Future Developments in Coronary Stenting

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Future DevelopmentsinCoronary Stenting

• Keith D Dawkins MD FRCP FACC
• Southampton University Hospital
• UK

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Conflicts of Interest

• Research Grant Support
• Boston Scientific Corporation
• Advisory Board/Consultant
• Abbott Vascular
• Boston Scientific Corporation
• Conor Medsystems
• Eli Lilly
• Medtronic
• Nycomed

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Angioscopy Doppler Flow Intravascular
Ultrasound Optical Coherence Tomography Palpograph
y Pressure Measurements Thermography Virtual
Histology
1977
Brachytherapy Cutting Balloon Directional
Atherectomy Extraction Atherectomy Laser
Atherectomy Perfusion Balloon Rotational
Atherectomy
2007
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Balloon
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gt3 Million Patients gt4.5 Million DES
Worldwide DES Penetration
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Changes in Stock Price (2005-2007)
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Drug Eluting Stent Use ()
98.1
Des Use ()
76.4
2006
Wessex Cardiac Unit
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The Players
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Drug Eluting Stents
Deliver on Ideal Stent Platform
Drug Selection
Elution Mechanism
SAFETY EFFICACY
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What are the Expectations of the available Stent
Technology ?
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Expectations of Stent Technology
Efficacy
Safety

• Deliverable
• Low TLR
• Low Restenosis
• Low Late Lumen Loss
• Cost-Effective

• No Device Malfunction
• No Early MACE
• Q AMI
• Non-Q AMI
• No Stent Thrombosis

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Real World Target Lesions

• Long Lesions 10
• Small Vessels 13
• Bifurcations 20
• Diabetics 24
• Simple 33

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Efficacy
The Patient
The Analyst
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Efficacy
The Patient
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Efficacy
The Analyst
Late Loss (mm)
Sirius
Taxus II
Endeavor II
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Coronary Artery
Stent
TLR
Late Loss
Restenosis gt50 (TLR)
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Late Loss vs. Restenosis
Example 3.0mm Bare Metal Stent Mean Late Loss
1.0 0.5mm
Angiographic Restenosis Late Loss gt1.5 mm (50
DS)
Clinical Restenosis (TLR) Late Loss gt2.1 mm
(70 DS)
Mean Late Loss
Distribution Density
Don Baim 2006 (Modified)
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ENDEAVOR I vs. RESOLUTE
QCA 4 months
Late Loss (mm)
N100
N30
Endeavor I
Resolute
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SPIRIT II
plt0.0001
QCA 6 months
Late Loss (mm)
N202
N73
Taxus
Xience V
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SPIRIT II
X
plt0.0001
QCA 6 months
Late Loss (mm)
N202
N73
Taxus
Promus
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Stent A
Stent B
Lower Late Loss
Higher Late Loss

• Low Restenosis
• Small Vessels
• Diabetes
• ? Low Thrombosis

• ? Low Restenosis
• ? Small Vessels
• ? Diabetes
• Low Thrombosis

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Paclitaxel

• Multi-functional activities with cell
• Dose dependent effects
• Anti-proliferative
• Anti-inflammatory
• Prevents SMC migration
• Promotes apoptosis at low doses
• Cytostatic within the therapeutic range

Taxus Brevifolia
Taxol
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Sirolimus (Rapamycin)
Streptomyces hygroscopicus Easter Island (Rapa
Nui)

• Macrolide antibiotic
• Potent immunosuppressant and anti-proliferative
  agent
• Binds to the cytosolic protein FK-binding protein
  12 (FKBP 12)
• Inhibits m-TOR
• Blockade of cell cycle progression at the G1/S
  transition
• Relaxation of smooth muscle

Sirolimus
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Cytokine/Growth Factor
Antigen
Receptor Tyrosine Kinase
TCR
Pimecrolimus
PLC
mTOR
PHAS-1
PIP2
InsP3 DAG
Sirolimus
Ca
Calcineurin??
Calmodulin
Translation
Calcineurin
MAPKKS
Removal of p21/p27
Pimecrolimus
Activation of CDKs
AP-1
NFAT
NFKB
IL-2
P
NFAT
Cell cycle progression
RNA
Nucleus
IL-2
NFAT
NFKB
AP-1
Modified from Donners 2003
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Spectrum of Limus Analogues
Everolimus Biolimus A9
Tacrolimus
Zotarolimus
Sirolimus
Pimecrolimus
Anti-proliferative mTOR Binding
Anti-inflammatory Calcineurin Inhibition
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Genous Stent (48 hour Balloon-injured Porcine
Model)
Bare Metal
EPC Capture
M Kutryk (unpublished)
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Polymer based Drug Delivery

• Local, targeted, short-term, low-dose drug
  delivery
• Controlled release of drug from polymer
• Homogeneous drug coverage along stent
• Retention of drug on stent during handling
• Prevention of
• Drug loss during implantation
• Overdose from non-uniform drug distribution and
  immediate burst release of total loaded dose

