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prospective identify vulnerable plaque
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A Natural History Study of Atherosclerosis Using Multimodality
Intracoronary Imaging to Prospectively Identify Vulnerable Plaque
Gregg W. Stone, MDPROSPECT Investigators
Providing Regional Observations to Study Predictors of Events in the Coronary Tree
The PROSPECT Trial
The PROSPECT Trial
• Gregg W. Stone Scientific Advisory Board, Abbott
Vascular Devices Consultant to InfraReDx
• 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
• 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
The PROSPECT TrialBackground
0
5
10
15
20
25
30
0 3 6 9 12 15 18 21 24 27 30
Months of Follow-up
PROVE-IT TIMI-224,162 Randomized Pts with ACS
16% RRP = 0.005
Pravastatin 40 mg/d
Atorvastatin 80 mg/d
26.3%
22.4%
Dea
th, M
I, U
A r
equ
irin
g h
osp
, re
vasc
>30
d, o
r st
roke
(%
)
Cannon CP et al. NEJM 2004;350:1495-1504
How many events were attributable to: 1) Restenosis, stent thrombosis, etc. vs. 2) Significant disease left behind, vs. 3) VP with rapid lesion progression?
How many events were attributable to: 1) Restenosis, stent thrombosis, etc. vs. 2) Significant disease left behind, vs. 3) VP with rapid lesion progression?
ACSmedian 7dPCI 69%
• 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
• 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 TrialBackground
700 pts with ACSUA (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
PCI of culprit lesion(s)Successful and uncomplicated
Formally enrolled
Metabolic S.• Waist circum• Fast lipids• Fast glu• HgbA1C• Fast insulin• Creatinine
Biomarkers• Hs CRP• IL-6• sCD40L• MPO• TNFα• MMP9• Lp-PLA2• others
PI: Gregg W. StoneSponsor: Abbott Vascular; Partner: Volcano
The PROSPECT Trial
3-vessel imaging post PCICulprit artery, followed by
non-culprit arteries
Angiography (QCA of entire coronary tree)
IVUS
Virtual histology
Palpography (n=~350)
Repeat imagingin pts with events
Meds recAspirinPlavix 1yrStatinRepeat biomarkers@ 30 days, 6 months
Proximal 6-8 cm of each coronary
artery
Proximal 6-8 cm of each coronary
artery
MSCTSubstudyN=50-100 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
The PROSPECT Trial
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 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 rehospitalizationMACE 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.
Hie
rarc
hic
al
Most severe
Least severe
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
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
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
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
IVUS/VH Core Lab Analysis
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: Methodology
Virtual histology lesion classification
Index 2/13/06 Event 2/6/07
QCA PLCX DS 28.6% QCA PLCX DS 71.3%
PROSPECT 82910-012: 52 yo♂
2/13/06: NSTEMI, PCI of MLAD
2/6/07 (51 weeks later): NSTEMI attributed to LCX
38
1. ThCFA
*OM
5.3mm2
Lesion
*
1
prox
PROSPECT 82910-012: Index 2/13/06
Baseline PLCXQCA: RVD 2.82 mm, DS 28.6%, length 6.8
mmIVUS: MLA 5.3 mm2
VH: ThCFA
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
• 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: Organization
700 pts enrolled between Oct. 2004 and June 2006 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
enro
llers
PROSPECT: Enrollment
PROSPECT: Baseline Features
N = 697*
*3 patients who were never consented were de-registered
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]
PROSPECT: Baseline Features
N = 697
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
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%
6.5%
59.4%
21.1%
13.0%
Dense calcium Fibrotic
Fibrofatty Necrotic core
PROSPECT: Imaging Summary
Per patient incidence of VH-TCFAs
48.8%
27.3%
12.0%6.2% 5.7%
0%
25%
50%
75%
100%
% P
ati
en
ts
0 1 2 3 ≥4
51.2% of pts have ≥1 VH-TCFA0.97 ±1.30 VH-TCFAs per pt
(range 0 – 7 per pt)Total of 594 VH-TCFA lesions in 615 pts
N lesions/patient:
PROSPECT: Imaging Summary
PROSPECT: MACEM
AC
E (
%)
Time in Years0 1 2 3
All Culprit lesion (CL) relatedNon culprit lesion (NCL) relatedIndeterminate
0
5
10
15
20
25
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
