1. Gregg W. Stone, MD PROSPECT Investigators
3/27/2017
The PROSPECT Trial
Providing Regional Observations to Study Predictors of Events in the Coronary Tree
A Natural History Study of Atherosclerosis Using Multimodality Intracoronary Imaging to Prospectively Identify Vulnerable Plaque
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Gregg W. Stone, MD
PROSPECT Investigators
TCT DRAFT 1 1

2. The PROSPECT Trial Gregg W. Stone
Scientific Advisory Board, Abbott Vascular Devices
Consultant to InfraReDx

3. The PROSPECT Trial Background
Most cases of sudden cardiac death and MI are believed to arise from plaque rupture with subsequent thrombotic coronary occlusion of angiographically mild lesions (“vulnerable plaques”), the prospective detection of which has not been achieved
The event rate attributable to progression of vulnerable plaque has never been prospectively assessed

4. PROVE-IT TIMI-22 4,162 Randomized Pts with ACS
26.3%
Pravastatin 40 mg/d
22.4%
16% RR
P = 0.005
Atorvastatin 80 mg/d
Death, MI, UA requiring hosp, revasc >30d, or stroke (%)
How many events were attributable to: ) Restenosis, stent thrombosis, etc. vs ) Significant disease left behind, vs ) VP with rapid lesion progression?
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ACS
median 7d
PCI 69%
Cannon CP et al. NEJM 2004;350:

5. The PROSPECT Trial Background
We therefore performed a prospective, multicenter natural history study using 3 vessel multimodality intracoronary imaging to quantify the clinical event rate due to atherosclerotic progression and to identify those lesions which place pts at risk for unexpected adverse cardiovascular events

6. The PROSPECT Trial 700 pts with ACS Formally enrolled
3/27/2017
The PROSPECT Trial
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
Metabolic S.
Waist circum
Fast lipids
Fast glu
HgbA1C
Fast insulin
Creatinine
Biomarkers
Hs CRP
IL-6
sCD40L
MPO
TNFα
MMP9
Lp-PLA2
others
PCI of culprit lesion(s)
Successful and uncomplicated
Formally enrolled
PI: Gregg W. Stone
Sponsor: Abbott Vascular; Partner: Volcano
TCT DRAFT 6 6

7. 3-vessel imaging post PCI
3/27/2017
The PROSPECT Trial
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 biomarkers
@ 30 days, 6 months
Proximal 6-8 cm of each coronary artery
MSCT
Substudy
N=50-100
F/U: 1 mo, 6 mo,
1 yr, 2 yr,
±3-5 yrs
TCT DRAFT 7 7

8. PROSPECT: Primary Endpoint
3/27/2017
PROSPECT: Primary Endpoint
MACE attributable to rapid angiographic progression of a non-culprit lesion*
Cardiac death
Cardiac arrest
Myocardial infarction
Unstable angina
- Requiring revascularization
- Requiring rehospitalization
Increasing angina
Hierarchical
Most severe
Least severe
MACE during FU were adjudicated by the CEC as attributable to culprit lesions (those treated during or before the index hospitalization) or non culprit lesions (untreated areas of the coronary tree) based on angiography (+ECGs, etc.) at the time of the event; events occurring in pts without angiographic follow-up were considered indeterminate in origin. Rapid lesion progression = ↑ in QCA DS by >20% from baseline to FU.
TCT DRAFT 8 8

9. PROSPECT: Methodology Angiographic Core Lab Analysis
Performed on every coronary artery (main vessel and branch) visually ≥1.5 mm in diameter
Detailed qualitative and quantitative parameters recorded for every 1.5 mm length segment
Distance from ostia and at major branch points were registered and corrected for foreshortening after IVUS co-registration
Lesions with DS ≥30% by visual assessment identified
Output available as lesions, CASS segments, and vessels, by every mm, or any other parameter

10. PROSPECT: Methodology IVUS/VH Core Lab Analysis
Gray-scale IVUS volumetric and cross-sectional analysis performed
Each IVUS/VH frame co-registered to corresponding QCA location using fiduciary branch points
IVUS lesions (≥3 consecutive frames with cross sectional plaque burden >40%) were characterized
IVUS-VH analysis performed using the latest classification tree (pcVH 2.1)
Plaque characterized as fibrotic, fibrofatty, necrotic core or dense calcium, and reported as absolute and relative area/volumes

