Interventional Strategy for Non-culprit Lesions With Major Vulnerability Criteria at OCT in Patients With ACS

Study Overview
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Brief Summary
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The INTERCLIMA (Interventional Strategy for Non-culprit Lesions With Major Vulnerability Criteria Identified by Optical Coherence Tomography in Patients With Acute Coronary Syndrome) is a multi-center, prospective, randomized trial of optical coherence tomography (OCT)-based versus physiology-based (i.e. fractional flow reserve[FFR]/instantaneous Wave-Free Ratio[iFR]/resting full-cycle ratio[RFR]) treatment of intermediate (40-70% diameter stenosis at quantitative coronary angiography), non-culprit coronary lesions in acute coronary syndrome (ACS) patients undergoing coronary angiography. About 1400 patients with ACS will be randomized into the study at approximately 40 sites worldwide.

Detailed Description
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The optimal strategy in patients with intermediated stenosis (40-70% diameter stenosis) at coronary angiography is currently under debate. Pure angiographic stenosis evaluation is often inadequate and alternative assessments of coronary plaques entered the clinical practice, such as functional assessment (FFR/iFR/RFR) and intravascular imaging (OCT and intravascular ultrasound [IVUS]). Based on preliminary data, current American College of Cardiology (ACC) and American Heart Association (AHA) revascularization guidelines recommend the use of flow fractional reserve (FFR, class IIa of evidence) to assess angiographic intermediate coronary lesions in patients with stable ischemic heart disease and guide intervention. However, controversial data has recently emerged on the role of functional assessment of intermediate coronary lesions in both acute and chronic setting. On the other hand, in recent studies the presence of coronary plaques with vulnerability criteria at OCT identified patients at high risk of cardiac mortality and target vessel MI. This study aims to assess the clinical effectiveness of an OCT-based strategy to guide revascularization in non-culprit intermediate coronary stenosis in patients with acute coronary syndrome (ACS), on the basis of the presence of morphological markers of plaque vulnerability. Patients with single intermediate coronary lesion in a non-culprit intervention-naïve major coronary segment (diameter ≥2.5 mm) and fulfilling all inclusion/exclusion criteria will be eligible. Enrolled patients will be randomized 1:1 to either OCT or iFR/FFR/RFR based treatment. In the OCT-guided arm, non-culprit intermediate lesions will be treated with percutaneous coronary intervention (PCI) with implantation of a second-generation drug eluting stent (DES) when a fibrous cap thickness (FCT) <75 µm plus at least 2 of 3 other OCT criteria of plaque vulnerability (i.e., minimum lumen area [MLA] <3.5 mm2, lipid arc with circumferential extension >180°, and the presence of clusters of macrophages) are detected by OCT. In the absence of the above-mentioned 4 vulnerability criteria, interventional procedures will be deferred regardless the observed MLA. In the physiology-guided arm, non-culprit intermediate lesions will be treated with PCI with implantation of a second-generation DES when an iFR or RFR ≤0.89 or an FFR ≤0.80 are measured, otherwise interventional procedures will be deferred. The primary endpoint, a composite of cardiac death and target vessel spontaneous myocardial infarction, will be assessed after 2, and 5 years.

Official Title
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An Interventional Strategy for Non-culprit Lesions With Major Vulnerability Criteria Identified by Optical Coherence Tomography in Patients With Acute Coronary Syndrome (the INTER-CLIMA Trial)

Conditions
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Coronary Artery Disease, Coronary Disease, Ischemic Heart Disease

Intervention / Treatment
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* Device: Optical coherence tomography
* Device: iFR/FFR/RFR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of at least 18 years. Diagnosis of acute coronary syndrome. Single intermediate lesion in an intervention-naïve major coronary segment (diameter ≥2.5 mm) determining a 40-70% diameter stenosis at quantitative coronary angiography analysis with no other significant stenosis (>70%) in the same vessel. Patient informed of the nature of the study, agreeing to it, and providing written informed consent as approved by the Ethics Committee of the respective clinical study site. Life expectancy >3 years. Exclusion criteria: Female with childbearing potential or lactating. Acute or chronic renal dysfunction (defined as creatinine greater than 2.0 mg/dl). Advanced heart failure (NYHA III-IV) Stroke within the previous 6 months or spontaneous intracranial hemorrhage at any time. Severe valvular disease or valvular disease likely to require surgery or percutaneous valve replacement during the trial. Coronary anatomy preventing complete imaging of the segment of interest (including at least 5 mm at both stenosis edges). Diffusely diseased coronary artery segment or presence of ≥1 significant untreated non-culprit lesions (preventing correct adverse event attribution) in the coronary arteries. Prior myocardial infarction or coronary artery bypass graft [CABG] or PCI revascularization in the target coronary vessel. Coronary anatomy unsuitable for PCI. Comorbidities that might interfere with completion of the study procedures. Planned major surgery necessitating interruption of dual antiplatelet. Participating in another investigational drug or device trial that has not completed the primary endpoint or would interfere with the endpoints of this study.

