Davide Capodanno, MD, PhD - oic.it · Catania, Italy Prognostic Role of In-Stent Restenosis Cassese...

Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 1

Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele

Catania, Italy

Davide Capodanno, MD, PhDAssociate Professor, University of Catania, Italy

V Simposio - 28 Novembre 2014 – 4.30PM-4.45PM

L’incubo del paziente e le incognite del cardiologo:la restenosi intrastent resta un problema

fisiopatologico ancora irrisolto?

Autumn in Lucca



Catania, Italy

Utilization of Stent Type and In-Stent Restenosis

Cassese S. et al. Heart. 2014;100:153-9

10,004 PCI patients with follow-up angiography from the DHZ Restenosis registry

First Generation

DES

SecondGeneration

DES

First Generation DES: 8/2002-12/2005

Second Generation DES: from 1/2006

Restenosis



Catania, Italy

Prognostic Role of In-Stent Restenosis

Cassese S. et al. Eur Heart J. 2014 [Epub ahead of print]

10,004 PCI patients with follow-up angiography from the DHZ Restenosis registry (26.4% ISR)

The impact of restenosis was confirmed in asymptomatic patients undergoing routine

control angiography. Mortality was not impacted by the decision to perform TVR

Predictors of 4-year mortality HR 95% CI P value

Restenosis at routine control angiography 1.23 1.03-1.46 0.02

Age (for each 10-year increase) 2.34 2.12-2.60 <0.001

Diabetes mellitus 1.68 1.41-1.99 <0.001

Current smoking habit 1.39 1.09-1.76 0.01

Left ventricular ejection fraction (for each 5% decrease) 1.39 1.31-1.48 <0.001

Female gender 0.73 0.60-0.88 <0.001



Catania, Italy

Restenosis: Angiographic Definition

Mehran R, et al. Circulation. 1999;100:1872-1878

Restenosis

“Recurrent diameter

stenosis >50% at

the stent segment

or its edges (5-mm

segments adjacent

to the stent)”



Catania, Italy

OCT: New Avenues for Tissue Characterization

Alfonso F, et al. J Am Coll Cardiol. 2014;63:2659-73

Homogeneous

bright neointimal

proliferation

Uniform neointimal

proliferation with

microvessels

Layered pattern

with multiple

microvessels in the

dark layer overlying

the stent struts

Multilayered pattern



Catania, Italy

BMS-ISR and DES-ISR: Different Entities?

Joner M, CVPath Inc., Gaithersburg, Maryland

Magnification images of restenosis within BMS and a DES, both implanted 5 years antemortem

BMS DES

smooth muscle

cell-rich neointimal

hyperplasia

chronic

inflammation with

neovascularization

around stent struts

neoatherosclerosis

with formation of a

necrotic core

neoatherosclerosis

with calcification



Catania, Italy

Features of Restenotic Tissue in BMS and DES


BMS restenosis DES restenosis

Imaging features

Angiographic morphology Diffuse pattern more common Focal pattern more common

OCT tissue propertiesHomogeneous, high-signal band

most commonLayered structure or

heterogeneous most common

Time course of late luminal loss Late loss maximal by 6-8 months Ongoing late loss out to 5 years

Histopathological features

Smooth muscle cellularity Rich Hypocellular

Proteoglycan content Moderate High

Peri-strut fibrin and inflammation Occasional Frequent

Complete endothelialization 3-6 months Up to 48 months

Thrombus present Occasional Occasional

Neoatherosclerosis Relatively infrequent, late Relatively frequent, accelerated



Catania, Italy

Underlying Mechanisms of Restenosis

1. Stent underexpansion

• Underdeployment due to undersizing

• Underlying heavily calcified lesion

2. Geographical missing (“candy wrapper” restenosis)

• Stent misplacement

• Stents not fully covering the underlying lesion

3. Stent fracture

4. Drug resistance and local hypersensitivity reactions




Catania, Italy

Management Strategies for ISR

Conventional balloon

angioplasty

Cutting

and scoring balloon

therapy

Debulking

techniques

Vascular

BrachiterapyRepeat Stenting

Drug-coated balloon

angioplasty



Catania, Italy



angioplasty

Cutting

and scoring balloon

therapy

Debulking

techniques

Vascular


Drug-coated balloon

angioplasty



Catania, Italy

Plain Old Balloon Angioplasty (POBA)

