implications from prospect and future directions gregg w. stone, md columbia university medical...

Implications from Implications from PROSPECTPROSPECT and Future and Future

Directions Directions Gregg W. Stone, MDGregg W. Stone, MDColumbia University Medical CenterColumbia University Medical Center

The Cardiovascular Research FoundationThe Cardiovascular Research Foundation

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

PROSPECTPROSPECT

PROSPECTPROSPECT

• Gregg W. StoneGregg W. Stone Scientific Advisory Board for an Scientific Advisory Board for an

honoraria from Abbott Vascular and honoraria from Abbott Vascular and Boston ScientificBoston Scientific

Research grants from InfraReDx and Research grants from InfraReDx and Volcano Volcano

700 pts with ACS700 pts with ACSUA (with ECGUA (with ECGΔΔ) ) oror NSTEMI NSTEMI oror STEMI >24º STEMI >24º

undergoing PCI of 1 or 2 major coronary arteriesundergoing PCI of 1 or 2 major coronary arteries

at 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• IL-6IL-6• sCD40LsCD40L• MPOMPO• TNFTNFαα• MMP9MMP9• Lp-PLA2Lp-PLA2• othersothers

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

PROSPECTPROSPECT

3-vessel imaging post PCI3-vessel imaging post PCICulprit artery, followed byCulprit artery, followed by

non-culprit arteriesnon-culprit arteries

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

IVUSIVUS

Virtual histologyVirtual histology

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

arteryartery

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

arteryartery

MSCTMSCTSubstudySubstudyN=50-100N=50-100 F/U: 1 mo, 6 mo,F/U: 1 mo, 6 mo,

1 yr, 2 yr,1 yr, 2 yr,±3-5 yrs±3-5 yrs

F/U: 1 mo, 6 mo,F/U: 1 mo, 6 mo,1 yr, 2 yr,1 yr, 2 yr,±3-5 yrs±3-5 yrs

PROSPECTPROSPECT

PROSPECT: PROSPECT: MACE (N=697)MACE (N=697)M

AC

E (

%)

MA

CE

(%

)

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 riskALLALL 697697 557 557 506 506 480480CL relatedCL related 697697 590590 543543 518518NCL relatedNCL related 697697 595595 553 553 521521IndeterminateIndeterminate 697697 634634 604 604 583583

12.9%12.9%

20.4%20.4%

11.6%11.6%

2.7%2.7%

MACE = cardiac death, cardiac arrest, MI, or rehospitalization for unstable or progressive anginaMACE = cardiac death, cardiac arrest, MI, or rehospitalization for unstable or progressive angina

PROSPECT:PROSPECT: MACE MACE

3-year follow-up, hierarchical3-year follow-up, hierarchical

AllAll Culprit Culprit lesion relatedlesion related

Non culprit Non culprit lesion relatedlesion related

Indeter-Indeter-minateminate

Cardiac deathCardiac death 1.9% (12)1.9% (12) 0.2% (1)0.2% (1) 0% (0)0% (0) 1.7% (11)1.7% (11)

Cardiac arrestCardiac arrest 0.3% (2)0.3% (2) 0.3% (2)0.3% (2) 0% (0)0% (0) 0% (0)0% (0)

MI (STEMI or NSTEMI)MI (STEMI or NSTEMI) 2.7% (17)2.7% (17) 1.7% (11)1.7% (11) 1.0% (6)1.0% (6) 0.2% (1)0.2% (1)

Rehospitalization for unstable Rehospitalization for unstable or progressive anginaor progressive angina 15.4% (101)15.4% (101) 10.4% (69)10.4% (69) 10.7% (68)10.7% (68) 0.8% (5)0.8% (5)

Composite MACEComposite MACE 20.4% (132)20.4% (132) 12.9% (83)12.9% (83) 11.6% (74)11.6% (74) 2.7% (17)2.7% (17)

Cardiac death, arrest or MICardiac death, arrest or MI 4.9% (31)4.9% (31) 2.2% (14)2.2% (14) 1.0% (6)1.0% (6) 1.9% (12)1.9% (12)

