Is In-Stent Restenosis After DES

a Clinical Problem?
Not Really…Infrequent and
Usually Easily Treated!

DES Revolution IV
American College of Cardiology
March 5, 2005; Orlando, FL

Martin B. Leon, M.D.

Columbia University Medical Center
The Cardiovascular Research Foundation
New York City
 Presenter Disclosure Information

The following relationships exist related to

ACC 2005 presentations:

Martin B. Leon, M.D.

Cordis (JNJ): stock, consultant and CRF

research grants
‘’Big Bad
‘’Big ’’ DES
Bad’’

Retreating… VBT
 ‘’Big Bad
‘’Big ’’ DES
Bad’’

Retreating… ISR!!!
 DES ISR Questions
• What is the « real world » frequency of ISR
after DES implantation?
• What are the patterns of ISR after DES
implantation?
• What are the treatment alternatives and
clinical outcomes after PCI management of
DES ISR?
• CONCLUSIONS
CYPHER Trials - Clinical Events
TLR and TVR (@ 9 months)
Sirolimus (n=1204) Control (n=870)

P<0.0001 P<0.0001
19.2%
17.1%
80% 70%
%

5.7%
3.5%

TLR TVR
TAXUS Trials - Clinical Events
TLR and TVR (@ 12 months)
Taxus (n=1141) Control (n=1148)

P<0.0001 P<0.0001

17.5%
69% 15.6% 57%
%

7.6%
4.9%

TLR TVR
 CYPHER and TAXUS Trials
TLR with and without Angio FU (@ 9 mos)
with Angio FU without Angio FU

44% 37%
%

4.1% 3.8%

2.3% 2.4%

CYPHER TAXUS
“Real World” CYPHER Registries
Overall TLR @ 6 months

n=13,060 n=2,338 n=1,407

%

1.7%
1.3% 1.3%

eCypher Columbia WHC

 WHC - Diabetics
TLR and MACE @ 6 months
TLR MACE

n=915 n=160 n=332

%

7.9% 8.0%
6.2%

1.5% 0.9%
0.4%

non-DM IDDM oral/diet DM

 Changing Patterns of ISR - CRF

0 22 0033
,
0
220 0
0 03 2
200 004
4
224 ,
4 ,2 2
244,, 4 ,2
eer
r il2 eerr l2
obb r bb ri
Occtto Ap c
cttoo A p
O O
O
one year
one year FU
FU SES
SES
39 pts with 44 ISR lesions

BareStents
Stents
Bare 86% Reduction
282 pts with 311 lSR lesions of ISR Cases!!
 DES ISR Conclusions
• Both in the rarified climate of RCTs and in
« real world » registries
registries,, the frequency of
ISR after DES is vanishing (< 2%).
 DES ISR Questions
• What is the « real world » frequency of ISR
after DES implantation?
• What are the patterns of ISR after DES
implantation?
• What are the treatment alternatives and
clinical outcomes after PCI management of
DES ISR?
• CONCLUSIONS
 Patterns of In-Stent
In-Stent Restenosis
FOCAL DIFFUSE

Articulation
Articulation or
or Margin
Gap Intra-stent Proliferative
Gap

Focal Multifocal
Body Total
Occlusion

Mehran R
Mehran R et
et al.
al. Circulation
Circulation 1999;100:1872-78
1999;100:1872-78
 SIRIUS – Morphology Patterns of
In -Stent Restenosis Lesions
In-Stent

Sirolimus Control
P-value
(n=31) (n=128)

I - focal 87% 42% <0.001

II/III – diffuse or
6.5% 50% <0.001
proliferative

IV - total occlusion 6.5% 8% 0.895

 Taxus IV – Morphology Patterns of
In -Stent Restenosis Lesions
In-Stent

Paclitaxel Control
P-value
(n=16) (n=65)

