InStent Restenosis and Late Stent Thrombosis

1
In-Stent Restenosis and Late Stent Thrombosis
Roxana Mehran, MD, FSCAI
2
Disclosures

• Research Grant
• Boston Scientific
• Abbott
• Cordis, JJ
• The Medicines Company

3
Drug-Eluting Stents. the good, the bad, and the
ugly!
DES
BMS
Late loss 0
Giant cells
DES
Angioscopy
BMS
Eos
Delayed Healing!
Inflammation
Incomplete apposition
Sirolimus Control
Abn Vasomotion
Late stent thrombosis

Plt0.001 vs. control

40 mos
IVUS
4
Clinical Importance of Stent Thrombosis Death
and MI
5
Academic Research Consortium (ARC)Proposed
Standard Definitions

• Definite/Confirmed
• Acute coronary syndrome AND
• Angiographic confirmation of thrombus or
  occlusion OR
• Pathologic confirmation of acute thrombosis
• Probable
• Unexplained death within 30 days
• Target vessel MI without angiographic
  confirmation of thrombosis or other identified
  culprit lesion
• Possible
• Unexplained death after 30 days

NOTE Patients who have a TLR prior to a
thrombosis are included by this set of
definitions, as opposed to the Per Protocol
definition
6
Thrombosis Can Occur Anytime Post-Stent
Implantation
gt 12 months (after clopidogrel stopped)
Very Late ST?
1 to 12 months (on clopidogrel)
Late ST
24 hours to 30 days
SAT
24 Hours
Acute ST
ST stent thrombosis SAT subacute stent
thrombosis LST late stent thrombosis VLST
very late stent thrombosis. Adapted from Bhatt. J
Invasive Cardiol. 200315(suppl B)3B.
7
Incidence of DES thrombosis from the Spanish
ESTROFA registry
13500 Pts treated with DES

lt 24 h
24 h to 30 days
30 days to 6 months
gt 6 months
Hernandez J et al. TCT 2006
8
Late Stent Thrombosis (LaST)
9
Late DES thrombosis afterdiscontinuation of
antiplatelet therapy
CYPHER TAXUS
335
343
375
442
Usually associated with minor surgical
procedures!
400
200
100
0
500
300
Day
McFadden EP et al. Lancet 2004 364151921
10
EVENT Registry WAVE 1 DataOff-Label vs.
On-Label Comparison
General Exclusions Primary angioplasty (200), no
DES attempted (167), missing angiographic or
biomarker data (397)
Slide Courtesy of David J. Cohen, MD.
11
Are DES Adverse Event Rates Increased in
Off-label Use? EVENT Registry (N3,323 non
STEMI pts, 51 SES, 49 PES, 55 off-label)
1-year Follow-up
Stent thrombosis
Death, MI or TLR
4
22
Off-label On-label
20
18
Log-rank test, P.02
Log-rank test, Plt.001
3
16
14
12
2
Percentage
Percentage
10
8
6
1
4
2
0
0
0
60
120
180
240
300
360
0
60
120
180
240
300
360
No. at Risk
No. at Risk
Time After Initial Procedure, d
Time After Initial Procedure, d
Off-label 1817 1769 1716 1711 1684 1551 1525 On-la
bel 1506 1476 1451 1450 1431 1340 1327
Off-label 1817 1757 1514 1476 1428 1313 1253 On-la
bel 1506 1475 1363 1343 1311 1215 1182
MV HR 95CI 2.29 1.02-5.16 Plt0.001
MV HR 95CI 2.16 1.74-2.17 Plt0.001
Off-label 1.6 On-label 0.9
Off-label 17.5 On-label 8.9
Win HK et al. JAMA 20072972001-9
12
The Bern-Rotterdam Experience
8146 pts. treated with SES (n3823) or PES
(n4323) at 2 academic centers.
20
2.0
Early stent thrombosis Late stent
thrombosis Cumulative events ()
1.5
15
Cumulative events ()
10
1.0
Number of events
0.5
5
0
0
0 3 6 9 13 18 24 31 46 85 146 192 224 260 336 356
381 441 464 491
551 568 606 670 762 822 925 1074
Days after PCI
Daemon J, et al, Lancet 2007 369667-78
13
Bern/Rotterdam 2 Center Experience
PES
P0.06
3.2
SES
0.6 per year
2.5
Stent Thrombosis ()
0 365 730 1095
Days after stenting
Days after PCI 9 30 365 730 1095 Incidence SES
() 1.0 1.1 1.3 1.9 2.5 Incidence PES ()
1.2 1.3 2.0 2.7 3.2 Pts at risk 8146 7162 7002 28
41 971
P. Wenaweser and P.W. Serruys, ESC 2006
14
BASKET LATE Trial Study Design
743 patients randomized in the BASKET trial and
WITHOUT AN EVENT DURING THE 6-MONTH CLOPIDOGREL
PHASE
Followed for 1 year off clopidogrel

