Carlo Di Mario Professore Ordinario di Cardiologia

AOU Careggi, Firenze

Imaging Coronarico Invasivo nella Prevenzione Cardiovascolare

DISCLOSURE INFORMATION

• Carlo Di Mario

negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario:

Relatore: Philips-Volcano, Abbott, Astra-Zeneca

Grant all’ospedale: Abbott, Medtronic, Edwards, Shockwave

1988-2017: 30 Years working with IVUS Erasmus University, Rotterdam, NL

Intracoronary Imaging

Histopathologic Determinants of Plaque Vulnerability

Narula J et al. Nat Clin Pract Cardiovasc Med 2008

1

2

3

4 5

My First OCT Images @RBH in 2004

1. 0.019” MicroOptic imaging

core (light source (wavelength

1310nm) and measures the

backscatter of light)

2. OTW occlusion balloon

catheter ( 2.7 Fr, balloon

inflated to 5 mm with low

pressure –0.3-0.5 Atm-) with

infusion of Ringer lactate max

0.5 – 1.0 ml/sec

Incidental findings, 73 yo man, 9 months post stenting, with 2 weeks crescendo angina

OCT

Barlis, .., Di Mario: JACC Imaging

IVUS OCT

MLD 4.1mm; MLA 11.6mm2 MLD 3.8mm; MLA 11.1 mm2

38

1. ThCFA

*OM

5.3 mm2

Lesion prox

Baseline PLCX

QCA: RVD 2.82 mm, DS 28.6%, length 6.8 mm

IVUS: MLA 5.3 mm2

VH: ThCFA

700 pts with ACS UA (with ECGΔ) or NSTEMI or STEMI >24 hrs undergoing PCI of 1 or 2 major coronary arteries at

40 sites in the U.S. and Europe

PROSPECT 2011

PROSPECT: MACE M

AC

E (%

)

Time in Years 0 1 2 3

All Culprit lesion (CL) related

Non culprit lesion (NCL) related Indeterminate

0

5

10

15

20

25

Number at risk

20.4%

12.9%

11.6%

2.7%

13.2%

7.9%

6.4%

0.9%

18.1%

11.4%

9.4%

1.9%

ALL 697 557 506 480

CL related 697 590 543 518

NCL related 697 595 553 521

Indeterminate 697 634 604 583

Stone GW et al. NEJM 2011;364:226-35

PROSPECT: Correlates of Non Culprit Lesion Related Events at 3 Years F-Up

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

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

PROSPECT Case Example

MLA 4.0 mm2; plaque burden 72%; TCFA

PROSPECT: NCL events arising from

stenoses with PB ≥70%

Prevalence* 10.1% 15.6% 5.6%

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

HR (95%CI) = 10.83 (5.55, 21.10)

P<0.0001

HR (95%CI) = 5.17 (2.59, 10.32)

P<0.0001

HR (95%CI) = 1.25 (0.17, 9.01)

P=0.83

Thin-cap fibroatheroma

Thick-cap fibroatheroma

Fibrocalcific Fibrotic

Pathologic intimal thickening

VIVA 2011

ATHEROREMO-IVUS 2014

Plaque with >40%CSA St and focal necrotic rich core >10% CSA in contact with lumen

From Rodrigues-Granillo, Serruys et al JACC 2005

Virtual Histology

Multiple components Variable scattering properties

Complex mixture spectra

÷

Low scatter

Medium scatter

High scatter

ms

l l l

ms

ms

Chemometric Algorithms

Algorithms extract the relevant portions of the mixture signal and create a probability map of lipid core plaque

NIRS Principle of Operation

Adapted from Bourantas, et al. JACC 2013;16(13):1369

Combined IVUS and NIRS Catheter

NIRS-IVUS with Histology

• Left • High plaque burden, calcium

shadowing and signal dropout on IVUS, but no lipid core plaque by NIRS

• Histology confirms calcified fibrous plaque

• Center • High plaque burden, calcium

shadowing and signal dropout on IVUS, and substantial lipid core plaque by NIRS

• Histology confirms large lipid core plaque

• Right • No plaque burden on IVUS and no

lipid core plaque by NIRS • Histology confirms normal vessel

Initial Angio

3

25

16

44 12

33

50

46

*

*

*

*

*

*

*

*

20

TIMI 3 Flow NIRS Initial Angio TIMI 3 Flow NIRS

STEMI culprit vs. non-culprit segments

STEMI culprit lesions:

maxLCBI4mm = 612 (438-817)

