Coracto Istanbul 2011

2,136 views
1,876 views

Published on

0 Comments
4 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,136
On SlideShare
0
From Embeds
0
Number of Embeds
317
Actions
Shares
0
Downloads
0
Comments
0
Likes
4
Embeds 0
No embeds

No notes for slide

Coracto Istanbul 2011

  1. 1. Comparing Vascular Remodeling andHealing of the Coracto DES to 1st and 2ndGeneration DES in a Rabbit Preclinical Model Renu Virmani, MD CVPath Institute 19 Firstfield Road Gaithersburg, MD USA www.cvpath.org
  2. 2. Requirements of a Drug Eluting StentMechanical Properties Stent Coating Drug-Design -Polymer type -Drug type/load-Material -Coating thickness -Elution Profile-Strut geometry -Biocompatibility -Toxicity Healing rates Inflammation Safety
  3. 3. Stenting of Human Coronary Arteries Drug Eluting versus Bare Metal Stents In Stent Re -stenosis [%] Bare Metal Stent (~15 months) 30 20 10 0 Drug Eluting Stent (~15 months) BMS DES Neointimal Thickness 2 [mm] 1 0 BMS DES
  4. 4. Incomplete Healing A Current Major Drawback of DES Late Stent Thrombosis (LST) BMS DES Thr 100 90Mean % Endothelialization 80 70 60 50 40 30 20 DES 10 BMS 0 1 2 4 5 6 9 19 20 24 50 Months Joner M & Finn AV. J Am Coll Cardiol. 2006;48(1):193-202. Langerqvist et al. Circulation Cardiovasc Interv 2009
  5. 5. Pathological Correlates of Late DES Thrombosis: Strut Coverage as a Marker of Endothelialization > 30 days implants > 30 days implantsuncovered covered uncovered covered 80 n=28 p<0.0001 70 % Uncovered struts 60 Thrombus 50 No Thrombus 40 30 n=34 20 10 0 % Uncovered Struts/section Finn AV, et al., Circulation 2007;115:2435-2441
  6. 6. Role of Endothelial Cells Anti-thrombotic activities-NO production through eNOS - Thrombomodulin- Prostacylin (PGI2) - Tissue Plasminogen activator-Heparin sulphate or chondroitine sulphate - Tissue factor pathway inhibitor
  7. 7. Endothelial Cell Intercellular Junctions Tight junction Adherens junction VEGF Ang-1 Ang-2 PECAM PECAM PECAM Endothelial cells Tie-1 Tie-2 VEGFR2 Claudin VE-cad β-cat GAP junction JAM apoptosisIntegrin Connexin Integrin β-cat αvβ5 αvβ3 Akt PI3K VT FN PDGF-BB PDGF-BB PDGFR-β SMC recruitment: PDGFR-β Ang-1, PDGF, uPA TGF-b, PIGF Smooth Muscle Cell Smooth Muscle Cell Tight Junctions: GAP junctions Adherens Junctions: Occludin Connexins VE-Cadherin Claudin JAM
  8. 8. Impact of Stent Design on Healing Mechanical Properties -Strut Patterns -Strut Thickness -Mechanical Integrity: Fractures Healing rates
  9. 9. Strut Thickness CYPHER® TAXUS® Express ENDEAVOR™ XIENCE V™Strut Thickness: Strut Thickness: Strut Thickness: Strut Thickness: 140 µm 132 µm 91 µm 81 µm
  10. 10. Incidence of angiographic and clinical restenosis Thin-strut (50μm) vs. Thick-strut (140μm) Total of 651 patients: 326 – thin strut, 325 – thick strut P=0.005 30 Thin-strut Thick-strutincidence (%) 25 (25.3) P=0.03 20 15 (14.7) (13.8) 10 (8.6) 5 0 Angiographic restenosis Clinical restenosis (DS≥50%) (TVR) Kastrati A, et al. Circulation 2001;103:2816-21
  11. 11. Stent Strut Thickness Thinner stent struts associated with improved clinical outcomes1-4 0.006 0.005Strut Thickness (inches) 0.004 1st Generation DES 2nd Generation 0.003 0.002 Cypher Taxus Taxus Endeavor Resolute Xience V Coracto Express Liberté 0.0055” 0.0036” 0.0036” 0.0032” 0.0031” 0.001 140 μm 0.0052” 0.0038” 91 μm 91 μm 81 μm 80 μm 132 μm 97 μm 0 1. Kastrati, A, et al. Circulation 2001;103: 2816-2821. 2. Rittersma, SZ, et al. Am J Cardiol 2004; 93: 477-480 3. Pache, J, et al. J Am Coll Cardiol 2003; 41: 1283-1288 4. Turco, M., et al., JACC CI 2008; 1: 699-709. Modified from Ian Meredith
  12. 12. Drug Eluting Stents Stent Coating -Polymer type-Coating thickness -Biocompatibility Inflammation