• Primary Endpoint Composite cardiac death or
  nonfatal MI.
• Other Endpoints Thrombosis-related events

Pfisterer M et al. ACC 2006
15
BASKET LATE Trial 6-18 Mo MACE N743 (pts with
early events excluded)
P0.01
P0.04
P0.50
P0.23
P0.09
Pfisterer M. ACC 2006
16
Stent Thrombosis in Randomized Clinical Trials of
Drug-Eluting Stents
Protocol and ARC definitions of stent
thrombosis SES and PES randomized trials
Follow-up to 4 yrs
Sirolimus Stent (Protocol)
Sirolimus Stent (ARC)
P0.20
1.7
1.5
Cumulative Incidence ()
Cumulative Incidence ()
1.2
0.6
P0.70
180
180
Days after Initial Procedure
Days after Initial Procedure
No. at Risk Sirolimus stent 878 863 848 824 789 B
are-metal stent 870 857 846 830 795
No. at Risk Sirolimus stent 878 863 848 823 788 B
are-metal stent 870 853 842 825 789
def prob
Mauri L. et al., NEJM 2007 356 1020-1029
17
Stent Thrombosis in Randomized Clinical Trials of
Drug-Eluting Stents
Protocol and ARC definitions of stent
thrombosis SES and PES randomized trials
Follow-up to 4 yrs
Paclitaxel Stent (Protocol)
Paclitaxel Stent (ARC)
P0.24
1.8
1.4
1.3
Cumulative Incidence ()
Cumulative Incidence ()
0.8
P0.52
180
180
Days after Initial Procedure
Days after Initial Procedure
No. at Risk Paclitaxel stent 1400 1352 1301 1118
717 Bare-metal stent 1397 1354 1305 1128 746
No. at Risk Paclitaxel stent 1400 1351 1300 1117
715 Bare-metal stent 1397 1353 1302 1123 743
def prob
Mauri L. et al., NEJM 2007 356 1020-1029
18
FDA DES Panel Meeting
Consensus Observations

• There is an increase in very late (gt1 yr) stent
  thrombosis associated with current DES
• 2-4 per 1000 pts per year (? continous hazard,
  ? patient and lesion predictors)
• Data from multiple sources indicate thatDES are
  associated with delayed healingresponses and
  increased inflammation
• The causes of late DES thrombosis are
  multi-factorial device, procedural, and
  patientfactors (often multiple perfect storm)

19
FDA DES Panel Meeting
Consensus Observations

• There may be a link between post-DES reduced
  neo-intimal hyperplasia (late loss) and delayed
  late healing responses which contributes to late
  stent thrombosis
• DES stent thrombosis is highly definition
  dependent need for revised standardizeddefiniti
  ons and adjudication methods (ARC) to facilitate
  inter-study comparisons

