Transcript Slide 1

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
Gregg W. Stone, MD
PROSPECT Investigators
The PROSPECT Trial
• Gregg W. Stone

Scientific Advisory Board, Abbott
Vascular Devices

Consultant to InfraReDx
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
PROVE-IT TIMI-22
Death, MI, UA requiring hosp,
revasc >30d, or stroke (%)
4,162 Randomized Pts with ACS
30
26.3%
Pravastatin 40 mg/d
25
22.4%
16% RR
P = 0.005
20
Atorvastatin 80 mg/d
15
How many events were attributable to:
1) Restenosis, stent thrombosis, etc. vs.
2) Significant disease left behind, vs.
3) VP with rapid lesion progression?
10
5
0
0
ACS
median 7d
PCI 69%
3
6
9
12
15
18
21
24
Months of Follow-up
Cannon CP et al. NEJM 2004;350:1495-1504
27
30
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
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
PCI of culprit lesion(s)
Successful and uncomplicated
Formally enrolled
PI: Gregg W. Stone
Sponsor: Abbott Vascular; Partner: Volcano
Biomarkers
• Hs CRP
• IL-6
• sCD40L
• MPO
• TNFα
• MMP9
• Lp-PLA2
• others
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)
Meds rec
Aspirin
Plavix 1yr
Statin
Repeat biomarkers
@ 30 days, 6 months
Proximal 6-8
cm of each
coronary
artery
MSCT
Substudy
F/U: 1 mo, 6 mo,
1 yr, 2 yr,
±3-5 yrs
N=50-100
Repeat imaging
in pts with events
PROSPECT: Primary Endpoint
Hierarchical
MACE attributable to rapid angiographic
progression of a non-culprit lesion*
Most severe
• Cardiac death
• Cardiac arrest
• Myocardial infarction
• Unstable angina
- Requiring revascularization
- Requiring rehospitalization
• Increasing angina
- Requiring revascularization
- Requiring rehospitalization
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.
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
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
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)
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
Event 2/6/07
QCA PLCX DS 28.6%
QCA PLCX DS 71.3%
PROSPECT 82910-012: Index 2/13/06
1
*
Baseline PLCX
QCA: RVD 2.82 mm,
DS 28.6%, length 6.8 mm
IVUS: MLA 5.3 mm2
VH: ThCFA
Lesion
prox
*OM
1. ThCFA
5.3
mm2
38
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
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
PROSPECT: Enrollment
700 pts enrolled between Oct. 2004 and June 2006
and followed for at least 3 years
Top 10 enrollers
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)
PROSPECT: Baseline Features
N = 697*
*3 patients who were never consented were de-registered
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)
Median [IQR] follow-up (years)
41% / 27% / 32%
3.4 [1.9, 3.9]
PROSPECT: Imaging Summary
Length of coronary arteries analyzed (core lab)
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
Mean (mm)
PROSPECT: Imaging Summary
Virtual histology
Plaque subtype
(N=2689 lesions in 615 pts) Fibrotic
- Mean plaque compositionDense calcium
Fibrotic
Fibrofatty
Necrotic core
13.0%
6.5%
21.1%
59.4%
Fibrocalcific
PIT
Fibroatheroma
- Thick cap
- VH-TCFA
- Single, - Ca
- Single, + Ca
- Multiple, - Ca
- Multiple, + Ca
Unclassified
N=2689
2.5%
1.1%
35.9%
59.9%
37.8%
22.1%
5.4%
0.5%
9.8%
6.4%
0.7%
PROSPECT: Imaging Summary
Per patient incidence of VH-TCFAs
N lesions/patient: 0
100%
% Patients
75%
50%
48.8%
1
2
3
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
27.3%
25%
12.0%
0%
≥4
6.2%
5.7%
PROSPECT: MACE
All
Culprit lesion (CL) related
Non culprit lesion (NCL) related
Indeterminate
25
MACE (%)
20
20.4%
15
12.9%
10
11.6%
5
2.7%
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
PROSPECT: MACE
All
Culprit lesion (CL) related
Non culprit lesion (NCL) related
Indeterminate
25
MACE (%)
20
20.4%
18.1%
13.2%
15
12.9%
11.4%
7.9%
10
9.4%
5
6.4%
1.9%
0.9%
11.6%
2.7%
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
PROSPECT: MACE
3-year follow-up, non hierarchical
All
Culprit
Non culprit
lesion related lesion related
Indeterminate
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)
4.9% (31)
2.2% (14)
1.0% (6)
1.9% (12)
