Near-Infrared Spectroscopy: Lipid-Rich Plaque Study Update Ron Waksman, MD, FACC, FSCAI Professor of Medicine, (Cardiology) Georgetown University Director, Cardiovascular Research Advanced Education, MedStar Heart & Vascular Institute, Washington DC

Disclosure Statement of Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial Relationship Company Boston Scientific Biotronik Biosensors Astra Zeneca Medtronic Vascular Abbott Vascular Symetis Med Alliance LifeTech Amgen Grant/Research Support Consulting Fees/Honoraria

Detection by Intracoronary Near-Infrared Spectroscopy of LipidCore Plaque at Culprit Sites in Survivors of Cardiac Arrest Ryan D. Madder, David H. Wohns, James E. Muller, J INVASIVE CARDIOL 2014;26(2)

Cardiac Arrest in 5K Race associated with LAD Stenosis and a Circular Lipid Core Plaque Ventricular Fibrillation Courtesy Dr. Madder et al, JIC, In pressR

Near Infrared Spectroscopy Can Differentiate Lipid Core Plaque From Fibrotic And Calcified Plaque A yellow spot on the chemogram shows lipid core plaque has been detected

Combination NIRS-IVUS Instrument TVC Imaging System™ Laser Computer with algorithms Pull-back and rotation device TVC Insight™ Catheter Single use, 3.2 Fr Dual modality Spectroscopy – lipid core plaque IVUS – plaque structure

Chemogram Findings in a Coronary Autopsy Specimen: Comparison with Histology 40 mm 36 mm 20 mm 26 mm

Five Anecdotal NIRS Event Cases with Chemogram Pre or Post Five Anecdotal NIRS Event Cases with Chemogram Pre or Post. All have yellow chemogram. Chemogram Pre event Chemograms Post event

LCBI in Non-culprit Artery Identifies: Vulnerable Patients Above the Median Median LCBI = 43 Rohit M. Oemrawsingh, MD, ET AL. JACC VOL . 6 4 , NO. 2 3 ,2014

Identification of Vulnerable Patients by Intra-coronary NIRS 121 Patients Post PCI with single vessel chemogram. maxLCBI4mm ≥500 at a non-stented site in 9.9% of patients. MACCE in 58.3% of patients with a maxLCBI4mm ≥500 compared to only 6.4% of those with a maxLCBI4mm <500 (p<0.001; relative risk=9.1). maxLCBI4mm ≥500 Madder et al, 2014

The Lipid-rich Plaque (LRP) Study Dr. Ron Waksman, PI 2 year MACE from a new lesion at patient and coronary segment level 1,562 PCI patients with ACS or SA with NIRS-IVUS imaging of 2 or more vessels

Terminate upon Discharge Study Flow Index N~1500 BLINDED Index Non Culprit Artery (IVUS is un-blinded) Suspected Index Culprit Lesion Index Culprit Lesion -or- Send to Core Lab BLINDED BLINDED Core Lab will Un-blind NIRS data N= 1260 Large LRP (MaxLCBI4mm ≥ 250) N= 240 Small/No LRP (MaxLCBI4mm < 250) N= 120 N= 120 2 Year Follow-Up 2 Year Follow-Up Terminate upon Discharge

LRP Study Endpoints For the Test of the Vulnerable Patient Hypothesis The primary endpoint for the test of the vulnerable patient hypothesis will be the increased incidence of NC-MACE within 24 months in patients with increased max 4mm LCBI in all scanned arteries as opposed to those without increased max 4mm LCBI For the Test of the Vulnerable Plaque Hypothesis The primary endpoint for the test of the vulnerable plaque hypothesis will be the increased incidence of NC-MACE within 24 months in coronary artery segments with increased max 4mm LCBI as opposed to those without increased max 4mm LCBI

Endpoint Assessment Flow Follow Up Patients N ~ 1563 Reported Patient-Level Event Reported by the site via EDC Cleveland Clinic will identify, if imaging is available, follow up event location Send to Cleveland Clinic Adjudication Team Collaborative Effort: Feedback Between Both Teams at Each Step Adjudicated Patient-Level Non-Event Adjudicated Patient-Level Endpoint Event The provided follow up event location guides and drives MCRN Plaque Adjudication Team Send to MCRN Plaque Adjudication Team Adjudicated Plaque-Level Non-Event Adjudicated Plaque-Level Endpoint Event