11. PROSPECT: Methodology Virtual histology lesion classification
Lesions are classified into 5 main types
1. Fibrotic
2. Fibrocalcific
3. Pathological intimal thickening (PIT)
4. Thick cap fibroatheroma (ThCFA)
5. VH-thin cap fibroatheroma (VH-TCFA)
(presumed high risk)

12. 2/6/07 (51 weeks later): NSTEMI attributed to LCX
PROSPECT : 52 yo♂
2/13/06: NSTEMI, PCI of MLAD
2/6/07 (51 weeks later): NSTEMI attributed to LCX
Event 2/6/07
QCA PLCX DS 28.6%
QCA PLCX DS 71.3%
Index 2/13/06

13. QCA: RVD 2.82 mm, DS 28.6%, length 6.8 mm
PROSPECT : Index 2/13/06
Baseline PLCX
QCA: RVD 2.82 mm, DS 28.6%, length 6.8 mm
IVUS: MLA 5.3 mm2
VH: ThCFA 1 *
Lesion
prox
*OM
1. ThCFA
5.3
mm2 38

14. PROSPECT: Event Categories
CEC adjudicated MACE during follow-up
• Culprit lesion (stent) related
- Stent thrombosis
- Restenosis
- New side branch lesion
• Non culprit lesion related
- With rapid lesion progression (by QCA) (classic “vulnerable plaque”)
- Without rapid lesion progression
• Indeterminate

15. PROSPECT: Organization
PI: Gregg W. Stone; Co-PI: Patrick W. Serruys European Co-PI: Bernard de Bruyne
Data management: Abbott Vascular; Zhen Zhang (lead statistician)
Clinical events committee: CRF, Roxana Mehran (Chair), George Dangas
Core laboratories
QCA: CRF, Alexandra Lansky (Director), Ecaterina Cristea
IVUS, Virtual Histology: CRF, Akiko Maehara (Director), Gary S. Mintz
Palpography: Cardialysis, Marie-Angèle Morel
MSCT: Thoraxcenter, Pim de Feyter (Director)
Biomarkers: CRL Medinet
DSMB: Steve Steinhubl (Chair)
Sponsor and Partner: Abbott Vascular and Volcano Corp.
Abbott Vascular Program Leads: Barry Templin and Wai-Fung Cheong

16. PROSPECT: Enrollment Top 10 enrollers
3/27/2017
PROSPECT: Enrollment
700 pts enrolled between Oct and June and followed for at least 3 years
Europe: 403 pts enrolled at 18 sites
U.S.: 297 pts enrolled at 19 sites
66 pts
Rotterdam (Serruys)
64 pts
St. Thomas (McPherson)
54 pts
Aalst (de Bruyne)
44 pts
Elyria Memorial Hosp (Farhat)
40 pts
St. Luke’s Hosp (Marso)
38 pts
Gothenburg (Wennerblom)
32 pts
Vigo (Iniguez)
31 pts
Toulouse (Fajadet)
30 pts
South Carolina Heart (Foster)
28 pts
Antwerp (Verheye)
Top 10 enrollers
TCT DRAFT 16 16

17. PROSPECT: Baseline Features
3/27/2017
PROSPECT: Baseline Features
N = 697*
p.42 - prospect_clinsynd.sas
Updated with 2008 data – BJW
*3 patients who were never consented were de-registered
TCT DRAFT

18. PROSPECT: Baseline Features
3/27/2017
PROSPECT: Baseline Features
N = 697
Age (yrs, median)
58 [50, 66]
Gender (female)
24.0%
Diabetes mellitus
16.9%
- Insulin requiring
3.0%
Current cigarette use
47.1%
Hypertension
45.8%
Hyperlipidemia
40.0%
Prior MI
10.5%
Single / double / triple vessel disease
20% / 41% / 39%
Total arteries with vs. without PCI
892, 1199
PCI performed in 1 or 2 arteries
72% / 28%
PCI of LAD / LCX / RCA (per artery)
41% / 27% / 32%
Median [IQR] follow-up (years)
3.4 [1.9, 3.9]
p.43 - prospect_xxxxx.sas (basedemog, diabstat, base risk) , PCI ??
Updated with September 2008 data – BJW
TCT DRAFT