12.9%
20.4%
11.6%
2.7%
PROSPECT: MACEM
AC
E (
%)
Time in Years0 1 2 3
All Culprit lesion (CL) relatedNon culprit lesion (NCL) relatedIndeterminate
0
5
10
15
20
25
Number at risk
20.4%
12.9%
11.6%
2.7%
13.2%
7.9%
6.4%
0.9%
18.1%
11.4%
9.4%
1.9%
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
AllCulprit
lesion relatedNon culprit
lesion relatedIndeter-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)
PROSPECT: MACE
Sensitivity analysis*: 3-year FU, non hierarchical
AllCulprit 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
MA
CE
(%
)
Time in Years0 1 2 3
NCL related, all 697 595 553 521
- without RLP 697 610 577 551
- with RLP 697 620 579 550
Number at risk
Non-culprit lesion (NCL) related, all - Without rapid lesion progression (RLP) - With rapid lesion progression (RLP)
PROSPECT: NCL MACE
0
2
4
6
8
10
12 11.6%
6.7%
6.4%
MA
CE
(%
)
Time in Years0 1 2 3
Number at risk
Non-culprit lesion (NCL) related, all - Without rapid lesion progression (RLP) - With rapid lesion progression (RLP)
0
2
4
6
8
10
12 11.6%
6.7%
6.4%
2.9%
4.1%
6.4%
5.5%
4.9%
9.4%
NCL related, all 697 595 553 521
- without RLP 697 610 577 551
- with RLP 697 620 579 550
PROSPECT: NCL MACE
Median time to eventNo RLP: 223 [85, 663] daysRLP: 401 [229, 666] days
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) HR [95% CI] HR [95% CI] P
Insulin DM (n=21) 41.4% (6) 4.07 [1.75, 9.46] 0.001Non insulin DM (n=96) 16.3% (14) 1.55 [0.86, 2.79] 0.14Non diabetic (n=569) 10.7% (56)
Hypertension (n=314) 14.7% (42) 1.64 [1.03, 2.60] 0.04No hypertension (n=369) 9.1% (31)
Prior PCI (n=75) 23.1% (15) 2.20 [1.25, 3.86] 0.006No prior PCI (n=613) 10.8% (61)
≥1 visible angio lsn* (n=582) 13.7% (73) 4.72 [1.49, 14.98] 0.008No visible angio lsn (n=107) 3.2% (3)
*Visually assessed DS >30%
01 5 10 15
Univariate, unadjusted. * 8 patients with indeterminate events were excluded.
Variable Rate (n) HR [95% CI] HR [95% CI] P
MLA < median 5.9 mm2 (n=1336) 3.4% (45) 7.53 [3.21, 17.65]<0.0001MLA ≥ median 5.9 mm2 (n=1337) 0.4% (6)
MLA ≤ 4.0 mm2 (n=496) 5.4% (27) 5.01 [2.89, 8.68] <0.0001MLA > 4.0 mm2 (n=2177) 1.1% (24)
PBMLA ≥ median 0.55 (n=1337) 3.3% (44) 6.37 [2.87, 14.15]<0.0001PBMLA < median 0.55 (n=1336) 0.5% (7)
PBMLA ≥ 0.70 (n=242) 9.1% (22) 7.94 [4.56, 13.81] <0.0001PBMLA < 0.70 (n=2431) 1.2% (29)
EEMMLA ≥ med 14.3 mm2 (n=1337) 1.4% (19) 0.60 [0.34, 1.06] 0.08EEMMLA < med 14.3 mm2 (n=1336) 2.4% (32)
Lsn length < med 11.6 mm (n=1336) 0.7% (10) 4.01 [2.01, 8.02] <0.0001Lsn length ≥ med 11.6 mm (n=1337) 3.1% (41)
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)
MLA = minimal luminal area; PBMLA = plaque burden at the MLA; EEMMLA = external elastic membrane at the MLA.Data represent univariate associations, unadjusted.
01 5 10 15
Variable Rate (n) HR [95% CI] HR [95% CI] P
VH-TCFA (n=590) 4.4% (26) 3.84 [2.22, 6.65] <0.0001Not VH-TCFA (n=2065) 1.2% (25)
ThCFA (n=1005) 1.8% (18) 0.89 [0.50, 1.58] 0.69Not ThCFA (n=1650) 2.0% (33)
PIT (n=964) 0.6% (6) 0.23 [0.10, 0.53] 0.001Not PIT (n=1691) 2.7% (45)
Fibrotic (n=67) 0% (0) - 0.99Not Fibrotic (n=2588)2.0% (51)
Fibrocalcific (n=29) 3.4% (1) 1.75 [0.24, 12.63] 0.58Not fibrocalcific (n=2626) 1.9% (50)
PROSPECT: Correlates of Non Culprit Lesion Related Events
TCFA = thin cap fibroatheroma; ThCFA = thick cap fibroatheroma; PIT = pathologic intimal thickening. Univariate, unadjusted.
Lesion level events (51 events from 2655 lesions in 609 pts at median 3.4 yrs)
Virtual Histology Plaque Type
01 5 10 15
PROSPECT: Multivariable Correlates of Non Culprit Lesion Related Events
Independent predictors of lesion level events by logistic regression analysis
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.
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
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 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <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
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 <0.0001 <0.0001 <0.0001 <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
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
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
• 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
• 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