Updated Results and Implications of the Lipid Rich Plaque Study Ron Waksman, MD, FACC, FSCAI,FESC Professor of Medicine Georgetown University Associate Director of Cardiology Director of Cardiovascular Research and Education MedStar Washington Hospital Center
Disclosures • Advisory boards: Abbott Vascular, Amgen, Boston Scientific, Medtronic, Philips Volcano, Pi-Cardia LTD, and Cardioset • Consultant: Abbott Vascular, Amgen,, Biotronik, Boston Scientific, Medtronic, Philips Volcano • Grant support: Abbott Vascular, AstraZeneca, Biotronik, Boston Scientific, and Chiesi • Speaker bureau: AstraZeneca • Equity: MedAlliance, DOMed, Pi-Cardia LTD, Cardioset
Clinical Unmet Need • Despite optimal medical therapy and risk modifications strategies, coronary events continue to occur, in contrast Many individuals with an apparently adverse risk factor profile remain asymptomatic • The quest for detecting patients at risk for secondary cardiovascular event (cardiac death, and MI) is a high priority • Lipid Rich Plaque is associated with ACS & MI and can be detected by Near Infrared Spectroscopy (NIRS) • The LRP study is the largest study ever to examine whether NIRS imaging can identify Vulnerable Patients and Vulnerable Plaques • during a 24-month period?
IVUS + NIRS Imaging Intravascular Imaging System & Catheter • Combines IVUS and NIRS in single imaging system • Cleared in the USA, Europe, Japan, and Korea • Only technology labeled for the detection of Lipid Core Plaques and detection vulnerable plaques and patients • 3.2Fr crossing profile • 0.014” wire compatible • 6Fr guide catheter compatible
NIRS Imaging Selected Region LCBI: 228 Chemogram display • Identifies locations of lipid core plaque in the artery maxLCBI 4mm : 824 No Lipid-Rich Plaque (RED) Lipid-Rich Plaque (YELLOW) Lipid Core Burden Index (LCBI) • Quantitative summary metric of Lipid Core in a scanned or selected region • LCBI scale is from 0 to 1000 LCBI = ( Yellow pixels ) x 1000 ( Total valid pixels ) • maxLCBI 4mm : The maximum 4mm LCBI value in a scanned or selected region Proxy for angular extent of lipid core plaque
The Lipid-Rich Plaque Study Ron Waksman, MD on behalf of the LRP Investigators MedStar Washington Hospital Cen Presented as LBT at TCT 2018
FDA expansion of labeling April 2019
September 27, 2019 Simultaneous Publication in the Lancet
LRP Study Endpoints Co-primary Endpoints Vulnerable Patient Association between maxLCBI 4mm in all imaged arteries and future patient-level non-culprit MACE* Vulnerable Plaque Association between maxLCBI 4mm in a segment and incidence of future non-culprit MACE* in same segment Key Secondary Endpoint A threshold of maxLCBI 4mm >400 will identify patients and plaques at increased risk of a non-culprit MACE* *Non-culprit MACE (independently adjudicated by CEC blinded to NIRS) • Revascularization by CABG or PCI • Cardiac death • Non-fatal myocardial infarction • Rehospitalization for progressive angina with • Cardiac arrest • Acute coronary syndrome >20% stenosis progression
Study Flow Diagram Screen Failures: Diagnostic only, no PCI (1356) Angiographic exclusion criteria (1045) No IVUS clinically required Feb 2014 - Mar 2016 (707) Physician discretion (452) Technical issues (72) Screened patients General exclusion criteria (46) n = 5273 Unknown (32) Patients with no analyzable Enrolled patients vessels n = 1563 n = 11 Patients randomized to no follow Pts with evaluable LCBI 4mm up n = 1552 n = 281 maxLCBI 4mm < 250 maxLCBI 4mm ≥ 250 Randomly assigned 1:1 All followed up to follow up Patients = 1271 Ware segments = 5755 Ware segment IVUS = 5743 NCT02033694 Waksman R, et al. Am Heart J. 2017 Oct;192:98-104.