Non-STEMI lesions:

maxLCBI4mm = 78 (0-234)

MaxLCBI4mm >400 was present

at the STEMI culprit site in

63 of the 78 cases

MaxLCBI4mm >400 was present

at the non-culprit site in

22 of the 304 segments

Mann-Whitney U test

Median ± interquartile

range

Culprit Non-culprit0

100

200

300

400

500

600

700

800

900

1000

ma

xL

CB

I

p = < 0.0001

In the cohort of 70 post PCI patients, only 4 had maxLCBI4mm >600 in non-stented area.

Stent placed in STEMI culprit

New culprit at vulnerable plaque site

Unstable Angina at 7 months

Intravascular Imaging in Secondary Prevention

Hypercholesterolemic rabbit aorta TCFAs

Adapted from Moreno PR. Cardiol Clin 2010;28:1-30

Stent

Neointima New Fibrous

Cap Thickness

Old Fibrous Cap Thickness

Lipid Core Strut

Adapted from Moreno PR. Cardiol Clin 2010;28:1-30

Hypercholesterolemic rabbit aorta TCFAs

Everolimus Strut Beta-Estradiol Strut

Metallic & Polymer Strut De Novo TCFA

De Novo Lsns and Stents Deployed on TCFAs Adapted from Moreno PR.

Cardiol Clin 2010;28:1-30

Everolimus Induced Autophagy of Macrophages

Verheye S et al. JACC 2007;49:706-15

EES and polymer only coated metallic stents implanted in atherosclerotic arteries of cholesterol-fed rabbits

EES resulted in marked

reduction of macrophage content, with

preservation of SMC content

Str

ut

cir

cu

mfe

ren

ce

su

rro

un

de

d b

y

ma

cro

ph

ag

es

of

SM

C (

%)

*** 0

20

40

60 Polymer control

Everolimus

MI SMC

RA

M-1

1 p

os

itiv

e a

rea

s

in p

laq

ue

(1

03 µ

m3)

*

0

20

40

100

Polymer

control

Evero- limus

60

80

Non- stented

RAM-11 stain; brown = macrophages

Polymer-coated stent Everolimus-eluting stent

Bioresorbable Vascular Scaffolds (BRS)

Igaki-Tamai PLLA

Magnesium

(eluting paclitaxel) Biotronik Biosolve

PLLA (w/PDLLA

coat eluting

everolimus)

Abbott ABSORB

Reva ReSolve Iodinated tyrosine-

derivative (eluting

sirolimus)

Elixir DESolve PPLLA (eluting

novolimus)

A B C D

A B C D

A B

C D

Lipid Rich Plaque Eccentric Plaque in a 39 Yrs Old Pt

A B C

D

A

B

D C

D C

A

B

After 3.5 x 23 mm Everolimus Eluting Bioabsorbable Stent Expanded to 4.0 at 24 Atm

PROSPECT II Study

PROSPECT ABSORB RCT

900 pts with ACS after successful PCI

3 vessel IVUS + NIRS (blinded)

≥1 IVUS lesion with ≥70% plaque burden present?