20
Potential Mechanisms of Late Stent Thrombosis
21
Stent Thrombosis
Patient, Procedure, Device
Patient

• Higher Risk
• AP Compliance

Stent Thrombosis
Device
Procedure

• Polymer
• Drug

• Stent apposition
• Flow/Runoff

22
Impact of premature thienopyridine
discontinuation The PREMIER registry500 pts
with AMI undergoing primary PCI with DES at 19
U.S. medical centers, alive and well at 30 days
68 (13.6) were no longer taking prescribed
thienopyridines at 30 days
Propensity adjusted for reasons to d/c thien HR
9.02 (1.3-60.6), P0.02
Plt0.0001
Spertus JA et al. Circulation 20061132803-9.
23
Duke Database Death/MI Analysis
Adjusted death/MI rates at 24 months in patients
without events at 6 months
Clopidogrel status at 6 months Overall P value
0.07 Pint 0.12
Clopidogrel status at 12 months Overall P value
lt0.001 Pint 0.003
Eisenstein EL et al. JAMA 2007297 on line
24
Milan Stent Thrombosis Experience2,160
consecutive pts with DES implanted
9/2079
4/1465
3/866
4/53
1/633
1/1212
4/28
1/22
0/22
Colombo A, TCT 2006
25
Safety of Long-Term Clopidogrel
3 Placebo Controlled Trials
P0.07
Plt0.001
P0.001
N15,603 2.5 year FU GUSTO major moderate bleed
NEJM 20063541706-17
26
U.S. Cost Implications of Long-term Clopidogrel
Therapy

• At 4 per day, Clopidogrel costs 1500 per year
• As many as 1 million U.S. patients per year
  receive DES ?
• One year of Clopidogrel would cost 1.5B
• For 4 million U.S. patients with DES implanted ?
• One year of Clopidogrel would cost 6.0B

27
Clopidogrel Responsiveness at the Time of PCI and
Stent Thrombosis After Cypher w/in 30 Days N280
75th percentile
Association with Stent Thrombosis Clop NR
p0.046 High post-Rx reactivity p0.06 Clop NR
high post-Rx reactivity p0.02
Inhibition by Clopidogrel ()
25th percentile
lt10 inhibition
Reactivity Post-Clopidogrel Treatment (PRUs)
Price MJ et al, TCT 2006
28
Platelet Responsiveness and Thrombosis804
patients, 25 def/prob thromboses
Buonamici et al, JACC 2007
29
Milan/Siegburg Experience
Stent thrombosis after DES (SES or PES) occurred
in 29/2229 pts (1.3) at 9 mos (45 mortality)
Iakovou I et al. JAMA 20052932126-2130
Several patient and lesion subgroups have an
unacceptably high stent thrombosis rate!
Unstable angina
Prior brachyRx
Thrombus
Diabetes
Unprot. left main
Bifurcation
Renal failure
Premature Plavix d/c
30
Predictors of Stent Thrombosis
Up to 6 months Stent Technique Lesion
complexity Long lesions Small
vessels Bifurcations Pharmacologic Clopidogrel
resistance Early discontinuation
After 6 months Less based upon lesion
complexity? Pharmacologic role less
well-defined Largely off clopidogrel ? Slow
endothelialization Genetics EPC levels ?
Polymer hypersensitivity
31
The Role of Stent Properties In Thrombosis

• Modular design
• Metal coverage
• Strut thickness
• Strut shape
• Surface smoothness
• Coating materials
• Drug properties

Hara H et al. Adv Drug Deliv Rev. 200658377-386
.
32
Potential Inflammatory Reaction

• Suggested by early preclinical data
• May be related to the polymers, the drug coatings
  themselves, or perhaps both.
• Heightened activity of
• Macrophages Multinucleated giant cells
• Lymphocytes Neutrophils
• Eosinophils
• Very late inflammatory response in animal models
  may, in and of itself, create thrombosis.
• Inflammation can cause positive remodeling of the
  artery, which results in stent malapposition

Hara H et al. Adv Drug Deliv Rev. 200658377-386
.
33
Localized Hypersensitivity and Late DES Thrombosis
Postmortem radio- and photomicrographs (A and B)
showing 2 LCx
sirolimus-eluting stents with
dense surrounding inflammation
Virmani, R. et al. Circulation 2004109701-705
34
Evidence for Delayed Healing with DES