Rates are 3-yr Kaplan-Meier estimates (n of events)Rates are 3-yr Kaplan-Meier estimates (n of events)

PROSPECT:PROSPECT: Multivariable Correlates Multivariable Correlates of Non-Culprit Lesion Related Eventsof Non-Culprit Lesion Related Events

Independent predictors of patient level Independent predictors of patient level events by Cox Proportional Hazards events by Cox Proportional Hazards

regressionregression

Variables entered into the model: age, gender, hypertension, insulin dependent Variables entered into the model: age, gender, hypertension, insulin dependent diabetes, prior PCI, CRP at baseline, family history diabetes, prior PCI, CRP at baseline, family history

VariableVariable HR [95% CI]HR [95% CI] P valueP value

Insulin dependent Insulin dependent diabetesdiabetes 3.32 [1.43, 7.72] 0.0050.005

Prior PCI Prior PCI 2.03 [1.15, 3.59] 0.020.02

PROSPECT:PROSPECT: Multivariable Correlates Multivariable Correlates of Non-Culprit Lesion Related Eventsof Non-Culprit Lesion Related Events

Variables entered: Variables entered: minimal lumen area (MLA), plaque burden at the MLA, external elastic membrane at the minimal lumen area (MLA), plaque burden at the MLA, external elastic membrane at the MLA, lesion length, distance from the coronary ostium to the MLA, remodeling index, thin-cap fibroatheroma, MLA, lesion length, distance from the coronary ostium to the MLA, remodeling index, thin-cap fibroatheroma,

insulin-requiring diabetes and prior percutaneous coronary interventioninsulin-requiring diabetes and prior percutaneous coronary intervention

VariableVariable HR [95% CI]HR [95% CI] P valueP value

PBPBMLAMLA ≥70% ≥70% 5.03 [2.51, 10.11] <0.0001<0.0001

VH-TCFA VH-TCFA 3.35 [1.77, 6.36] 0.00020.0002

MLA ≤4.0 mmMLA ≤4.0 mm22 3.21 [1.61, 6.42] 0.0010.001

Independent predictors of lesion level events Independent predictors of lesion level events by Cox Proportional Hazards regressionby Cox Proportional Hazards regression

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

0.3

4.8

10.5

18.2

0

5

10

15

20

Zero One Two Three

PB = plaque burden at the MLAPB = plaque burden at the MLA

Number of factors present: PBMLA ≥70%, MLA ≤4.0mm2 or TCFA

Me

dia

n 3

.4 y

r M

AC

E r

ate

per

lesi

on (

%)

5/1650 46/1059 24/253 5/29

PROSPECT:PROSPECT: VH-TCFA and Non- VH-TCFA and Non- Culprit Lesion Related EventsCulprit Lesion Related Events

Lesion HRLesion HR 3.90 (2.25, 6.76) 6.55 (3.43, 12.51) 10.83 (5.55, 21.10) 11.05 (4.39, 27.82) P valueP value <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001<0.0001 Prevalence*Prevalence* 46.7%46.7% 15.9%15.9% 10.1%10.1% 4.2% 4.2%

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

PROSPECT:PROSPECT: Thick CFA and Non- Thick CFA and Non- Culprit Lesion Related EventsCulprit Lesion Related Events

Lesion HRLesion HR 0.92 (0.52, 1.63) 3.41 (1.75, 6.65) 5.17 (2.59, 10.32) 5.02 (1.99, 12.63) P valueP value 0.770.77 0.0003 0.0003 <0.0001 <0.0001 <0.0001<0.0001 Prevalence*Prevalence* 67.6%67.6% 22.7%22.7% 15.6%15.6% 8.3% 8.3%



PROSPECT:PROSPECT: Non Fibroatheromas Non Fibroatheromas and Non-Culprit Lesion Eventsand Non-Culprit Lesion Events

