Implications from PROSPECT and Future Directions Gregg W. Stone, MD Columbia University Medical Center The Cardiovascular Research Foundation Providing Regional Observations to Study Predictors of Events in the Coronary Tree PROSPECT

PROSPECT Gregg W. Stone Gregg W. Stone  Scientific Advisory Board for an honoraria from Abbott Vascular and Boston Scientific  Research grants from InfraReDx and Volcano

700 pts with ACS UA (with ECGΔ) or NSTEMI or STEMI >24º undergoing PCI of 1 or 2 major coronary arteries at up to 40 sites in the U.S. and Europe at up to 40 sites in the U.S. and Europe PCI of culprit lesion(s) Successful and uncomplicated Formally enrolled Metabolic S. Waist circumWaist circum Fast lipidsFast lipids Fast gluFast glu HgbA1CHgbA1C Fast insulinFast insulin CreatinineCreatinineBiomarkers Hs CRPHs CRP IL-6IL-6 sCD40LsCD40L MPOMPO TNFαTNFα MMP9MMP9 Lp-PLA2Lp-PLA2 othersothers PI: Gregg W. Stone Sponsor: Abbott Vascular; Partner: Volcano PROSPECT

3-vessel imaging post PCI Culprit artery, followed by non-culprit arteries Angiography (QCA of entire coronary tree) IVUS Virtual histology Palpography (n=~350) Repeat imaging in pts with events Meds rec Aspirin Plavix 1yr Statin Repeat 30 days, 6 months Proximal 6-8 cm of each coronary artery MSCTSubstudyN= F/U: 1 mo, 6 mo, 1 yr, 2 yr, ±3-5 yrs F/U: 1 mo, 6 mo, 1 yr, 2 yr, ±3-5 yrs PROSPECT

PROSPECT: MACE (N=697) MACE (%) Time in Years 0123 All Culprit lesion (CL) related Non culprit lesion (NCL) related Indeterminate Number at risk ALL CL related NCL related Indeterminate % 20.4% 11.6% 2.7% MACE = cardiac death, cardiac arrest, MI, or rehospitalization for unstable or progressive angina

PROSPECT: MACE 3-year follow-up, hierarchical All Culprit lesion related Non culprit lesion related Indeter- minate Cardiac death 1.9% (12) 0.2% (1) 0% (0) 1.7% (11) Cardiac arrest 0.3% (2) 0% (0) MI (STEMI or NSTEMI) 2.7% (17) 1.7% (11) 1.0% (6) 0.2% (1) Rehospitalization for unstable or progressive angina 15.4% (101) 10.4% (69) 10.7% (68) 0.8% (5) Composite MACE 20.4% (132) 12.9% (83) 11.6% (74) 2.7% (17) Cardiac death, arrest or MI 4.9% (31) 2.2% (14) 1.0% (6) 1.9% (12) Rates are 3-yr Kaplan-Meier estimates (n of events)

PROSPECT: MACE 3-year follow-up, hierarchical All Culprit lesion related Non culprit lesion related Indeter- minate Cardiac death 1.9% (12) 0.2% (1) 0% (0) 1.7% (11) Cardiac arrest 0.3% (2) 0% (0) MI (STEMI or NSTEMI) 2.7% (17) 1.7% (11) 1.0% (6) 0.2% (1) Rehospitalization for unstable or progressive angina 15.4% (101) 10.4% (69) 10.7% (68) 0.8% (5) Composite MACE 20.4% (132) 12.9% (83) 11.6% (74) 2.7% (17) Cardiac death, arrest or MI 4.9% (31) 2.2% (14) 1.0% (6) 1.9% (12) Rates are 3-yr Kaplan-Meier estimates (n of events)

PROSPECT: Multivariable Correlates of Non-Culprit Lesion Related Events Independent predictors of patient level events by Cox Proportional Hazards regression Variables entered into the model: age, gender, hypertension, insulin dependent diabetes, prior PCI, CRP at baseline, family history VariableHR [95% CI] P value Insulin dependent diabetes0.005 diabetes3.32 [1.43, 7.72]0.005 Prior PCI 0.02 Prior PCI 2.03 [1.15, 3.59]0.02

