Impact of EMpagliflozin on Cardiac Function and Biomarkers of Heart Failure in Patients With Acute MYocardial Infarction

Phase 3

Completed

Conditions: Acute Myocardial Infarction

Interventions: Drug: Placebo Oral Tablet
Drug: Empagliflozin 10 mg

Registration Number: NCT03087773

Lead Sponsor: Medical University of Graz

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 476

Inclusion Criteria

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
18 - 80 years of age
Informed consent has to be given in written form
estimated glomerular filtration rate (eGFR) > 45 ml/min/1.73m2
Blood pressure before first drug dosing: Riva Rocci (RR) systolic >110 mmHg
Blood pressure before first drug dosing: Riva Rocci (RR) diastolic >70 mmHg
≤72h after myocardial infarction (after the performance of a coronary angiography)

Exclusion Criteria

Any other form of diabetes mellitus than type 2 diabetes mellitus, history of diabetic ketoacidosis
Blood potential hydrogen (pH) < 7,32
Known allergy to SGLT-2 inhibitors
Hemodynamic instability as defined by intravenous administration of catecholamine, calcium sensitizers or phosphodiesterase inhibitors
>1 episode of severe hypoglycemia within the last 6 months and treatment with insulin or sulfonylurea
Females of childbearing potential without adequate contraceptive methods (i.e. sterilization, intrauterine device, vasectomized partner; or medical history of hysterectomy)
Acute symptomatic urinary tract infection (UTI) or genital infection
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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo Oral Tablet	Placebo Oral Tablet	The subjects will receive placebo.
Empagliflozin	Empagliflozin 10 mg	The subjects will receive Empagliflozin 10mg.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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 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.
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.

Trial Locations

Locations (11): Barmherzige Brüder Eisenstadt
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Eisenstadt, Burgenland, Austria
Klinikum Klagenfurt am Wörthersee
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Klagenfurt, Kärnten, Austria
Universitätsklinikum St. Pölten
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St.Pölten, Niederösterreich, Austria
Kardinal schwarzenberg Klinikum Schwarzach
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Schwarzach Im Pongau, Salzburg, Austria
Landeskrankenhaus Graz II Standort West
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Graz, Austria
Medical University of Graz
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Graz, Austria
Allgemeines Krankenhaus Vienna
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Vienna, Austria
Krankenanstalt Rudolfstiftung
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Vienna, Austria
VIVIT Institut am akademischen Lehrkrankenhaus Feldkirch
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Feldkirch, Vorarlberg, Austria
Kepler Universitätsklinikum Linz
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Linz, Oberösterreich, Austria
Uniklinikum Salzburg
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Salzburg, Austria