Lesion HRLesion HR 0.22 (0.10, 0.49) 0.22 (0.10, 0.49) 1.22 (0.44, 3.39) 1.22 (0.44, 3.39) 1.25 (0.17, 9.01) 1.25 (0.17, 9.01) 2.60 (0.36, 18.84) 2.60 (0.36, 18.84) P valueP value 0.0002 0.0002 0.70 0.70 0.83 0.83 0.34 0.34 Prevalence*Prevalence* 67.9%67.9% 19.7%19.7% 5.6%5.6% 2.7% 2.7%

PathologicalIntimal

thickening

Fibrotic Fibrocalcific

Complications adjudicated to the 3-vessel IVUS imaging procedure (n=697)Complications adjudicated to the 3-vessel IVUS imaging procedure (n=697)

Death

MI

- Q-wave (from dissection)

- non Q-wave (from dissection)

PCI or CABG

- CABG (from perforation)

- CABG (from dissection)

- PCI (from dissection)

0 (0%)0 (0%)

3 (0.4%)3 (0.4%)

11

22

10 (1.4%)10 (1.4%)

11

22

99

Any imaging complication*Any imaging complication* 11 (1.6%)11 (1.6%)

*Some pts had more than one complication *Some pts had more than one complication

Was 3-vessel VH-IVUS imaging safe?Was 3-vessel VH-IVUS imaging safe?

PROSPECT: PROSPECT: QuestionsQuestions


How much disease was left behind after the How much disease was left behind after the original PCI in 697 patients?original PCI in 697 patients?

N=283N=620

mean 0.9 ± 1.1 per ptmean 0.9 ± 1.1 per pt

meanmean0.4 ± 0.70.4 ± 0.7per ptper pt

By angiographyBy angiography1,814 untreated lesions 1,814 untreated lesions

(visual DS >30%)(visual DS >30%) in the entire coronary treein the entire coronary tree- mean 2.6 ± 1.8 per pt - - mean 2.6 ± 1.8 per pt -

QCAQCADS%DS%

DS <50%N=1704(93.9%)

DS ≥50%-<70%DS ≥50%-<70%N=98N=98(5.4%)(5.4%)

DS ≥70%DS ≥70%N=12N=12(0.7%)(0.7%)

DS% mean 33.7 ± 15.7%DS% mean 33.7 ± 15.7%

By IVUS (n=673)By IVUS (n=673)3,160 untreated lesions 3,160 untreated lesions

(PB ≥40%) in the proximal-(PB ≥40%) in the proximal-to-mid coronary treeto-mid coronary tree

- mean 4.7 ± 2.0 per pt -- mean 4.7 ± 2.0 per pt -


How much disease was left behind after the How much disease was left behind after the original PCI in 697 patients?original PCI in 697 patients?

TCFATCFAN=596 (21.9%)N=596 (21.9%)

By VH-IVUS (n=623)By VH-IVUS (n=623)2,811 untreated classified 2,811 untreated classified lesions in the proximal-to-lesions in the proximal-to-

mid coronary treemid coronary tree

FibroticFibroticN=104 (3.8%)N=104 (3.8%)

FibrocalcificFibrocalcificN=33 (1.2%)N=33 (1.2%)

PITPITN=1008 (37.0%)N=1008 (37.0%)

ThCFAThCFAN=1018 (37.3%)N=1018 (37.3%)

0.98 ± 1.31 per pt(range 0 – 7 per pt)


What were the What were the baseline angiographic characteristicsbaseline angiographic characteristics of the of the lesions that were later responsible for non-culprit events?lesions that were later responsible for non-culprit events?

The mean angiographic QCA DS of the 106 lesions subsequently responsible for non-culprit MACE in 76 pts was 32.3% ± 20.6% at

baseline and 65.4% ± 16.3% at the time of the follow-up event (P<0.001).

Lesion locationLesion location

32 lesions (30.2%) were angiographically inconspicuous (<30% stenotic) by visual assessment)

Baseline QCA %DSBaseline QCA %DS

ProxProx 24.3%MidMid 19.6%DistalDistal 15.9%BranchBranch 40.2%


What were the What were the baseline VH-IVUS characteristicsbaseline VH-IVUS characteristics of the of the lesions that were later responsible for non-culprit events?lesions that were later responsible for non-culprit events?

