PROSPECT

P roviding R egional O bservations to S tudy P redictors of E vents in the C oronary T ree

Implications from PROSPECT and Future Directions

Gregg W. Stone, MD

Columbia University Medical Center The Cardiovascular Research Foundation

PROSPECT

•

Gregg W. Stone



Scientific Advisory Board for an honoraria from Abbott Vascular and Boston Scientific



Research grants from InfraReDx and Volcano

PROSPECT

700 pts with ACS

UA (with ECG Δ) 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

• • • • • •

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 α MMP9 Lp-PLA2 others

PROSPECT

3-vessel imaging post PCI

Culprit artery, followed by non-culprit arteries Angiography (QCA of entire coronary tree) IVUS Virtual histology Palpography (n=~350)

Proximal 6-8 cm of each coronary artery

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 MSCT Substudy N=50-100 Repeat imaging in pts with events

PROSPECT:

MACE (N=697)

25 20 All Culprit lesion (CL) related Non culprit lesion (NCL) related Indeterminate 20.4% 15 12.9% 10 11.6% 5 2.7% 0 0 1 2 3 Time in Years Number at risk ALL CL related NCL related Indeterminate 697 697 697 697 557 590 595 634 506 543 553 604

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

480 518 521 583

Cardiac death Cardiac arrest

PROSPECT: MACE

3-year follow-up, hierarchical

All 1.9% (12) Culprit Non culprit lesion related lesion related Indeter minate 0.2% (1) 0% (0) 1.7% (11) 0.3% (2) 0.3% (2) 0% (0) 0% (0) MI (STEMI or NSTEMI) Composite MACE 2.7% (17) 1.7% (11) Rehospitalization for unstable or progressive angina 15.4% (101) 10.4% (69) 20.4% (132) 12.9% (83) 1.0% (6) 10.7% (68) 0.8% (5) 11.6% (74) 0.2% (1) 2.7% (17) Cardiac death, arrest or MI 4.9% (31) Rates are 3-yr Kaplan-Meier estimates (n of events) 2.2% (14) 1.0% (6) 1.9% (12)

Cardiac death Cardiac arrest

PROSPECT: MACE

3-year follow-up, hierarchical

All 1.9% (12) Culprit Non culprit lesion related lesion related Indeter minate 0.2% (1) 0% (0) 1.7% (11) 0.3% (2) 0.3% (2) 0% (0) 0% (0) MI (STEMI or NSTEMI) Composite MACE 2.7% (17) 1.7% (11) Rehospitalization for unstable or progressive angina 15.4% (101) 10.4% (69) 20.4% (132) 12.9% (83) 1.0% (6) 10.7% (68) 0.8% (5) 11.6% (74) 0.2% (1) 2.7% (17) Cardiac death, arrest or MI 4.9% (31) Rates are 3-yr Kaplan-Meier estimates (n of events) 2.2% (14) 1.0% (6) 1.9% (12)

PROSPECT: Multivariable Correlates of Non-Culprit Lesion Related Events

Independent predictors of patient level events by Cox Proportional Hazards regression

Variable HR [95% CI] P value Insulin dependent diabetes 3.32 [1.43, 7.72] Prior PCI 2.03 [1.15, 3.59] 0.005

0.02

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

PROSPECT: Multivariable Correlates of Non-Culprit Lesion Related Events

Independent predictors of lesion level events by Cox Proportional Hazards regression

HR [95% CI] P value Variable PB MLA ≥70% VH-TCFA MLA ≤4.0 mm 2 5.03 [2.51, 10.11] 3.35 [1.77, 6.36] 3.21 [1.61, 6.42] <0.0001

0.0002

0.001

Variables entered: 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, insulin-requiring diabetes and prior percutaneous coronary intervention

PROSPECT: Correlates of Non-Culprit Lesion Related Events

Number of factors present: PB MLA ≥70%, MLA ≤4.0mm

2 or TCFA 20 15 10 5 0.3

0

Zero

5/1650 PB = plaque burden at the MLA 4.8

One

46/1059 10.5

Two

24/253 18.2

Three

5/29

PROSPECT: VH-TCFA and Non Culprit Lesion Related Events

Lesion HR P value Prevalence* 3.90 (2.25, 6.76) <0.0001 46.7% 6.55 (3.43, 12.51) <0.0001