• Animal data demonstrate delayed healing
• Lack of endothelialization
• Inflammation / allergic reactions
• Autopsy case reports indicate that DES can induce
  hypersensitivity reactions and delayed
  endothelialization compared to BMS
• In-vivo invasive coronary imaging up to 1 year
  after stenting
• OCT/Angioscopy Absence or incomplete strut
  coverage, mural thrombosis
• Sequential IVUS Virtual Histology shows changes
  in plaque size behind stent struts
• Functional studies of endothelium-dependent
  vasomotion show abnormal vasoconstriction with
  DES, but not with BMS

35
59- year old Female with TAXUS stent in the LAD
for 130 days
LAD 6
LAD1
LAD3
Fibrin
Giant cells
Eosinophils
80 Surface Endothelialized
36
Healing After Stent Implantation in Humans
Differences Between BMS and DES
P0.001
90
Plt0.001
66
27
Endothelialization
BMS Patent DES Thrombosed DES
Joner M et al. J Am Coll Cardiol.
200648193-202. Colombo A, Corbett SJ. J Am Coll
Cardiol. 200648203-205.
37
Healing After DES Implantation in Humans
Importance of Strut Coverage
Finn AV et al, Circulation 2007
38
Late Incomplete Apposition After DES
PlacementDrug Eluting Stent Group
Baseline
Follow-up
Struts may be potentially vulnerable
39
Incomplete Stent Apposition And (Very) Late
Thrombosis
Incomplete Stent Apposition
Plt0.001

Very Late ST (N13)
DES Controls (N144)
Cook S et al, Circulation 2007
40
Causes, Patterns and Treatment Options for
In-stent DES Restenosis
41
DES Restenosis

• Mechanisms
• Predictors
• Morphological patterns
• Therapy approach

42
Mechanisms of DES Restenosis
43
DES fractures
a
a
Follow-up
Post
b
b
Stent
c
Restenosis
c
Aoki J. et al. CCI 200769 380-6
44
Definitions Used for Stent Fracture
Type 5 implies spiral fracture of stent
1 Allie et al Endovascular Today 2004
July/August 22-34 2 Scheinert et al J Am Coll
Cardiol 2005 45312-315
Popma JJ. et al. DES revolution IV, 2007
45
Stent Fracture Analysis Review of Adverse Event
Reports submitted to Cordis between August 2003 -
July 2006
Follow-up findings
In-stent restenosis
In-stent late loss
mm

Plt0.001
Plt0.001
N38
N350
N38
N350
Popma JJ. et al. DES revolution IV, 2007
46
Incidence and clinical presentation of stent
fractures
Among 188 pts with DES restenosis, stent
fracture was identified in 35 (18.5) cases.


Shaikh F et al. TCT 2006
47
Technical factors
Stent underexpansion
48
Technical factors
Stent underexpansion
Post-Procedure MSA and Binary Restenosis
(sensitivity and specificity curves)
Cypher
Taxus
100
90
80
70
60
50
40
30
20
10
0
8.0
3.5
4.0
4.5
5.5
6.0
6.5
7.0
7.5
8.5
5.5
5.0
Minimum Stent Area (MSA, mm2)
Minimum stent area (mm2)
Weissman N. TCT 2006
Sonoda S. et al. J Am Coll Cardiol 2004431959-63
49
Technical factors
Gap
Incomplete stent coverage
Stent edge restenosis is frequently associated
with local trauma outside the stent. In-stent
restenosis occurs as a localized lesion, commonly
associated with a discontinuity in stent coverage.
Lemos A. et al. Circulation 2003 108 257-60
50
Freedom from 1-Year Clinically Driven TLR by
Type of Geographic Miss in 1557 patients
S.T.L.L.R. Trial
Costa MA et al. TCT 2006
51
Tentative Correlation Between Mechanisms and
Sites of DES ISR
Biological
Edge/Gaps
Body
Mechanical
Bifurcation
Technical
Costa MA. et al. Circulation 2005 111 2257-73
52
DES Restenosis

