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Drug-Eluting Stents 2013: Current Data and Future Advances

BL. 2Y. Drug-Eluting Stents 2013: Current Data and Future Advances. Hilton La Jolla Torrey Pines La Jolla, California - Oct 3 rd , 2013.

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Drug-Eluting Stents 2013: Current Data and Future Advances

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  1. BL 2Y Drug-Eluting Stents 2013: Current Data and Future Advances Hilton La Jolla Torrey Pines La Jolla, California - Oct 3rd, 2013 James Hermiller, MD, FACC, FSCAI The St Vincent Medical Group The St Vincent Heart Center of Indiana Indianapolis, IN

  2. Consulting Fees/Honoraria Speaker Bureau Abbott, BSC, Medtronic and St Jude Medicines Company Disclosures Company Affiliation/Financial Relationship

  3. Outline • Introduction • Current Data • Advances to Date • Future Directions • Metallic DES Bioabsorbable Polymer • Metallic DES with No Polymer • CompletetlyBioabsorbable DES • Conclusions and Summary

  4. Introduction: DES Talks

  5. First Generation DES PES Paclitaxel Polyolefin derivative Express2 Drug Polymer Stent SES Sirolimus PEVA + PBMA blend BX Velocity

  6. 7 years 1st Gen Drug-Eluting Stents The good, the bad, and the ugly! DES Late loss = 0 BMS Giant cells DES Angioscopy BMS Eos Delayed Healing! Inflammation Incomplete apposition Sirolimus Control Abn Vasomotion Late stent thrombosis *P<0.001 vs. control * * 40 mos IVUS

  7. Second Generation DES ZES O H O O O O O O HO Zotarolimus BioLinx copolymer Integrity Drug Polymer Stent N O O O O O H O EES Vision Everolimus VDF + HFP copolymer Omega

  8. Current Stent Attributes

  9. Current Stent Attributes

  10. Bern-Rotterdam Cohort Study Räber L, ESC 2011 EES vs. SES Hazard Ratio* = 0.41, 95% CI 0.27–0.62, P<0.0001 EES vs. PES Hazard Ratio* = 0.33, 95% CI 0.23-0.48, P <0.0001 5 ARC Definite ST @ 4 Years 4 Paclitaxel Stent 4.4% 3 Cumulative incidence (%) Sirolimus Stent 2.9% 2 1 Everolimus Stent 1.4% 0 0 6 12 18 24 30 36 42 48 Months after index PCI No. at risk PES 4214 3916 3797 3176 2905 2344 1880 1077 686 SES 3784 3617 3569 3499 3404 3080 2521 2118 1734 EES 4135 3913 3793 3284 2604 1856 1041 514 208

  11. Bern-Rotterdam Cohort Study VeryLate ST (1-4 yrs) 5 EES vs. SES HR* = 0.33, 95% CI 0.15 – 0.72, P=0.006 EES vs. PES HR* = 0.24, 95% CI 0.13-0.47, P <0.0001 4 3 PaclitaxelStent 2.4% Cumulative incidence (%) 2 1 SirolimusStent 1.6% EverolimusStent 0.6% 0 0 6 12 18 24 30 36 42 48 Months after index PCI *from Cox proportional hazards model Räber L, ESC 2011

  12. SPIRIT II, III, IV and COMPARE trials Pooled database analysis (n=6,789) Ischemic TLR EES (n=4,247) HR: 0.60 [0.48, 0.75] PES (n=2,542) 10 P<0.001 6.6% Ischemic TLR (%) ∆=2.5% 4.7% 5 4.1% ∆=2.4% 2.3% 0 0 3 6 9 12 15 18 21 24 Time in Months Number at risk XIENCE 4247 4143 4004 3891 3363 TAXUS 2542 2416 2328 2260 2018 Kereiakes DJ et al. EuroIntervention 2011:7:74-83

  13. SPIRIT II, III, IV and COMPARE trials Pooled database analysis (n=6,789) Stent thrombosis (ARC definite/probable) HR: 0.30 [0.19, 0.47] EES (n=4,247) 3 PES (n=2,542) p<0.001 2.3% 2 Stent thrombosis ARC def or prob (%) 1 0.7% 0 0 3 6 9 12 15 18 21 24 Time in Months Number at risk XIENCE 4247 4177 4082 3998 3479 TAXUS 2542 2463 2408 2350 2110 Kereiakes DJ et al. EuroIntervention 2011:7:74-83

  14. RESOLUTE All Comers Target Lesion Failure to 2 Years (Cardiac Death, TV-MI, CD-TLR) 20% Resolute ZES (N = 1140) Log rank P = 0.73 Xience V EES (N = 1152) 15% 11.2% 10.7% 10% Cumulative Incidence of Events 5% 0% 0 6 12 18 24 Time after Initial Procedure (Months) Silber S, et al. Lancet. 2011;377:1241-47.