19. PROSPECT: Imaging Summary
3/27/2017
PROSPECT: Imaging Summary
Length of coronary arteries analyzed (core lab)
Mean (mm)
Angiography
(N=697)
IVUS and VH
(N=615) LM
9.3 ± 4.3
9.0 ± 6.3
LAD
155.7 ± 41.0
72.6 ± 33.2
LCX
135.4 ± 49.9
61.7 ± 35.9
RCA
149.9 ± 44.7
81.6 ± 38.0
Total per pt
446.2 ± 84.0
193.3 ± 81.6
Total all pts
311,016
118,670
TCT DRAFT 19

20. PROSPECT: Imaging Summary
3/27/2017
PROSPECT: Imaging Summary
Virtual histology
(N=2689 lesions in 615 pts)
- Mean plaque composition-
Plaque subtype
N=2689
Fibrotic
2.5%
Fibrocalcific
1.1%
PIT
35.9%
Fibroatheroma
59.9%
- Thick cap
37.8%
- VH-TCFA
22.1%
- Single, - Ca
5.4%
- Single, + Ca
0.5%
- Multiple, - Ca
9.8%
- Multiple, + Ca
6.4%
Unclassified
0.7%
p.78- TCT_IT_T22_t_nonculp_Companalysis_IVUS_vess_regroup p3 for the left pie chart.
TCT_IT_t23_nonculp_Lesiontype_IVUS_vess for the right side percentages.
Updated with September 2008 data - BJW
TCT DRAFT

21. PROSPECT: Imaging Summary
3/27/2017
PROSPECT: Imaging Summary
Per patient incidence of VH-TCFAs
N lesions/patient:
51.2% of pts have ≥1 VH-TCFA
0.97 ±1.30 VH-TCFAs per pt
(range 0 – 7 per pt)
Total of 594 VH-TCFA lesions in 615 pts
p.80: Table 12 (June meeting) – Percentages are based on 614 pats total).
Total of 361 pats with 581 TCFA lesions.
\TCT_MLA_t12.t_nonculp_lestype_ivusVH_pat2.sas
Updated with September data - BJW
TCT DRAFT 21

22. PROSPECT: MACE MACE (%) 20.4% 12.9% 11.6% 2.7% Time in Years All
Culprit lesion (CL) related
Non culprit lesion (NCL) related
Indeterminate 25
20.4% 20
12.9% 15
MACE (%)
11.6% 10 5
2.7% 1 2 3
Time in Years
Number at risk
ALL
697
557
506
480
CL related
590
543
518
NCL related
595
553
521
Indeterminate
634
604
583

23. PROSPECT: MACE MACE (%) 20.4% 12.9% 11.6% 2.7% Time in Years All
Culprit lesion (CL) related
Non culprit lesion (NCL) related
Indeterminate 25
20.4% 20
18.1%
13.2%
12.9% 15
MACE (%)
11.4%
11.6% 10
7.9%
9.4% 5
6.4%
2.7%
1.9%
0.9% 1 2 3
Time in Years
Number at risk
ALL
697
557
506
480
CL related
590
543
518
NCL related
595
553
521
Indeterminate
634
604
583

24. 3-year follow-up, non hierarchical
PROSPECT: MACE
3-year follow-up, non hierarchical
All
Culprit lesion related
Non culprit lesion related
Indeter-minate
Cardiac death
1.9% (12)
0.2% (1)
0% (0)
1.8% (11)
Cardiac arrest
0.5% (3)
0.3% (2)
MI (STEMI or NSTEMI)
3.3% (21)
2.0% (13)
1.0% (6)
Unstable angina
8.0% (51)
4.5% (29)
Increasing angina
14.5% (93)
9.2% (59)
8.5% (54)
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)
Rates are 3-yr Kaplan-Meier estimates (n of events)

25. Sensitivity analysis*: 3-year FU, non hierarchical
PROSPECT: MACE
Sensitivity analysis*: 3-year FU, non hierarchical
All
Culprit lesion related
Non culprit lesion related*
Cardiac death
1.9% (12)
0.2% (1)
1.8% (11)
Cardiac arrest
0.5% (3)
0.3% (2)
MI (STEMI or NSTEMI)
3.3% (21)
2.0% (13)
1.3% (8)
Unstable angina
8.0% (51)
4.5% (29)
3.8% (24)
Increasing angina
14.5% (93)
9.2% (59)
8.8% (56)
Composite MACE
20.4% (132)
12.9% (83)
13.3% (85)
Cardiac death, arrest or MI
4.9% (31)
2.2% (14)
2.9% (18)
Rates are 3-yr Kaplan-Meier estimates (n of events)
*Assuming all indeterminate events are non culprit related