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DES Release Profiles
100
ENDEAVOR
CYPHER
80
XIENCE
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Cumulative Drug Release ()
40
20
TAXUS
0
0
5
10
15
20
25
30
Days
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Normal appearance of DES Polymer
TAXUS
CYPHER
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Problems with polymers
Polymer damaged by expansion in air at room
temperature
Bare areas
Redundant polymer
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59 Year Old Female with TAXUS Stent in the LAD
for 130 Days
80 surface endothelialized
Circ 2004109701-705
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Polymer ThicknessTaxus, Cypher Xience
Coating Thickness (µm)
Cypher
Xience
Taxus
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New Polymers Coatings

• Reduced Polymer Volume
• Bioabsorbable Polymers
• No Polymer
• Depot Technology
• Setagon Nano Technology
• Surface Modifications
• Nano-membranous Filters
• Photolithographic Etching
• Hydroxyappetite HA

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Reservoir Technology (Conor Medsystems)

• The reservoir system provides the ability to load
  drug and control the delivery time and rate
• A bioresorbable polymer with minimal contact with
  the vessel wall thus, reduced polymer tissue
  interaction and no long term residual drug or
  polymer
• GENESIS Trial assesses the combination of
  Pimecrolimus (an anti-inflammatory), and
  Paclitaxel (an anti-restenotic)
• GENESIS is the first dual-drug RCT

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Polymer Degradation (Porcine Model)
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Paclitaxel and Pimecrolimus Dual Drug Components
Thrombosis
Extra-Cellular Matrix Production
Inflammation
Proliferation
This drug combination targets two separate
aspects of the restenotic process
Adapted from Nikol, Atherosclerosis 199612317-31
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TAXUS Element Stent Platform

• Geometry designed for drug delivery
• Four stent models
• Consistent surface-to-artery ratios
• Apex balloon
• Bi-component balloon
• Multilayer
• Platinum Enriched Stainless Steel
• Radio-opaque
• Thin Struts
• High radial strength

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TAXUS Odyssey Stent Program
Asymmetric Polymer Coating
Optimized Drug Release
Bioresorbable Polymer
Pro-healing Surface
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BMJ January 20th 2007
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Bifurcations
Devax
BSC (Petal)
Medtronic
YMed
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Intra-coronary stentsAnticoagulant
Antiplatelet therapy
?
Year
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Thrombus
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The Platelet, the enemy of the interventionist
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History of Stent Thrombosis
Stent Thrombosis ()
PS1 1991
STRESS2 1993
Colombo3 1995
ISAR4 1996
STARS5 1997
1. Schatz et al. Circulation.199183148 2.
Fischman et al. N Engl J Med. 1994331496 3.
Colombo et al. Circulation.1995911676 4.
Schömig et al.Circulation.1994,902716 5. Leon
et al. N Engl J Med. 19983391665 6. Joner et
al. J Am Coll Cardiol. 200648193
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Pooled Analysis of the Safety and Efficacy of
Sirolimus and Paclitaxel eluting Stents
p0.3
Stent Thrombosis ()
1 4 years
30 days 1 year
0-30 days
N Engl J Med 2006356000-000
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Sirolimus Eluting Stent vs. Bare Metal Stent
n
n
D
Cypher 16 months after deployment
BMS 24 months after deployment
Circulation 20031071340-1341
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Delayed Endothelialization in DES compared with
BMS
100 80 60 40 20 0
BMS (n25)
DES (n23)
Percentage Endothelialization ()
0 2 4 6 8 10 12 14 16 18 20
gt40
Duration Post-Implant (months)
JACC 200648000-000
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Sirolimus Eluting Stent vs. Bare Metal Stent
BMS
Confluent endothelial cells longitudinally
aligned
Confluent endothelial cells with few adherent
platelets
Cypher
Rare non-confluent endothelial cells with minute
platelet thrombus
Pavement-shaped endothelial cells
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Endothelial Dysfunction after Sirolimus-Eluting
Stent Implantation
Baseline angiogram 6/12 post SES implant (LAD)
Post acetylcholine (IC) 0.14 µgm/min (2mins)
Post GTN (IC) 250 µgm/min bolus
Circulation 2006113e850-851
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Biodegradable Stents
and many more
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Clopidogrel Non-Responsiveness
Distribution of Changes in ADP-induced Platelet
Aggregation
J Am Coll Cardiol 200545246-251
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Coronary Imaging
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Drug Eluting Stents vs. Bare Metal Stents
BENEFIT
RISK
?
Reduced Restenosis
Stent Thrombosis
Death, AMI, TLR
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Lancet 20063681421-1428
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2.5
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www.gapminder.org
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Conclusions

• The importance of Late Loss in relation to DES
  thrombosis is yet to be defined
• Polymer based drug delivery is likely to be
  responsible for some MACE
• Bioerodable polymers may be associated with less
  complications
• Multiple drug delivery may allow pacification of
  the arterial response to stent implantation
• Developments in dedicated bifurcation stent
  technology offer some promise
• Bioerodable stents (the Holy Grail) may be
  clinically relevant within five years
• Developments in coronary imaging (MR, CT) will
  impact stent design
• Anti-platelet responsiveness should be further
  investigated