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: 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%
*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
*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: 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
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 -
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?
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)
PROSPECT: PROSPECT: QuestionsQuestions
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%
PROSPECT: PROSPECT: QuestionsQuestions
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.
PROSPECT:PROSPECT: Implications Implications
• 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.
PROSPECT:PROSPECT: Implications Implications