drug-eluting stents
DESCRIPTION
Drug-eluting stents. Χρήστος Ν. Μπακογιάννης. Μεταπτυχιακό πρόγραμμα Ιατρικής Σχολής ΕΚΠΑ « Ενδαγγειακές Τεχνικές ». Endothelial injury post implantation. Implanted stent. Plaque. - PowerPoint PPT PresentationTRANSCRIPT
Drug-eluting stents
Χρήστος Ν. Μπακογιάννης
Μεταπτυχιακό πρόγραμμαΜεταπτυχιακό πρόγραμμα
Ιατρικής Σχολής ΕΚΠΑΙατρικής Σχολής ΕΚΠΑ
« Ενδαγγειακές Τεχνικές»« Ενδαγγειακές Τεχνικές»
2
Endothelial injurypost implantation
Stent implantation causes arterial injury, which can initiate restenosis. The restenosisStent implantation causes arterial injury, which can initiate restenosis. The restenosisprocess includes process includes inflammation, migration of smooth muscle cells, smooth muscle cellinflammation, migration of smooth muscle cells, smooth muscle cellproliferation and extracellular matrix formation. proliferation and extracellular matrix formation.
Implanted Implanted stentstent
PlaquePlaque
3
Platelet aggregationand activation
Drug-eluting stent strutsDrug-eluting stent struts
PlateletsPlatelets
Inflammatory cellsInflammatory cells
Platelet deposition and activation occur at the injury site, leading to the release ofPlatelet deposition and activation occur at the injury site, leading to the release ofcell-signaling molecules. cell-signaling molecules.
Red blood cellsRed blood cells
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Transmigration ofinflammatory cells
Smooth muscle cellsSmooth muscle cells
Inflammatory cellsInflammatory cellssecreting cell-signalingsecreting cell-signalingmoleculesmolecules
Transmigration ofTransmigration ofinflammatory cellsinflammatory cells
Once activated, these inflammatory cells roll across the endothelial surface andOnce activated, these inflammatory cells roll across the endothelial surface andtransmigrate into the lesion. transmigrate into the lesion.
Endothelial cellsEndothelial cells
5
Activation of smoothmuscle cells
Cell signaling Cell signaling molecules activatemolecules activatesmooth muscle cellssmooth muscle cells
Smooth muscle cellSmooth muscle cellsurface receptorsurface receptor
The activated inflammatory cells secrete molecules that bind to specific receptorsThe activated inflammatory cells secrete molecules that bind to specific receptorson smooth muscle cells. on smooth muscle cells.
Smooth muscle cell extracellular viewSmooth muscle cell extracellular view
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Activation of smoothmuscle cells
ActivatedActivatedsmooth musclesmooth musclecell receptorcell receptor
mTOR activatesmTOR activatessmooth musclesmooth musclecells to entercells to entercell cyclecell cycle
Bound smooth muscle cell receptors activate various intracellular smooth muscleBound smooth muscle cell receptors activate various intracellular smooth musclecell proteins. One such protein, mTOR, plays a central regulatory role in the cell cyclecell proteins. One such protein, mTOR, plays a central regulatory role in the cell cycle. .
Smooth muscle cell intracellular viewSmooth muscle cell intracellular view
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Activation of smoothmuscle cells (III)
Cell responds to growth factor stimulationCell responds to growth factor stimulation
DNA synthesisDNA synthesisCell prepares Cell prepares for mitosisfor mitosis
MitosisMitosis
Cell resting phase Cell resting phase Restriction pointRestriction point
Activated mTOR stimulates smooth muscle cells to advance from the G1 phase toActivated mTOR stimulates smooth muscle cells to advance from the G1 phase tothe S phase where DNA replication occurs, causing the smooth muscle cells tothe S phase where DNA replication occurs, causing the smooth muscle cells toundergo mitosis (ie, cell proliferation). undergo mitosis (ie, cell proliferation).
Differential Events Leading to In-Stent Restenosis
Matrix deposition
Leukocyte recruitment
VSMC migration / proliferation
Platelet Deposition
Frac
tion
of M
axim
al R
espo
nse
Time
0
1
Επαναστένωση
There are three major components to a drug-eluting stent:
Type of stent that carries the drug coating
Method by which the drug is delivered (eluted) by the coating to the arterial wall (polymeric or other)
The drug itself – how does it act in the body to prevent restenosis?
Cordis CYPHER™ sirolimus-eluting stent
Boston Scientific TAXUS™ paclitaxel-eluting stent system,
Medtronic's Endeavor stent which uses ABT-578
XIENCE PRIME Everolimus Eluting Coronary Stent System
Drug-eluting stents στην SFA
Duda SH. Circulation 2002; 106:1505–1509.