Plaque Adjudication Flow Plaque adjudication is triggered upon adjudication of a patient level endpoint event if an angiogram or cardiac CT is available Cleveland Clinic Physician Adjudication team provides the following information: Culprit Lesion CASS Code Culprit Lesion Location Ex: proximal, mid, distal, ostial, etc. Here is a visual representation of how we have defined segments and subsegments for both the purposes of index procedure analysis and event adjudication. For a given vessel, in this example the LCX, we divide the pullback into 30 mm segments with a maximum of 4 segments. These segments, the proximal, mid, distal, and distal distal, comprise a possible total 120 mm of scanned vessel. Each of these segments are further divided into 10mm segments that we refer to as subsegments. As visualized in this blue proximal segment, we have the three 10mm subsegments denoted with the nomenclautre prox 1, prox 2, and prox 3. The same nomenclature with use of numbers would be used to describe the subsegments of the mid, distal, or distal distal segments. In order to adjudicate a plaque level event, the adjudicator will need to identify the event culprit lesion and determine its location on a segment and subsegment level. A MCRN Plaque Coordinator will create still images of the index and event angiograms and indicate segment borders for ease of adjudication by a separate, blinded Plaque Adjudicator. As we move through the steps of a plaque level adjudication we will provide an example.

Ware Segments: A Standardized Method of Plaque Adjudication The MCRN Plaque Adjudication Team confirms the culprit lesion provided by Cleveland Clinic and translates the culprit vessel into standardized Ware Segments and Subsegments Ware Segments 30 mm each; 120 mm total Proximal, Mid, Distal, and Distal Distal Ware Subsegments 10 mm; 3 per segment Ex: prox 1, prox 2, prox 3 1 2 3 Proximal Mid Distal Distal Distal Prox 3 Prox 2 Prox 1 Here is a visual representation of how we have defined segments and subsegments for both the purposes of index procedure analysis and event adjudication. For a given vessel, in this example the LCX, we divide the pullback into 30 mm segments with a maximum of 4 segments. These segments, the proximal, mid, distal, and distal distal, comprise a possible total 120 mm of scanned vessel. Each of these segments are further divided into 10mm segments that we refer to as subsegments. As visualized in this blue proximal segment, we have the three 10mm subsegments denoted with the nomenclautre prox 1, prox 2, and prox 3. The same nomenclature with use of numbers would be used to describe the subsegments of the mid, distal, or distal distal segments. In order to adjudicate a plaque level event, the adjudicator will need to identify the event culprit lesion and determine its location on a segment and subsegment level. A MCRN Plaque Coordinator will create still images of the index and event angiograms and indicate segment borders for ease of adjudication by a separate, blinded Plaque Adjudicator. As we move through the steps of a plaque level adjudication we will provide an example.

Final Plaque Adjudication The MCRN Plaque Adjudicator identifies the Ware Segments and Subsegments that contain the endpoint event culprit lesion based off of the adjudicated lesion information provided by Cleveland Clinic MCRN Plaque Adjudicator is blinded to all NIRS data Cleveland Clinic Physician Adjudication team confirms adjudication 1 2 3 Plaque-Level Endpoint Event: Adjudicated Ware Segments and Subsegments Here is a visual representation of how we have defined segments and subsegments for both the purposes of index procedure analysis and event adjudication. For a given vessel, in this example the LCX, we divide the pullback into 30 mm segments with a maximum of 4 segments. These segments, the proximal, mid, distal, and distal distal, comprise a possible total 120 mm of scanned vessel. Each of these segments are further divided into 10mm segments that we refer to as subsegments. As visualized in this blue proximal segment, we have the three 10mm subsegments denoted with the nomenclautre prox 1, prox 2, and prox 3. The same nomenclature with use of numbers would be used to describe the subsegments of the mid, distal, or distal distal segments. In order to adjudicate a plaque level event, the adjudicator will need to identify the event culprit lesion and determine its location on a segment and subsegment level. A MCRN Plaque Coordinator will create still images of the index and event angiograms and indicate segment borders for ease of adjudication by a separate, blinded Plaque Adjudicator. As we move through the steps of a plaque level adjudication we will provide an example.

Methodology for the Vulnerable Plaque Endpoint Ware Segment containing Endpoint Event Culprit Lesion Developed a standardized method of determining location of plaques using Ware Segments and Subsegments Utilizing systematic, blinded adjudication process guided by Cleveland Clinic Suspected Vulnerable plaque in non-culprit artery scanned at index Cause of Index Procedure Cause of Follow Up Endpoint Event

LRP Enrollment Complete 1563 patients Completed 2 years follow up Currently, 1518 pt years of follow up Subjects Sites

Conclusions Detection of vulnerable plaque is a priority Near-Infrared Spectroscopy of lipid core plaque is detected in patients with ACS and post cardiac arrest Preliminary studies support the predictability of lipid core findings of future events The Lipid Rich Plaque (LRP) Study is the largest trial to detect vulnerable plaque, Complete enrollment and detect evaluable events Expected presentation in 2017 If the LRP study meets the co-primary hypotheses then target technology will be applied for the treatment of vulnerable plaques

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