1. Technically straigthforward

2. Satisfactory acute results, particularly in focal patterns, but

high long-term restenosis rates

3. Technique

• Review the index procedure• Favors noncompliant balloons to avoid “dog bone” effects, with a

1.1:1 balloon-to-artery ratio. • Target the narrowing rather than the entire stented segment• Avoid balloon slippage outside the stent (“watermelon seeding”

phenomenon)

4. Outdated



Catania, Italy



angioplasty

Cutting

and scoring balloon

therapy

Debulking

techniques

Vascular


Drug-coated balloon

angioplasty



Catania, Italy

Cutting balloon

Standard balloon catheter with lateral blades

•Offers protection against “watermelon

seeding”, anchoring the balloon within

the target lesion, preventing balloon

slippage–related problems

•Deeply incises neointimal tissue and,

at least theoretically, may favor

subsequent extrusion

•Superior than POBA in reducing

slippage and need for unplanned stent

implantation (RESCUT trial)



Catania, Italy

Scoring balloon (Angiosculpt)

Takano et al. Int J Cardiol. 2010;141:51-3

Nitinol scoring element with three spiral struts that wrap around the balloon

OCT Image ISR Lesion Prior- and Post-

AngioSculpt demonstrating scoring



Catania, Italy

NCT01632371

N=250 Patients undergoing DCB

angioplasty of DES-ISR

Scoring ballon + DCB DCB alone

Primary Endpoint

In-segment percent diameter stenosis

at 6-8 months follow-up angiography

R1:1

Estimated Study Completion Date: December 2015

Scoring ballons in DES-ISR treated with DCBISAR-DESIRE 4



Catania, Italy



angioplasty

Cutting

and scoring balloon

therapy

Debulking

techniques

Vascular


Drug-coated balloon

angioplasty



Catania, Italy

Debulking Techniques

1 Mehran R, et al. Circulation 2000;101:2484–92 Von Dahl J, et al. Circulation 2002;105:583–8

Excimer Laser

Showed good results in selected cases

but eventually proved to have poorer

ablation capability compared with

rotational atherectomy1

Rotational atherectomy

Failed to show benefit compared with

balloon angioplasty alone in BMS-ISR

(ARTIST trial). May still be required as a

bailout strategy in patients with

undilatable ISR lesions2



Catania, Italy



angioplasty

Cutting

and scoring balloon

therapy

Debulking

techniques

Vascular


Drug-coated balloon

angioplasty



Catania, Italy

Brachytherapy versus DES for BMS-ISR

Holmes Dr Jr et al, JAMA 2006;295:1264–73Stone GW, et al, JAMA 2006;295:1253–63

SIRS: 384 patients with BMS-ISR 2:1 randomized to vascular brachytherapy or SES

TAXUS V ISR: 396 patients with BMS-ISR 1:1 randomized to vascular brachytherapy or PES

Angiographic restenosis at Follow-up

P=0.07 P<0.001



Catania, Italy



angioplasty

Cutting

and scoring balloon

therapy

Debulking

techniques

Vascular


Drug-coated balloon

angioplasty



Catania, Italy

POBA versus BMS for BMS-ISR

Alfonso F, et al. J Am Coll Cardiol 2003;42:796–805

RIBS: 450 patients with BMS-ISR randomized to POBA or “sandwich” BMS

Stent(N=224)

POBA(N=226)

P value

After the procedure

Minimal lumen diameter (mm) 2.77±0.4 2.25±0.5 <0.001

Stenosis (% of lumen diameter) 12±10 23±10 <0.001

Acute gain (mm) 2.08±0.5 1.58±0.5 <0.001

After the procedure (“in-lesion”)

Minimal lumen diameter (mm) 1.69±0.8 1.54±0.7 0.046

Stenosis (% of lumen diameter) 43±24 45±23 0.31

Restenosis (%) 33% 38% 0.36

Late loss (mm) 1.06±0.7 0.72±0.7 <0.001

In patients with large vessels (≥3 mm) and restenosis located at the stent edge,

stenting exhibited better results



Catania, Italy

POBA versus DES for BMS-ISR

Kastrati A, et al. JAMA 2005;293:165–71Alfonso F. J. Am Coll Cardiol 2006;47:2152-60