  13. 13. What is the ideal drug eluting stent polymer?• Inert Polymer that is completely biocompatible Note: Important to distinguish between “short” and “long term” biocompatibility. Most if not all biocompatible polymers may cause some foreign body reactions months or years later• Ability to control drug release at desired rate over a prescribed time period• Good adhesion to stent struts & high flexibility – No acute or late peeling!• High drug carrying capacity (ie, “carrying efficiency”) – Low polymer “dose” critical to minimize chronic inflammatory response
  14. 14. Polymer Coatings Durable vs. Biodegradable Durable (non-biodegradable) Biodegradable CE mark BioMatrix - Poly(lactide) (PLA)Xience V – Fluoropolymer (Europe)Cypher - PEVA (polyethylene-co-vinyl Poly(glycolic-co-lactic acid)acetate) + PBMA (poly(n-butyl) (PLGA)methacrylate) FDA Approved Poly(glycolide) (PGA)Taxus - SIBBS (poly (styrene-b-isobutylene-b-styrene)) Poly(e-caprolactone) (PCL)Endeavor - PC (Phosphorylcholine) Poly(dioxanone) (PDS) Why the push towards biodegradable polymers?
  15. 15. Hypersensitivity – Chronic Inflammation40 yrs old female, Underwent Cypher stents implantation in RCA and LAD2years antemortem, She died suddenly after surgery. (Plavix and aspirindiscontinued prior to surgery)LADRCA
  16. 16. Patients with Hypersensitivity Reaction (7 of 95 patients; 7.4%) Stent Indication Number Stent length Duration ofCase Age Sex Location Cause of death type for PCI of stent (mm) implant (months) AMI (LST) 1 58 M Cypher UAP LCX 2 18+18 18 Cardiac rupture LAD 1 23 32 2 46 M Cypher AMI AMI (LST) RCA 2 15+15 32 3 61 M Cypher SAP PDA 1 18 4 SCD (LST) LAD 1 27 17 4 40 F Cypher AMI SCD (LST) RCA 1 25 17 Removed 5 62 F Cypher SAP LAD 3 23+23+18 33 surgically LAD 1 18 13 6 61 M Cypher SAP Non-cardiac LD 1 17 13 7 72 M Cypher SAP LAD 1 18 13 Non-cardiac
  17. 17. CORACTOTM Coronary Drug Eluting StentCORACTO is coated with a very thin layer (4 μm) of bioabsorbablepolymer loaded with 1.7 μg/mm2 Rapamycin (sirolimus)Polylactic-co-glycolic acid based copolymer is used as drug carrier.
  18. 18. Drug Eluting Stents Drug -Drug type/load -Elution Profile -Toxicity Safety
  19. 19. FDA Approved DES Release Dose Kinetics Stents Drug Polymer (µg) (28 days %)Xience V Everolimus Fluoropolymer 1.0 µg/mm2 80 Taxus Paclitaxel SIBBS (poly (styrene-b- 1.0 µg/mm2 10 isobutylene-b-styrene))Cypher Sirolimus PEVA (polyethylene-co-vinyl 1.4 µg/mm2 68.4 acetate) + PBMA (poly(n- butyl) methacrylate)Endeavor Zotarolimus PC (Phosphorylcholine) 10 µg/mm2 100
  20. 20. Comparative Elution Profiles FDA Approved DES 100 ENDEAVOR™ CYPHER®Cumulative % Released 80 XIENCE™ 60 40 20 TAXUS® 0 5 10 15 20 25 30 Days
  21. 21. How to assess variations in DES? Impact on endothelialization 100 ? 90 Peak Percentage of 80 70 Neointima 60 Animals 50 Humans 40 30 20 10 0 3 7 14 28 3 6 12 18 Days Months Time After Stent Implantation Virmani, R, et al. Heart 2003;89:133
  22. 22. Evaluation of Endothelium has Evolved in Pre-Clinical ModelsHistological Scanning Electron En-FaceVisual Microscopy ConfocalEstimation Microscopy EC-Specific Markers
  23. 23. Comprehensive Endothelial Cell Coverage of FDA approved DES Comparison of Endothelialization following Implantation of CYPHER (S-ES), TAXUS (P-ES), ENDEAVOR (Z-ES) and XIENCE V (E-ES) Stents in Rabbit Iliac Arteries at 14 and 28 days 1st generation 2nd generation CYPHER TAXUS ENDEAVOR™ XIENCE VJoner M et al.Endothelial Cell Recovery Between Comparator Polymer-Based Drug-Eluting Stents. JACC 2008
  24. 24. Scanning Electron Microscopy of 14-Day Comparator Stents S-ES P-ES Z-ES E-ES BMS
  25. 25. Scanning Electron Microscopy of 28-Day Comparator Stents S-ES P-ES Z-ES E-ES BMS
