Peri-treatment of SGLT-2 Inhibitor on Myocardial Infarct Size and Remodeling Index in Patients With Acute Myocardial Infarction and High Risk of Heart Failure Undergoing Percutaneous Coronary Intervention

Study Overview
=================
Brief Summary
-----------------
We aimed to identify whether SGLT-2 inhibitor administration before and after coronary intervention is effective in reducing the size of infarction and myocardial remodeling in patients with acute myocardial infarction (AMI) and high risk of heart failure, and its mechanism. For this reason, we compared cardiac magnetic resonance imaging (CMR) parameters and clinical outcomes between the SGLT-2 inhibitor group and the control group to confirm the efficacy and safety of SGLT-2 inhibitors.

Detailed Description
-----------------
After the introduction of percutaneous coronary intervention (PCI) as a method to normalize blood flow in the treatment of coronary artery disease, not only the technical aspects of coronary intervention but also the devices and medications have been improved over the past 30 years. However, despite these advances, morbidity, and mortality of AMI are still high. In particular, in patients with ST-segment elevation MI (STEMI), the 1-year mortality rate and hospitalization rate due to heart failure are 10%, and 22%, respectively. Accordingly, various efforts are being made to improve the prognosis of AMI and to reduce the infarct size, which is a major prognostic factor. The most effective method for achieving this goal to early and successful revascularization by PCI. However, restoring blood flow, which is a prerequisite for relieving ischemia, can paradoxically cause damage to the myocardium and death of the myocardium by itself. This phenomenon is called myocardial reperfusion injury. Several pharmacological and mechanical treatments targeting this phenomenon have been studied, and the experimental and small-scale clinical trials have been shown to have the effect of reducing infarct size and relieving myocardium.4 However, to date, large-scale clinical trials have not demonstrated clinical benefits. SGLT-2 inhibitors are developed to lower blood sugar and treat type 2 diabetes mellitus (DM) by inhibiting Sodium glucose co-transporter-2 in proximal renal tubule, releasing glucose into the urine and preventing reabsorption. However, SGLT-2 inhibitors are known to have an effect on lowering cardiovascular events in addition to lowering blood sugar. In three large-scale, multicenter, randomized trials to evaluate the effects of SGLT-2 in type 2 diabetic patients, the combined outcome consisting of cardiac death or readmission due to heart failure was significantly lowered compared to the placebo group. In particular, DECLARE-TIMI 58 trial confirmed that this effect was consistent regardless of the history of atherosclerotic cardiovascular disease or heart failure.8 In addition, DAPA-CKD trial showed that SGLT-2 inhibitor significantly reduced the composite outcome consisting of cardiovascular death or readmission due to heart failure as well as the kidney-related outcome compared to the placebo group in patients with chronic kidney disease regardless of type 2 DM. Similarly, EMPEROR-Reduced and DAPA-HF trials consistently demonstrated that SGLT-2 inhibitor was associated with significantly lower risk of a composite of cardiovascular death or worsening heart failure in patients with heart failure with reduced ejection fraction. Therefore, the current guideline recommended the use of SGLT-2 inhibitor in patients with heart failure with reduced ejection fraction, with a conjunction of goal-directed medical therapy. Nevertheless, the mechanism that can explain this has been extensively investigated, but it is not clear yet. Several potential hypotheses have been proposed as mechanisms such as increased natriuresis, decreased blood pressure, decreased inflammation, and decreased reactive oxidative stress. In this regard, it is anticipated that the use of SGLT-2 inhibitors will benefit even in patients with AMI and high risk of heart failure in both acute and chronic phases. Therefore, we aimed to identify whether SGLT-2 inhibitor administration before and after coronary intervention is effective in reducing the size of infarction and myocardial remodeling in patients with AMI and high risk of heart failure, and its mechanism. For this reason, we compared CMR parameters and clinical outcomes between the SGLT-2 inhibitor group and the control group to confirm the efficacy and safety of SGLT-2 inhibitors.

Official Title
-----------------
Peri-tREatment of SGLT-2 Inhibitor on Myocardial Infarct Size and Remodeling Index Measured by Cardiac maGnetic rEsonance Imaging in Patients With Acute Myocardial Infarction and High Risk of Heart Failure Undergoing Percutaneous Coronary Intervention

Conditions
-----------------
Acute Myocardial Infarction, Heart Failure

Intervention / Treatment
-----------------
* Drug: SGLT2 inhibitor
* Other: Control


