Pathology of Stent Restenosis Josiah Wilcox PhD Medtronic, Inc'

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Pathology of Stent Restenosis Josiah Wilcox
PhDMedtronic, Inc.
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Endothelial injurypost implantation
Implanted stent
Plaque
Stent implantation causes arterial injury, which
can initiate restenosis. The restenosisprocess
includes inflammation, migration of smooth muscle
cells, smooth muscle cellproliferation and
extracellular matrix formation.
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Platelet aggregationand activation
Drug-eluting stent struts
Platelets
Red blood cells
Inflammatory cells
Platelet deposition and activation occur at the
injury site, leading to the release
ofcell-signaling molecules.
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Transmigration ofinflammatory cells (I)
Activated inflammatory cells
Intima
Cell surface receptors
Media
Inflammatory cells
The cell-signaling molecules induce expression of
cell surface receptors that bindto circulating
inflammatory cells.
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Transmigration ofinflammatory cells (II)
Endothelial cells
Transmigration ofinflammatory cells
Smooth muscle cells
Inflammatory cellssecreting cell-signalingmolecu
les
Once activated, these inflammatory cells roll
across the endothelial surface andtransmigrate
into the lesion.
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Activation of smoothmuscle cells (I)
Smooth muscle cell extracellular view
Cell signaling molecules activatesmooth muscle
cells
Smooth muscle cellsurface receptor
The activated inflammatory cells secrete
molecules that bind to specific receptorson
smooth muscle cells.
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Activation of smoothmuscle cells (II)
Smooth muscle cell intracellular view
Activatedsmooth musclecell receptor
mTOR activatessmooth musclecells to entercell
cycle
Bound smooth muscle cell receptors activate
various intracellular smooth musclecell
proteins. One such protein, mTOR, plays a central
regulatory role in the cell cycle.
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Activation of smoothmuscle cells (III)
Cell responds to growth factor stimulation
Mitosis
Cell resting phase
Restriction point
DNA synthesis
Cell prepares for mitosis
Activated mTOR stimulates smooth muscle cells to
advance from the G1 phase tothe S phase where
DNA replication occurs, causing the smooth muscle
cells toundergo mitosis (ie, cell
proliferation).
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Activation of smoothmuscle cells (IV)
Extracellularmatrix
Proliferating smoothmuscle cells
Proliferation of smooth muscle cells increases
the cellular mass in the neointima,leading to
restenosis.
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Drug diffusion
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How much late loss is clinically relevant?
Late loss 0.2 mm DS 6
Late loss 0.6 mm DS 17
Late loss 1.2 mm DS 34
Diameter stenosis 3.5-mm vessel
Patent lumen
Exposed struts?
Late loss 0.2 mm DS 8
Late loss 0.6 mm DS 24
Late loss 1.2 mm DS 48
Diameter stenosis 2.5-mm vessel
Patent lumen
Exposed struts?
Illustrations for demonstration purposes only.
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Clinical relevance of low late loss
Preprocedure
Postprocedure
Source HCRI EIII 9 month (IVUS 8 months).
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Clinical relevance of low late loss
8 months
0.2 mm
Source HCRI EIII 9 month (IVUS 8 months).
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Clinical relevance of low late loss
Preprocedure
Postprocedure
Source HCRI EIII 9 month (IVUS 8 months).
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Clinical relevance of low late loss
8 months
0.4 mm
Source HCRI EIII 9 month (IVUS 8 months).
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Clinical relevance of low late loss
Preprocedure
Postprocedure
Source HCRI EIII 9 month (IVUS 8 months).
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Clinical relevance of low late loss
8 months
0.6 mm
Source HCRI EIII 9 month (IVUS 8 months).
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Clinical relevance of low late loss
0.2 mm
0.4 mm
0.6 mm
Late loss
3.59 mm
2.97 mm
2.70 mm
RVD
Patent lumen
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Safety parameters
Broader definitions decrease specificity
MI/QWMI and all-cause mortality
Expanded ARC stent Thrombosis definition Possible
, probable, definite
Prespecified HCRI CEC Definition ST
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9 prospective, double-blind, randomized
trialsFreedom from ischemic TLR
TAXUS I, II, IV, V, VI (n 3506)
RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS (n 1748)
92.2 (66)
89.9 (164)
P lt 0.0001
P lt 0.0001
76.4 (202)
80.0 (337)
Time after initial procedure (years)
Time after initial procedure (years)
Independent CRF patient-level meta-analysis from
TCT 2006.
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9 prospective, double-blind, randomized
trialsFreedom from (protocol) stent thrombosis
TAXUS I, II, IV, V, VI (n 3506)
RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS (n 1748)
Time after initial procedure (years)
Time after initial procedure (years)
Independent CRF patient-level meta-analysis from
TCT 2006.
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9 prospective, double-blind, randomized
trialsFreedom from death or myocardial infarction
TAXUS I, II, IV, V, VI (n 3506)
RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS (n 1748)
89.7 (88)
88.2 (182)
P 0.39
P 0.77
88.4 (100)
87.6 (186)
Time after initial procedure (years)
Time after initial procedure (years)
Independent CRF patient-level meta-analysis from
TCT 2006.
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Current status of DES