PROSPECT: Multivariable Correlates of Non-Culprit Lesion Related Events Variables entered: minimal lumen area (MLA), plaque burden at the MLA, external elastic membrane at the MLA, lesion length, distance from the coronary ostium to the MLA, remodeling index, thin-cap fibroatheroma, insulin-requiring diabetes and prior percutaneous coronary intervention VariableHR [95% CI] P value PB MLA ≥70%< PB MLA ≥70%5.03 [2.51, 10.11] < VH-TCFA VH-TCFA 3.35 [1.77, 6.36] MLA ≤4.0 mm MLA ≤4.0 mm [1.61, 6.42]0.001 Independent predictors of lesion level events by Cox Proportional Hazards regression

PROSPECT: Correlates of Non-Culprit Lesion Related Events PB = plaque burden at the MLA Number of factors present: PB MLA ≥70%, MLA ≤4.0mm 2 or TCFA Median 3.4 yr MACE rate per lesion (%) 5/165046/105924/2535/29

PROSPECT: VH-TCFA and Non- Culprit Lesion Related Events Lesion HR Lesion HR 3.90 (2.25, 6.76) 6.55 (3.43, 12.51) (5.55, 21.10) (4.39, 27.82) P value < < <0.0001< P value < < <0.0001< Prevalence*46.7%15.9%10.1% 4.2% Prevalence*46.7%15.9%10.1% 4.2% *Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA

PROSPECT: Thick CFA and Non- Culprit Lesion Related Events Lesion HR Lesion HR 0.92 (0.52, 1.63) 3.41 (1.75, 6.65) 5.17 (2.59, 10.32) 5.02 (1.99, 12.63) P value <0.0001< P value <0.0001< Prevalence*67.6%22.7%15.6% 8.3% Prevalence*67.6%22.7%15.6% 8.3% *Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA

PROSPECT: Non Fibroatheromas and Non-Culprit Lesion Events Lesion HR 0.22 (0.10, 0.49) 1.22 (0.44, 3.39) 1.25 (0.17, 9.01) 2.60 (0.36, 18.84) Lesion HR 0.22 (0.10, 0.49) 1.22 (0.44, 3.39) 1.25 (0.17, 9.01) 2.60 (0.36, 18.84) P value P value Prevalence*67.9%19.7%5.6% 2.7% Prevalence*67.9%19.7%5.6% 2.7% Pathological Intimal thickening FibroticFibrocalcific

Complications adjudicated to the 3-vessel IVUS imaging procedure (n=697) Death MI - Q-wave (from dissection) - non Q-wave (from dissection) PCI or CABG - CABG (from perforation) - CABG (from dissection) - PCI (from dissection) 0 (0%) 3 (0.4%) (1.4%) 129 Any imaging complication* 11 (1.6%) *Some pts had more than one complication Was 3-vessel VH-IVUS imaging safe? PROSPECT: Questions

How much disease was left behind after the original PCI in 697 patients? N=283N=620 mean 0.9 ± 1.1 per pt mean 0.4 ± 0.7 per pt By angiography 1,814 untreated lesions (visual DS >30%) in the entire coronary tree in the entire coronary tree - mean 2.6 ± 1.8 per pt - QCADS% DS <50% N=1704 (93.9%) DS ≥50%-<70% N=98(5.4%) DS ≥70% N=12(0.7%) DS% mean 33.7 ± 15.7% By IVUS (n=673) 3,160 untreated lesions (PB ≥40%) in the proximal- to-mid coronary tree - mean 4.7 ± 2.0 per pt -

PROSPECT: Questions How much disease was left behind after the original PCI in 697 patients? TCFA N=596 (21.9%) By VH-IVUS (n=623) 2,811 untreated classified lesions in the proximal-to- mid coronary tree Fibrotic N=104 (3.8%) Fibrocalcific N=33 (1.2%) PIT N=1008 (37.0%) ThCFA N=1018 (37.3%) 0.98 ± 1.31 per pt (range 0 – 7 per pt)

