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Drug-eluting stents
Χρήστος Ν. Μπακογιάννης
Επίκουρος ΚαθηγητήςΑγγειοχειρουργικής Πανεπιστημίου Αθηνών
Α΄ Χειρουργική Κλινική ΕΚΠΑ
Λαϊκό Νοσοκομείο
Μεταπτυχιακό πρόγραμμα
Ιατρικής Σχολής ΕΚΠΑ
« Ενδαγγειακές Τεχνικές»
7/03/14
S
Endothelial injury
post implantation
Implanted
stent
Plaque
Stent implantation causes arterial injury, which can initiate restenosis. The restenosis
process includes inflammation, migration of smooth muscle cells, smooth muscle cell
proliferation and extracellular matrix formation.
2
Platelet aggregation
and activation
Drug-eluting stent struts
Platelets
Red blood cells
Inflammatory cells
Platelet deposition and activation occur at the injury site, leading to the release of
cell-signaling molecules.
3
Transmigration of
inflammatory cells
Endothelial cells
Transmigration of
inflammatory cells
Smooth muscle cells
Inflammatory cells
secreting cell-signaling
molecules
Once activated, these inflammatory cells roll across the endothelial surface and
transmigrate
into the lesion.
4
Activation of smooth
muscle cells
Smooth muscle cell extracellular view
Cell signaling
molecules activate
smooth muscle cells
Smooth muscle cell
surface receptor
The activated inflammatory cells secrete molecules that bind to specific receptors
5 smooth muscle cells.
on
Activation of smooth
muscle cells
Smooth muscle cell intracellular view
Activated
smooth muscle
cell receptor
mTOR activates
smooth muscle
cells to enter
cell cycle
Bound smooth muscle cell receptors activate various intracellular smooth muscle
cell6proteins. One such protein, mTOR, plays a central regulatory role in the cell cycle.
Activation of smooth
muscle cells (III)
Cell responds to growth factor stimulation
Mitosis
Cell resting phase
Restriction point
Cell prepares
for mitosis
DNA synthesis
Activated mTOR stimulates smooth muscle cells to advance from the G1 phase to
the S phase where DNA replication occurs, causing the smooth muscle cells to
undergo
mitosis (ie, cell proliferation).
7
Fraction of Maximal Response
Differential Events Leading to
In-Stent Restenosis
1
0
Time
Platelet Deposition
Leukocyte recruitment
VSMC migration / proliferation
Matrix deposition
Επαναστένωση
There are three major components to a drug-eluting stent:
S
Type of stent that carries the drug coating
S
Method by which the drug is delivered (eluted) by the coating to the arterial wall (polymeric or
other)
S
The drug itself – how does it act in the body to prevent restenosis?
S
Cordis CYPHER™ sirolimus-eluting stent
S
Boston Scientific TAXUS™ paclitaxel-eluting stent system,
S
Medtronic's Endeavor stent which uses ABT-578
S
XIENCE PRIME Everolimus Eluting Coronary Stent System
Drug-eluting stents στην SFA
Πρώτη εφαρμογή: τυχαιοποιημένη κλινική
μελέτη με 36 ασθενείς
• 0% επαναστένωση στους 6 μήνες ύστερα από
τοποθέτηση sirolimus-eluting stents
• 23.5% επαναστένωση στους 6 μήνες ύστερα από
τοποθέτηση bare-metal stents
Duda SH. Circulation 2002; 106:1505–1509.
Τύποι drug-eluting stents με εφαρμογή στην
αγγειοχειρουργική
Sirolimus-eluting stents
(SMART stents)
Paclitaxel-eluting non–
polymer-based stent
(Zilver PTX)
Self-expanding polymerbased everolimus-eluting
stent (Dynalink-E)
Rapamycin Analogs
EVEROLIMUS
SIROLIMUS
Chiral
OH
H
H
H
O
H
CH3
H
O
O
O
H
H3C
H3C
O
H3C
CH3
H3C
O
H
H3C
O
O
H
OH
OH
O
O
HO
OH
H3C
H3C
H3C
O
O
H3C
O
CH3
N
O
HO
HO
O
O
H3C
CH3
O
H3C
H3C
O
O
CH3
CH3
CH3
O
CH3
O
O
O
H
H
N
CH3
O
H3C
CH3
O
N
O
O
H
H
N NN
N
N N
Chiral
OH
O
ABT-578
H3C
CH3
O
H3C
O
O
CH3
CH3
CH3
CH3
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
Approvals
OUS
US – H2 04 (Est.)