• The data on the two previously approved DES have
  demonstrated a significant reduction in the need
  for repeat revascularization vs BMS
• Recently the rare but catastrophic event of late
  stent thrombosis was shown to be increased with
  these DES compared to BMS
• However, any increased incidence of LST appears
  to be offset by a reduction in downstream
  revascularization events prevented by DES

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DES AMI rates higher than BMS

• Swedish SCAAR and RIKS-HIA databases
• 2005 report does not include Endeavor to 3 yrs
• Increase in AMI for DES after 1.5 years
• 2-3 AMI per year

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DES n 19,190
8




6
BMS n 23,588
AMI
4
2
0

0
1
2
3
Years after stenting
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Incidence and predictors of stent thrombosis in
bare metal stent era
6186 patients, 0.9 30-day ST
Cutlip et al. Circulation. 20011031967-1971.
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Timing of stent thrombosis with BMS
(A) incidence of stent thrombosis (n number of
stent thromboses per day) following bare-metal
stent implantation.Acute and subacute stent
thrombosis ( 30 days) are in yellow, late stent
thrombosis (gt 30 days) in yellow.(B) Cumulative
incidence of stent thrombosis following
bare-metal stent implantation.
Wenaweser P et al. EHJ. 2005261180-1187.
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Rates of stent thrombosis
BMS bare metal stent DES drug-eluting stent
PES paclitaxel-eluting stent SES sirolimus
eluting stent.
Barvy P et al. The American Journal of Medicine.
20061191056-1061.
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Stent thrombosis
Procedure, product, patient
Procedure
Stent apposition dissection
Stent thrombosis
Product
Patient
Polymerdrug
Higher risk AP compliance
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Late stent thrombosisDES Factors to consider
Discontinuation of antiplatelet therapy
Late stentthrombosis
Delayedendothelialization
Late incompleteapposition
Polymer hypersensitivity/ inflammation
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Late stent thrombosisfactors to consider
Discontinuation of antiplatelet therapy
Late stentthrombosis
Delayedendothelialization
Late incompleteapposition
Polymer hypersensitivity/ inflammation
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Stent thrombosis rates
According to select patient characteristics
Antiplatelettherapydiscontinuation
Diabetes
Priorbrachy
Renalfailure
Bifurcations
ULM
UA
Premature discontinuation. Iakovou et al. JAMA.
20052932126-2130.
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Premature discontinuationof anti-platelet therapy
Iakovou et al. JAMA. 20052932126-2130.
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Clopidogrel therapy
Prevalence of adverse events

• 8.8 major bleeding
• 5.3 minor bleeding
• 15.8 skin rash and appendage disorders

increased potential for patient noncompliance
Steinhubl SR et al. JAMA. 2002288(19)2411-2420.
PLAVIX Prescribing Information.
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Is long-term clopidogrelthe answer?
P .07
P lt .001
P .001
N 15,603 2.5 year FU GUSTO major moderate
bleed
N 12,563 1 year FU CURE major bleed
N 2116 1 year FU TIMI major bleed
JAMA. 20022882411-2420.
NEJM. 2001345494-502.
NEJM. 20063541706-1717.
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Late stent thrombosisfactors to consider
Discontinuation of antiplatelet therapy
Late stentthrombosis
Delayedendothelialization
Late incompleteapposition
Polymer hypersensitivity/ inflammation
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Late incomplete apposition
Potential for stent thrombosis
Follow-up
Baseline
In a Taxus and Cypher study of patients with late
incomplete apposition upon clopidogrel
discontinuation
20 had stent thrombosis
No remodeling
Positive remodeling
Study by Dr. Abizaid, presented at TCT 2005.
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Late stent thrombosis from LIA
Case of LaST with Cypher stent
44 year-old man was admitted with AMI,31 months
after a initial SES placement
Total occlusion
Eur Heart J. 21 Oct 2005.
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Late stent thrombosisfactors to consider
Discontinuation of antiplatelet therapy
Late stentthrombosis
Delayedendothelialization
Late incompleteapposition
Polymer hypersensitivity/ inflammation
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Predictors of DES thrombosis
35 autopsy examinations following stentplacement
(N 32 DES, 7 BMS)

• SAT 8/39 stents, LST 29/39 stents
• All BMS with complete endothelialization
• Predictors
• Stent across ostia of major sidebranch
• Strut penetration of necrotic core
• Stent malapposition
• Increasing stent length
• Hypersensitivity
• Focal delayed no healing(absence of intima)

