Revascularization Versus Medical Treatment in Patients With Ischemic Left Ventricular Dysfunction

Study Overview
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Brief Summary
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Randomized trial to compare clinical outcomes between revascularization versus medical treatment alone in patients with ischemic cardiomyopathy and left ventricular dysfunction.

Detailed Description
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Ischemic cardiomyopathy, the term used to describe systolic dysfunction due to chronic myocardial ischemia from ischemic heart disease, is the most common form of heart failure. To adapt to this ischemic environment, myocardium is known to undergo downregulation that may revert after adequate perfusion is re-established, a phenomenon known as myocardium hibernation. This phenomenon has been a background for the main concept of management for ischemic cardiomyopathy via revascularization. Indeed, the recent 10-year follow-up reports from STICH trial demonstrated improved long-term clinical outcomes after coronary bypass graft surgery than optimal medical therapy (OMT) in patients with ischemic cardiomyopathy. Percutaneous coronary intervention (PCI) is another intervention that is commonly used to revascularize significant coronary stenosis. Despite common belief that revascularization by PCI would improve perfusion to ischemic myocardium and improve clinical outcomes, several clinical trials have failed to show beneficial impact of PCI over OMT in stable ischemic heart disease other than symptomatic improvement. Recently published REVIVED trial compared effect of PCI and OMT in ischemic cardiomyopathy patients with left ventricular ejection fraction < 35% and demonstrable viable myocardial segments, and found no significant difference in clinical outcomes of both groups. However, whether PCI optimized by additional information can make a difference in this setting remains unanswered. It is known that intravascular imaging and coronary physiologic testing using intravascular ultrasound (IVUS), optical coherence tomography (OCT) or fractional flow reserve (FFR) result in better outcomes compared to conventional angiography alone. IVUS provides anatomical information regarding the lumen, plaque, and plaque characteristics, and can optimize stent placement minimizing stent-related problems and lead to better 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. Unfortunately, proportion of IVUS and FFR use is not disclosed in REVIVED trial, and it is possible there is a room for improvement if the PCI is further guided by these adjunctive diagnostic procedures in regard to the clinical outcomes. In this regard, it is our hypothesis that PCI guided and optimized by intravascular imaging and FFR-guided strategy would bring additional benefit that may result in significant difference of prognosis for ischemic cardiomyopathy compared to OMT alone. Randomized controlled trial to test this hypothesis would provide valuable evidence to guide treatment strategy for ischemic cardiomyopathy. Therefore, RESTORE-PCI trial has been designed to compare clinical outcomes after state-of-the-art PCI or OMT for ischemic cardiomyopathy. The aim of the study is to compare clinical outcomes between revascularization versus medical treatment alone in patients with ischemic cardiomyopathy and left ventricular dysfunction. Primary hypothesis is that revascularization guided by invasive physiologic indexes and optimized by intravascular imaging device plus optimal medical treatment (OMT) would reduce risk of primary composite end point (major adverse cardiac events [MACE], a composite of death, myocardial infarction (MI), admission for heart failure, or advanced heart failure requiring LVAD or transplantation) than OMT alone in patients with ischemic cardiomyopathy.

Official Title
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Randomized Controlled Trial of Revascularization Versus Medical Treatment on Clinical Outcomes in Patients With Reduced Left Ventricular Function

Conditions
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Heart Failure With Reduced Ejection Fraction, Ischemic Cardiomyopathy

Intervention / Treatment
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* Procedure: Percutaneous coronary intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be at least 19 years of age Patients with stage C heart failure and left ventricular ejection fraction<40% Patients with significant coronary artery stenosis (diameter stenosis>50% with proven inducible myocardial ischemia by invasive physiologic assessment) Coronary artery disease is amenable for percutaneous coronary intervention (PCI) Subject is able to verbally confirm understandings of risks, benefits and treatment alternatives of receiving invasive approach and he/she or his/her legally authorized representative provides written informed consent prior to any study related procedure. Exclusion Criteria: Myocardial infarction by universal definition within 4 weeks of randomization Non-viable myocardium in myocardial viability test (cardiac magnetic resonance, dobutamine-stress echocardiography, delayed single-photon emission computerized tomography, or aneurysmal change in echocardiography) Target lesions not amenable for PCI by operators' decision Patients who need left ventricular assisted device (LVAD) or heart transplantation at the time of randomization 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) 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, multi-center, open-label, randomized controlled, superiority trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Guideline-directed medical treatment group<br>In the GDMT group, medical treatment for patients with left ventricular dysfunction will be performed under current ACC/AHA/SCAI or ESC/EACTS guidelines for heart failure. | |
| Experimental: Revascularization group<br>In the revascularization group, patients will undergo percutaneous coronary intervention (PCI) using standard techniques under current ACC/AHA/SCAI or ESC/EACTS guidelines. In the revascularization group, the procedure must be within 2 weeks of randomization. Revascularization criteria is presented as below. Revascularization indication Diameter stenosis >90% by visual assessment Functionally significant stenosis (FFR≤0.80 or non-hyperemic pressure ratios≤0.89) Chronic total occlusion with substantial ischemic territory. The below locations will be judged as having substantial ischemic territory. Left main artery Proximal to mid left anterior descending artery Proximal left circumflex artery in left dominant coronary arterial system Proximal to distal right coronary artery in right dominant coronary arterial system | Procedure: Percutaneous coronary intervention<br>* Revascularization indication Diameter stenosis >90% by visual assessment Functionally significant stenosis (FFR≤0.80 or non-hyperemic pressure ratios≤0.89) Chronic total occlusion with substantial ischemic territory. The below locations will be judged as having substantial ischemic territory. Left main artery Proximal to mid left anterior descending artery Proximal left circumflex artery in left dominant coronary arterial system Proximal to distal right coronary artery in right dominant coronary arterial system<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| major adverse cardiac events [MACE] | a composite of death, myocardial infarction (MI), admission for heart failure, or advanced heart failure requiring LVAD or transplantation | 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 | 
| Any myocardial infarction | Any myocardial infarction by Forth Universal definition of MI | 2 years after last patient enrollment | 
| Spontaneous myocardial infarction | Spontaneous myocardial infarction by Forth Universal definition of MI | 2 years after last patient enrollment | 
| Procedure-related myocardial infarction | Procedure-related myocardial infarction by ARC II definition | After index procedure | 
| Admission for heart failure | Admission for acute decompensated heart failure | 2 years after last patient enrollment | 
| Advanced heart failure requiring LVAD or transplantation | Advanced heart failure requiring LVAD or transplantation | 2 years after last patient enrollment | 
| Implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy (CRT-D) | Incidence of Implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy (CRT-D) for documented ventricular tachycardia or ventricular fibrillation (secondary prevention). | 2 years after last patient enrollment | 
| Clinically-indicated unplanned revascularization | Clinically-indicated unplanned revascularization | 2 years after last patient enrollment | 
| Stroke | Stroke (ischemic or hemorrhagic) | 2 years after last patient enrollment | 
| EQ-5D-5L (quality of life) | EQ-5D-5L (quality of life) | at 6 month after index procedure | 
| SAQ (angina severity) | SAQ (angina severity) | at 6 month after index procedure | 
| Left ventricular ejection fraction | Left ventricular ejection fraction by echocardiography | at 6 month - 1 year follow-up after index procedure | 
| NT-proBNP | NT-proBNP, pg/mL | at 6 month - 1 year follow-up after index procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ischemic cardiomyopathy, percutaneous coronary intervention, ejection fraction, guideline-directed medical treatment