Routine angio/3V IVUS-NIRS FU at 2 years

Yes (N=300)

No (n=600)

ABSORB BVS + GDMT (N~150)

GDMT (N=150)

R 1:1

Clinical FU for MACE for ≥3 years

Co-Pis Dr. Gregg Stone Dr. David Erlinge

The Lipid Rich Plaque (LRP) Study Dr. Ron Waksman, PI

PI, Japan, Dr. Takeshi Akasaka Co-PI, Japan, Dr. Yasunori Ueda

PI, Europe, Dr. Carlo Di Mario

9,000 PCI patients with ACS or SA will undergo NIRS-IVUS imaging of 2 or more vessels

3,000 with Max 4 mm LCBI >250 for 100% FU

6,000 with Max 4 mm LCBI ≤ 250 for 50% FU

2 year MACE from a new lesion at patient and coronary segment level

1400 patients enrolled; F-up expected to be completed end 2017

European Heart Journal (2016) 37, 1883–1890

Lifestyle Changes

Intravascular Imaging in Primary Prevention

Di Mario C. , European Heart Journal (2016) 37, 1883–1890

What About Primary Prevention? From Primary to Secondary via CT

9 months 82 NSTE ACS Total Atheroma V/ FCT by OCT IVUS

Total Atheroma V/ FCT by OCT IVUS

AUTHOR / JOURNAL YEAR AIM No. PTS INTERVENTION Follow-up AT CHANGES OBSERVED

Takarada et al.

Atherosclerosis 2009

to determine whether

lipidlowering

therapy with statins could

increase the fibrous-cap

thickness of coronary

plaques

40 patients with AMI Statin use

RETROSPECTIVE 9 months

Although the

fibrous-cap thickness was

significantly increased in

both the statin treatment

group (151±110 to

280±120_m, p < 0.01) and

the control group (153±116

to 179±124_m, p < 0.01),

the degree of increase was

significantly greater in the

statin treatment

group than in the control

group (188±64% vs.

117±39%, p < 0.01).

Takarada et al.

JACC Cardiovasc

Interventions.

2010

to determine the

relationship between the

morphological changes of

nonculprit lipid-rich

plaques

82 patients with

NSTEACS - 9 months

FCT increased significantly

(95± 32 µm to 112 ± 45

µm,p = 0.05).

Statin use was an

independent predictor FCT

increase.

Uemura et al.

European Heart Journal 2012

to clarify the

morphological

characteristics of NSCPs in

patients with

CAD

53 patients (69

plaques) - 6-9 months

Compared with NSCPs

without progression, those

with progression showed a

significantly higher incidence

of intimal laceration,

microchannel, lipid pools ,

TCFA, macrophage images,

and intraluminal thrombi .

Hattori et al.

JACC Cardiovasc Imaging. 2012

to comprehensively assess

the impact of pitavastatin

on plaque characteristics

using a combination of

OCT, grayscale and IB-IVUS

42 patients with SAP 4 mg pitavastatin (26

patients) 9 months

A significant increase in FCT

(140 ± 42 μm, 189 ± 46

μm; p = 0.001) in statin arm.

Such changes were not

observed in the diet-only

group (140 ± 35 μm, 142 ±

36 μm; p = NS).

OCT Studies dealing with progression/changes unstable plaques over time

A significant increase in FCT (140 ± 42 μm, 189 ± 46 μm; p = 0.001) in statin arm. Such changes were not observed in the diet-only group (140 ± 35 μm, 142 ± 36 μm; p = NS

2628 screened patients 1276 enrolled patients 970 randomized patients

evolocumab 420 mg administered monthly via subcutaneous injection for 76 weeks

JAMA 2016, (Epub ahead of print)

Nicholls et al. JAMA 2016, (Epub ahead of print)

Is It Reasonable to Apply Conventional Prevention Measures if CV Risk is 30% at 1 Year?

Fight to achieve lowest possible cholesterol, best diabetic control, true normalisation body weight, appropriate 24 hour BP reduction

Have low threshold to apply “unconventional” prevention measures: strongest maximal doses statins +/- ezitimibe, PCSK9 inhibitors, apheresis, modern antidiabetics +/- bariatric surgery

If bleeding risk low and previous history ACS/IC images showing vulnerable plaque, long term (>1 year) double antiplatelet therapy

Enrol them into a strict follow-up program to monitor results

Have low threshold to repeat non-invasive/invasive tests to monitor progression

Stent if lesion is functionally critical (irrespective of symptoms)

Stent irrespective of presence of flow reduction if ongoing trials show advantage