Drug eluting stents
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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 /03/1 4. Endothelial injury post implantation. Implanted stent.

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Drug eluting stents

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


Endothelial injury post implantation

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.


Platelet aggregation and activation

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.


Transmigration of inflammatory cells

Transmigration ofinflammatory cells

Endothelial cells

Transmigration ofinflammatory cells

Smooth muscle cells

Inflammatory cellssecreting cell-signalingmolecules

Once activated, these inflammatory cells roll across the endothelial surface andtransmigrate into the lesion.


Activation of smooth muscle cells

Activation of smoothmuscle cells

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.


Activation of smooth muscle cells1

Activation of smoothmuscle cells

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.


Activation of smooth muscle cells iii

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).


Differential events leading to in stent restenosis

Differential Events Leading to In-Stent Restenosis

1

Fractionof Maximal Response

0

Time

Platelet Deposition

Leukocyte recruitment

VSMC migration / proliferation

Matrix deposition


Drug eluting stents

Επαναστένωση


Drug eluting stents

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 sfa

Drug-eluting stents στην SFA

Duda SH. Circulation2002; 106:1505–1509.


Drug eluting stents1

Τύποι drug-eluting stents με εφαρμογή στην αγγειοχειρουργική


Rapamycin analogs

N

N

N

O

Chiral

N

O

H

H

C

H

3

O

H

H

O

N

C

H

3

O

O

O

O

H

O

H

C

3

O

H

C

3

H

O

H

H

C

3

H

C

C

H

H

C

O

3

3

3

O

O

H

C

3

C

H

3

Rapamycin Analogs

EVEROLIMUS

SIROLIMUS

ABT-578

N

N

N

N

N

N


Smart stents sfa

SMART stents στην SFA

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

Duda SH. Circulation2002; 106:1505–1509.

Duda SH.J Vasc Interv Radiol 2005; 16:331–338


Smart stents sfa1

SMART stents στην SFA

Duda SH.J Vasc Interv Radiol 2005; 16:331–338


Zilver ptx paclitaxel

Zilver PTX (paclitaxel)

Paclitaxel is a mitotic inhibitor used in cancerchemotherapy. 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


Drug eluting stents sfa1

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

Oliva VL. J Vasc Interv Radiol. 2005;16:313–315.


Drug eluting stents

Drug eluting Ballons


Drug eluting ballons

Drug-eluting Ballons


Drug coated balloons for femoropopliteal pta paccocath cotavance balloon

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

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)

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.


Drug eluting stents

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

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


Percent struts endothelialized

Taxus and Cypher

BMS

1

2

3

4

5

6

7

8

9

11

15

16

17

20

> 40

  • 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

Percent struts endothelialized

Human analysis: DES vs BMS

100

90

80

70

60

50

Percentage endothelialization

40

30

20

10

0

Duration in months

Joner, Virmani et al. Circulation. 2005;112:3210.


Exposed stent struts at 6 months

Exposed stent struts at 6 months

> 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. 2006;47:2108-2111.


Endothelial dysfunction reduction in enos and nitric oxide no production

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 production

7:840-844.

Bonetti PO et al. ATVB. 2003;23:168-175.


Drug eluting stents

Σασευχαριστω για την Προσοχησασ!

Μεταπτυχιακό πρόγραμμα Ιατρικής Σχολής ΕΚΠΑ «Ενδαγγειακές Τεχνικές» 7/03/14


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