2 Endothelial injury post implantation 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. Implanted stent Plaque
3 Platelet aggregation and activation Drug-eluting stent struts Platelets Inflammatory cells Platelet deposition and activation occur at the injury site, leading to the release of cell-signaling molecules. Red blood cells
4 Transmigration of inflammatory cells Smooth muscle cells Inflammatory cells secreting cell-signaling molecules Transmigration of inflammatory cells Once activated, these inflammatory cells roll across the endothelial surface and transmigrate into the lesion. Endothelial cells
5 Activation of smooth muscle cells 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. Smooth muscle cell extracellular view
6 Activation of smooth muscle cells 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. Smooth muscle cell intracellular view
7 Activation of smooth muscle cells (III) Cell responds to growth factor stimulation DNA synthesis Cell prepares for mitosis Mitosis Cell resting phase Restriction point 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 Matrix deposition Leukocyte recruitment VSMC migration / proliferation Platelet Deposition Fraction of Maximal Response Time 0 1
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? 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 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% ε π αναστένωση στους 6 μήνες ύστερα α π ό το π οθέτηση sirolimus-eluting stents 23.5% ε π αναστένωση στους 6 μήνες ύστερα α π ό το π οθέτηση bare-metal stents Πρώτη εφαρμογή : τυχαιο π οιημένη 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 Chemical Formula C 53 H 83 NO 14 Molecular Wt: 958.25 C 51 H 79 NO 13 Molecular Wt: 914.2 C 52 H 79 NO 12 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 & USNone EVEROLIMUSSIROLIMUSABT-578 N N N N N N N N N N
SMART stents στην SFA SIROCCO I & SIROCCO II trials μη στατιστικά σημαντική διαφορά μεταξύ των ασθενών π ου έφεραν sirolimus-eluting stents και αυτών π ου έφεραν bare- metal stents στους 6 μήνες 0% Vs. 7.7% ε π αναστένωση στην SFA δεν ε π ιβεβαίωσαν την α π οτελεσματικότητα του sirolimus 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
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 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 'mitotic inhibitorcancerchemotherapyNational Cancer Institute Research Triangle InstituteMonroe E. Wall Mansukh C. WaniPacific YewTaxus brevifolia
Paclitaxel-eluting non–polymer-based stent (Zilver PTX) 435 ασθενείς – 6 μήνες π αρακολούθηση 94% ε π ιβίωση ελεύθερης νόσου 96% ε π αναγγείωση βλαβών - στόχων 1% κατάγμα του stent 200 ασθενείς – 12 μήνες π αρακολούθηση 84% ε π ιβίωση ελεύθερης νόσου 88% ε π αναγγείωση 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 α π ό το Βέλγιο Αναμένονται τα α π οτελέσματά της Bosiers M. Vasc Health Risk Manag. 2008;4:553–559.
Διαφορετική αποτελεσματικότητα drug-eluting stents στην SFA & στα στεφανιαία. ΓΙΑΤΙ; Η SFA έχει μεγαλύτερο μήκος, μεγαλύτερη διάμετρο και δέχεται μηχανική κατα π όνηση Η μηχανική της π λάκας είναι διαφορετική Τα stent διαφέρουν μεγαλύτερο μήκος, μεγαλύτερη διάμετρο, διαφορετική δοσολογία ε π ικάλυψης με φάρμακο κ. α. 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-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) 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 thrombosis Baseline Positive remodeling 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 BMS 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 Percentage endothelialization Duration in months 1234567891115161720> 40 Taxus and Cypher BMS 0 10 20 30 40 50 60 70 80 90 100 Joner, Virmani et al. Circulation. 2005;112:3210.
32 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;8 This 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.