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Avances en Cardiología IntervencionistaSección de Hemodinámica y Cardiología Intervencionista.
Tratamiento de la Reestenosis Intra-Stent:
Cual es el Mejor Tratamiento?
Fernando Alfonso Hospital Universitario de La Princesa
UAM. Madrid.
Cursos Casa del CorazónSEC
Jueves 17 Septiembre 2015
Restenosis “Activity”
Baz A, et al. Rev Esp Cardiol 2008;61:1298-314
2007 Official Spanish Registry(Working Group on Hemodynamics and Coronary Interventions)
60,457 Procedures(94.5%) De Novo
3,277 (5.5%)Restenosis
En el 2012 la reestenosis representó el 4,9% de los casos (el 5% en 2011 y el 5,3% en 2010), y se aprecia
una tendencia a la disminución.
DES Restenosis Neointimal Proliferation
Predominant Mechanism Neointimal hyperplasia (SMC)
Curfman GDN. Egl J Med 2007;356(10):1059-60.
Neoatherogenesis
Fibroatheroma. Lipid-laden Macrophages, calcium (Necrotic Core)
DES 30%, Earlier than BMS Young, Unstable, Time, DES
Nakazawa G, Virmani R. J Am Coll Cardiol 2011;57:1314–22
112 (9.5%)
ISR: Clinical Presentation
Chen M, et al. Am Heart J 2006;151:1260-1264
1,186 Patients BMS ISR
313 (26.4%) 761 (64.1%)
MI UA
SA
Treatment of DES ISR:
Pattern I: 19%Pattern II: 34%Pattern III: 50%Pattern IV: 83%
TLR 1 Y
Mehran R, Circulation. 1999;100:1872-1878.)
DES Fracture DES Gap Geographic Miss Uneven/Undelivered Drug
Non-uniform Strut Distribution DES Damage
DES Underexpansion (***) Hypersensitivity Drug Resistance
Biological Factors
Focal
Diffuse
Mechanical Factors
IVUS / OCT
Treatment of DES ISR:
Medical Management (including oral antiproliferative agents)
Repeated PCI: Balloon angioplasty (BA) Non-compliant balloons Cutting /Scoring balloons (CB) Drug-Eluting Ballons (DEB) Brachytherapy (VBT) Rotational atherectomy / Laser Bare-Metal Stents (BMS) Drug-Eluting Stents (DES)
Homo-DES Hetero-DES (Switch)
Coronary Surgery
Treatment of ISR:
IVUS Severe Underexpansion
AMLA & EEL
B “Sand Glass”
DES Restenosis
Calcified DES ISRA
+ +
+
+
+
+
B
C
D
E*
*
*
Alfonso F. Calcified In-Stent Restenosis : A Rare Cause of Dilation Failure Requiring Rotational Atherectomy. Circ Cardiovasc Interv 2012;5;e1-e2.
Calcified DES ISR
++
+
*
A B
C
Alfonso F. Calcified In-Stent Restenosis : A Rare Cause of Dilation Failure Requiring Rotational Atherectomy. Circ Cardiovasc Interv 2012;5;e1-e2.
Treatment of In-Stent RestenosisBalloon Angioplasty
Alfonso F, et al Am J Cardiol 1999;83:1268-70
RIBS: 125BD: 5114
MLD: QCA
1.1 mm
Intravascular UltrasoundImmediate Recoil After Ballon PTCA for ISR
3.0x12 Bar2 mm
20’1,4 mm
Angiographic Results: MLD
%100
80
60
40
20
00 0.5 1.0 1.5 2.0 2.5 3.0 3.5
MLD (mm)
baseline
PTCAROTA
post interv.6 month
RE51%65%
% Stenosis Post 1y TVR
In-ST RE "The Great Equalizer"
Malhotra S et al, JACC 1999:62A.
