IVUS Versus FFR for Non-infarct Related Artery Lesions in Patients With Multivessel Disease and Acute STEMI

Study Overview
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Brief Summary
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The aim of the study is to compare clinical outcomes between intravascular ultrasound (IVUS)-guided treatment decision versus fractional flow reserve (FFR)-guided treatment decision for non-infarct related artery stenosis in patients with ST-segment elevation MI (STEMI) and multivessel disease.

Detailed Description
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The treatment of choice of ST-segment elevation myocardial infarction (STEMI) is acute reperfusion therapy, preferably with primary percutaneous coronary intervention (PCI). While need of treating the infarct related artery (IRA) is obvious, need for routine revascularization of non-infarct related artery (non-IRA) has been a topic of debate until recent years. Through a number of observational studies, randomized trials and meta-analyses, the benefits of non-IRA PCI have been continuously implied, and COMPLETE trial with 4041 patients of STEMI and multivessel coronary artery disease in 2019 demonstrated superiority of complete revascularization to culprit-only PCI in terms of cardiovascular death or MI (primary end point) and cardiovascular death, MI, or ischemia-driven revascularization (co-primary end point).8 As such, complete revascularization of a significant non-IRA stenosis is recommended after successful primary PCI in STEMI patients in current clinical guidelines. Nevertheless, it has been unclear which criteria should be used to decide non-IRA PCI. Although potential significance of non-IRA lesions can be estimated by angiography, the limitation of angiographic visual assessment or quantitative coronary angiography has been well known. Various measurements are used for incremental information in addition to angiographic assessment in guiding PCI - namely, intravascular ultrasound (IVUS) and fractional flow reserve (FFR). IVUS provides anatomical information regarding the lumen, plaque, and plaque characteristics, and can optimize stent placement minimizing stent-related problems and lead to better clinical outcomes. On the other hand, FFR provides information on amount of ischemia which the stenosis in question is causing, and also improves the quality of PCI which has been demonstrated by multiple previous trials, and current practice guidelines recommend the use of FFR to determine revascularization strategy as Class IA recommendation. Recent trials evaluated comparative prognosis between FFR-guided versus angiograph-guided PCI for non-IRA in patients with acute MI and multivessel disease. FLOWER-MI trial showed comparable clinical outcome between FFR-guided versus angiography-guided PCI for non-IRA in STEMI patients at 1-year follow-up. FRAME-AMI trial showed superiority of FFR-guided PCI over angiography-guided PCI in reducing death, MI, or repeat revascularization during median 3.5 years of follow-up. Although IVUS and FFR differ in underlying basic concepts, previous studies demonstrated clinical outcomes following treatment decision by IVUS and FFR was similar between the 2 groups. However, these studies mainly evaluated low-risk stable ischemic heart disease patients with intermediate stenosis, and does not reflect population with acute myocardial infarction undergoing complete revascularization. Currently, the data directly comparing the benefit of IVUS and FFR for non-IRA PCI in STEMI is lacking. Considering that coronary atherosclerotic plaque in non-IRA of STEMI patients is associated with significantly higher risk of future clinical events, IVUS would have potential strength of detecting high risk plaque in non-IRA and treatment decision based on plaque characteristics. Conversely, FFR-guided treatment decision for non-IRA would detect functionally significant non-IRA stenosis and treatment decision based on functional significance would reduce unnecessary PCI, as demonstrated by previous trials. In this regard, randomized controlled trial comparing clinical outcome following non-IRA PCI in STEMI patients with multivessel disease guided by IVUS or FFR would provide valuable evidence to enhance patient's prognosis after treatment of STEMI. Therefore, FRAME-AMI 2 trial is designed to compare clinical outcomes after non-IRA PCI using either IVUS-guided or FFR-guided strategy.

Official Title
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Randomized Controlled Trial of Intravascular Ultrasound Versus Fractional Flow Reserve for Non-infarct Related Artery Lesions in Patients With Multivessel Disease and Acute STEMI

Conditions
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ST Elevation Myocardial Infarction

