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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 2
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 3
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 4
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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)”
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 5
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 6
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 7
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Features of Restenotic Tissue in BMS and DES
Alfonso F, et al. J Am Coll Cardiol. 2014;63:2659-73
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 8
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Alfonso F, et al. J Am Coll Cardiol. 2014;63:2659-73
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 9
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Management Strategies for ISR
Conventional balloon
angioplasty
Cutting
and scoring balloon
therapy
Debulking
techniques
Vascular
BrachiterapyRepeat Stenting
Drug-coated balloon
angioplasty
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 10
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Management Strategies for ISR
Conventional balloon
angioplasty
Cutting
and scoring balloon
therapy
Debulking
techniques
Vascular
BrachiterapyRepeat Stenting
Drug-coated balloon
angioplasty
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 11
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 12
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Management Strategies for ISR
Conventional balloon
angioplasty
Cutting
and scoring balloon
therapy
Debulking
techniques
Vascular
BrachiterapyRepeat Stenting
Drug-coated balloon
angioplasty
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 13
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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)
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 14
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 15
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 16
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Management Strategies for ISR
Conventional balloon
angioplasty
Cutting
and scoring balloon
therapy
Debulking
techniques
Vascular
BrachiterapyRepeat Stenting
Drug-coated balloon
angioplasty
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 17
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 18
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Management Strategies for ISR
Conventional balloon
angioplasty
Cutting
and scoring balloon
therapy
Debulking
techniques
Vascular
BrachiterapyRepeat Stenting
Drug-coated balloon
angioplasty
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 19
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 20
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Management Strategies for ISR
Conventional balloon
angioplasty
Cutting
and scoring balloon
therapy
Debulking
techniques
Vascular
BrachiterapyRepeat Stenting
Drug-coated balloon
angioplasty
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 21
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 22
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 23
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 24
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 25
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
Catania, Italy
Management Strategies for ISR
Conventional balloon
angioplasty
Cutting
and scoring balloon
therapy
Debulking
techniques
Vascular
BrachiterapyRepeat Stenting
Drug-coated balloon
angioplasty
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 26
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 27
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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%
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 28
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 29
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 30
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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.
Restenosis - Capodanno CardioLucca, November 28, 2014 – Slide 31
Ferrarotto HospitalAOU Policlinico-Vittorio Emanuele
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.