I - focal 63% 31% <0.001

II/III – diffuse or
24% 66% <0.001
proliferative

IV - total occlusion 13% 3% 0.245

Cypher CRF – Morphology Patterns of
In -Stent Restenosis Lesions
In-Stent

Cypher CRF Cypher SIRIUS

(n=44) (n=31)

I - focal 88.7% 87%

II/III – diffuse or
6.8% 6.5%
proliferative

IV - total
4.5% 6.5%
occlusion
 Causes of DES ISR
• Stent under-expansion or ssymmetric strut
geometry (incomplete vessel wall coverage)
• Inhomogeneous drug elution
• Polymer peeling or cracking
• Late struts fractures resulting in stent
separation and restenosis
• Peri-stent vessel wall injury (balloon injury)
• Drug failure or resistance (simply ineffective)
• Polymer (or drug) hypersensitivity (including
variable inflammatory responses)
 DES failed to cross a
heavily calcified lesion…oops!

Undamaged
Severe
polymer
polymer
damage
 Patterns of In-Stent
In-Stent Restenosis
282 lesions; restenosis patterns classified by
angiography and confirmed by IVUS
42
42
83
83
30

Year
30

@ 11 Year
Frequency
% Frequency

22
22 50
50

TLR @
35
35

TLR
%

19
19
66

Focal
Focal Intrastent
Intrastent Proliferative
Proliferative Total
Total Focal
Focal Intrastent
Intrastent Proliferative
Proliferative Total
Total
Occusion
Occusion Occusion
Occusion

Predictors of TLR : diabetes, previous ISR and ISR patterns

Mehran R
Mehran R et
et al.
al. Circulation
Circulation 1999;100:1872-78
1999;100:1872-78
 DES ISR Conclusions
• Both in the rarified climate of RCTs and in
« real world » registries
registries,, the frequency of
ISR after DES is vanishing (< 2%).
• The pattern of ISR after DES, in contra
contra--
distinction to bare metal stents, is
predominantly focal in nature (~90%).
 DES ISR Questions
• What is the « real world » frequency of ISR
after DES implantation?
• What are the patterns of ISR after DES
implantation?
• What are the treatment alternatives and
clinical outcomes after PCI management of
DES ISR?
• CONCLUSIONS
 Rx Alternatives of DES ISR
• Balloon PCI
• Athero-ablative modalities (RA, DCA, or
Athero-ablative
ELCA)
• Atherotomy devices ((cutting
cutting balloon
balloon,,
Fx minirail
minirail,, or Angiosculpt
Angiosculpt))
• Bare metal stent
• Drug-eluting stent
Drug-eluting
• Vascular brachytherapy
 SIRIUS – TLR-free at 2 Years
533 Evaluable Sirolimus Patients
TLR @ 9 Months

No Yes

95.9% (511) 4.1% (22)

mean 246 days

Freedom from TLR: repeat PCI
1ry
ry success @ 9 mos
mos:: 95.9%

19 2 1
bare stent balloon VBT
 SIRIUS – TLR-free at 2 Years
22 DES (sirolimus) ISR Patients
2nd
nd TLR @ 1 year

No Yes

77.3% (17) 22.7% (5)

mean 324 days

Freedom from TLR:
2nd
nd repeat PCI
1ry
ry + 2ry
ry success @ 2 yrs: 99.1%

2 1 2
bare stent balloon VBT
CRF Cypher – TLR-free at 2 Years
2,338 Evaluable Cypher Patients
TLR @ 9 Months

No Yes

98.3% (2,299) 1.7% (39)