15.9% 10.83 (5.55, 21.10) <0.0001

10.1% 11.05 (4.39, 27.82) <0.0001

*Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA 4.2%

PROSPECT: Thick CFA and Non Culprit Lesion Related Events

Lesion HR P value Prevalence* 0.92 (0.52, 1.63) 0.77

67.6% 3.41 (1.75, 6.65) 0.0003

22.7% 5.17 (2.59, 10.32) <0.0001

15.6% 5.02 (1.99, 12.63) <0.0001

*Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA 8.3%

PROSPECT: Non Fibroatheromas and Non-Culprit Lesion Events

Pathological Intimal thickening Fibrotic Fibrocalcific Lesion HR P value Prevalence* 0.22 (0.10, 0.49) 0.0002 67.9% 1.22 (0.44, 3.39) 0.70

19.7% 1.25 (0.17, 9.01) 0.83

5.6% 2.60 (0.36, 18.84) *Likelihood of one or more such lesions being present per patient. PB = plaque burden at the MLA 0.34

2.7%

PROSPECT:

Questions

Was 3-vessel VH-IVUS imaging safe?

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) Any imaging complication* *Some pts had more than one complication 0 (0%) 3 (0.4%) 1 2 10 (1.4%) 1 2 9 11 (1.6%)

PROSPECT:

Questions

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

By angiography 1,814 untreated lesions (visual DS >30%) in the entire coronary tree - mean 2.6 ± 1.8 per pt By IVUS (n=673) 3,160 untreated lesions (PB ≥40%) in the proximal to-mid coronary tree - mean 4.7 ± 2.0 per pt -

QCA DS%

DS <50% N=1704 (93.9%) DS ≥50%-<70% N=98 (5.4%) DS ≥70% N=12 (0.7%)

DS% mean 33.7 ± 15.7%

25 20 19,6 mean 0.9 ± 1.1 per pt 15 10 5 9,0 N=283 mean 0.4 ± 0.7

per pt N=620 0 MLA ≤4.0mm2

Plaque burden ≥70%

PROSPECT:

Questions

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

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

TCFA N=596 (21.9%) ThCFA N=1018 (37.3%) 0.98

±

1.31 per pt (range 0 – 7 per pt) Fibrotic N=104 (3.8%) Fibrocalcific N=33 (1.2%) PIT N=1008 (37.0%)

PROSPECT:

Questions

What were the baseline angiographic characteristics of the 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). Baseline QCA %DS Lesion location 32 lesions (30.2%) were angiographically inconspicuous (<30% stenotic) by visual assessment) Prox Mid Distal Branch 24.3% 19.6% 15.9% 40.2%

PROSPECT:

Questions

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

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.

51 non-culprit MACE lesions with baseline VH-IVUS

TCFAs N=26 (51%) PB ≥70% and/or MLA ≤4.0mm

2 N=18 (35%) TCFA only N=8 (16%) Not TCFAs N=25 (49%)

18 ThCFA 6 PIT 1 FC 0 F

PB ≥70% and/or MLA ≤4.0mm

2 N=20 (39%) Not TCFA only N=5 (10%)

PROSPECT:

Questions

What types of events were responsible for CULPRIT lesion MACE during follow-up?

• Stent thrombosis (n=13 lesions) • Restenosis (n=107 lesions) • New stent-related sidebranch lesions (n=5 lesions) Baseline grayscale and VH-IVUS will be analyzed for correlates of future events Possible predictors of stent thrombosis Totally covered FA FA behind stent FA behind stent, abutting into lumen Partially uncovered FA Separate untreated adjacent FA

PROSPECT: Implications

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

►No 1.

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

2.

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

3.

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

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

PROSPECT: Implications

• What if during routine IVUS-guided stenting (e.g. in the MLAD), a high-risk non ischemia-producing lesion happens to be found (e.g. a TCFA with PB of 75% in the PLAD) – is prophylactic stenting justified? ►No 1.

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

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

PROSPECT: Implications

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

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

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

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