Τύποι drug-eluting stents με εφαρμογή στην αγγειοχειρουργική
Rapamycin Analogs
Chemical Formula
C53H83NO14
Molecular Wt: 958.25
C51H79NO13
Molecular Wt: 914.2
C52H79NO12
Molecular Wt: 966.23
Intended Pharma
Indications
Chronic & Acute Rejection – Heart,
Kidney, Lung
Acute Rejection – Kidney, Liver None
ApprovalsOUS
US – H2 04 (Est.)OUS & US None
EVEROLIMUS SIROLIMUS ABT-578
NNNN
N
OO
O
CH3
O
O
O
H3C
O
HO
CH3
CH3
CH3
HOH3C
H
O
OH
H3C
H
CH3
H
OOH
OH3C H3C
Chiral NNNN NN
SMART stents στην SFA
Duda SH. Circulation 2002; 106:1505–1509.Duda SH. J Vasc Interv Radiol 2005; 16:331–338
The only study which reported local drug delivery in the SFA was the Sirolimus-Coated Cordis Self-Expandable Stent (SIROCCO) trial, in which sirolimus-coated stents were not significantly superior to uncoated stents
SMART stents στην SFA
Duda SH. J Vasc Interv Radiol 2005; 16:331–338
Zilver PTX (paclitaxel)
First, it allows targeted delivery of a drug (paclitaxel) proven to reduce the renarrowing (restenosis) of arteries opened using balloon angioplasty.
Second, by eliminating the need for a polymer, Zilver PTX avoids the potential patient risks posed by leaving a permanent foreign, plastic substance in the body.
Zilver PTX mechanisms of action:
Hydrophobic—PTX won't wash off. It adheres to the stent without the need for a synthetic polymer Lipophilic—PTX seeks the lipids in the vessel wall and attaches
Antiproliferative—once in the cell, PTX blocks cell division (proliferation) for the life of the cell
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific Yew
tree, Taxus brevifolia and named it 'taxol'
Paclitaxel-eluting non–polymer-based stent (Zilver PTX)
Brunk D. American College of Surgeons: Surgery News. 2008; 4(September):12.
Self-expanding polymer-based everolimus-eluting stent (Dynalink-E)
Bosiers M. Vasc Health Risk Manag. 2008;4:553–559.
Διαφορετική αποτελεσματικότητα drug-eluting stents στην SFA & στα στεφανιαία.
ΓΙΑΤΙ;
Oliva VL. J Vasc Interv Radiol. 2005;16:313–315.
the distance between the stent struts of the Smart stent was much larger compared to the Cypher stent, leading to a lower drug dose in the SFA compared to the coronary arteries
Drug eluting Ballons
Drug-eluting Ballons
Drug-coated balloons for femoropopliteal PTA: Paccocath (Cotavance) balloon)
Scheller B et al. Circulation. 2004;110:810–814.Scheller B et al. N Engl J Med. 2006;355:2113–2124.Scheller B. EuroIntervention. 2008;4(suppl C):C63–C66.Scheller B et al. Heart. 2007;93:539–541.
Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries
(THUNDER) trial 154 patients (24% smokers, 49% diabetics) with
femoropopliteal lesions
Paccocath (n=48 patients)
no adverse event
6 months mean late lumen loss 0.461.2 mm vs. 1.761.8 mm for controls (p=0.001)
6-month & 12-month angiographic binary restenosis were 10% and 25% for the Paccocath patients vs. 41% and 59% for the control patients (p=0.01)
Tepe G, et al. N Engl J Med.2008;358:689– 99.
Currently, the use of antiproliferative agents, either exposed by stents or balloon catheters in preventing restenosis in infrainguinal arteries, is still investigational.
Ανεπιθύμητες ενέργειες Vascular toxicity rather than cytotoxicity
– Late incomplete apposition– Medial thinning– Aneurysm/rupture– Delayed re-endothelialization
High dose, fast release Low dose, slow release
Rogers C et al. Circ. 2000.
Vasculo-toxic effects in pig coronaries: 90 days
Late incomplete apposition
Potential for stent thrombosisPotential for stent thrombosisBaseline
Positiveremodeling
No remodeling
Follow-up
In a Taxus and Cypher study of patients with late incomplete apposition upon clopidogrel discontinuation:
20% had stent thrombosis*
30
Percent struts endothelialized
Human analysis: DES vs BMSHuman analysis: DES vs BMS
Conclusions:Conclusions:DES (solid line) consistently show less endothelialization compared with BMS DES (solid line) consistently show less endothelialization compared with BMS (dashed line) regardless of time point, even beyond 40 months(dashed line) regardless of time point, even beyond 40 monthsDES are not fully endothelialized, whereas BMS are completely covered by 6 DES are not fully endothelialized, whereas BMS are completely covered by 6 to 7 monthsto 7 months
Per
cent
age
endo
thel
ializ
atio
n
Duration in months1 2 3 4 5 6 7 8 9 11 15 16 17 20 > 40
Taxus and CypherBMS
0
10
20
30
40
50
60
70
80
90
100
Joner, Virmani et al. Circulation. 2005;112:3210.
31Kotani et al. JACC. 2006;47:2108-2111.
> 80% Cypher struts exposed vs BMS struts> 80% Cypher struts exposed vs BMS struts
Exposed stent struts at 6 months
0
25
50
75
100
Incomplete coverage Complete coverage
Sirolimus-eluting stent
Bare-metal stent
Grade 0 Grade 1 Grade 2 Grade 3
250
5075
100
Per
cent
Per
cent
32
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
Cai H, Harrison DG. Circ Res. 2000;8This is explained by either a loss ofendothelial cells or loss of eNOS expressionand NO production7:840-844.Bonetti PO et al. ATVB. 2003;23:168-175.