821 Pts In-ST-RE Washington Hospital Center
ANOVA * p<0.05
2117
22
10
2731
2327
PTCA 314 ELCA 250 RA 126 ST 13105
101520253035
(%)
*
Baseline Demographics Similar Among Groups
Holmes DR, et al. JAMA 2006;295;1264-73
SES vs Brachytherapy
TVF = Cardiac Death, MI, TVR at 9 Mo
(%)
*
Primary End Point: Target Vessel Failure (TVF) : (RR 1.7, 95%CI 1.1 – 2.8)
12,4
21,6
0
5
10
15
20
25
SES
VBT
p<0.05*
MLD FU: 1.8+0.6 vs 1.52+0.6 mm, p<0.001
SISR (Sirolimus-Eluting Stent for In-Stent Restenosis Trial). 384 Pts (125 Brachy, 259 SES)
10 Pre-Specified Variables:RIBS
RR (95% CI)ST Better BA Better
Restenosis
Age >65y
Female
Diabetes
UA
Time RE (> 6Mo)
LAD
RE Length (>10mm)
ST # 1 Coil
B/A > 1.10.1 1Log RR
0.55 (0.35-0.85)p=0.007
4 Pts treated prevent 1 RE
Vessel QCA (> 3mm)
450 P with ISR
RIBS
“WMS” 42 P (9%)
No WMS 408 P (91%) “WMS” on “Complications” at the
(Case Report Form). Detailed “Drawings” required.
Material scrutinized. Detailed Analysis of every balloon
inflation (all filmed by protocol requirement).
Centralized Review at the angiographic “Core-Lab”.
“Watermelon Seeding” Phenomenon
More severe and diffuse ISR More inflations & longer time Never during “stent deployment” Cross-over or residual dissections Poorer Acute and Long-term
Angiographic Results
1 2 3
Gomez-Recio M, New Orleans ACC 2004
RESCUT
25
7
0
5
10
15
20
25
30
Slippage (%)
BA CBA* p<0.05
*31 30
0
5
10
15
20
25
30
35(%)
Restenosis(%)
1516
02468
1012141618
MACE
MACE: Death, MI, TLRAlbiero R, et al. J Am Coll Cardiol 2004;43:943-949
Restenosis Cutting Balloon Evaluation Trial
450 P with ISR
RIBS
“EDG” ISR 52 P (12%)
No EDG ISR 398 P (88%) “EDG” ISR “Predefined” by
protocol (Case Report Form). “Detailed Drawings” required.
ISR RIBS (>3 mm or >25% RE length: intra-ST).
Centralized Review at the angiographic “Core-Lab”.
“EDG” ISR
More benign CRF profile Shorter and less severe lesions Higher cross-over requirement Similar Clinical & Angio outcome
Angel J, et al. Circulation 2002;106:II-481.
ST
EDG ISR
RIBS
1 Year Clinical FU 1,0
,9
,8
,7
,6
,5
12 11 10 9 8 7 6543210
Time (months)
(Freedom from Death, MI, TVR)__ BA __ ST
Log Rank p = 0.01
52%
83%
Breslow p = 0.008
“EDG” ISR
Angel J, et al. Circulation 2002;106:II-481.
1st STEDGISR
Where Are DCB Useful Today?
¨ ISR (BMS & DES)¨ De novo Lesions:
¨ Bifurcation (DEBUIT, PEPCAD V, BABILON)
¨ Small vessels (PEPCAD I, PICOLLETO, BELLO, RAMSES)
¨ Difusse disease (STARDUST)
¨ Diabetics (PEPCAD IV)
¨ AMI (DEB-AMI, PEPSI, PAPPA)
¨ CTO (PEPCAD CTO)
(Combined with BMS : before or after)
Scheller B, et al. N Engl J Med 2006;355;2113-24
DCB in BMS ISR
Late Loss
Restenosis Rate
(mm)
(%)
P-BA
BA
DCB vs PES in BMS ISR
Unverdoben M et al , Circulation 2009:119(23):2986-94
0,17
0,38
0
0,05
0,1
0,15
0,2
0,25
0,3
0,35
0,4
Late Loss(mm)
MLD Event Free Survival
p=0.03 FU 2.03 vs 1.96, p=0.60 p=0.08
P-BA PES
Late Loss
(mm)
(%)
PEB
BAHabara S. J Am Coll Cardiol Intv 2011;4:149 –54
RCT: 50 Pts SES ISR25 PEB vs 25 BA
(%) TLR
DCB in SES ISR
Restenosis
PEB for ISR (Acute)
D E F ***
A B C* *
*
2/6/2011 RIBS IV (DB #52323, #1838961)Sandoval J, Alfonso F. J Invasive Cardiol. 2012 Oct;24(10):E215-8.