  26. 26. En Face SEM Analysis of Comparator Stents (%)A 100 P< 0.0001 P= NS 80 * * *14-Day 60 40 20 S-ES (Cypher) 0 P-ES (Taxus) Above Struts Between Struts Z-ES (Endeavor)B (%) P= NS P= NS E-ES (Xience V) 100 BMS 8028-Day 60 40 20 0 Above Struts Between Struts
  27. 27. Confocal AnalysisPECAM-1 (CD31) Thrombomodulin (TM) Merged
  28. 28. Confocal Analysis Example imagesEndothelialized Strut Non-Endothelialized Strut
  29. 29. Confocal AnalysisS-ES P-ES Z-ES E-ES BMS 14-day Comparator Stents
  30. 30. En Face Confocal Analysis (PECAM-1) of Comparator Stents (%) P=0.02 P= NS 100 * * * 80 6014-Day 40 20 S-ES 0 P-ES Above Struts Between Struts Z-ES (%) P= NS P= NS E-ES 100 BMS 80 6028-Day 40 20 0 Above Struts Between Struts
  31. 31. CORACTO Pre-clinical StudyComparison of vascular healing and endothelialization of theCoracto DES to 1st and 2nd generation DES, along with a baremetal stent, in the rabbit iliac stent model. Alvimedica DES 1st generation DES 2nd generation DES Bare Metal Stent Coracto Cypher Xience V Constant
  32. 32. Study Parameters Endothelialization Vascular Healing (14-days) (28-days)Constant Coracto Xience V Cypher Constant Coracto Xience V Cypher n=6 n=6 n=6 n=6 n=8 n=8 n=8 n=8Evaluated by: Evaluated by:o Scanning electron microscopy (SEM) o Light Microscopy (H&E and Movat)o Confocal Microscopy Injury, Strut Coverage Fibrin, Inflammation SEM Confocal
  33. 33. Scanning Electron Microscopic Findings Above and in between the Stent struts SEM % endothelial coverage SEM % endothelial coverage above stent struts @ 14 days between stent struts @ 14 days 100 100 P=0.066 ★ P<0.0001 80 80 60 ★ 60 ★ 40 40 ★ 20 20 0 0 CONSTANT CORACTO Xience V Cypher CONSTANT CORACTO Xience V Cypher = significantly different from control ANOVA and Dunnett post hoc test (CONSTANT as control)
  34. 34. Constant Coracto Xience Cypher
  35. 35. Confocal Microscopic Findings of PECAM-1 Above and in between the Stent struts % PECAM-1 positive endothelial cells % PECAM-1 positive endothelial cells above stent struts @ 14 days between stent struts @ 14 days 100 100 80 80 P= 0.0003 P=0.0087 60 ★ ★ ★ 60 ★ ★ 40 40 20 20 0 0 CONSTANT CORACTO Xience V Cypher CONSTANT CORACTO Xience V Cypher �= significantly different from control (Dunnett post hoc test, CONSTANT as control)
  36. 36. Confocal Microscopy following PECAM-1 staining in Rabbit at 14-days CONSTANT CORACTO CYPHER XIENCE V
  37. 37. Morphometric Measurements Neointimal Thickness at 28 days 0.10 BMS * CoractoNeointimal Thickness [mm] 0.08 0.06 0.04 Xience V Cypher 0.02 0 Cypher Xience V Coracto BMS
  38. 38. 28-day Light Microscopy Results p < 0.0001 75 * * BMS 60 Coracto % Fibrin 45 30 15 CORACTO Xience V Cypher 0 CONSTANT Xience V Cypher P < 0.0001 2 * *Fibrin Score 1 CORACTO 0 Cypher Xience 0 CONSTANT
  39. 39. 28-day Light Microscopy Results P < 0.0001Inflammation Score 2 * BMS Coracto 1 CORACTO Xience V Cypher 0 0 CONSTANT 80 P < 0.0001 * Xience V Cypher % Giant Cells 60 40 20 CONSTANT CORACTO Xience V Cypher 0 0
  40. 40. Summary• Endothelial integrity is the key to prevention of late stent thrombosis• 1st generation DES are not fully re-endothelialize as demonstrated by SEM and Confocal microscopy (PECAM-1 staining) especially above stent struts at 14- and 28-days• 2nd generation DES show greater endothelialization than 1st generation DES• The Coracto stent shows higher degree of reendothelialization as compared to other DES and less inflammation as compared to Cypher.
  41. 41. AcknowledgmentsFundingAlvimedicaCVPath InstituteFrank D Kolodgie, PhD CVPath InstituteElena Ladich, MDMasataka Nakano, MDFumiyuki Otsuka, MDEd Acampado, DVMYouhui Liang, MDAbebe Atiso, HTJinky BeyerGiselle MagsalinHedwig Avallone, HTCarma Cooney, HT WashingtonHengying Ouyang, MD DCRoberto Calvo

×