26. PROSPECT: NCL MACE MACE (%) 11.6% 6.7% 6.4% Time in Years
Non-culprit lesion (NCL) related, all
- Without rapid lesion progression (RLP)
- With rapid lesion progression (RLP)
11.6% 12 10 8
6.7%
MACE (%) 6
6.4% 4 2 1 2 3
Time in Years
Number at risk
NCL related, all
697
595
553
521
- without RLP
610
577
551
- with RLP
620
579
550

27. PROSPECT: NCL MACE MACE (%) 11.6% 6.7% 6.4% Median time to event
Non-culprit lesion (NCL) related, all
- Without rapid lesion progression (RLP)
- With rapid lesion progression (RLP)
11.6% 12
9.4% 10 8
6.4%
6.7%
MACE (%)
5.5% 6
6.4%
4.1%
4.9% 4
Median time to event
No RLP: 223 [85, 663] days
RLP: 401 [229, 666] days 2
2.9% 1 2 3
Time in Years
Number at risk
NCL related, all
697
595
553
521
- without RLP
610
577
551
- with RLP
620
579
550

28. PROSPECT: Correlates of Non Culprit Related Events
Baseline variables examined (n=152)
Demographic, history and PE (n=19)
Labs (n=7; including CrCl, lipids, hgbA1C, CRP)
Angio non core lab (n=1; visible lesions >30% DS)
QCA measures (n=12)
IVUS area and volumetric measures (n=22)
Virtual histology measures (n=74)
Treatment related (n=1; # vessels stented)
Medications in-hosp. and at discharge (n=16)

29. PROSPECT: Correlates of Non Culprit Lesion Related Events
Patient level events at median 3.4 yrs (76 events in 689 pts*)
Baseline Demographic and Angiographic Variables
Variable KM Rate (n) HR [95% CI] HR [95% CI] P
Insulin DM (n=21) 41.4% (6) [1.75, 9.46] 0.001
Non insulin DM (n=96) 16.3% (14) [0.86, 2.79] 0.14
Non diabetic (n=569) 10.7% (56)
Hypertension (n=314) 14.7% (42) [1.03, 2.60] 0.04
No hypertension (n=369) 9.1% (31)
Prior PCI (n=75) 23.1% (15) [1.25, 3.86] 0.006
No prior PCI (n=613) 10.8% (61)
≥1 visible angio lsn* (n=582) 13.7% (73) [1.49, 14.98] 0.008
No visible angio lsn (n=107) 3.2% (3) 1 5 10 15
*Visually assessed DS >30%
Univariate, unadjusted. * 8 patients with indeterminate events were excluded.

30. PROSPECT: Correlates of Non Culprit Lesion Related Events
Lesion level events (51 events from 2673 lesions in 609 pts at median 3.4 yrs)
IVUS Characteristics (area data)
Variable Rate (n) HR [95% CI] HR [95% CI] P
MLA < median 5.9 mm2 (n=1336) 3.4% (45) [3.21, 17.65] <0.0001
MLA ≥ median 5.9 mm2 (n=1337) 0.4% (6)
MLA ≤ 4.0 mm2 (n=496) 5.4% (27) [2.89, 8.68] <0.0001
MLA > 4.0 mm2 (n=2177) 1.1% (24)
PBMLA ≥ median 0.55 (n=1337) 3.3% (44) [2.87, 14.15] <0.0001
PBMLA < median 0.55 (n=1336) 0.5% (7)
PBMLA ≥ 0.70 (n=242) 9.1% (22) [4.56, 13.81] <0.0001
PBMLA < 0.70 (n=2431) 1.2% (29)
EEMMLA ≥ med 14.3 mm2 (n=1337) 1.4% (19) [0.34, 1.06] 0.08
EEMMLA < med 14.3 mm2 (n=1336) 2.4% (32)
Lsn length < med 11.6 mm (n=1336) 0.7% (10) [2.01, 8.02] <0.0001
Lsn length ≥ med 11.6 mm (n=1337) 3.1% (41) 1 5 10 15
MLA = minimal luminal area; PBMLA = plaque burden at the MLA; EEMMLA = external elastic membrane at the MLA.
Data represent univariate associations, unadjusted.

