receptor-neprilysin inhibitor | 7 Participants | 9 Participants | 2 Participants |
| Anticoagulatoin drugs | 21 Participants | 37 Participants | 16 Participants |
| Aspartate aminotransferase | 212 U/L | 204 U/L | 203 U/L |
| Aspirin | 239 Participants | 474 Participants | 235 Participants |
| Beta-blocker | 234 Participants | 457 Participants | 223 Participants |
| Body Mass Index | 27.2 kg/m² | 27.6 kg/m² | 27.7 kg/m² |
| Calcium channel blocker | 12 Participants | 21 Participants | 9 Participants |
| Coronary 1-vessel disease | 123 Participants | 228 Participants | 105 Participants |
| Coronary 2-vessel disease | 80 Participants | 162 Participants | 82 Participants |
| Coronary 3-vessel disease | 36 Participants | 86 Participants | 50 Participants |
| Coronary artery disease | 25 Participants | 53 Participants | 28 Participants |
| Creatine kinase | 1,701 U/L | 1,673 U/L | 1,668 U/L |
| Depression | 9 Participants | 24 Participants | 15 Participants |
| Diastolic blood pressure | 78 mmHg | 78 mmHg | 78 mmHg |
| Dipeptidyl peptidase 4 inhibitor | 6 Participants | 13 Participants | 7 Participants |
| Dyslipidaemia | 64 Participants | 135 Participants | 71 Participants |
| Estimated glomerular filtration rate | 91 ml/min/1.73m² | 92 ml/min/1.73m² | 92 ml/min/1.73m² |
| Ezetimibe | 30 Participants | 59 Participants | 29 Participants |
| Gamma glutamyltransferase | 32 U/L | 31 U/L | 29 U/L |
| Glucagon-like peptide-1 receptor agonist | 2 Participants | 4 Participants | 2 Participants |
| HbA1c | 5.7 percentage of HbA1c | 5.6 percentage of HbA1c | 5.6 percentage of HbA1c |
| High-density lipoprotein | 43 mg/dL | 44 mg/dL | 44 mg/dL |
| History of carcinoma | 13 Participants | 24 Participants | 11 Participants |
| History of coronary artery bypass graft | 1 Participants | 2 Participants | 1 Participants |
| History of myocardial infarction | 9 Participants | 23 Participants | 14 Participants |
| History of stroke | 1 Participants | 6 Participants | 5 Participants |
| Hypertension | 107 Participants | 199 Participants | 92 Participants |
| Insulin | 6 Participants | 11 Participants | 5 Participants |
| Loop diuretic | 24 Participants | 51 Participants | 27 Participants |
| Low-density lipoprotein | 121 mg/dL | 120 mg/dL | 118 mg/dL |
| Metformin | 20 Participants | 41 Participants | 21 Participants |
| Mineralcorticoid receptor antagonist | 94 Participants | 180 Participants | 86 Participants |
| N-terminal prohormone of brain natriuretic peptide | 1,373 pg/mL | 1,294 pg/mL | 1,272 pg/mL |
| Obesity | 70 Participants | 138 Participants | 68 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Austria | 239 Participants | 476 Participants | 237 Participants |
| Sex: Female, Male Female | 42 Participants | 84 Participants | 42 Participants |
| Sex: Female, Male Male | 197 Participants | 392 Participants | 195 Participants |
| Smoking active or former | 170 Participants | 341 Participants | 171 Participants |
| Statin | 233 Participants | 462 Participants | 229 Participants |
| Sulfonylurea | 2 Participants | 4 Participants | 2 Participants |
| Systolic blood pressure | 125 mmHg | 125 mmHg | 125 mmHg |
| Total cholesterol | 188 mg/dL | 188 mg/dL | 188 mg/dL |
| Troponin T | 3,029 ng/L | 3,039 ng/L | 3,059 ng/L |
| Type 2 diabetes | 33 Participants | 63 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 237 | 0 / 239 |
| other Total, other adverse events | 18 / 237 | 9 / 239 |
| serious Total, serious adverse events | 31 / 237 | 32 / 239 |
Outcome results
Primary
Changes of Nt-proBNP (N-terminales Pro Brain Natriuretic Peptide) Levels
Difference in the change of nt-proBNP (N terminales pro brain natriuretic peptide) levels between treatment groups from randomization to week 26