Clinical Presentation 60% 46.3% 50% 36.8% 40% 30% 20% 14.3% 10% 2.5% 0% Stabilized Non-STEMI Unstable Stable STEMI Angina Angina
Baseline Medications Medication Pre-admission Discharge Aspirin 75.5% 94.6% ADP Receptor inhibitor 45.8% 89.8% DAPT 41.3% 86.7% Lipid-lowering agent 74.7% 92.0% Statin Any 73.1% 91.1% Statin Only 68.8% 85.8% Non-statin Any 5.8% 6.2% Non-statin Only 1.6% 0.9% Fibrate 2.0% 2.2% Bile-acid sequestrant 0.6% 0.4%
Overall Cumulative MACE Incidence 8.8% 8.7% 2.3%
Cumulative Incidence Rates of Patient Level Events at 2 Years NC-MACE Series 1 10.0% 8.0% 4.7% 6.0% 4.0% n=57 n=47 3.0% 4.0% n=35 2.1% n=24 1.1% 2.0% 0.7% 0.3% n=13 n=8 n=4 0.0% Cardiac Death Cardiac Arrest ACS Non-fatal MI Rehosp, PCI CABG Progressive Angina, >20% DS progression
Vulnerable Patient Level Endpoint – Results HR p Value Conclusion [95% CI] Primary Endpoint: For each 100 unit increase of 1.18 maxLCBI 4mm as a 0.004 maxLCBI 4mm the risk of NC- [1.05-1.32] continuous variable MACE increased by 18% Secondary Endpoint: A patient with maxLCBI 4mm 1.89 maxLCBI 4mm >400 0.002 greater than 400 is at 89% higher [1.26-2.83] risk of NC-MACE Adjusted by age, male gender, diabetes, hypertension, smoking history, prior PCI, ACS, and renal insufficiency
Patient Cumulative NC-MACE Incidence p logrank <0.001 13% 6%
57 Plaque Level Events by Clinical Event Type 50 45 63.2% 40 36 35 38.6% 30 Count 25 22 20 17.5% 17.5% 15 10 10 7.0% 10 4 5 0 ACS Non-Fatal MI Rehosp, PCI CABG Progressive Angina, >20% DS progression Ware segment may be associated with multiple event types
Vulnerable Plaque Level Endpoint - Results HR p Value Conclusion [95% CI] Primary Endpoint: For each 100 unit increase of 1.45 maxLCBI 4mm as a <0.0001 maxLCBI 4mm the risk of NC- [1.30-1.60] continuous variable MACE increases by 45% 4.22 Secondary Endpoint: <0.0001 A coronary segment with [2.39-7.45] maxLCBI 4mm >400 maxLCBI 4mm greater than 400 is at 322% higher risk of NC-MACE Patient cluster adjusted via WLW methodology
Plaque Cumulative NC-MACE Incidence p logrank <0.001 3.2% 0.8%
IVUS Core Laboratory Data Ware Segment Level within maxLCBI 4mm Variable Value (n=5743) Lumen area(mm 2 ) 7.8 ± 4.3 Vessel area(mm 2 ) 13.2 ± 6.8 Vessel volume (mm 3 ) 52.2 ± 27.4 Lumen Volume (mm 3 ) 30.6 ± 17.1 Plaque Volume (mm 3 ) 21.5 ± 14.4 Plaque area (mm 2 ) 5.4 ± 3.6 Plaque Burden (%) 38.9 ± 14.0 MLA (mm 2 ) 6.6 ± 3.7 Plaque burden at the MLA (%) 43.9 ± 15.9 Summation of the total scanned length excluding the stented region and 5mm edges Ware segment analysis restricted to only include segments with an evaluable maxLCBI 4mm value
Co-primary endpoint Vulnerable Plaque Level Multivariable-Adjusted Cox Proportional Hazards Models 00 Variable Hazard Ratio [95% CI] maxLCBI 4mm continuous maxLCBI 4mm > 400 Unadjusted LCBI alone 1.45 [1.28-1.64] 4.04 [2.28-7.15] maxLCBI 4mm Multivariable-Adjusted Model maxLCBI 4mm >400 3.46 [1.89-6.35] Plaque burden within maxLCBI 4mm ≥70% ǂ 3.99 [1.37-11.61] MLA within maxLCBI 4mm ≤4mm² § 1.84 [1.04-3.26]
MaxLCBI 4mm Location Lumen Area 7.26 7.87 7.58 6.28 4.38 MAR 2016 (mm 2 ) Plaque 32.29 29.77 34.88 49.85 62.35 Burden (%) MaxLCBI 4mm = 583 JUN 2016
Longitudinal distribution of vulnerable plaque/lipid rich plaque in non-culprit lesions: A Lipid Rich Plaque (LRP) Study Sub-analysis Evan Shlofmitz , Rebecca Torguson, Paige Craig, Kazuhiro Dan, Corey Shea, Priti Shah, Hector Garcia- Garcia, Ron Waksman MedStar Washington Hospital Center TCT 2019
“Ware Segment” Distribution *RCA 22.3% *LAD 46.3% *LCX 31.4% LM 1% Prox LAD 16.7% Prox RCA *Prox 39.1% Professor James Ware Harvard T.H. Chan School 6.9% of Public Health Prox LCX Mid LAD 15.4% 14.4% Mid RCA 7.1% Mid LCX Distal LAD 12.0% 12.0% Distal RCA Distal LCX 6.0% 3.7% Far Distal LAD 3.1% Far Distal LCX Far Distal RCA 0.3% 2.3%
Multivariable Plaque Level NC-MACE Hazard Model maxLCBI 4mm as a continuous variable HR [95% CI] p Value maxLCBI 4mm as a 100 unit 1.31 [1.14-1.50] 0.0001 continuous variable Proximal location 2.60 [1.41-4.79] 0.002 Plaque burden >70% 2.42 [0.77-7.56] 0.13 MLA ≤4 2.46 [1.34-4.53] 0.004 Patient cluster adjusted via random effects methodology. Interaction terms between maxLCBI4mm with proximal location, plaque burden >70, and MLA ≤4, respectively, were not significant (p>0.05).
Multivariable Plaque Level NC-MACE Hazard Model maxLCBI 4mm >400 HR [95% CI] p Value maxLCBI 4mm >400 2.56 [1.38-4.77] 0.003 Proximal location 3.12 [1.71-5.70] 0.0002 Plaque burden >70% 3.13 [1.03-9.48] 0.04 MLA ≤4 2.56 [1.39-4.72] 0.003 Patient cluster adjusted via random effects methodology. Interaction terms between maxLCBI4mm >400 with proximal location, plaque burden >70, and MLA ≤4, respectively, were not significant (p>0.05).
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