A Natural History Study of Atherosclerosis Using Multimodality Intracoronary Imaging to Prospectively Identify Vulnerable Plaque

1
A Natural History Study of Atherosclerosis Using
Multimodality Intracoronary Imaging to
Prospectively Identify Vulnerable Plaque
The PROSPECT Trial
Providing Regional Observations to Study
Predictors of Events in the
Coronary Tree

• Gregg W. Stone, MD
• PROSPECT Investigators

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-224,162 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 gt30d, or
stroke ()
How many events were attributable to
1) Restenosis, stent thrombosis, etc. vs.
2) Significant disease left
behind, vs. 3) VP
with rapid lesion progression?
ACS median 7d PCI 69
Cannon CP et al. NEJM 20043501495-1504
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 UA (with ECG?) or NSTEMI or
STEMI gt24º 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
• TNFa
• MMP9
• Lp-PLA2
• others

PCI of culprit lesion(s) Successful and
uncomplicated
Formally enrolled
PI Gregg W. Stone Sponsor Abbott Vascular
Partner Volcano
7
3-vessel imaging post PCI
The PROSPECT Trial
F/U 1 mo, 6 mo, 1 yr, 2 yr, 3-5 yrs
8
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
• - Requiring revascularization
• - Requiring rehospitalization

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 gt20 from baseline to FU.
9
PROSPECT MethodologyAngiographic 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 MethodologyIVUS/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 gt40) 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 MethodologyVirtual 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
PROSPECT 82910-012 52 yo? 2/13/06 NSTEMI, PCI
of MLAD 2/6/07 (51 weeks later) NSTEMI
attributed to LCX
Index 2/13/06
13
PROSPECT 82910-012 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.
  SerruysEuropean 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