Cardiac death, arrest or MI
Rates are 3-yr Kaplan-Meier estimates (n of events)
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)
4.9% (31)
2.2% (14)
2.9% (18)
Cardiac death, arrest or MI
Rates are 3-yr Kaplan-Meier estimates (n of events)
*Assuming all indeterminate events are non culprit related
PROSPECT: NCL MACE
10
MACE (%)
11.6%
Non-culprit lesion (NCL) related, all
- Without rapid lesion progression (RLP)
- With rapid lesion progression (RLP)
12
8
6.7%
6
6.4%
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
PROSPECT: NCL MACE
Non-culprit lesion (NCL) related, all
- Without rapid lesion progression (RLP)
- With rapid lesion progression (RLP)
12
MACE (%)
10
8
11.6%
9.4%
6.4%
6.7%
5.5%
6
4.1%
4.9%
4
2
6.4%
Median time to event
No RLP: 223 [85, 663] days
RLP: 401 [229, 666] days
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
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)
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)
Insulin DM (n=21)
Non insulin DM (n=96)
Non diabetic (n=569)
HR [95% CI]
HR [95% CI]
P
41.4% (6)
16.3% (14)
10.7% (56)
4.07 [1.75, 9.46]
1.55 [0.86, 2.79]
0.001
0.14
Hypertension (n=314)
No hypertension (n=369)
14.7% (42)
9.1% (31)
1.64 [1.03, 2.60]
0.04
Prior PCI (n=75)
No prior PCI (n=613)
23.1% (15)
10.8% (61)
2.20 [1.25, 3.86]
0.006
≥1 visible angio lsn* (n=582)
No visible angio lsn (n=107)
13.7% (73)
3.2% (3)
4.72 [1.49, 14.98] 0.008
01
*Visually assessed DS >30%
5
10
15
Univariate, unadjusted. * 8 patients with indeterminate events were excluded.
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)
MLA ≥ median 5.9 mm2 (n=1337)
3.4% (45)
0.4% (6)
7.53 [3.21, 17.65]
<0.0001
MLA ≤ 4.0 mm2 (n=496)
MLA > 4.0 mm2 (n=2177)
5.4% (27)
1.1% (24)
5.01 [2.89, 8.68]
<0.0001
PBMLA ≥ median 0.55 (n=1337)
PBMLA < median 0.55 (n=1336)
3.3% (44)
0.5% (7)
6.37 [2.87, 14.15]
<0.0001
PBMLA ≥ 0.70 (n=242)
PBMLA < 0.70 (n=2431)
9.1% (22)
1.2% (29)
7.94 [4.56, 13.81]
<0.0001
EEMMLA ≥ med 14.3 mm2 (n=1337)
EEMMLA < med 14.3 mm2 (n=1336)
1.4% (19)
2.4% (32)
0.60 [0.34, 1.06]
0.08
Lsn length < med 11.6 mm (n=1336)
Lsn length ≥ med 11.6 mm (n=1337)
0.7% (10)
3.1% (41)
4.01 [2.01, 8.02]
<0.0001
01
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.
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)
Not VH-TCFA (n=2065)
4.4% (26)
1.2% (25)
3.84 [2.22, 6.65] <0.0001
ThCFA (n=1005)
Not ThCFA (n=1650)
1.8% (18)
2.0% (33)
0.89 [0.50, 1.58]
0.69
PIT (n=964)
Not PIT (n=1691)
0.6% (6)
2.7% (45)
0.23 [0.10, 0.53]
0.001
Fibrotic (n=67)
Not Fibrotic (n=2588)
0% (0)
2.0% (51)
-
0.99
Fibrocalcific (n=29)
Not fibrocalcific (n=2626)
3.4% (1)
1.9% (50)
1.75 [0.24, 12.63]
0.58
01
5
10
15
TCFA = thin cap fibroatheroma; ThCFA = thick cap fibroatheroma; PIT = pathologic intimal thickening. Univariate, unadjusted.
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
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 <14.3 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) <median; lesion length ≥ median (mm); VH-TCFA.
PROSPECT: Correlates of
Non Culprit Lesion Related Events
Lesion HR 3.8 (2.2, 6.6)
P value
<0.0001
Prevalence* 51.2%
5.0 (2.9, 8.7)
<0.0001
49.1%
7.9 (4.6, 13.8) 6.4 (3.4, 12.2)
<0.0001
30.7%
<0.0001
17.4%
6.7 (3.4, 13.0) 10.8 (5.5, 21.0) 10.8 (4.3, 27.2)
<0.0001
15.4%
<0.0001
11.0%
*Likelihood of one or more such lesions being identified per patient. PB = plaque burden at the MLA
<0.0001
4.6%
PROSPECT: VH-TCFA and Non
Culprit Lesion Related Events
Lesion HR
3.84 (2.22, 6.65)
P value
<0.0001
Prevalence*
51.2%
6.41 (3.35, 12.24)
<0.0001
17.4%
10.77 (5.53, 21.00)
<0.0001
11.0%
10.81 (4.30, 27.22)
<0.0001
4.6%
*Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA
PROSPECT: PIT and Non Culprit
Lesion Related Events
Lesion HR
0.24 (0.10, 0.56)
P value
0.001
Prevalence*
68.6%
1.15 (0.36 3.70)
0.81
17.2%
1.36 (0.19, 9.86)
0.76
5.7%
2.85 (0.39, 20.67)
0.30
2.6%
*Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA
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
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