A Natural History Study of A Natural History Study of Atherosclerosis Using Multimodality Atherosclerosis Using Multimodality

Intracoronary Imaging to Prospectively Intracoronary Imaging to Prospectively Identify Vulnerable PlaqueIdentify Vulnerable Plaque

Gregg W. Stone, MDGregg W. Stone, MDPROSPECT InvestigatorsPROSPECT Investigators

PProviding roviding RRegional egional OObservations to bservations to SStudy tudy PPredictors redictors of of EEvents in the vents in the CCoronary oronary TTreeree

The The PROSPECTPROSPECT TrialTrial

700 pts with ACS700 pts with ACSUA (with ECGUA (with ECG∆∆) ) oror NSTEMI NSTEMI oror STEMI >24STEMI >24ºº

undergoing PCI of 1 or 2 major coronary arteriesundergoing PCI of 1 or 2 major coronary arteriesat up to 40 sites in the U.S. and Europeat up to 40 sites in the U.S. and Europe

PCI of culprit lesion(s)PCI of culprit lesion(s)Successful and uncomplicatedSuccessful and uncomplicated

Formally enrolledFormally enrolled

Metabolic S.Metabolic S.•• Waist circumWaist circum•• Fast lipidsFast lipids•• Fast gluFast glu•• HgbA1CHgbA1C•• Fast insulinFast insulin•• CreatinineCreatinine

BiomarkersBiomarkers•• Hs CRPHs CRP•• ILIL--66•• sCD40LsCD40L•• MPOMPO•• TNFTNFαα•• MMP9MMP9•• LpLp--PLA2PLA2•• othersothers

PI: Gregg W. StonePI: Gregg W. StoneSponsor: Abbott Vascular; Partner: VolcanoSponsor: Abbott Vascular; Partner: Volcano

The The PROSPECTPROSPECT TrialTrial

33--vessel imaging post PCIvessel imaging post PCICulprit artery, followed byCulprit artery, followed by

nonnon--culprit arteriesculprit arteries

Angiography (QCA of entire coronary tree)Angiography (QCA of entire coronary tree)IVUSIVUS

Virtual histologyVirtual histologyPalpography (n=~350)Palpography (n=~350)

Repeat imagingRepeat imagingin pts with events in pts with events

Meds recMeds recAspirinAspirinPlavix 1yrPlavix 1yrStatinStatinRepeat biomarkersRepeat biomarkers@ 30 days, 6 months @ 30 days, 6 months

Proximal 6-8 cm of each coronary

artery

Proximal 6Proximal 6--8 8 cm of each cm of each coronary coronary

arteryartery

MSCTMSCTSubstudySubstudyN=50N=50--100100F/U: 1 mo, 6 mo,

1 yr, 2 yr,±3-5 yrs

F/U: 1 mo, 6 mo,F/U: 1 mo, 6 mo,1 yr, 2 yr,1 yr, 2 yr,±±33--5 yrs5 yrs

The The PROSPECTPROSPECT TrialTrial

Lesions are classified into 5 main typesLesions are classified into 5 main types

1.1. FibroticFibrotic

2.2. FibrocalcificFibrocalcific

3.3. Pathological intimal thickening (PIT)Pathological intimal thickening (PIT)

4.4. Thick cap fibroatheroma (ThCFA)Thick cap fibroatheroma (ThCFA)

5. 5. VHVH--thin cap fibroatheroma (VHthin cap fibroatheroma (VH--TCFA)TCFA)(presumed high risk)(presumed high risk)

PROSPECT:PROSPECT: MethodologyMethodologyVirtual histology lesion classificationVirtual histology lesion classification

PROSPECT: PROSPECT: Primary EndpointPrimary 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 MACE attributable to rapid angiographic progression of a progression of a nonnon--culpritculprit lesion*lesion*••Cardiac deathCardiac death••Cardiac arrestCardiac arrest••Myocardial infarctionMyocardial infarction••Unstable anginaUnstable angina

-- Requiring revascularizationRequiring revascularization-- Requiring rehospitalizationRequiring rehospitalization

••Increasing anginaIncreasing angina-- Requiring revascularizationRequiring revascularization-- Requiring rehospitalizationRequiring rehospitalization

MACE during FU were adjudicated by the CEC as attributable to cuMACE during FU were adjudicated by the CEC as attributable to culprit lesions (those treated during or before lprit lesions (those treated during or before the index hospitalization) or non culprit lesions (untreated arethe index hospitalization) or non culprit lesions (untreated areas of the coronary tree) based on angiography as of the coronary tree) based on angiography (+ECGs, etc.) at the time of the event; events occurring in pts (+ECGs, etc.) at the time of the event; events occurring in pts without angiographic followwithout angiographic follow--up were considered up were considered indeterminate in origin. Rapid lesion progression = indeterminate in origin. Rapid lesion progression = ↑↑ in QCA DS by >20% from baseline to FU.in QCA DS by >20% from baseline to FU.

