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

ACS
median 7d
PCI 69%

Pravastatin 40 mg/d

26.3%
22.4%

16% RR

P = 0.005
Atorvastatin 80 mg/d

How many events were attributable to:

1) Restenosis, stent thrombosis,
etc. vs.
2) Significant
disease left behind, vs.
3) VP with rapid lesion progression?

Cannon CP et al. NEJM 2004;350:1495-1504

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 ECG) or NSTEMI or STEMI >24
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
TNF
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

F/U: 1 mo, 6 mo,

1 yr, 2 yr,
3-5 yrs

Proximal 6-8
cm of each
coronary
artery
MSCT
Substudy
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

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:
MSCT:

Cardialysis, Marie-Angle Morel

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. 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)

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 composition-

N=2689
2.5%

Fibrocalcific
PIT
Fibroatheroma
- Thick cap

1.1%
35.9%
59.9%
37.8%

- VH-TCFA
- Single, - Ca
- Single, + Ca
- Multiple, - Ca

22.1%
5.4%
0.5%
9.8%

- Multiple, + Ca
Unclassified

6.4%
0.7%

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

PROSPECT: MACE
All
Culprit lesion (CL) related
Non culprit lesion (NCL) related
Indeterminate

25

MACE (%)

20

20.4%

15

12.9%

10

11.6%

2.7%

0
0

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

11.4%
7.9%

10

9.4%
5

6.4%

1.9%

0.9%

12.9%
11.6%
2.7%

0
0

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

6.7%

6.4%

4
2
0
0

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

Median time to event

No RLP: 223 [85, 663] days
RLP: 401 [229, 666] days

2.9%

0
0

6.4%

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)

HR [95% CI]

HR [95% CI]

Insulin DM (n=21)
Non insulin DM (n=96)
Non diabetic (n=569)

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%

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)
Variable

IVUS Characteristics
(area data)
Rate (n)
HR [95% CI]
HR [95% CI]

MLA < median 5.9 mm2 (n=1336)

<0.0001
MLA median 5.9 mm2 (n=1337)

3.4% (45)

MLA 4.0 mm2 (n=496)

<0.0001
MLA > 4.0 mm2 (n=2177)

5.4% (27)

PBMLA median 0.55 (n=1337)

<0.0001
PBMLA < median 0.55 (n=1336)

3.3% (44)

PBMLA 0.70 (n=242)

<0.0001
PBMLA < 0.70 (n=2431)

9.1% (22)

7.53 [3.21, 17.65]

0.4% (6)
5.01 [2.89, 8.68]

1.1% (24)
6.37 [2.87, 14.15]

0.5% (7)
7.94 [4.56, 13.81]

1.2% (29)

10
15
EEMMLA med 14.3 mm2 (n=1337)
1.4% (19) 01 5
0.60 [0.34, 1.06]
2
EEM
< med
(32) = external elastic membrane at the MLA.
MLA = MLA
minimal
luminal14.3
area; mm
PB =(n=1336)
plaque burden at the2.4%
MLA; EEM
MLA

Data represent univariate associations, unadjusted.

MLA

0.08

PROSPECT: Correlates of
Non Culprit Lesion Related Events
Lesion level events (51 events from 2655 lesions in 609 pts at median
3.4 yrs)
Variable

Virtual
Histology
Plaque
Rate
(n) HR [95%
CI] HR [95%
CI] P

VH-TCFA (n=590)
4.4% (26)
Not VH-TCFA (n=2065) 1.2% (25)

3.84 [2.22, 6.65] <0.0001

ThCFA (n=1005)
Not ThCFA (n=1650)

0.89 [0.50, 1.58] 0.69

1.8% (18)
2.0% (33)

Type

PIT (n=964)
0.6% (6)
0.23 [0.10, 0.53] 0.001
Not PIT (n=1691)
2.7% (45)
Fibrotic (n=67) 0% (0)
Not Fibrotic (n=2588)

2.0% (51)

0.99

Fibrocalcific (n=29)
3.4% (1)
1.75 [0.24, 12.63] 0.58
Not fibrocalcific (n=2626)
1.9% (50)

01

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 (PB MLA);
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,

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