PEB for DES ISR (Follow-up)
D E F* * *
** *
A B C
2/6/2011 RIBS IV (DB #52323, #1838961)Sandoval J, Alfonso F. J Invasive Cardiol. 2012 Oct;24(10):E215-8.
ISAR-DESIRE 3
DesignDESIGN: Prospective, randomized, active controlled, multicenter clinical trial
INCLUSION CRITERIA: 1. Stenosis > 50% in “limus”-eluting DES2. Symptoms/signs of ischemia
EXCLUSION CRITERIA: 3. Lesion in left main stem4. Acute STEMI5. Cardiogenic shock
SPONSOR: Deutsches Herzzentrum
ISAR-DESIRE 3: Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis: 3 Treatment Approaches
402 patients with DES-restenosis enrolled between August 2009 and October 2011 in 3
centers in Germany
Angiographic follow-up at 6-8 months in 84.1% (N=338)
Clinical follow-up at 12 months in 97.5% (N=392)
Paclitaxel-eluting stent
(Taxus)(N=131)
Balloon angioplasty
alone(N=134)
Paclitaxel-eluting balloon
(SeQuent) (N=137)
No significant differences across groupsRobert A. Byrne
Primary Endpoint: Diameter Stenosis at FU
Diameter Stenosis at Follow-up Angiography (%)
Cum
ulat
ive
Freq
uenc
y (%
)
0 20 40 60 80 1000
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%
ISAR-DESIRE 3: Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis: 3 Treatment Approaches
ISAR-DESIRE 3
Secondary EndpointBinary Restenosis
P = .61
ISAR-DESIRE 3: Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis: 3 Treatment Approaches
P = .09
PEB versus BAPES versus BA
P <0.001
PEB versus BAPES versus BA
P <0.001
Target Lesion Revascularization
PEB BAPESPEB BAPES
% %
ISAR-DESIRE 4 Trial DesignDesign
DESIGN: Prospective, randomized, active controlled, multicenter clinical trial
INCLUSION CRITERIA: 1. Stenosis >50% in “limus”-DES2. Symptoms/signs of ischemia
PRIMARY ENDPOINT: Percentage diameter stenosis at follow-up angiography
Planned Enrollment250 patients
Scoring balloon(Angiosculpt)
+Paclitaxel-
eluting balloon(Pantera Lux)
Paclitaxel-eluting balloon
(Pantera Lux)
ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Drug Eluting Balloons for In-Stent Restenosis 4
DEB for Patients with DES ISR
• By removing the need for an additional stent layer, DEB might become the treatment of choice for patients with DES ISR.
• Nevertheless, information about the relative efficacy of DEB vs second-generation DES in these patients is needed. Studies addressing this question are underway (RIBS V & IV).
• So far, treatment of ISR has been perceived as an endless and largely fruitless research effort.
• DEB have changed the treatment of patients with DES ISRAlfonso F, Pérez-Vizcayno MJ. Lancet. 2013 Feb 9;381(9865):431-3.
Windeker S, Kolh P, Alfonso F, et al. Eur Heart J. 2014 Aug 29. pii: ehu278.
New ESC Guidelines on Revascularization
Windeker S, Kolh P, Alfonso F, et al. Eur Heart J. 2014 Aug 29. pii: ehu278.
