Drug-eluting stents

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Drug-eluting stents. Χρήστος Ν. Μπακογιάννης. Μεταπτυχιακό πρόγραμμα Ιατρικής Σχολής ΕΚΠΑ « Ενδαγγειακές Τεχνικές ». Endothelial injury post implantation. Implanted stent. Plaque. - PowerPoint PPT Presentation

Transcript of Drug-eluting stents

  • *Endothelial injurypost 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 stentPlaque

  • *Platelet aggregationand activation Drug-eluting stent strutsPlateletsInflammatory cellsPlatelet deposition and activation occur at the injury site, leading to the release of cell-signaling molecules. Red blood cells

  • *Transmigration ofinflammatory cellsSmooth muscle cellsInflammatory cells secreting cell-signaling moleculesTransmigration of inflammatory cellsOnce activated, these inflammatory cells roll across the endothelial surface and transmigrate into the lesion. Endothelial cells

  • *Activation of smoothmuscle cells Cell signaling molecules activate smooth muscle cellsSmooth muscle cell surface receptorThe activated inflammatory cells secrete molecules that bind to specific receptors on smooth muscle cells. Smooth muscle cell extracellular view

  • *Activation of smoothmuscle cells Activated smooth muscle cell receptormTOR activates smooth muscle cells to enter cell cycleBound 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

  • *Activation of smoothmuscle cells (III)Cell responds to growth factor stimulationDNA synthesisCell prepares for mitosisMitosisCell resting phase Restriction pointActivated 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 RestenosisMatrix depositionLeukocyte recruitmentVSMC migration / proliferationPlatelet DepositionFraction of Maximal ResponseTime01

  • Drug-eluting stents SFADuda SH. Circulation 2002; 106:15051509.

  • drug-eluting stents

  • Rapamycin AnalogsEVEROLIMUSSIROLIMUSABT-578NNNNNN

    Chemical FormulaC53H83NO14Molecular Wt: 958.25C51H79NO13Molecular Wt: 914.2C52H79NO12Molecular Wt: 966.23Intended PharmaIndicationsChronic & Acute Rejection Heart, Kidney, LungAcute Rejection Kidney, LiverNoneApprovalsOUSUS H2 04 (Est.)OUS & USNone

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  • SMART stents SFADuda SH. Circulation 2002; 106:15051509.Duda SH. J Vasc Interv Radiol 2005; 16:331338

  • SMART stents SFADuda SH. J Vasc Interv Radiol 2005; 16:331338

  • 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'

  • Paclitaxel-eluting nonpolymer-based stent (Zilver PTX)Brunk D. American College of Surgeons: Surgery News. 2008; 4(September):12.

  • Self-expanding polymer-based everolimus-eluting stent (Dynalink-E)Bosiers M. Vasc Health Risk Manag. 2008;4:553559.

  • drug-eluting stents SFA & .;Oliva VL. J Vasc Interv Radiol. 2005;16:313315.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;110:810814.Scheller B et al. N Engl J Med. 2006;355:21132124.Scheller B. EuroIntervention. 2008;4(suppl C):C63C66.Scheller B et al. Heart. 2007;93:539541.

  • Local Taxane with Short Exposure for Reduction of Restenosis in Distal Arteries (THUNDER) trial154 patients (24% smokers, 49% diabetics) with femoropopliteal lesionsPaccocath (n=48 patients)no adverse event6 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.

  • Vascular toxicity rather than cytotoxicity Late incomplete appositionMedial thinningAneurysm/ruptureDelayed re-endothelialization

    High dose, fast releaseLow dose, slow releaseRogers C et al. Circ. 2000.Vasculo-toxic effects in pig coronaries: 90 days

  • Late incomplete appositionPotential for stent thrombosisBaselinePositiveremodelingNo remodelingFollow-upIn a Taxus and Cypher study of patients with late incomplete apposition upon clopidogrel discontinuation:20% had stent thrombosis*

  • *Percent struts endothelializedHuman analysis: DES vs BMSPercentage endothelializationDuration in months0102030405060708090100Joner, Virmani et al. Circulation. 2005;112:3210.

  • *Kotani et al. JACC. 2006;47:2108-2111.> 80% Cypher struts exposed vs BMS strutsExposed stent struts at 6 months0255075100Incomplete coverageComplete coverageSirolimus-eluting stentBare-metal stentGrade 0Grade 1Grade 2Grade 32505075100PercentPercent

  • *Endothelial dysfunction

    Reduction in eNOS and nitric oxide (NO) productionNormal vessels dilate in response to exercise or acetylcholine (ACH)This response is dependent on endothelial production of NOAtherosclerotic 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 production7:840-844.Bonetti PO et al. ATVB. 2003;23:168-175.

  • **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.**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)