Time frame: 26 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Empagliflozin | Changes of Nt-proBNP (N-terminales Pro Brain Natriuretic Peptide) Levels | -84.9 pg/mL |
| Placebo Oral Tablet | Changes of Nt-proBNP (N-terminales Pro Brain Natriuretic Peptide) Levels | -82.2 pg/mL |
Secondary
Changes in E/è Ratio From Baseline to Week 26
E/E' ratio is a measure of left ventricular filling pressure. The E/e' ratio is a parameter for diastolic function assessment that is frequently used for Heart failure with preserved ejection fraction evaluation. To derive the E/e´ ratio one must divide the maximum velocity of the E-wave of mitral valve inflow by the maximal velocity of E. In normal individuals the E/e´ ratio is \<8. In the presence of diastolic dysfunction / impaired relaxation, e´ will be rather low. In contrast, the E-wave increases with elevated filling pressures. Thus the E/e´ ratio will increase in the presence of diastolic dysfunction. An E/e´ratio \>14 is highly suggestive of elevated filling pressures.
Time frame: From Baseline to Week 26
Population: Total ultrasound measurements were just available from 212 (empagliflozin group) and 209 patients (placebo group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Empagliflozin | Changes in E/è Ratio From Baseline to Week 26 | -9.7 Ratio |
| Placebo Oral Tablet | Changes in E/è Ratio From Baseline to Week 26 | -0.7 Ratio |
Secondary
Changes in Ejection Fraction
Difference in the change of ejection fraction between treatment groups from randomization to week 26 Ejection fraction was measured by ultrasound.
Time frame: 26 weeks
Population: Total ultrasound measurements were just available from 212 (empagliflozin group) and 209 patients (placebo group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Empagliflozin | Changes in Ejection Fraction | 4.7 percentage of ejection fraction |
| Placebo Oral Tablet | Changes in Ejection Fraction | 2.8 percentage of ejection fraction |
Secondary
Changes in Left Ventricular End-diastolic Volume
Difference in the change of left ventricular end-diastolic volume from randomization to week 26 (measured by ultrasound)
Time frame: 26 weeks
Population: Total ultrasound measurements were just available from 212 (empagliflozin group) and 209 patients (placebo group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Empagliflozin | Changes in Left Ventricular End-diastolic Volume | 3.4 ml |
| Placebo Oral Tablet | Changes in Left Ventricular End-diastolic Volume | 13.5 ml |
Secondary
Changes in Left Ventricular End-systolic Volume (LVESV) From Baselin to Week 26
End-systolic volume (ESV) is the volume of blood in a ventricle at the end of contraction, or systole, and the beginning of filling, or diastole. Left ventricular end-systolic volume (LVESV) was measured at baseline and after 26 weeks by echocardiography.
Time frame: Baseline to Week 26
Population: Total ultrasound measurements were just available from 212 (empagliflozin group) and 209 patients (placebo group).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Empagliflozin | Changes in Left Ventricular End-systolic Volume (LVESV) From Baselin to Week 26 | -3.6 ml |
| Placebo Oral Tablet | Changes in Left Ventricular End-systolic Volume (LVESV) From Baselin to Week 26 | 4.3 ml |
Secondary
Duration of Hospital Stay
Difference in the duration of hospital stay between the treatment groups after initiation of the study treatment. This outcome measure includes all days of an inpatient stay in a hospital after the initial discharge.
Time frame: 30 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Empagliflozin | Duration of Hospital Stay | 6.0 days |
| Placebo Oral Tablet | Duration of Hospital Stay | 6.0 days |