P<0.0001

P=0.03

ISAR-DESIRE: 300 patients with BMS-ISR randomized to POBA, SES or PES

RIBS 2: 150 patients with BMS-ISR randomized to POBA or PES

Target vessel revascularization at 9 months



Catania, Italy

Same DES versus “Switch DES” for DES-ISR

Mehilli J. Et al. J Am Coll Cardiol 2010;55:2710–6

ISAR-DESIRE 2: 450 patients with SES-ISR randomized to SES or PES

P=0.69

P=0.52



Catania, Italy

Bioresorbable Scaffolds for DES-ISR?

Alfonso F, et al. J Am Coll Cardiol 2014;63:2875

RationaleThe device should eventually

disappear from the vessel wall,

avoiding the presence of multiple

stent layers (“onion skin”)

Unkowns•Lumen crowding due to strut

thickness

•Device flexibility that may affect

access to restenotic lesions

•Questions regarding radial

strength and recoil



Catania, Italy



angioplasty

Cutting

and scoring balloon

therapy

Debulking

techniques

Vascular


Drug-coated balloon

angioplasty



Catania, Italy

DCB versus EES for BMS-ISR

Alfonso F., et al. J Am Coll Cardiol 2014;63:1378–86

RIBS V: 189 patients with BMS-ISR randomized to DCB or EES

Minimum Lumen Diameter at Follow-up

P<0.0001 P<0.0001

Binary restenosis and clinical events at 1 year were low and similar in both groups



Catania, Italy

DCB versus PES versus POBA for DES-ISR

Byrne RA, et al. Lancet 2013;381:461–7

ISAR DESIRE 3: 402 patients with BMS-ISR randomized to DCB or EES

Diameter Stenosis at Follow-up Angiography (%)

Cum

ula

tive F

requency (

%)

0 20 40 60 80 100

0

20

40

60

80

100

Balloon Angioplasty (BA)

Paclitaxel-Eluting Balloon (PEB)Paclitaxel-Eluting Stent (PES)

PEB versus PESPnon-inferiority =0.007

PEB versus BAPES versus BAPsuperiority <0.001

PEB 38.0%

PES 37.4%

BA 54.1%



Catania, Italy

DCB versus EES for DES-ISR

Alfonso F., et al. TCT 2014, Washington DC

RIBS IV: 189 patients with BMS-ISR randomized to DCB or EES

Minimum Lumen Diameter at Follow-up

EES also provided better late clinical results, driven by a significant reduction in TLR

P=0.004 P<0.001



Catania, Italy

2014 ESC/EACTS Guidelines on myocardial revascularization

Windecker et al. Euro Heart J 2014 [Ahead of print]

Repeat PCI is recommended, if technically feasible. I C

DES are recommended for the treatment of in-stent re-stenosis (within BMS or DES).

I A

Drug-coated balloons are recommended for the treatment of in-stent restenosis (within BMS or DES).

I A

IVUS and/or OCT should be considered to detect stent-related mechanical problems.

IIa C

Management of restenosis



Catania, Italy

Closing Remarks / 1

1. Although the advent of DES has reduced the incidence of ISR, treatment of this clinical entity remains a prevailing

clinical problem.

2. The substrate of ISR encompasses a pathological spectrum

ranging from smooth muscle cell proliferation to

neoatherosclerosis.

3. Intracoronary imaging provides unique insights into the

underlying etiology of ISR, but its role in optimizing the clinical results of these reinterventions still remains

unsettled.



Catania, Italy

Closing Remarks / 2

4. Among currently available therapeutic modalities, DES and DCB provide the best clinical and angiographic results in

patients with ISR

• In a fast-evolving field, second generation DES were recently found to be better than DCB for DES-ISR in RIBS IV

• DCB may be preferred over DES in patients with ISR and multiple metal layers, in those with large side branches, and in those at high bleeding risk undergoing prolonged dual antiplatelet therapy.

5. CABG should be considered for “frequent flyers” patients, although this will usually be dictated by the prognostic

relevance of the restenotic lesion.

[email protected]

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Davide Capodanno, MD, PhD - oic.it · Catania, Italy Prognostic Role of In-Stent Restenosis Cassese...

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