Joner, Virmani et al. Circulation. 20051123210.
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DES safety
Drug vs polymer
Cytostatic drug

Drug
Polymer
Cypher
Taxus
Inflammatory polymer
Inert polymer
-
Cytotoxic drug
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Inflammation
Drug vs polymer

• Conclusions
• DES further delay arterial healing and promote
  inflammation
• Compared to SES, PES induce greater
• Fibrin deposition
• Medial cell loss
• WBC infiltration
• Late neointimal hyperplasia

Finn et al. Circulation. 2005112270-278.
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Delayed endothelialization
Overlapping SES vs PES
BMS
PES
SES
BMS
Overlap
Overlap

• Conclusions
• BMS showed far greater endothelialization than
  DES
• Lack of coverage highlighted in areas of overlap
• Less surface coverage by endothelial cells in PES
  than SES

Finn et al. Circulation. 2005112270-278.
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Percent struts endothelialized
Human analysis DES vs BMS
100
90
80
70
60
Percentage endothelialization
50
40
30
20
10
0
Duration in months
Joner, Virmani et al. Circulation. 20051123210.
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Lack of endothelial strut coverage
DES vs BMS gt 3 years in humans
P .0001
Percentage endothelialization
Duration in months
Joner, Virmani et al. Circulation. 20051123210.
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Exposed stent struts at 6 months
gt 80 Cypher struts exposed vs BMS struts
100
Sirolimus-eluting stent
75
50
Percent
25
0
Incomplete coverage
Complete coverage
Grade 0
Grade 1
Grade 2
Grade 3
0
25
50
Percent
75
Bare-metal stent
100
Kotani et al. JACC. 2006472108-2111.
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Delayed endothelialization
Cypher vs BMS

• Conclusions
• 86.7 of Cypher stents had incomplete coverage
  (Grades 0-1)
• 0 of BMS had incomplete coverage(Grades 0-1)

Sirolimus-eluting stent
100
75
Percent
50
25
0
Incomplete coverage
Complete coverage
Grade 0
Grade 1
Grade 2
Grade 3
0
25
Percent
50
75
100
Bare-metal stent
Grade 0 was defined as stent struts that were
fully visible, similar to immediately after
implantation. Grade 1 was defined as stent struts
that bulged into the lumen and, although covered,
were still transparently visible. Grade 2 was
defined as stent struts that were visible, but
not clearly seen (ie, they were translucent).
Grade 3 was defined as stent struts that were
not visible by angioscopy (ie, they were embedded
in the neointima).Kotani et al. JACC.
2006472108-2111.
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Endothelial dysfunction Reduction in eNOS and
nitric oxide (NO) production

• Normal vessels dilate in response to exerciseor
  acetylcholine (ACH)
• This response is dependent on endothelial
  production of NO
• Atherosclerotic vessels are characterized
  byhaving endothelial dysfunction and
  constrictin response to exercise or ACH
• This is explained by either a loss ofendothelial
  cells or loss of eNOS expressionand NO production

Cai H, Harrison DG. Circ Res. 200087840-844. Bon
etti PO et al. ATVB. 200323168-175.
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Nitric oxide (NO)
Roles in vasculature
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Functional endothelium
SES vs BMS
Hofma SH et al. EHJ. 200527166-170.
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Expression of eNOS mRNA
Proximal region
Stented region
28 day
Endeavor implanted vessel expressed eNOS mRNA
significantly higher than both Cypher and Taxus
P lt .05 vs Endeavor.
Haraguchi et al. TCT. 2006.
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NO and endothelial cell function
Endothelial nitric oxide synthase (eNOS)
eNOS
eNOS
Stented vessel
Proximal vessel
Haraguchi et al. TCT. 2006.
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Endeavor has normal endothelial function
Assessed by eNOS protein immunohistochemistry
Haraguchi et al. TCT. 2006.
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Endeavor Endothelial function
ACH challenge 28 days after stenting
Driver (n 15)
Endeavor (n 7)
Ach (10-6M)
Baseline
Ach (10-6M)
Baseline
Cypher (n 9)
Taxus (n 8)
Ach (10-6M)
Baseline
Ach (10-6M)
Baseline
Cypher and Taxus constrict in response to
acetylcholine (ACH) suggesting EC dysfunction.
Endeavor and Driver show normal vasodilation in
response to ACH suggesting normal EC function.
Haraguchi et al. TCT. 2006.
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ACH responses compared to baseline
Endeavor demonstrated rapid recovery of EC
function
Ach/Baseline P lt .05 vs Endeavor

Driver
Endeavor
Cypher
Taxus
Haraguchi et al. TCT. 2006.