  15. TWENTE (n=1,387)Target Vessel Failure at 2-Year Follow-up 30 30 Xience V (n=692) 25 Resolute (n=695) P = 0.67 20 TVF (%) 15 11.6% 10.9% 10 5 0 0 60 120 180 240 300 360 420 480 540 600 660 720 Follow-up (days) Von Birgelen C. TCT 2012

  16. EES Pt-Cr vs EES Co-Cr3-Year Clinical Results p = 0.21 p = 0.40 p = 0.27 p = 0.81 p= 0.40 p= 0.30 p= 0.75 Incidence Rate (%) Promus PtCr EES XiencaCoCrEES Presented by Ian T Meredith MBBS, PhD at ACC 2013

  17. Longitudinal stent deformation: Angiographic patterns Longitudinal compression Longitudinal compression Longitudinal elongation with pseudo-fracture Longitudinal compression • Longitudinal stent compression: Manifests itself as a dark band in the region of compression (also called stent “accordion”, “concertina”, “wrinkling”, etc.) • Longitudinal stent elongation: Appears like a fracture in the stent (pseudo-fracture)

  18. Retrospective analysis of longitudinal stent deformation in the “real world”: Study 2,936 Promus Element stents implanted in 2,839 lesions in 1,295 pts at a single center over 22 months LSD occurred in: 1.4% (n=20) of pts (95%CI 0.9%-2.2%) 0.7% of lesions (95%CI 0.4%-1.1%) 0.7% of Promus Element stents (95%CI 0.4%-1.1%) Multivariable predictors of LSD: # and length of stents, ostial and bifurcation lesions 30 Day MACE in pts with LSD = 5.0% (1 NQMI) Leibundgut G et al. CCI 2012: doi: 10.1002/ccd.24472

  19. Promus PREMIEREverolimus-Eluting Stent Customized Platinum Chromium (PtCr) Stent Architecture Additional connectors on proximal end Provide increased axial strength 2 connectors throughout body Enhanced Stent Delivery System • PTFE Coating on hypotubeto reduce friction • Shorter tip to improve flexibility

  20. SCAAR Registry (94,384 pts)Adjusted Risks of Adverse Events at 2 yrs Restenosis Definite Stent Thrombosis Restenosis Definite ST BMS BMS “Old DES” “Old DES” “New DES” “New DES” Old DES = SES, PES, ZES-Endeavor; New DES = EES, ZS-Resolute Sarno et al, Eur Heart J 2012

  21. Network Meta-analysisEndpoints: Death, MI, ST, TVR early (<1 yr) and late 77 RCTs, 57,138 pts, 117,762 pt-yrs of FU BMS 24 11 25 Sirolimus-Eluting Paclitaxel-Eluting 8 4 Evidence network 7 2 1 7 1 Everolimus-Eluting Zotarolimus-Eluting 2 Zotarolimus-Eluting- Resolute Bangalore S et al. Circulation 2012:On-line

  22. Network Meta-analysis: 1-year TLR 77 RCTs, 57,138 pts, 117,762 pt-yrs of FU Favors Treatment Favors Control OR (95% Crl) Control Treatment OR [95% CrI] BMS (Ref) Sirolimus 0.20 (0.16, 0.25) Paclitaxel 0.39 (0.31, 0.49) Everolimus 0.21 (0.14, 0.29) Zotarolimus-E 0.46 (0.32, 0.65) Zotarolimus-R 0.29 (0.15, 0.60) Sirolimus (Ref) Paclitaxel 1.95 (1.60, 2.38) Everolimus 1.03 (0.75, 1.45) Zotarolimus-E 2.30 (1.67, 3.22) Zotarolimus-R 1.47 (0.74, 3.04) Paclitaxel (Ref) Everolimus 0.53 (0.38, 0.73) Zotarolimus-E 1.18 (0.85, 1.64) Zotarolimus-R 0.76 (0.38, 1.53) Everolimus (Ref) Zotarolimus-E 2.23 (1.45, 3.47) Zotarolimus-R 1.43 (0.78, 2.71) Zotarolimus-E (ref) Zotarolimus-R 0.64 (0.30, 1.37) 0.10 1.00 10.00 Bangalore S et al. Circulation 2012:On-line

