Χρήστος Ν. Μπακογιάννης Drug-eluting stents Χρήστος Ν. Μπακογιάννης Μεταπτυχιακό πρόγραμμα Ιατρικής Σχολής ΕΚΠΑ « Ενδαγγειακές Τεχνικές»

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.

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.

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.

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 on smooth muscle cells.

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 cell proteins. 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 DNA synthesis Cell prepares for mitosis 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).

Differential Events Leading to In-Stent Restenosis 1 Fraction of Maximal Response Time Platelet Deposition Leukocyte recruitment VSMC migration / proliferation Matrix deposition

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 0% επαναστένωση στους 6 μήνες ύστερα από τοποθέτηση sirolimus-eluting stents 23.5% επαναστένωση στους 6 μήνες ύστερα από τοποθέτηση bare-metal stents Πρώτη εφαρμογή: τυχαιοποιημένη κλινική μελέτη με 36 ασθενείς 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 polymer-based everolimus-eluting stent (Dynalink-E)

Rapamycin Analogs EVEROLIMUS SIROLIMUS ABT-578 Chemical Formula 3 Chiral N 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 Everolimus, Sirolimus and ABT-578 are all Rapamycin Analogs with similar chemical formulas and molecular weights. The difference lies in one small chain which is not part of the cells FKBP12 binding site. Everolimus and Sirolimus were developed to prevent organ transplant rejection.

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 SIROCCO I & SIROCCO II trials μη στατιστικά σημαντική διαφορά μεταξύ των ασθενών που έφεραν sirolimus-eluting stents και αυτών που έφεραν bare-metal 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

Paclitaxel-eluting non–polymer-based stent (Zilver PTX) 435 ασθενείς – 6 μήνες παρακολούθηση 94% επιβίωση ελεύθερης νόσου 96% επαναγγείωση βλαβών-στόχων 1% κατάγμα του stent 200 ασθενείς – 12 μήνες παρακολούθηση 84% επιβίωση ελεύθερης νόσου 88% επαναγγείωση βλαβών-στόχων 2% κατάγμα του stent Brunk D. American College of Surgeons: Surgery News. 2008; 4(September):12.

Self-expanding polymer-based everolimus-eluting stent (Dynalink-E) Σε εξέλιξη μελέτη από το Βέλγιο Αναμένονται τα αποτελέσματά της Bosiers M. Vasc Health Risk Manag. 2008;4:553–559.

Η μηχανική της πλάκας είναι διαφορετική 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) 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 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) 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: 20% had stent thrombosis* No remodeling Explain late incomplete apposition: at baseline, the vessel is fully opposed; however, at follow-up one of two conditions occur: 1. No remodeling: Intimal tissue decreases in size and causes a dissociation between the struts and vessel wall. 2. Aneurysmal remodeling: the vessel wall (media and adventia) pulls away from the stent struts. Emphasize LIA upon discontinuation of clopidogrel has been associated with a high thrombosis rate. Be sure to transition to the Cypher case (in the re-print) to give a real world example of LaST (next slide) Positive remodeling

Percent struts endothelialized Human analysis: DES vs BMS 100 90 80 70 60 Percentage endothelialization 50 40 30 20 Taxus and Cypher BMS 10 1 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 100 Sirolimus-eluting stent 75 Percent 50 25 Incomplete coverage Complete coverage Grade 0 Grade 1 Grade 2 Grade 3 25 Percent 50 75 100 Bare-metal stent Kotani et al. JACC. 2006;47:2108-2111.

Endothelial dysfunction Reduction in eNOS and nitric oxide (NO) production Normal vessels dilate in response to exercise or acetylcholine (ACH) This response is dependent on endothelial production of NO 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. Bonetti PO et al. ATVB. 2003;23:168-175.

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