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1) Subject must be at least 18 years of age 2) Subject is able to verbally confirm understandings of risks, benefits and treatment alternatives of receiving SGLT-2 inhibitor and he/she or his/her legally authorized representative provides written informed consent prior to any study related procedure 3) Diagnosis of Type 1 myocardial infarction (MI) (ST-segment elevation MI [STEMI] or Non-ST-segment elevation MI [NSTEMI]) i) Detection of a rise and/or fall of cardiac troponin values with at least 1 value above the 99th percentile upper reference limit ii) Symptoms or electrocardiographic changes suggesting myocardial ischemia 4) High risk of heart failure (at least one of the two criteria below are met) i) Left ventricular ejection fraction < 50% ii) Symptoms or signs of pulmonary congestion requiring treatment Exclusion Criteria: 1) Target lesion is not suitable for PCI by operator's decision 2) Patients requiring cardiopulmonary resuscitation due to cardiac arrest before randomization 3) Rescue PCI after thrombolysis or facilitated PCI 4) Previous MI 5) Previous history of heart failure 6) Patients who have been taking SGLT-2 inhibitor 7) Patients with glomerular filtration rate < 30ml/min/1.73m2 or on dialysis 8) Type 1 diabetes mellitus (DM) 9) Known hypersensitivity or contraindications to study medications (SGLT-2 inhibitor) 10) Pregnant or lactating women 11) Non-cardiac co-morbid conditions are present with life expectancy <1 year or that may result in protocol non-compliance (per site investigator's medical judgment)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization will be performed 1:1 between SGLT-2 inhibitor and control. Stratification will be done by DM and clinical presentation (STEMI vs. NSTEMI).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SGLT-2 inhibitor<br>The SGLT-2 inhibitor group will receive SGLT-2 inhibitor once daily until the end of the study period. | Drug: SGLT2 inhibitor<br>* In patients with AMI and high risk of heart failure, 1:1 randomization will be performed to either SGLT2 inhibitor or control group.<br>|
| Placebo Comparator: Control<br>The control group will not receive any additional drugs. | Other: Control<br>* In patients with AMI and high risk of heart failure, 1:1 randomization will be performed to either SGLT2 inhibitor or control group.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial infract size (IS) | IS measured using CMR | at 6-month follow-up | 
| ∆Left ventricular end-systolic volume | Difference of left ventricular end-systolic volume measured by CMR | Between index hospitalization and 6-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute kidney injury | According to KDIGO guideline | Within 3 days after index PCI | 
| Myocardial IS | IS measured using CMR | Within 3 days after index PCI | 
| Myocardial salvage index (MSI) | MSI measured using CMR | Within 3 days after index PCI | 
| Microvascular obstruction (MVO) | MVO measured using CMR | Within 3 days after index PCI | 
| Hemorraghic infarction (HI) | HI measured using CMR | Within 3 days after index PCI | 
| IS | measured by peak cardiac enzyme | Within 3 days after index PCI | 
| Thrombolysis in myocardial infarction (TIMI) flow grade | TIMI flow grade after successful PCI | Immediate after index PCI | 
| ST resolution after PCI | ST segment change after PCI | Immediate after index PCI | 
| ∆left ventricular end-diastolic volume | Difference of left ventricular end-diastolic volume measured using CMR | Between index hospitalization and 6-month follow-up | 
| ∆left ventricular ejection fraction | Difference of left ventricular ejection fraction measured using CMR | Between index hospitalization and 6-month follow-up | 
| LV adverse remodeling | measured by CMR | Between index hospitalization and 6-month follow-up | 
| LV reverse remodeling | measured by CMR | Between index hospitalization and 6-month follow-up | 
| MSI | measured using CMR | at 6-month follow-up | 
| MVO | measured using CMR | at 6-month follow-up | 
| HI | measured using CMR | at 6-month follow-up | 
| Changes of NT-proBNP level | Difference of NT-proBNP | Between index hospitalization and 6-month follow-up | 
| Estimated glomerular filtration rate | Kidney function | 6 months after index PCI | 
| Cardiac death or re-hospitalization due to heart failure | a composite of cardiac death or re-hospitalization due to heart failure | 6 months after index PCI | 
| All-cause death or re-hospitalization due to heart failure | a composite of all-cause death or re-hospitalization due to heart failure | 6 months after index PCI | 
| Target lesion failure | a composite of cardiac death, MI, or clinically indicated target-lesion revascularization | 6 months after index PCI | 
| Target vessel failure | a composite of cardiac death, MI, or clinically indicated target-vessel revascularization | 6 months after index PCI | 
| All-cause death | All-cause death during follow-up | 6 months after index PCI | 
| Cardiac death | Cardiac death during follow-up | 6 months after index PCI | 
| Target vessel MI | Target vessel MI during follow-up | 6 months after index PCI | 
| Target lesion revascularization | Target lesion revascularization during follow-up | 6 months after index PCI | 
| Re-hospitalization due to heart failure | Re-hospitalization due to heart failure during follow-up | 6 months after index PCI | 
| Any re-hospitalization | Any re-hospitalization during follow-up | 6 months after index PCI | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Percutaneous Coronary Intervention, Infarct size, Cardiac Magnetic Resonance Imaging