New ESC Guidelines on Revascularization
DEB for BMS-ISR or DES-ISR (I A)
A “class effect” of DEB has not been demonstrated
Long-Term (5 Years) Safety and Efficacy of DCB
TLR , MI, stroke, death
Scheller B, et al. JACC CV Interv 2012;5:323-30.
Safety of DCB at 2 years
220 Pts DES-ISR (DCB vs PES)PEPCAD China ISR
TCT 2014. JACC Vol 64/11/Suppl B; September 13–17, 2014
Safety of DCB at 3 years
ISAR-DESIRE III (DCB vs PES vs BA)3 years FU
• At a median follow-up of 3 years, the risk of TLR was comparable with PEB versus PES (HR: 1.46, 95% CI, 0.91-2.33; P=0.11) and lower with PEB versus BA (HR: 0.51, 95% CI,0.34-0.74; P<0.001).
• The risk of death/MI tended to be lower with PEB versus PES (HR: 0.55, 95% CI, 0.28-1.07; P=0.08), due to a lower risk of death (HR: 0.38, 95% CI, 0.17–0.87; P=0.02).
Kufner JACC Cardiovasc Interv 2015 Jun;8(7):877-84.
DEB for Patients with DES ISR
Alfonso F, Cuesta J. JACC Cardiovasc Interv. 2015 Jun;8(7):885-8.
The current study by Kufner et al. confirms the1) safety 2) durable antirestenotic efficacy Of DCB for DES-ISR: results similar to 1st-Gen DES (PES).…. 2nd Gen DES?
Second vs First Gen DES
RIBS III (Rx DES ISR). Hetero-DES (Switch)363 Pts DES ISR from 12 Spanish sites. 274 (75%) Hetero-DES vs 89 (25%) No Hetero-DES
Time (Years)
MACE (Cardiac death, MI, TLR)
Restenosis: 2nd Gener DES:Total: 16 vs 31%, p=0.009
Any DES: 16 vs 28%, p=0.04
Hetero-DES: 15 vs 26%, p=0.08
Alfonso F et al. TCT 2011 Presentation (Featured Research)
“Implications of a Third Metal Layer in
Human Coronary Arteries”21 consecutive Pts
Stenting for recurrent ISR after stenting for ISR
Alfonso F, et al. J Am Coll Cardiol 2009;53:2053-60
High Pressures 20+4 atm (p<0.05 as compared with 2nd ST)
Angiographic Restenosis 21%
2nd ISR BA 3rd ST FU
DES Restenosis
RIBS V
189 Pts BMS ISRRandomization
Inclusion CriteriaInformed Consent
Rx CentralizedStratification: ISR Length & Edge
95 PtsDEB
94 PtsEES
3 Died1 Thrombosis7 Refused
84 PtsAngio FU
8 Refused
86 PtsAngio FU Mean: 270 days Mean: 271 days
(170 Patients: 92% of Eligible)
QCAPrimary
End-point
100% Angiographic Success
SeQuent Please (B. Braun Surgical)
Xience Prime(Abbott Vascular)
(January 2010 to January 2012)
RIBS V1ry Endpoint: MLD at FU
0
0,5
1
1,5
2
2,5
0
0,5
1
1,5
2
2,5
SegLesion
p < 0.0001
(mm)
2.032.44
MLD-FU
MLD-FU DEBEES
p < 0.0001
2.36 2.01
(mm)
In-Segment
In-LesionAdjusted (age, smoker, stenosis, diabetes) p = 0.001