Freedom from TLR: repeat PCI

1ry
ry success @ 9 mos
mos:: 98.3%

39
Cypher stents
CRF Cypher – TLR-free at 2 Years
39 DES (sirolimus) ISR Patients
2nd
nd TLR @ 1 year

No Yes

100% (39) 0

• Death 0
Freedom from TLR: • MI 0
1ry
ry + 2ry
ry success @ 2
2 yrs:
yrs: 100% • TLR 0
• TVR 1 (2.6%)
• Stent 0
thrombosis
• MACE 1 (2.6%)
 DES ISR Conclusions
• Both in the rarified climate of RCTs and in
« real world » registries
registries,, the frequency of
ISR after DES is vanishing (< 2%).
• The pattern of ISR after DES, in contra
contra--
distinction to bare metal stents, is
predominantly focal in nature (~90%).
• ISR after DES is usually easily treated with
balloons
balloons,, bare metal stents, or DES and
2ry
ry success rates appear excellent.
 Gamma-1: Five-Year FU
Clinical Outcomes (0-60 months)
P = 0.380 P = 1.000 P = 0.064 P = 0.254
60 54.5
48.9 47.9
40.5
40
per cent

20 17.6
9.9 9.9 9.1

0
MACE Death MI TLR
Placebo Ir - 192
 Gamma-1: Five-Year FU
Changes in MACE and TLR
from 9 – 60 months
3X greater late TLR after Ir-192
30

19.9
20
per cent

15.3
9.9
10 5.8

0
MACE TLR
Placebo Ir - 192
 Gamma and Scripps Trials

Study # Ir-192 Anti-platelet

Study Ir-192 dose
design pts regimen
ASA + Ticlid x
Gamma 1 RCT 131 8-30 Gy
8 wks
ASA + Ticlid x
Gamma 2 Registry 125 14 Gy
8 wks

ASA + Plavix
Scripps 3 Registry 500 14 Gy
x 6 mos
ASA + Plavix
Scripps 4 RCT 358 14 vs 17 Gy
x 6 mos

Total Ir-192 pts = 1114

 Gamma and Scripps Trials:
Freedom from MACE @ 3 Yrs
100
1114 Pts with Ir-192
Freedom from 3-year MACE (%)

GAMMA 1
90 GAMMA 2
SCRIPPS 3
SCRIPPS 4

80
p=0.4512

70

60

50
0 0.5 1 1.5 2 2.5 3
Time in years
 VBT for DES ISR?
• A biologic « double whammy » … the
ultimate vascular biology insult …
• Will require permanent dual anti-platelet
anti-platelet
therapy (major safety concerns
concerns))
• Late catch-up will still be an issue
catch-up
• Logistic nightmares for VBT in seldom used
clinical scenarios
• IT’S NOT NECESSARY ((other
IT’S other simpler
treatments will work as well or better
better))
 Your coronaries after VBT…
14 Gy 15 Gy

20X

Serious late
patho-biologic
responses after
radiation Rx!

Courtesy: Keith Robinson

 SECURE - Events In & Out of
Hospital to 1 year
252 patients with 1 yr follow-up
Radiation No Radiation
Failure* Failure P-value
(n=178 pts) (n=74 pts)
TLR (%) 47.8 29.7 0.012
TVR (%) 51.1 32.4 0.008
TVF (%) 54.5 33.8 0.004
Stent thromb <30
1.7 2.7 0.63
days (%)
Stent thromb >30
3.4 0 0.18
days (%)
VBT for DES ISR?
 So who is there left to treat with VBT?

• Assume 2% TLR after DES and 90% of ISR

lesions are focal and easily treatable
• Assume that all diffuse DES ISR lesions are
treated with VBT (? longshot
longshot))
• That leaves 0.2% of all lesions (1 in 500) that
may be candidates for VBT!!! Is this really a
viable treatment strategy
strategy??
 DES ISR Questions
• What is the « real world » frequency of ISR
after DES implantation?
• What are the patterns of ISR after DES
implantation?
• What are the treatment alternatives and
clinical outcomes after PCI management of
DES ISR?
• CONCLUSIONS
 Final Conclusions
• ISR as a disease entity is vanishing
vanishing..
• VBT as a therapy for ISR is dead (let it die
in peace
peace))
• ISR after DES is usually focal and easily
treated with simple PCI techniques
((balloons,
balloons, BMS, DES)
• The 1ry
ry + 2ry
ry success rates after DES are

~99% ((even
even in complex lesion subsets
subsets))
• I REST MY CASE