31. PROSPECT: Correlates of Non Culprit Lesion Related Events
Lesion level events (51 events from 2655 lesions in 609 pts at median 3.4 yrs)
Virtual Histology Plaque Type
Variable Rate (n) HR [95% CI] HR [95% CI] P
VH-TCFA (n=590) 4.4% (26) [2.22, 6.65] <0.0001
Not VH-TCFA (n=2065) 1.2% (25)
ThCFA (n=1005) 1.8% (18) [0.50, 1.58] 0.69
Not ThCFA (n=1650) 2.0% (33)
PIT (n=964) 0.6% (6) [0.10, 0.53] 0.001
Not PIT (n=1691) 2.7% (45)
Fibrotic (n=67) 0% (0)
Not Fibrotic (n=2588) 2.0% (51)
Fibrocalcific (n=29) 3.4% (1) [0.24, 12.63] 0.58
Not fibrocalcific (n=2626) 1.9% (50) 1 5 10 15
TCFA = thin cap fibroatheroma; ThCFA = thick cap fibroatheroma; PIT = pathologic intimal thickening. Univariate, unadjusted.

32. PROSPECT: Multivariable Correlates of Non Culprit Lesion Related Events
Independent predictors of lesion level events by logistic regression analysis
Variable OR [95% CI] P value
PBMLA ≥70% 4.99 [2.54, 9.79] <0.0001
VH-TCFA [1.68, 5.37]
MLA ≤4.0 mm [1.32, 5.81] 0.007
Lesion length ≥11.6 mm 1.97 [0.94, 4.16] 0.07
EEMMLA <14.3 mm [0.62, 2.75] 0.49
Variables entered into the model: Minimal luminal area (MLA); plaque burden at the MLA (PBMLA); external elastic membrane at the MLA (EEMMLA) <median; lesion length ≥ median (mm); VH-TCFA.

33. PROSPECT: Correlates of Non Culprit Lesion Related Events
If this number is for MLA <=4 then the previouse prevalence was wrong
Lesion HR 3.8 (2.2, 6.6) 5.0 (2.9, 8.7) 7.9 (4.6, 13.8) 6.4 (3.4, 12.2) 6.7 (3.4, 13.0) (5.5, 21.0) (4.3, 27.2)
P value < < < < < < <0.0001
Prevalence* 51.2% 49.1% 30.7% 17.4% 15.4% 11.0% 4.6%
*Likelihood of one or more such lesions being identified per patient. PB = plaque burden at the MLA

34. PROSPECT: VH-TCFA and Non Culprit Lesion Related Events
Lesion HR (2.22, 6.65) (3.35, 12.24) (5.53, 21.00) (4.30, 27.22)
P value < < < <0.0001
Prevalence* 51.2% 17.4% 11.0% 4.6%
*Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA

35. PROSPECT: PIT and Non Culprit Lesion Related Events
Lesion HR (0.10, 0.56) ( ) (0.19, 9.86) (0.39, 20.67)
P value
Prevalence* 68.6% 17.2% 5.7% 2.6%
*Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA

36. PROSPECT: Conclusions
From this trial, the first prospective, natural history study of atherosclerosis using multimodality imaging to characterize the coronary tree, we can conclude that:
Approximately 20% of pts with ACS successfully treated with stents and contemporary medical Rx develop MACE within years, with adverse events equally attributable to recurrence at originally treated culprit lesions (treatment failure) and to previously untreated non culprit coronary segments
Approximately 12% of pts develop MACE from non culprit lesions during 3 years of follow-up
Patients treated with contemporary medical therapy who develop non culprit lesion events present most commonly with progressive or unstable angina, and rarely with cardiac death, cardiac arrest or MI

37. PROSPECT: Conclusions
While plaques which are responsible for unanticipated future MACE are frequently angiographically mild, most untreated plaques which become symptomatic have a large plaque burden and a small lumen area (which are detectable by IVUS but not by angiography)
Only about half of new events due to non culprit lesions exemplify the classic notion of vulnerable plaque (rapid lesion progression of mild angiographically lesions), while half are attributable to unrecognized and untreated severe disease with minimal change over time
The prospective identification of non culprit lesions prone to develop MACE within 3 years can be enhanced by characterization of underlying plaque morphology with virtual histology, with VH-TCFAs representing the highest risk lesion type
The combination of large plaque burden (IVUS) and a large necrotic core without a visible cap (VH-TCFA) identifies lesions which are at especially high risk for future adverse cardiovascular events