Drug-eluting stents

Χρήστος Ν. Μπακογιάννης

Επίκουρος ΚαθηγητήςΑγγειοχειρουργικής Πανεπιστημίου ΑθηνώνΑ΄ Χειρουργική Κλινική ΕΚΠΑ

Λαϊκό Νοσοκομείο

Μεταπτυχιακό πρόγραμμαΜεταπτυχιακό πρόγραμμα

Ιατρικής Σχολής ΕΚΠΑΙατρικής Σχολής ΕΚΠΑ

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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

6

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

Fra

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Res

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Time

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Επαναστένωση

http://content.nejm.org/content/vol355/issue19/images/large/01f1.jpeg

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'

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.

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*

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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 months

DES 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

cen

tag

e e

ndot

helia

liza

tion

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.

29Kotani 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

25

0

50

75

100

Per

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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

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.

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