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