PROSPECT: Questions What were the baseline angiographic characteristics of the lesions that were later responsible for non-culprit events? The mean angiographic QCA DS of the 106 lesions subsequently responsible for non-culprit MACE in 76 pts was 32.3% ± 20.6% at baseline and 65.4% ± 16.3% at the time of the follow-up event (P<0.001). Lesion location 32 lesions (30.2%) were angiographically inconspicuous (<30% stenotic) by visual assessment) Baseline QCA %DS Prox24.3%Mid19.6% Distal15.9% Branch40.2%

PROSPECT: Questions What were the baseline VH-IVUS characteristics of the lesions that were later responsible for non-culprit events? 51 non-culprit MACE lesions with baseline VH-IVUS TCFAs N=26 (51%) NotTCFAsN=25(49%) PB ≥70% and/or MLA ≤4.0mm 2 N=18 (35%) TCFA only N=8 (16%) PB ≥70% and/or MLA ≤4.0mm 2 N=20 (39%) Not TCFA only N=5 (10%) 18 ThCFA 6 PIT 1 FC 0 F Baseline IVUS was performed in 55/106 sites that subsequently resulted in non-culprit MACE. All 55 sites had plaque burden ≥40% by baseline IVUS imaging. Conversely, no imaged coronary segment with <40% plaque burden resulted in a non-culprit event during the median 3.4 year FU period.

PROSPECT: Questions For the lesion level multivariable predictors of non-culprit MACE, why did you choose plaque burden ≥70% and MLA ≤4.0 mm 2 ? Isn’t this arbitrary and biased? HR [95% CI] P value Model 1: Pre-specified (C-statistic 0.82)* Plaque burden ≥70% 5.03 [2.51, 10.11] <0.001 Thin-cap fibroatheroma 3.35 [1.77, 6.36] <0.001 Minimal lumen area ≤4.0 mm [1.61, 6.42] Model 2: ROC (C-statistic 0.84) Plaque burden ≥63% 6.50 [3.19, 13.26] <0.001 Thin-cap fibroatheroma 2.72 [1.48, 5.00] Minimal lumen area ≤4.58 mm [1.72, 6.78] <0.001 Model 3: Continuous (C-statistic 0.84) Plaque burden (per 10% increase) 2.39 [1.60, 3.57] <0.001 Thin-cap fibroatheroma 2.78 [1.52, 5.08] <0.001 Minimal lumen area (per 1.0mm 2 decrease) 1.44 [1.16, 1.79] Variables entered: MLA, PB at the MLA, EEM at the MLA, lesion length, distance from the coronary ostium to the MLA, remodeling index, TCFA, insulin-requiring diabetes and prior PCI

PROSPECT: Questions What types of events were responsible for CULPRIT lesion MACE during follow-up? Stent thrombosis (n=13 lesions) Stent thrombosis (n=13 lesions) Restenosis (n=107 lesions) Restenosis (n=107 lesions) New stent-related sidebranch lesions (n=5 lesions) New stent-related sidebranch lesions (n=5 lesions) Baseline grayscale and VH-IVUS will be analyzed for correlates of future events Possible predictors of stent thrombosis FA behind stent FA behind stent, abutting into lumen Partially uncovered FA Separate untreated adjacent FA Totally covered FA