• Mechanisms
• Predictors
• Morphological patterns
• Therapy approach

53
Independent predictors of TLR after DES
implantation
Randomized trials (on label)

• SES arm in SIRIUS Odds ratio
• Post procedure in-stent MLD 0.1840
• Total implanted stent length 1.0270
• PES arm in TAXUS IV Hazard ratio (95 CI)
• No study stents implanted 5.86 (1.36 - 25.27)
• No prior MI 3.70 ( 1.11 12.50)
• Female gender 2.33 (1.08 5.00)
• Lesion length 1.05 (1.01 1.10)

54
Independent predictors of DES restenosis
Registries (including off-label)

• Rotterdam (Circulation. 2004)
• In-stent restenosis lesion
• Ostial lesions
• DM
• Vessel size
• LAD
• Munich (Circulation. 2006)
• Vessel size
• Final Diameter stenosis
• DES type
• Seoul (Am J Cardiol. 2006)
• DES type
• Final MLD
• Lesion length

• Washington (ACC. 2007)
• Age
• Hypertension
• Procedural length
• Lack of IVUS guidance
• Total stented length
• Milan (AHA. 2006)
• DM
• Unstable angina
• Reference vessel diameter
• Number of stents per lesion

55
DES Restenosis

• Mechanisms
• Predictors
• Morphological patterns
• Therapy approach
•  Delayed  restenosis

56
Morphological Patterns of DESIn-Stent Restenosis
Lesions
57
Patterns of In-Stent Restenosis Cypher vs Taxus
Cypher
Taxus
N149
N150
Milan Corbett SJ. et al. Eur Heart J 2006
N80
N97

• Seoul
• Park CB. et al.
• AHA 2006

Focal
Diffuse
Proliferative
Occlusive
58
Patterns of In-Stent Restenosis Milan experience
Cypher, N150
Taxus, N149
Plt0.001
Plt0.001
Corbett SJ. et al. Eur Heart J 2006 272330-2337
59
DES Restenosis

• Mechanisms
• Predictors
• Morphological patterns
• Therapy approach

60
Conventional therapies vs SES for DES Failures
6-month angiographic outcomes
In-stent restenosis

mm
In-stent late loss
1
50
P0.006
P0.021
0.76
40
35
0.75
30
0.5
20
0.27
0.25
10
4
0
0
Conventional
SES
Conventional
SES
N33
N33
N25 Cutting balloon 11 VBT 14
N25 Cutting balloon 11 VBT 14
Kim YH. et al. Am J Cardiol 2006981451-4
61
Radiation (IRT) vs DES for DES Failures RESCUE
trial
Clinical outcomes _at_ 8 months
IRT (N 61)
15.0
DES (N 50)
p 1.0
10.0
10.0
8.0

p 0.59
p 1.0
5.0
4.0
2.0
2.0
2.0
0.0
0.0
0.0
Death
Q-MI
TLR
Late
thrombosis
Torguson R. et al. Am J Cardiol 2006981340-4
62
SES vs PES for SES FailuresMulticenter Registry
in Asia
Restenosis _at_ 1 year
TLR _at_ 1 year


Plt0.05
Plt0.05
N198 lesions
N161 lesions
N156 pts
N152 pts
Nakamura S. et al. ACC 2007
63
Same DES vs other DES vs. POBA for DES
FailuresDoes the switch therapy work?
TLR _at_ 1 year

P0.03
N37 pts
N62 pts
N19 pts
Solinas E. et al. TCT 2006
64
Same DES vs other DES vs. other treatment for DES
FailuresDoes the switch therapy work?
Clinical outcomes _at_ 1 year

P0.81
40
P0.70
35
32.6
30.8
30
26.8
Same DES
N43
20
P0.24
P0.62
Different DES
N40
7.7
7.5
10
2.7
0
0
Death
Q-MI
TVR
MACE
Garg S. et al. CCI. 200770 9-14
65
Same DES vs other DES vs other treatment for DES
FailuresDoes the switch therapy work?
In-stent restenosis _at_ mean 25.7 months
TLR _at_ mean 25.7 months