51 non-culprit MACE lesions with baseline VH-IVUS

TCFAsTCFAsN=26 N=26 (51%)(51%)

NotNotTCFAsTCFAsN=25N=25(49%)(49%)

PB ≥70% and/or MLA ≤4.0mm2

N=18 (35%)

TCFA onlyN=8 (16%)

PB ≥70% and/or MLA ≤4.0mm2

N=20 (39%)

Not TCFA onlyN=5 (10%)

18 ThCFA6 PIT1 FC0 F

Baseline IVUS was performed in 55/106 sites that subsequently resulted in non-culprit MACE. All 55 sites had plaque burden ≥40% by baseline IVUS imaging. Conversely,

no imaged coronary segment with <40% plaque burden resulted in a non-culprit event during the median 3.4 year FU period.

PROSPECT: PROSPECT: QuestionsQuestionsWhat types of events were responsible for What types of events were responsible for

CULPRITCULPRIT lesion MACE during follow-up? lesion MACE during follow-up?

• Stent thrombosis (n=13 lesions)Stent thrombosis (n=13 lesions)• Restenosis (n=107 lesions)Restenosis (n=107 lesions)• New stent-related sidebranch lesions (n=5 lesions)New stent-related sidebranch lesions (n=5 lesions)

Baseline grayscale and VH-IVUS will be analyzed for correlates of future eventsBaseline grayscale and VH-IVUS will be analyzed for correlates of future events

Possible predictors of stent thrombosisPossible predictors of stent thrombosis

FA behind stentFA behind stent

FA behind stent, FA behind stent, abutting into lumenabutting into lumen

Partially Partially uncovered FAuncovered FA

Separate Separate untreated untreated adjacent FAadjacent FA

Totally Totally covered FAcovered FA

PROSPECT:PROSPECT: Implications Implications

• Following successful and uncomplicated PCI in pts with ACS Following successful and uncomplicated PCI in pts with ACS who undergo careful clinical FU, is 3-vessel VH-IVUS to who undergo careful clinical FU, is 3-vessel VH-IVUS to identify and prophylactically stent non-culprit lesions at high identify and prophylactically stent non-culprit lesions at high risk for future MACE warranted based on PROSPECT?risk for future MACE warranted based on PROSPECT?

►►No No

1.1. The prevalence of high-risk lesions is relatively low The prevalence of high-risk lesions is relatively low (~1 in 4 pts).(~1 in 4 pts).

2.2. 3-vessel imaging is not risk-free (1.6% major 3-vessel imaging is not risk-free (1.6% major complication rate).complication rate).

3.3. When high-risk lesions become symptomatic they When high-risk lesions become symptomatic they usually present with angina and not death or MI.usually present with angina and not death or MI.

►►This suggests that absent a randomized trial, optimal This suggests that absent a randomized trial, optimal medical therapy and close follow-up is more appropriate.medical therapy and close follow-up is more appropriate.

• Following successful and uncomplicated PCI in pts with ACS Following successful and uncomplicated PCI in pts with ACS who undergo careful clinical FU, is 3-vessel VH-IVUS to who undergo careful clinical FU, is 3-vessel VH-IVUS to identify and prophylactically stent non-culprit lesions at high identify and prophylactically stent non-culprit lesions at high risk for future MACE warranted based on PROSPECT?risk for future MACE warranted based on PROSPECT?

►►No No

1.1. The prevalence of high-risk lesions is relatively low The prevalence of high-risk lesions is relatively low (~1 in 4 pts).(~1 in 4 pts).

2.2. 3-vessel imaging is not risk-free (1.6% major 3-vessel imaging is not risk-free (1.6% major complication rate).complication rate).

3.3. When high-risk lesions become symptomatic they When high-risk lesions become symptomatic they usually present with angina and not death or MI.usually present with angina and not death or MI.

►►This suggests that absent a randomized trial, optimal This suggests that absent a randomized trial, optimal medical therapy and close follow-up is more appropriate.medical therapy and close follow-up is more appropriate.