  23. EXAMINATION Trial 1504 pts with STEMI undergoing PCI within 48 (85% primary PCI within 12) were randomized to Xience V EES vs. Vision BMS Stent thrombosis (Def/prob) within 1 year 2.6% p = 0.01 0.9% Definite ST was reduced with Xience V from 1.9% to 0.5%, p=0.01 Sabate M. ESC 2011

  24. EES CoCr vs BMS: Lower Def. Stent ThrombosisEvidence from 5 RCT Network Meta-Analyses. ARC Definite Stent Thrombosis:EES CoCrvs. BMS Favors EES CoCr

  25. Late ST Rates (30 Days - 1 Year)After DAPT Interruption Overall Standard Risk Subsequent Late ST (ARC Def/Prob) (%) 13/3500 2/1272 2/435 0/157 1/378 0/147 0/292 0/120 No Interruption Interruption After 30 Days* Interruption After 180 Days* Interruption After 90 Days* Hermiller, JB, PCR 2010 – In Press JACC Int 2011

  26. EES Co-Cr Demonstrates 0% Stent Thrombosis Rate After DAPT Interruption from 3 to 12 Months1 Timing of First DAPT Interruption and Stent Thrombosis Through 12 Months 1 in every 6 patients who receive stents may interrupt or discontinue DAPT within 12 months post-PCI Never Interrupted3 DAPT Interrupted N=11,156 3-12 Months 0-3 Months Palmerini, T. Stent Thrombosis and DAPT Interruption in XIENCE V Real-World Patients. PCR 2012 Combined XIENCE USA, SPIRIT V, XIENCE India. SPIRIT women

  27. DES Progress Evolution of Drug-Eluting Stents: Better than Man’s

  28. TCFA Development in Neointimal Hyperplasia is More Common with DES than BMS, and can Rupture Causing Stent Thrombosis and Occlusion Nakazawa G et al. J Am Coll Cardiol 2011;57:1314–22

  29. Late Incomplete Apposition in SIRTAX Late ISA at 8 month IVUS was seen in 39/221 lesions (18%) treated with SES or PES, and was more common with SES p<0.001 Cook et al Eur Heart J 2012

  30. SPIRIT IV: Target Lesion Failure @3 years 25 XIENCE V (n=2,458) TAXUS Express (n=1,229) 20 HR [95%CI] = 0.78 [0.63, 0.97] HR [95%CI] = 0.61 [0.46, 0.81] HR [95%CI] = 0.71 [0.56, 0.90] p=0.02 15 p=0.001 p=0.004 11.7% Target lesion failure (%) Δ 2.5% 10 6.7% 9.2% Δ 2.7% 5 ~2.6%/yr event rate after year 1 4.0% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months TLF = cardiac death, target vessel MI, or ischemic-driven TLR Stone GW et al. JACC 2011 (abstract)

  31. Outline • Introduction • Current Data • Advances to Date • Future Directions • Metallic DES Bioabsorbable Polymer • Metallic DES with No Polymer • CompletetlyBioabsorbable DES • Conclusions and Summary

  32. Persistent Limitations • Uncovered stent struts with or without late malapposition(thrombosis) • Chronic inflammation due to late foreign body reactions and polymer hypersensitivity • Strut fracture • Lack of vasomotion • Neoatherosclerosis

  33. Biolimus is a semi-synthetic sirolimus analogue with 10x higher lipophilicity and similar potency as sirolimus. Biolimus is immersed at a concentration of 15.6 g/mm into a biodegradable polymer, polylactic acid, and applied solely to the abluminal stent surfaceby a fully automated process. Biolimus is co-released with polylactic acid and completely desolves into carbon dioxide and water after a 6-9 months period. The stainless steel stent platform has a strut thickness of 120 m with a quadrature link design. Biolimus-A9 Eluting Stent

  34. Serruys P, et al. J Am CollCardiolIntv 2013;6:777–89 LEADERS 5-Year Results

  35. Serruys P, et al. J Am Coll Cardiol Intv 2013;6:777–89 LEADERS: Definate Stent Thrombosis

  36. Serruys P, et al. J Am CollCardiolIntv 2013;6:777–89 LEADERS: Definate Stent Thrombosis Landmark Analyses at 0-1 and 1-5 years RR (95%CI); p value 0-1 yr: 0.99 (0.51-1.95); p= 0.98 1-5 yrs: (0.20-0.68); p=0.003 %

