Prospect trial

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 rehospitalization

MACE attributable to rapid angiographic progression of a non-culprit lesion* • Cardiac death• Cardiac arrest• Myocardial infarction• Unstable angina


- Requiring rehospitalization• Increasing angina


- 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


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)


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


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: MACEM

AC

E (

%)

Time in Years0 1 2 3

All Culprit lesion (CL) relatedNon culprit lesion (NCL) relatedIndeterminate

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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 (

%)


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

(%

)


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

(%

)


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)


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)


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


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

Prospect trial

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