Tratamiento de la Reestenosis Intra-Stent: ¿Cuál es el mejor tratamiento?

1. Avances en Cardiología Intervencionista
Sección 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 Corazón
SEC
Jueves 17 Septiembre 2015

2. 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.

3. 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

4. 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

5. 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.)

6.  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:

7.  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:

8. IVUS Severe Underexpansion
A
MLA & EEL
B
“Sand Glass”
DES Restenosis

9. Calcified DES ISR
A + +
+
+
+
+
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.

10. 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.

11. Treatment of In-Stent Restenosis
Balloon Angioplasty
Alfonso F, et al Am J Cardiol 1999;83:1268-70

12. RIBS: 125
BD: 5114
MLD: QCA
1.1 mm
Intravascular Ultrasound
Immediate Recoil After Ballon PTCA for ISR
3.0x12 Bar
2 mm
20’
1,4 mm

13. Angiographic Results: MLD
%
100
80
60
40
20
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
MLD (mm)
baseline
PTCA
ROTA
post interv.
6 month
RE
51%
65%

14. % 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
21
17
22
10
27
31
23
27
PTCA 314 ELCA 250 RA 126 ST 131
0
5
10
15
20
25
30
35
(%)
*
Baseline Demographics Similar Among Groups

15. 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)

16. 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 > 1.1
0.1 1Log RR
0.55 (0.35-0.85)p=0.007
4 Pts treated
prevent 1 RE
Vessel QCA (> 3mm)

17. 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

18. 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
(%)
15
16
0
2
4
6
8
10
12
14
16
18
MACE
MACE: Death, MI, TLR
Albiero R, et al. J Am Coll Cardiol 2004;43:943-949
Restenosis Cutting Balloon Evaluation Trial

19. 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

20. RIBS
1 Year Clinical FU
1,0
,9
,8
,7
,6
,5
1211109876543210
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 ST
EDG
ISR

21. 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)

22. Scheller B, et al. N Engl J Med 2006;355;2113-24
DCB in BMS ISR
Late Loss
Restenosis Rate
(mm)
(%)
P-BA
BA

23. 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

24. Late Loss
(mm)
(%)
PEB
BA
Habara S. J Am Coll Cardiol Intv 2011;4:149 –54
RCT: 50 Pts SES ISR
25 PEB vs 25 BA
(%)
TLR
DCB in SES ISR
Restenosis

25. 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.

26. 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.

27. ISAR-DESIRE 3
Design
DESIGN:
Prospective, randomized, active
controlled, multicenter clinical trial
INCLUSION CRITERIA:
1. Stenosis > 50% in
“limus”-eluting DES
1. Symptoms/signs of ischemia
EXCLUSION CRITERIA:
1. Lesion in left main stem
2. Acute STEMI
3. 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 groups
Robert A. Byrne

28. Primary Endpoint: Diameter Stenosis at FU
Diameter Stenosis at Follow-up Angiography (%)
CumulativeFrequency(%)
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 PES
Pnon-inferiority =0.007
PEB versus BA
PES versus BA
Psuperiority <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

29. Secondary Endpoint
Binary 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 BA
PES versus BA
P <0.001
PEB versus BA
PES versus BA
P <0.001
Target Lesion Revascularization
PEB BAPESPEB BAPES
% %

30. ISAR-DESIRE 4 Trial Design
Design
DESIGN:
Prospective, randomized, active
controlled, multicenter clinical trial
INCLUSION CRITERIA:
1. Stenosis >50% in “limus”-DES
2. Symptoms/signs of ischemia
PRIMARY ENDPOINT:
Percentage diameter stenosis at
follow-up angiography
Planned Enrollment
250 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

31. 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 ISR
Alfonso F, Pérez-Vizcayno MJ. Lancet. 2013 Feb 9;381(9865):431-3.

32. Windeker S, Kolh P, Alfonso F, et al. Eur Heart J. 2014 Aug 29. pii: ehu278.
New ESC Guidelines on Revascularization

33. 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

34. Long-Term (5 Years) Safety and Efficacy of DCB
TLR , MI, stroke, death
Scheller B, et al. JACC CV Interv 2012;5:323-30.

35. 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

36. 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.