Cumulative Frequency Distribution CurvesRIBS V
(%) StenosisIn-Segment Intention to Treat
-20 -10 0 10 20 30 40 50 60 70 80 90 100
__ DEB __ EES
0
20
PRE
40
60
80
(%)100
p < 0.001FU
RE4 (4.7%)8 (9.5%)p = 0.22
POSTp < 0.001
0
RIBS VClinical Follow-up:
0 1 2 3 4 5 6 7 8 9 10 11 120
20
40
60
80
100%
Time (months)
Freedom from MACE (Cardiac Death, MI, TVR)
__
EES__ DEB
1 Year FU 189 P (100%); FU Time 361+28 days
Breslow, p = 0.65Log Rank, p = 0.60
94%
91%
309 Pts DES-ISRRandomization
Inclusion CriteriaInformed Consent
Rx CentralizedStratification: ISR Length & Edge
154 PtsDEB
155 PtsEES
3 Died12 Refused
139 PtsAngio FU
4 Died 18 Refused
133 PtsAngio FU Mean: 279 days
(Median: 248) Mean: 266 days
(Median: 246)(272 Patients: 90% of Eligible)
QCAPrimary
End-point
100% Angiographic Success
SeQuent Please (B. Braun)
Xience Prime(Abbott Vascular)
RIBS IV(Januray 2010 – August 2013)
QCA: MLD at FU
0
0,5
1
1,5
2
2,5
0
0,5
1
1,5
2
2,5
MLD-FU DEBEES
Seg
p = 0.004
2.03 1.80
Lesionp < 0.001 (mm)
1.892.20
MLD-FU
(mm)
In-Segment(Primary Endpoint)
In-Lesion
RIBS IV
Cumulative Frequency Distribution Curves
(%) StenosisIn-Segment Intention to Treat
(%)
0
20
40
60
80
100
-20 -10 0 10 20 30 40 50 60 70 80 90 100
PREPOSTp < 0.001
p = 0.009
__ DEB __ EES
RE15 (11%)27 (19%)p = 0.06
RR (95%CI) 1.44 (0.94-2.20)
FU
RIBS IV
Clinical Follow-up:
0 1 2 3 4 5 6 7 8 9 10 11 120
20
40
60
80
100%
Time (months)
Freedom from TLR
__
EES__ DEB
1 Year FU 309 P (100%); FU Time 360+35 days
Breslow, p = 0.008Log Rank, p = 0.008
96%
87%
RIBS IV
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
DEB vs BA in the RIBS Trials
Late Loss
DEB RIBS IV
0.14+0.5
0.77+0.7 p < 0.05
(QCA) In-Segment Analysis
DEB RIBS V0
0,5
1
1,5
2
2,5
MLD FU(mm)(mm)
BA RIBS I BA RIBS II
1.52+0.7
2.01+0.6
1.52+0.7
0.73+0.7p < 0.01
BA RIBS I BA RIBS II DEB RIBS IVDEB RIBS V
1.80+0.6
0.30+0.6
RIBS IV
BMS-ISR BMS-ISRDES-ISR DES-ISR
DES Restenosis
58% Rupture, 52% TCFA, 58% Thrombus
Kang SJ, Mintz GS. Circulation. 2011;123:2954-2963
Rupture TCFA
TCFAThrombus
OCT in 50 Pts with DES ISR
A B
C D +
+
+*
*
*
*
Neoatherosclerois After Paclitaxel-Eluting BalloonPEB for DES ISR
Alfonso F, et al. Circulation 2014;129:923-5.
“The elusive link between very late ISR and ST”Ruptured Neoatherosclerosis
B *
PRESTIGE (13/08/2012)
E
*
+
+
+
D
*
+
+
+
A
BCDE *
T
C
DES Restenosis
Alfonso F, et al. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt A):2875.