P1.0
P1.0

N107
N94
N107
N94
Cosgrave J. et al. AHJ.2007153 354-9
66
Do patterns of in-stent restenosis predict
outcomes in the DES era?
Focal (N 132) Repeat DES 57.1, POBA 42.9
Non focal (N 71) Repeat DES 69, POBA 31
P0.11
Clinical outcomes _at_ median 13.7 months
P0.25
P0.04
P0.69
P0.12
Cosgrave J. et al. JACC 200647 2399-404
67
Do patterns of in-stent restenosis predict
outcomes in the DES era?
QCA data _at_ 9 months
Late loss
In-stent restenosis
P0.0001
mm
P0.0001

N101
N47
N101
N47
Cosgrave J. et al. JACC 200647 2399-404
68
Current therapeutic options according to
potential mechanisms of DES restenosis
Costa MA. et al. AHJ.2007153 447-9
69
DES Restenosis
Summary

• Restenosis after DES still occurs and at a
  disturbing frequency in the highest risk
  lesion/patient subsets.
• Underlying mechanism of DES restenosis involve a
  complex interplay of biological, mechanical, and
  technical (operator-dependent) factors.
• Strut fractures are more frequent than previously
  suspected, occurring most commonly at the edge of
  an overlap segment and they have been implicated
  in many clinical events, including restenosis,
  thrombosis, and aneurysm formation .

70
DES Restenosis
Summary

• The morphologic patterns of DES restenosis are
  different from BMS, favoring a more focal and
  easily treated pattern with expected improved
  clinical outcomes.
• The treatment of DES restenosis is based on
  appreciation of underlying mechanisms and can
  vary from simple POBA, to DES when appropriate,
  to CABG in the most extreme cases.
• Late DES restenosis remains an infrequent
  clinical event, despite the differing helaing
  patterns relative to BMS.

71
DES Use - 2007
Just do the right thing!

• Assess patient and lesion characteristics to
  establish restenosis risk profile
• Determine relative value of DES vs. BMS inevery
  patient (no more unrestricted use)
• Consider both on-label and off-label situations
  (ironically, off-label use scenarios may be more
  compelling)
• Increased restenosis risk favor DES
• Increased safety concerns favor No DES

72
DES Use - 2007
Just do the right thing!

• Assess patient factors which may preclude
  long-term (at least one year) dual AP therapy
• Planned or possible intercurrent surgery
• Bleeding Hx or tendencies
• Other concomitant medications (e.g. coumadin)
• Socio-economic factors which may affect Plavix
  compliance

73
DES Use - 2007
Just do the right thing!

• Consider alternatives to DES, if risk-benefit
  assessments prove unfavorable
• CABG unprotected LM disease, complex MVD (esp.
  diabetics), recurrent ISR (esp. VBT)
• BMS Plavix dependence concerns, large (gt4mm
  diameter) vessels, ? AMI pts, ? low restenosis
  risk lesions
• Balloon PCI sidebranch in bifurcations
  (provisional stent only), small vessels in distal
  locations

74
DES Use - 2007
Just do the right thing!

• Optimize DES implantation techniques
• Adequate lesion preparation (pre-dilatation)
• High pressure implantation methodologies (like
  previous BMS strategies)
• Avoid undersizing and inflow/outflow obstruction
  (mod stenoses or dissections)
• Implant stent edges into normal references
  segments
• Consider IVUS guidance (esp. LAD)

75
DES Use - 2007
Just do the right thing!

• Careful explanations and open communication with
  patients and families
• Careful pre-treatment history
• Discussion with EVERY pt re risks and benefits
  of DES vs. alternative therapies
• Ongoing (post-Rx) communication and careful FU
  re dual AP compliance (instructions NO Plavix
  discontinuation without MD approval)!

76
The search for a Better DES

• Reduce the incidence of repeat revascularization
  and its downstream events and provide equivalent
  or better safety results compared with BMS
• Such a stent would then be associated with a
  lower overall death and MI rate compared with
  BMS