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700 pts enrolled between Oct. 2004 and June 2006
and followed for at least 3 years
PROSPECT Enrollment
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. Lukes 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
17
PROSPECT Baseline Features
N 697
3 patients who were never consented were
de-registered
18
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
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PROSPECT Imaging Summary
Length of coronary arteries analyzed (core lab)
Mean (mm) Angiography (N697) IVUS and VH (N615)
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
20
PROSPECT Imaging Summary
Virtual histology (N2689 lesions in 615 pts) -
Mean plaque composition-
Plaque subtype N2689
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
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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
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PROSPECT MACE
All Culprit lesion (CL) related Non culprit
lesion (NCL) related Indeterminate
25
20
15
MACE ()
10
5
0
0
1
2
3
Time in Years
Number at risk
ALL 697 557 506 480
CL related 697 590 543 518
NCL related 697 595 553 521
Indeterminate 697 634 604 583
23
PROSPECT MACE
All Culprit lesion (CL) related Non culprit
lesion (NCL) related Indeterminate
25
20
18.1
13.2
15
MACE ()
11.4
7.9
10
9.4
5
6.4
1.9
0.9
0
0
1
2
3
Time in Years
Number at risk
ALL 697 557 506 480
CL related 697 590 543 518
NCL related 697 595 553 521
Indeterminate 697 634 604 583
24
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) 0 (0) 0.2 (1)
MI (STEMI or NSTEMI) 3.3 (21) 2.0 (13) 1.0 (6) 0.3 (2)
Unstable angina 8.0 (51) 4.5 (29) 3.3 (21) 0.5 (3)
Increasing angina 14.5 (93) 9.2 (59) 8.5 (54) 0.3 (2)
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)
25
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) 0.2 (1)
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
11.6
Non-culprit lesion (NCL) related, all - Without
rapid lesion progression (RLP) - With rapid
lesion progression (RLP)
12
10
8
MACE ()
6
4
2
0
0
1
2
3
Time in Years
Number at risk
NCL related, all 697 595 553 521
- without RLP 697 610 577 551
- with RLP 697 620 579 550
27
PROSPECT NCL MACE
11.6
Non-culprit lesion (NCL) related, all - Without
rapid lesion progression (RLP) - With rapid
lesion progression (RLP)
12
9.4
10
8
6.4
5.5
MACE ()
6
4.1
4.9
4
Median time to event No RLP 223 85, 663
days RLP 401 229, 666 days
2
2.9
0
0
1
2
3
Time in Years
Number at risk
NCL related, all 697 595 553 521
- without RLP 697 610 577 551
- with RLP 697 620 579 550
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PROSPECT Correlates of Non
Culprit Related Events
Baseline variables examined (n152) Demographic,
history and PE (n19) Labs (n7 including CrCl,
lipids, hgbA1C, CRP) Angio non core lab (n1
visible lesions gt30 DS) QCA measures
(n12) IVUS area and volumetric measures
(n22) Virtual histology measures
(n74) Treatment related (n1 vessels
stented) Medications in-hosp. and at discharge
(n16)
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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 (n21) 41.4 (6) 4.07 1.75,
9.46 0.001 Non insulin DM (n96) 16.3
(14) 1.55 0.86, 2.79 0.14 Non diabetic
(n569) 10.7 (56) Hypertension (n314) 14.7
(42) 1.64 1.03, 2.60 0.04 No hypertension
(n369) 9.1 (31) Prior PCI (n75) 23.1
(15) 2.20 1.25, 3.86 0.006 No prior PCI
(n613) 10.8 (61) 1 visible angio lsn
(n582) 13.7 (73) 4.72 1.49, 14.98 0.008 No
visible angio lsn (n107) 3.2 (3)
0
1
5
10
15
Visually assessed DS gt30
Univariate, unadjusted. 8 patients with
indeterminate events were excluded.
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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
lt median 5.9 mm2 (n1336) 3.4 (45) 7.53 3.21,
17.65 lt0.0001 MLA median 5.9 mm2 (n1337) 0.4
(6) MLA 4.0 mm2 (n496) 5.4 (27) 5.01
2.89, 8.68 lt0.0001 MLA gt 4.0 mm2 (n2177)
1.1 (24) PBMLA median 0.55 (n1337) 3.3
(44) 6.37 2.87, 14.15 lt0.0001 PBMLA lt median
0.55 (n1336) 0.5 (7) PBMLA 0.70 (n242) 9.1
(22) 7.94 4.56, 13.81 lt0.0001 PBMLA lt 0.70
(n2431) 1.2 (29) EEMMLA med 14.3 mm2
(n1337) 1.4 (19) 0.60 0.34,
1.06 0.08 EEMMLA lt med 14.3 mm2 (n1336) 2.4
(32) Lsn length lt med 11.6 mm (n1336) 0.7
(10) 4.01 2.01, 8.02 lt0.0001 Lsn length med
11.6 mm (n1337) 3.1 (41)
0
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.
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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 (n590) 4.4 (26) 3.84 2.22,
6.65 lt0.0001 Not VH-TCFA (n2065) 1.2
(25) ThCFA (n1005) 1.8 (18) 0.89 0.50,
1.58 0.69 Not ThCFA (n1650) 2.0 (33) PIT
(n964) 0.6 (6) 0.23 0.10, 0.53 0.001 Not PIT
(n1691) 2.7 (45) Fibrotic (n67) 0
(0) - 0.99 Not Fibrotic (n2588) 2.0
(51) Fibrocalcific (n29) 3.4 (1) 1.75 0.24,
12.63 0.58 Not fibrocalcific (n2626) 1.9 (50)
0
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 lt0.0001 VH-TCFA 3.00 1.68,
5.37 0.0002 MLA 4.0 mm2 2.77 1.32,
5.81 0.007 Lesion length 11.6 mm 1.97 0.94,
4.16 0.07 EEMMLA lt14.3 mm2 1.30 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)
ltmedian lesion length median (mm) VH-TCFA.
33
PROSPECT Correlates of Non
Culprit Lesion Related Events
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)
10.8 (5.5, 21.0) 10.8 (4.3, 27.2) P value
lt0.0001 lt0.0001 lt0.0001 lt0.0001 lt0.0001
lt0.0001 lt0.0001 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 3.84 (2.22, 6.65) 6.41 (3.35,
12.24) 10.77 (5.53, 21.00) 10.81 (4.30, 27.22)
P value lt0.0001 lt0.0001 lt0.0001 lt0.0001
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 0.24 (0.10, 0.56) 1.15 (0.36 3.70)
1.36 (0.19, 9.86) 2.85 (0.39, 20.67) P value
0.001 0.81 0.76 0.30 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 3 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