PROSPECT: Implications Following successful and uncomplicated PCI in pts with ACS who undergo careful clinical FU, is 3-vessel VH-IVUS to identify and prophylactically stent non-culprit lesions at high risk for future MACE warranted based on PROSPECT?Following successful and uncomplicated PCI in pts with ACS who undergo careful clinical FU, is 3-vessel VH-IVUS to identify and prophylactically stent non-culprit lesions at high risk for future MACE warranted based on PROSPECT?►No 1.The prevalence of high-risk lesions is relatively low (~1 in 4 pts). 2.3-vessel imaging is not risk-free (1.6% major complication rate). 3.When high-risk lesions become symptomatic they usually present with angina and not death or MI. ►This suggests that absent a randomized trial, optimal medical therapy and close follow-up is more appropriate. Following successful and uncomplicated PCI in pts with ACS who undergo careful clinical FU, is 3-vessel VH-IVUS to identify and prophylactically stent non-culprit lesions at high risk for future MACE warranted based on PROSPECT?Following successful and uncomplicated PCI in pts with ACS who undergo careful clinical FU, is 3-vessel VH-IVUS to identify and prophylactically stent non-culprit lesions at high risk for future MACE warranted based on PROSPECT?►No 1.The prevalence of high-risk lesions is relatively low (~1 in 4 pts). 2.3-vessel imaging is not risk-free (1.6% major complication rate). 3.When high-risk lesions become symptomatic they usually present with angina and not death or MI. ►This suggests that absent a randomized trial, optimal medical therapy and close follow-up is more appropriate.

PROSPECT: Implications What if during routine IVUS-guided stenting (e.g. in the MLAD), a high-risk non ischemia-producing lesion happens to be found (e.g. a TCFA with PB of 75% in the PLAD) – is prophylactic stenting justified?What if during routine IVUS-guided stenting (e.g. in the MLAD), a high-risk non ischemia-producing lesion happens to be found (e.g. a TCFA with PB of 75% in the PLAD) – is prophylactic stenting justified?►No 1.As long as the patient is medically compliant and is closely followed, when high-risk lesions become symptomatic they usually present with progressive angina and not death or MI. ►A randomized controlled trial is required to demonstrate the safety and efficacy of prophylactic stenting of non ischemia-producing lesions before this practice can be recommended. What if during routine IVUS-guided stenting (e.g. in the MLAD), a high-risk non ischemia-producing lesion happens to be found (e.g. a TCFA with PB of 75% in the PLAD) – is prophylactic stenting justified?What if during routine IVUS-guided stenting (e.g. in the MLAD), a high-risk non ischemia-producing lesion happens to be found (e.g. a TCFA with PB of 75% in the PLAD) – is prophylactic stenting justified?►No 1.As long as the patient is medically compliant and is closely followed, when high-risk lesions become symptomatic they usually present with progressive angina and not death or MI. ►A randomized controlled trial is required to demonstrate the safety and efficacy of prophylactic stenting of non ischemia-producing lesions before this practice can be recommended.

So where should our efforts for future investigation be focused?So where should our efforts for future investigation be focused? The prognosis for pts with ACS after successful PCI who are medically compliant is favorable.The prognosis for pts with ACS after successful PCI who are medically compliant is favorable. However, millions of persons per year who have not been diagnosed with CAD and are not receiving optimal medical therapy die, arrest or develop MI every year.However, millions of persons per year who have not been diagnosed with CAD and are not receiving optimal medical therapy die, arrest or develop MI every year. ►This suggests that future investigation should focus on identifying asymptomatic or minimally symptomatic pts with large plaque burden, small MLA and TCFAs through noninvasive screening (e.g. MSCT), for intensive medical therapy and possibly invasive imaging and Rx. So where should our efforts for future investigation be focused?So where should our efforts for future investigation be focused? The prognosis for pts with ACS after successful PCI who are medically compliant is favorable.The prognosis for pts with ACS after successful PCI who are medically compliant is favorable. However, millions of persons per year who have not been diagnosed with CAD and are not receiving optimal medical therapy die, arrest or develop MI every year.However, millions of persons per year who have not been diagnosed with CAD and are not receiving optimal medical therapy die, arrest or develop MI every year. ►This suggests that future investigation should focus on identifying asymptomatic or minimally symptomatic pts with large plaque burden, small MLA and TCFAs through noninvasive screening (e.g. MSCT), for intensive medical therapy and possibly invasive imaging and Rx. PROSPECT: Implications