• What if during routine IVUS-guided stenting (e.g. in the What if during routine IVUS-guided stenting (e.g. in the MLAD), a high-risk non ischemia-producing lesion happens MLAD), a high-risk non ischemia-producing lesion happens to be found (e.g. a TCFA with PB of 75% in the PLAD) – is to be found (e.g. a TCFA with PB of 75% in the PLAD) – is prophylactic stenting justified? prophylactic stenting justified?

►►No No

1.1. As long as the patient is medically compliant and is As long as the patient is medically compliant and is closely followed, when high-risk lesions become closely followed, when high-risk lesions become symptomatic they usually present with progressive symptomatic they usually present with progressive angina and not death or MI.angina and not death or MI.

►►A randomized controlled trial is required to demonstrate A randomized controlled trial is required to demonstrate the safety and efficacy of prophylactic stenting of non the safety and efficacy of prophylactic stenting of non ischemia-producing lesions before this practice can be ischemia-producing lesions before this practice can be recommended.recommended.

• What if during routine IVUS-guided stenting (e.g. in the What if during routine IVUS-guided stenting (e.g. in the MLAD), a high-risk non ischemia-producing lesion happens MLAD), a high-risk non ischemia-producing lesion happens to be found (e.g. a TCFA with PB of 75% in the PLAD) – is to be found (e.g. a TCFA with PB of 75% in the PLAD) – is prophylactic stenting justified? prophylactic stenting justified?

►►No No

1.1. As long as the patient is medically compliant and is As long as the patient is medically compliant and is closely followed, when high-risk lesions become closely followed, when high-risk lesions become symptomatic they usually present with progressive symptomatic they usually present with progressive angina and not death or MI.angina and not death or MI.

►►A randomized controlled trial is required to demonstrate A randomized controlled trial is required to demonstrate the safety and efficacy of prophylactic stenting of non the safety and efficacy of prophylactic stenting of non ischemia-producing lesions before this practice can be ischemia-producing lesions before this practice can be recommended.recommended.

• So where should our efforts for future investigation be So where should our efforts for future investigation be focused?focused?

• The prognosis for pts with ACS after successful PCI who The prognosis for pts with ACS after successful PCI who are medically compliant is favorable.are medically compliant is favorable.

• However, millions of persons per year who have not been However, millions of persons per year who have not been diagnosed with CAD and are not receiving optimal diagnosed with CAD and are not receiving optimal medical therapy die, arrest or develop MI every year.medical therapy die, arrest or develop MI every year.

►►This suggests that future investigation should focus on This suggests that future investigation should focus on identifying asymptomatic or minimally symptomatic pts identifying asymptomatic or minimally symptomatic pts with large plaque burden, small MLA and TCFAs through with large plaque burden, small MLA and TCFAs through noninvasive screening (e.g. MSCT), for intensive medical noninvasive screening (e.g. MSCT), for intensive medical therapy and possibly invasive imaging and Rx.therapy and possibly invasive imaging and Rx.

• So where should our efforts for future investigation be So where should our efforts for future investigation be focused?focused?

• The prognosis for pts with ACS after successful PCI who The prognosis for pts with ACS after successful PCI who are medically compliant is favorable.are medically compliant is favorable.

• However, millions of persons per year who have not been However, millions of persons per year who have not been diagnosed with CAD and are not receiving optimal diagnosed with CAD and are not receiving optimal medical therapy die, arrest or develop MI every year.medical therapy die, arrest or develop MI every year.

►►This suggests that future investigation should focus on This suggests that future investigation should focus on identifying asymptomatic or minimally symptomatic pts identifying asymptomatic or minimally symptomatic pts with large plaque burden, small MLA and TCFAs through with large plaque burden, small MLA and TCFAs through noninvasive screening (e.g. MSCT), for intensive medical noninvasive screening (e.g. MSCT), for intensive medical therapy and possibly invasive imaging and Rx.therapy and possibly invasive imaging and Rx.


implications from prospect and future directions gregg w. stone, md columbia university medical...

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