Hie

rarc

hica

lH

iera

rchi

cal

Most severeMost severe

Least severeLeast severe

PROSPECT: PROSPECT: MACEMACEM

AC

E (%

)M

AC

E (%

)

Time in YearsTime in Years00 11 22 33

All All Culprit lesion (CL) relatedCulprit lesion (CL) relatedNon culprit lesion (NCL) relatedNon culprit lesion (NCL) relatedIndeterminateIndeterminate

00

55

1010

1515

2020

2525

Number at riskNumber at risk

20.4%20.4%

12.9%12.9%

11.6%11.6%

2.7%2.7%

13.2%13.2%

7.9%7.9%

6.4%6.4%

0.9%0.9%

18.1%18.1%

11.4%11.4%

9.4%9.4%

1.9%1.9%

ALLALL 697697 557 557 506 506 480480

CL relatedCL related 697697 590590 543543 518518

NCL relatedNCL related 697697 595595 553 553 521521

IndeterminateIndeterminate 697697 634634 604 604 583583

MA

CE

(%)

MA

CE

(%)

Time in YearsTime in Years00 11 22 33

Number at riskNumber at risk

NonNon--culprit lesion (NCL) related, allculprit lesion (NCL) related, all-- Without rapid lesion progression (RLP)Without rapid lesion progression (RLP)-- With rapid lesion progression (RLP)With rapid lesion progression (RLP)

00

22

44

66

88

1010

1212 11.6%11.6%

6.7%6.7%

6.4%6.4%

2.9%2.9%

4.1%4.1%

6.4%6.4%

5.5%5.5%

4.9%4.9%

9.4%9.4%

NCL related, allNCL related, all 697697 595595 553 553 521 521

-- without RLPwithout RLP 697697 610610 577 577 551 551

-- with RLPwith RLP 697697 620620 579 579 550 550

PROSPECT: PROSPECT: NCL NCL MACEMACE

Median time to eventNo RLP: No RLP: 223 [85, 663] days223 [85, 663] daysRLP: RLP: 401 [229, 666]401 [229, 666] days

PROSPECT:PROSPECT: Correlates of Correlates of Non Culprit Lesion Related EventsNon Culprit Lesion Related Events

Lesion HRLesion 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 valueP value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001<0.0001 <0.0001<0.0001 <0.0001<0.0001 <0.0001<0.0001Prevalence*Prevalence* 51.2%51.2% 49.1%49.1% 30.7%30.7% 17.4% 17.4% 15.4%15.4% 11.0%11.0% 4.6%4.6%

**Likelihood of one or more such lesions being present per patientLikelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA. PB = plaque burden at the MLA

PROSPECT:PROSPECT: ConclusionsConclusions• From this trial, the first prospective, natural history study ofatherosclerosis 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 topreviously 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 ofFrom this trial, the first prospective, natural history study ofatherosclerosis using multimodality imaging to characterize the atherosclerosis using multimodality imaging to characterize the coronary tree, we can conclude that:coronary tree, we can conclude that:•• Approximately 20% of pts with ACS successfully treated with Approximately 20% of pts with ACS successfully treated with stents and contemporary medical Rx develop MACE within stents and contemporary medical Rx develop MACE within 3 years, with adverse events equally attributable to recurrence 3 years, with adverse events equally attributable to recurrence at originally treated culprit lesions (treatment failure) and toat originally treated culprit lesions (treatment failure) and topreviously untreated non culprit coronary segmentspreviously untreated non culprit coronary segments

•• Approximately 12% of pts develop MACE from Approximately 12% of pts develop MACE from non culprit non culprit lesionslesions during 3 years of followduring 3 years of follow--upup

•• Patients treated with contemporary medical therapy who Patients treated with contemporary medical therapy who develop non culprit lesion events present most commonly with develop non culprit lesion events present most commonly with progressive or unstable angina, and rarely with cardiac death, progressive or unstable angina, and rarely with cardiac death, cardiac arrest or MIcardiac arrest or MI

PROSPECT:PROSPECT: ConclusionsConclusions• 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 angiographic 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 MACWhile plaques which are responsible for unanticipated future MACE E are frequently angiographically mild, most untreated plaques whiare frequently angiographically mild, most untreated plaques which ch become symptomatic have a large plaque burden and a small lumen become symptomatic have a large plaque burden and a small lumen area (which are detectable by IVUS but not by angiography)area (which are detectable by IVUS but not by angiography)

•• Only about half of new events due to non culprit lesions exempliOnly about half of new events due to non culprit lesions exemplify the fy the classic notion of vulnerable plaque (rapid lesion progression ofclassic notion of vulnerable plaque (rapid lesion progression of mild mild angiographic lesions), while half are attributable to unrecognizangiographic lesions), while half are attributable to unrecognized and ed and untreated severe disease with minimal change over timeuntreated severe disease with minimal change over time

•• The prospective identification of non culprit lesions prone to dThe prospective identification of non culprit lesions prone to develop evelop MACE within 3 years can be enhanced by characterization of MACE within 3 years can be enhanced by characterization of underlying plaque morphology with virtual histology, with VHunderlying plaque morphology with virtual histology, with VH--TCFAs TCFAs representing the highest risk lesion typerepresenting the highest risk lesion type

•• The combination of large plaque burden (IVUS) and a large necrotThe combination of large plaque burden (IVUS) and a large necrotic ic core without a visible cap (VHcore without a visible cap (VH--TCFA) identifies lesions which are at TCFA) identifies lesions which are at especially high risk for future adverse cardiovascular eventsespecially high risk for future adverse cardiovascular events