Ages Eligible for Study
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Minimum Age: 18 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: Two groups: one group receiving functional assessment of intermediate coronary lesions and the other group undergoing OCT assessment.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermediate lesion OCT-based management<br>At OCT analysis, lesion features prompting intervention instead of conservative approach will be the following: FCT <75 µm, plus at least 2 of 3 other OCT criteria of plaque vulnerability (i.e., MLA <3.5 mm2, lipid arc with circumferential extension >180°, and the presence of macrophages). The presence of intracoronary thrombus at a non-culprit site, irrespective of the presence of other vulnerability criteria, may prompt treatment with DES, at the operator's discretion. All lesions fulfilling these interventional criteria will be treated with an OCT guided DES implantation in order to achieve an optimal stent implantation. In presence of a MLA <2.0 mm2, best cut-off showing correlation with fractional-flow reserve positive functional (FFR) assessment, clinical decision whether to treat the lesion will be based on FFR assessment irrespective of the presence of other criteria of vulnerability. Alternatively authors will have the option to treat the lesion with a DES. | Device: Optical coherence tomography<br>* OCT images will be acquired by means of the FD C7 XR system or the OPTIS system (both St. Jude Medical, St. Paul, MN, USA) with a non-occlusive technique.(33) The acquired OCT coronary images will be analyzed on-line using a proprietary OCT console (St Jude Medical, Inc., USA). Definitions and cut-offs for OCT vulnerability parameters derived from available consensus documents and from main IVUS/OCT studies.<br>|
| Active Comparator: Intermediate lesion physiology-based management<br>The iFR/FFR/RFR measurements will be obtained using a coronary-pressure guidewire. For FFR, hyperemia will be induced with the administration of intravenous adenosine, in accordance with the clinical practice at each participating center. Lesion features prompting intervention instead of conservative medical approach will be the following: iFR ≤0.89, or FFR ≤0.80.(32) All lesions fulfilling these interventional criteria will be treated with an FFR guided DES implantation. PCI will be performed with the aim of achieving a post-stenting FFR ≥0.90 (i.e. optimal FFR result). If post-stenting FFR was <0.90 a further post-dilation of the stent could be performed and if FFR remained at <0.90, a pullback of the wire to identify another possible pressure drop and/or a subsequent stent implantation at least 5 mm from the stent will be performed according to physician's preference. | Device: iFR/FFR/RFR<br>* The iFR and FFR measurements will be obtained using a coronary-pressure guidewire (Pressure Wire / Certus or Aeris for FFR assessment and PressureWire™ X Guidewire/QUANTIEM™ for the RFR assessment by Abbott Vascular, Abbott Park, Illinois, U.S.A; Comet by Boston Scientific, Marlborough, MA, USA), OptoWire by Opsens, Quebec, Canada, or Verrata by Philips, San Diego, CA, USA.).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with cardiac death or non-fatal spontaneous target-vessel myocardial infarction | Composite outcome. Cardiac death will be defined as any death due to heart disease, including heart failure, myocardial infarction, arrhythmia, and sudden unexpected death. Any spontaneous myocardial infarction will be attributed to the randomized intermediate lesion if not clearly attributable to the non-target vessels. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with cardiac death | Cardiac death will be defined as any death due to heart disease, including heart failure, myocardial infarction, arrhythmia, and sudden unexpected death. | 2 years | 
| Number of patients with non-fatal spontaneous target-vessel Myocardial infarction (excluding peri-procedural MI) | Any spontaneous myocardial infarction will be attributed to the randomized intermediate lesion if not clearly attributable to the non-target vessels. | 2 years | 
| Number of patients with target lesion revascularization (either percutaneous or surgical) | Repeated lesion revascularization will be considered in case of repeated percutaneous coronary intervention and coronary artery bypass grafting the enrolled lesions. | 2 years | 
| Number of patients with composite of cardiac death and any myocardial infarction | Composite outcome. Cardiac death will be defined as any death due to heart disease, including heart failure, myocardial infarction, arrhythmia, and sudden unexpected death. Any spontaneous myocardial infarction will be collected regardless of the culprit vessel involved. | 2 years | 
| Number of patients with target vessel failure | Composite endpoint including cardiac death, non-fatal target-vessel MI, ischemia-driven target lesion revascularization. | 2 years | 
| Number of patients with composite endpoint of peri-procedural complications | contrast-induced nephropathy: a 25% increase in serum creatinine (SCr) from baseline or a 0.5 mg/dL (44 µmol/L) increase in absolute SCr value-within 48-72 hours after intravenous contrast administration. dissection requiring bail-out stenting. post-procedural MI: an increase within 48 hours after the index procedure of creatine kinase[CK]-MB (U/L) >5 times or Troponin (ng/L) >35 times above the normal value along with at least one of the followings: 1) symptoms of ischemia; 2) new or presumed new significant ST or T changes or new left bundle branch block; 3) new pathologic Q waves on an electrocardiogram; 4) new loss of viable myocardium or new regional wall motion abnormality; 5) reduced flow or major dissection in the coronary at angiography; or 6) intracoronary thrombus by angiography or autopsy. A stand-alone biomarker definition will be accepted in case of increase in the cardiac biomarker CK-MB >10 times or Troponin >70 times above the upper normal values. | Peri-procedural | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary artery disease, Vulnerable plaque, Optical coherence tomography