  37. Drug-Eluting Technology Progression Current DES SYNERGY DES Conformal Biostable Polymer Abluminal Bioabsorbable Polymer Vessel Wall Polymer + Drug Polymer + Drug Polymer + Drug BMS on luminal side Abluminal Thin strut (0.0029”) PtCrstent Platinum Chromium Platinum Chromium PLGAbioabsorbablepolymer + everolimus on abluminal side of stent Coating weight on 16 mm stent ~200 µg (vs ~675 µg for Xience / Promus) Everolimus elutes over ~3 months (similar to Xience / Promus) PLG absorbs by ~4 months, leaving behind a BMS

  38. BioFreedom Stent (Biosensors) Hypothesis: Polymer-free drug release via porous-eluting stents may reduce late events caused by polymer stent coatings. Selectively micro-structured surface holds drug in abluminal surface structures • Potential advantages • Avoid long term late adverse effects that might be attributable to the polymer • Improved surface integrity since there is no polymer to be sheared or pealed away from the stent struts • Possible shorter need of dual antiplatelet therapy Biolimus A9 - lipophilic

  39. DFS: Drug Filled Stent (Medtronic)Drug elution controlled by diffusion physics Elution Holes

  40. Bioresorbable Vascular Scaffolds (BVS) Igaki-Tamai PLLA Abbott Absorb PLLA (w/PDLLA coat eluting everolimus) Iodinated tyrosine- derivative (eluting sirolimus) RevaReSolve PPLLA (eluting myolimus) Elixir DESolve Magnesium (eluting paclitaxel) Biotronik Dreams

  41. What is the Minimum Duration of Radial Scaffolding?After DES Placement, Scaffolding of the Vessel is Only a Transient Need Quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months n = 342 patients (n = 93 at 30-day F/U; n = 79 at 60-day F/U; n = 82 at 90-day F/U; n = 88 at 120-day F/U) p < 0.00001 p < 0.00001 The lumen appears to stabilize approximately three months after PTCA. Serruys PW, et al., Circulation 1988; 77: 361.

  42. ABSORB Extend Clinical Results - MACE Similar Rates of MACE Compared to Historical XIENCE Data Intent to Treat (ITT) Analysis; Interim Snapshot Dudek D. ABSORB Cohort B 2-year data, ACC 2012.

  43. Absorb Trial (BVS cohort A): OCT Results 6-month 24-month Post-stenting Late acquired incomplete stent apposition with tissue bridges between fractured struts Corrugated endolumen Smooth endoluminal lining Struts largely disappeared although remnant just visible (arrow) Complete strut apposition Serruys PW et al. Lancet 2009;373:897-910.

  44. Sealing and shielding of plaques as a result of scaffold implantation : can the scaffold cap the plaque? … and Late lumen enlargement 6 months The Final Golden tube 60 months Presented by PW Serruys at TCT2012, accessed at www.tctmd.com

  45. ABSORB Cohort BTemporal Lumen Dimensional Changes Post-PCI 6 Months 2 Years n = 33 n = 33 n = 33 Scaffold Area ABSORB Lumen Area 6.53 mm2  1.7% Cohort B 6.36 mm2 6.85 mm2 Serial Analysis* Lumen Area  7,2% • Very late lumen enlargement noted from 6 months to 2 years *Serruys, PW., TCT 2011

  46. ABSORB Vasomotor Function Testing 1 12 Months2 6 Months1 24 Months3 ABSORB Cohort B1 ABSORB Cohort B2 ABSORB Cohort A (n=6) (n=13) (n=9) (n=7) (n=15) (n=19) 0.5 Vasodilation  in Vessel Diameter (mm) (pre-drug infusion to post-drug infusion) 0 Vasoconstriction -0.5 Acetylcholine Methergine -1 Adapted from Serruys, PW. ACC 2011 Adapted from Serruys, PW. ACC 2011 Adapted from Serruys, PW, et al. Lancet 2009; 373: 897-910.

  47. Outline • Introduction • Current Data • Advances to Date • Future Directions • Metallic DES Bioabsorbable Polymer • Metallic DES with No Polymer • CompletetlyBioabsorbable DES • Conclusions and Summary

  48. Conclusions: Current and future directions in stenting • Current DES have appreciably improved safety and efficacy profiles in ACS and stable CAD compared to first generation devices • By utilizing small amounts of a bioabsorbable polymer, polymer-free systems, or fully bioresorbable scaffolds, future generation DES will likely further reduce stent thrombosis and improve late outcomes

  49. The Bar is High – For Advanced Devices

  50. Thanks for your attention!

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