OUS & US
None
SMART stents στην SFA
The only study which reported local drug delivery in the SFA was the SirolimusCoated Cordis Self-Expandable Stent (SIROCCO) trial, in which sirolimus-coated
stents were not significantly superior to uncoated stents
SIROCCO I & SIROCCO II trials
μη στατιστικά σημαντική διαφορά μεταξύ των ασθενών που
έφεραν sirolimus-eluting stents και αυτών που έφεραν baremetal stents στους 6 μήνες
0% Vs. 7.7% επαναστένωση στην SFA
δεν επιβεβαίωσαν την αποτελεσματικότητα του sirolimus
Duda SH. Circulation 2002; 106:1505–1509.
Duda SH. J Vasc Interv Radiol 2005; 16:331–338
SMART stents στην SFA
Duda SH. J Vasc Interv Radiol 2005; 16:331–338
Zilver PTX (paclitaxel)
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'
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
Διαφορετική αποτελεσματικότητα drug-eluting
stents στην SFA & στα στεφανιαία.
ΓΙΑΤΙ;
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
Η SFA έχει μεγαλύτερο μήκος, μεγαλύτερη
διάμετρο και δέχεται μηχανική καταπόνηση
Η μηχανική της πλάκας είναι διαφορετική
Τα stent διαφέρουν
• μεγαλύτερο μήκος, μεγαλύτερη διάμετρο, διαφορετική
δοσολογία επικάλυψης με φάρμακο κ.α.
Oliva VL. J Vasc Interv Radiol. 2005;16:313–315.
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.
standard
angioplasty balloon
catheter with a
paclitaxel coating
(a mixture of
paclitaxel and
contrast)
10% to 20% of the
drug is taken up by
the vessel wall
short-term contact
prolonged
inhibition of
neointimal
proliferation
Local Taxane with Short Exposure for Reduction of
Restenosis in Distal Arteries
(THUNDER) trial
S 154 patients (24% smokers, 49% diabetics) with
femoropopliteal lesions
S Paccocath (n=48 patients)
S no adverse event
S 6 months  mean late lumen loss 0.461.2 mm vs. 1.761.8 mm
for controls (p=0.001)
S 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)
Currently, the use of antiproliferative agents,
either exposed by stents or balloon catheters
in preventing restenosis in infrainguinal
arteries,
is still investigational.
Tepe G, et al. N Engl J Med.2008;358:689–
99.
Ανεπιθύμητες ενέργειες
 Vascular toxicity rather than cytotoxicity
–
–
–
–
Late incomplete apposition
Medial thinning
Aneurysm/rupture
Delayed re-endothelialization
Vasculo-toxic effects in pig coronaries: 90 days
High dose, fast release
Low dose, slow release
Rogers C et al. Circ. 2000.
Late incomplete apposition
Potential for stent thrombosis
Baseline
Follow-up
In a Taxus and Cypher study
of patients with late
incomplete apposition upon
clopidogrel discontinuation:
No
remodeling
Positive
remodeling
20% had stent thrombosis*
Percent struts endothelialized
Human analysis: DES vs BMS
Percentage endothelialization
100
90
80
70
60
50
40
30
20
Taxus and Cypher
BMS
10
0
1
28
2
3
4
5
6 7 8 9 11 15 16 17 20 > 40
Duration in months
Conclusions:
DES (solid line) consistently show less endothelialization compared with BMS
(dashed line) regardless of time point, even beyond 40 months
DES are not fully endothelialized, whereas BMS are completely covered by 6
to 7 months
Joner, Virmani et al. Circulation. 2005;112:3210.
Exposed stent struts at 6 months
> 80% Cypher struts exposed vs BMS struts
Percent
100
Sirolimus-eluting stent
75
50
25
0
Incomplete coverage
Grade 0
Complete coverage
Grade 1
Grade 2
Percent
0
25
50
75
100
29 et al. JACC. 2006;47:2108-2111.
Kotani
Bare-metal stent
Grade 3
Endothelial dysfunction
Reduction in eNOS and nitric oxide (NO)
production
S
Normal vessels dilate in response to exercise
or acetylcholine (ACH)
This response is dependent on endothelial production of NO
S
Atherosclerotic vessels are characterized by
having endothelial dysfunction and constrict
in response to exercise or ACH
Cai H, Harrison DG. Circ Res. 2000;8This
is explained by either a loss of
endothelial cells or loss of eNOS expression
and NO production
7:840-844.
30 PO et al. ATVB. 2003;23:168-175.
Bonetti
Μεταπτυχιακό πρόγραμμα Ιατρικής Σχολής ΕΚΠΑ «Ενδαγγειακές Τεχνικές» 7/03/14