B
D
C
E*
+*
*
*
**
T
++
+
+
+
+
A
Neoatherosclerosis Causing Late STDES Restenosis
T
NCA B
Neoatherosclerosis Causing Late ST
DES Restenosis
(Jimenez-Quevedo P HCSC)
Meta-analysis on ISRAuthor Date Patients/Trials Network
MetaanalysisInterventions 1ry End-Point Main Result
(Better>Worse)OR (95%CI)
Radke et al16 2003 3012/28 VBTvsBA MACE VBT>BA -37.7+4.0%*
Costantini et al17 2003 133 VBTvsPlacebo BR VBT>placebo 0.06 (0.02- 0.17)(+)
Uchida et al18 2006 1310/5 VBTvsPlacebo MACE VBT > placebo 0.19 (0.09-0.29)
Dibra et al19 2007 1230/4 DESvsVBT TLR DES>VBT 0.35 (0.25-0.49)
Oliver et al20 2008 3103/14 DESvsVBTvsBA MACE DES=VBT>BA 0.72 (0.61-0.85)
Alfonso et al21 2008 300/2 DESvsBMS BR DES>BMS 0.11 (0.03-0.36)(+)
Lu et al22 2011 1942/12 DESvsVBT TVR DES>VBT 0.44 (0.23-0.81)
Yu et al23 2013 349/5 DCBvsDES/BA TLR DCB>DES/BA 0.17 (0.07-0.38)
Navarese et al24 2013 399/4 DCBvsDES/BA TLR DCB>DES/BA 0.20 (0.11-0.36)
Indermuehle et al25 2014 801/5 DCBvsPES/BA MACE DCB>PES/BA 0.46 (0.31-0.70)
Sun et al26 2014 6330/28 DESvsOther TLR DES>BMS>other 0.46 (0.34-0.62)
Vyas et al27 2014 1680/10 SameDESvsDifDES TLR DES>DES 0.73 (0.45-0.93)
Piccolo et al 28 2014 1586/7 X DCBvsDESvsBA %DS DCB=DES>BA -17.7 (-25- -11)**
Mamuti et al29 2014 864/5 DCBvsDES/BA MACE DCB>DES>BA 0.49
Mamuti et al30 2015 803/4 DCBvsDES MACE DCB=DES 1.04
Li et al31 2015 1448/9 DCBvsDESvsBA MACE DCB=DES>BA 0.21 (0.13-0.33)
Benjo et al32 2015 1375/5 VBTvsDES TLR DES>VBT 2.4 (1.5-3.6)
Siontis et al33 2015 5923/27 X Multiple %DS EES>DCB>other -9 (-15.8- -2.2)**
Lee et al6 2015 2059/11 X DCBvsDESvsBA TLR DCB=DES>BA 0.22 (0.10-0.42)
%DS: Percent diameter stenosis; EES: Everolimus Eluting Stent; DCB: Drug Coated Balloon; VBT: Vascular Brachytherapy; TLR: Target Lesion revascularization; DES: Drug Eluting Stent; MACE: Mayor Adverse Cardiac Events;DifDES: different (hetero) DES; SameDES: Similar (homo) DES; TVR: Target Lesion Revascularization. (+) Simple pooled analysis of randomized clinical trials. Other : more than
2 different interventions. ; (*): Probability of MACE (in %)(**): %DS
Alfonso F, Rivero F. J Thorac Dis 2015. In press.
Sointis GT, et al Lancet. 2015 Aug 15;386(9994):655-64.
Percutaneous coronary interventional strategies for treatment of in-stent restenosis: a network meta-analysis.
“Network” Meta-analysis
27 trials eligible, including 5,923 patients• EES was the most effective treatment for % diameter
stenosis, with a difference of:-9.0% vs DCB
-9.4% vs SES-10.2% vs PES -19.2% vs brachytherapy, -23.4% vs BMS -24.2% vs BA, -31.8% vs rotablation.
• DCB were ranked as the second most effective treatment, but without significant differences from SES or PES
DES RestenosisA
B C D E
**
**
+
+ + ++
+
^^
F G H I
*
** *
Absorb for ISRAlfonso F, et al J Am Coll Cardiol 2014:63:2875
Algorithm for DES ISR Treatment DES ISR
Medical Rx
FFR (IVUS/OCT)
(-)
Asymptomatic
Severity ? IVUS / OCT
Underlying Mechanism
DES
DES
DES
Focal
Gap
Fracture
Edge
Body
Diffuse
Underexpansion ?
2nd DES / PEB
Optimization
Pressure NC BA
Cutting/Scoring (?)
Avoid Geo Miss
Prefered DES: Hetero & 2nd G Favor PEB: Multiple ST layers, major SB