37. 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 the
1) safety
2) durable antirestenotic efficacy
Of DCB for DES-ISR: results similar to 1st-Gen DES (PES).
…. 2nd Gen DES?

38. 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)

39. “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

40. RIBS V
189 Pts BMS ISR
Randomization
Inclusion Criteria
Informed Consent
Rx Centralized
Stratification:
ISR Length & Edge
95 Pts
DEB
94 Pts
EES
3 Died
1 Thrombosis
7 Refused
84 Pts
Angio FU
8 Refused
86 Pts
Angio FUMean: 270 days Mean: 271 days
(170 Patients: 92% of Eligible)
QCA
Primary
End-point
100% Angiographic Success
SeQuent Please
(B. Braun Surgical)
Xience Prime
(Abbott Vascular)
(January 2010 to January 2012)

41. RIBS V
1ry Endpoint: MLD at FU
0
0,5
1
1,5
2
2,5
0
0,5
1
1,5
2
2,5
Seg
Lesion
p < 0.0001(mm)
2.03
2.44
MLD-FU
MLD-FU DEBEES
p < 0.0001
2.36
2.01
(mm)
In-Segment
In-Lesion
Adjusted (age, smoker, stenosis, diabetes) p = 0.001

42. Cumulative Frequency Distribution Curves
RIBS 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 < 0.001
FU
RE
4 (4.7%)
8 (9.5%)
p = 0.22
POST
p < 0.001
0

43. RIBS V
Clinical Follow-up:
0 1 2 3 4 5 6 7 8 9 10 11 12
0
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 = 0.65
Log Rank, p = 0.60
94%
91%

44. 309 Pts DES-ISR
Randomization
Inclusion Criteria
Informed Consent
Rx Centralized
Stratification:
ISR Length & Edge
154 Pts
DEB
155 Pts
EES
3 Died
12 Refused
139 Pts
Angio FU
4 Died
18 Refused
133 Pts
Angio FUMean: 279 days
(Median: 248)
Mean: 266 days
(Median: 246)
(272 Patients: 90% of Eligible)
QCA
Primary
End-point
100% Angiographic Success
SeQuent Please
(B. Braun)
Xience Prime
(Abbott Vascular)
RIBS IV
(Januray 2010 – August 2013)

45. 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
Lesion
p < 0.001(mm)
1.89
2.20
MLD-FU
(mm)
In-Segment
(Primary Endpoint)
In-Lesion
RIBS IV

46. 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
PREPOST
p < 0.001
p = 0.009
__ DEB
__ EES
RE
15 (11%)
27 (19%)
p = 0.06
RR (95%CI) 1.44 (0.94-2.20)
FU
RIBS IV

47. Clinical Follow-up:
0 1 2 3 4 5 6 7 8 9 10 11 12
0
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 = 0.008
Log Rank, p = 0.008
96%
87%
RIBS IV

48. 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 V
0
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+0.7
p < 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

49. DES Restenosis
58% Rupture, 52% TCFA, 58% Thrombus
Kang SJ, Mintz GS. Circulation. 2011;123:2954-2963
Rupture
TCFA
TCFA
Thrombus
 OCT in 50 Pts with DES ISR

50. A B
C D +
+
+
*
*
*
*
Neoatherosclerois After Paclitaxel-Eluting Balloon
PEB for DES ISR
Alfonso F, et al. Circulation 2014;129:923-5.

51. “The elusive link between very late ISR and ST”
Ruptured Neoatherosclerosis
B *
PRESTIGE (13/08/2012)
E
*
+
+
+
D
*
+
+
+
A
B
C
D
E
*
T
C
DES Restenosis
Alfonso F, et al. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt A):2875.

52. B
D
C
E*
+
*
*
*
*
*
T
+
+
+
+
+
+
A
Neoatherosclerosis Causing Late ST
DES Restenosis

53. T
NC
A B
Neoatherosclerosis Causing Late ST
DES Restenosis
(Jimenez-Quevedo P HCSC)

54. Meta-analysis on ISR
Author Date Patients/Trials Network
Metaanalysis
Interventions 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.

55. 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

56. DES Restenosis
A
B C D E
*
*
*
*
+
+ +
+
+
+
^
^
F G H I
*
*
* *
Absorb for ISRAlfonso F, et al J Am Coll Cardiol 2014:63:2875

57. 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