Intervention / Treatment
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* Diagnostic Test: IVUS-guided PCI group
* Diagnostic Test: FFR-guided PCI group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be at least 19 years of age Acute ST-segment elevation myocardial infarction (STEMI) *STEMI: ST-segment elevation ≥0.1 mV in ≥2 contiguous leads or documented newly developed left bundle-branch block1 Successful primary percutaneous coronary intervention (PCI) for IRA in <12 h after the onset of symptoms Multivessel disease (at least one stenosis of >50% in a non-IRA ≥2.25 mm by visual estimation) Subject is able to verbally confirm understandings of risks, benefits and treatment alternatives of receiving invasive physiologic evaluation and PCI and he/she or his/her legally authorized representative provides written informed consent prior to any study related procedure. Exclusion Criteria: Non-IRA stenosis not amenable for PCI treatment by operators' decision Cardiogenic shock (Killip class IV) already at presentation or the completion of IRA PCI Intolerance to Aspirin, Clopidogrel, Prasugrel, Ticagrelor, Heparin, or Everolimus Known true anaphylaxis to contrast medium (not allergic reaction but anaphylactic shock) Pregnancy or breast feeding Non-cardiac co-morbid conditions are present with life expectancy <2 year or that may result in protocol non-compliance (per site investigator's medical judgment) Other primary valvular disease with severe degree: severe mitral regurgitation, mitral stenosis, severe aortic regurgitation, or aortic stenosis Unwillingness or inability to comply with the procedures described in this protocol.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, multicenter, randomized controlled non-inferiority trial to compare clinical outcomes between IVUS-guided PCI versus FFR-guided PCI in patients with STEMI and multivessel disease.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fractional flow reserve-guided PCI<br>FFR measurement for non-IRA stenosis (>50% visual estimation) will be performed by continuous infusion of adenosine (140 180 ug/kg/min) or intracoronary nicorandil (2 mg bolus) injection. The FFR ≤0.80 will be targeted for PCI. In case of non-IRA stenosis >90%, we will judge FFR value of ≤0.80. | Diagnostic Test: FFR-guided PCI group<br>* In FFR-guided PCI group, FFR measurement for non-IRA stenosis (>50% visual estimation) will be performed by continuous infusion of adenosine (140 180 ug/kg/min) or intracoronary nicorandil (2 mg bolus) injection. The FFR ≤0.80 will be targeted for PCI. In case of non-IRA stenosis >90%, we will judge FFR value of ≤0.80.<br>|
| Experimental: Intravascular Ultrasound-guided PCI<br>In IVUS-guided PCI group, the current trial evaluates clinical outcome following IVUS-guided treatment decision for revascularization of non-IRA stenosis. According to pre-defined criteria, the decision of revascularization will be made. Revascularization criteria in the IVUS-guided PCI group is 1) minimal lumen area (MLA) ≤ 3mm2 or 2) 3mm2 < MLA ≤4mm2 and plaque burden >70%. | Diagnostic Test: IVUS-guided PCI group<br>* In IVUS-guided PCI group, the current trial evaluates clinical outcome following IVUS-guided treatment decision for revascularization of non-IRA stenosis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient-Oriented Composite Outcome | a composite of death, myocardial infarction, or repeat revascularization | 2 years after last patient enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause death | All-cause death | 2 years after last patient enrollment | 
| Cardiac death | Cardiac death | 2 years after last patient enrollment | 
| Spontaneous myocardial infarction | Spontaneous myocardial infarction, defined by Forth Universal definition of myocardial infarction | 2 years after last patient enrollment | 
| Procedure-related myocardial infarction | Procedure-related myocardial infarction, defined by ARC II definition | 2 years after last patient enrollment | 
| Any revascularization | Any revascularization (clinically-driven or ischemia-driven) | 2 years after last patient enrollment | 
| Infarct-related artery revascularization | Infarct-related artery revascularization | 2 years after last patient enrollment | 
| Non-Infarct-related artery revascularization | Non-Infarct-related artery revascularization | 2 years after last patient enrollment | 
| Definite or probable stent thrombosis | Definite or probable stent thrombosis | 2 years after last patient enrollment | 
| Stroke (ischemic or hemorrhagic) | Stroke (ischemic or hemorrhagic) | 2 years after last patient enrollment | 
| Total procedural time | Total procedural time (from the end of primary PCI for IRA to the completion of non-IRA PCI including amount of staged procedure) | at least 1 week after index procedure | 
| Total fluoroscopy time | Total fluoroscopy time (from the end of primary PCI for IRA to the completion of non-IRA PCI including amount of staged procedure) | at least 1 week after index procedure | 
| Total amount of contrast use | Total amount of contrast use (from the end of primary PCI for IRA to the completion of non-IRA PCI including amount of staged procedure) | at least 1 week after index procedure | 
| Incidence of contrast-induced nephropathy | Incidence of contrast-induced nephropathy, defined as an increase in serum creatinine of ≥0.5mg/dL or ≥25% from baseline within 48-72 hours after contrast agent exposure. | at least 1 week after index procedure | 
| A composite of all-cause death or myocardial infarction | A composite of all-cause death or myocardial infarction | 2 years after last patient enrollment | 
| A composite of cardiac death or non-procedure-related myocardial infarction | A composite of cardiac death or non-procedure-related myocardial infarction | 2 years after last patient enrollment | 
| Angina severity by Seattle Angina Questionnaire | Angina severity by Seattle Angina Questionnaire | At 2 years from index procedure | 
| Quality of life by EQ-5D-5L Questionnaire | Quality of life by EQ-5D-5L Questionnaire | At 2 years from index procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ST-segment elevation MI, Fractional flow reserve, intravascular ultrasound, Multivessel disease, Complete revascularization