NOW YOU SEE IT, NOW YOU DON’T STENT UPDATE
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NOW YOU SEE IT, NOW YOU DON’T STENT UPDATE GAGAN D. SINGH, MD Division of Cardiovascular Medicine UC Davis Medical Center Sacramento CA Outline § A Brief History of Coronary Interventions § Rationale Behind Coronary Stents § Evolution to Bioabsorbable Vascular Scaffolds § Case Examples § Future Directions Outline § A Brief History of Coronary Interventions § Rationale Behind Coronary Stents § Evolution to Bioabsorbable Vascular Scaffolds § Case Examples § Future Directions A Brief History § 1700’s: Catheterization: ú Procedures where catheters are inserted into cardiac chambers for sampling of blood § 1940: Cournand, Forssmann, and Richards A Brief History § 1958: An Accident A Brief History § 1977 – A poster presentation that changed the world – 1st Revolution First PTCA and 23-­‐Year Follow Up 1977 2000 A.B. ,the 1 st PTCA by Andreas Gruentzig on September 2 9, 1 977, a ttended a nd s poke a t the 3 0 th Anniversary on September 3 0, 2 007 in Zurich, a n incredible tribute to the breakthrough made by Andreas 3 0 y ears a go1 Restenosis PTCA - 1977 • Percutaneous Transluminal Coronary Angioplasty • Non-compliant balloon Angioplasty • Abrupt and threatened closure • ~50% Restenosis - A new disease • Elastic recoil • Vascular negative remodeling • Neointimal hyperplasia - NIH POBA 4 Months The 2nd Revolution in Coronary Intervention Bare Metal Coronary Stent - 1994 The 2nd Revolution in Coronary Intervention Bare Metal Coronary Stent - 1994 • Coronary Stent • Restenosis reduce to ~25-50% • Prevents elastic recoil • Prevents negative vascular remodeling • Increase Neointimal hyperplasia - NIH What to Do Next? • Pathophysiology of restenosis defined • Smooth muscle cell migration • Smooth muscle cell proliferation • Extracellular matrix formtion • Sirolimus, Paclitaxel, Everolimus, Zotarolimus • Polymer coating to bind drug, control release, vascular biocompatible The 3rd Revolution in Coronary Intervention Drug Eluting Stents - 2003 Progression in Stent Platform Design Strut Thickness and Biomaterials 2nd Generation 1st Generation Cypher® Stent TAXUS® Express® Stent TAXUS® Liberté® Stent Endeavor® Stent 3rd Generation Xience V® ION™ / and TAXUS® Xience Element™ Prime® Stent Stents PROMUS Element™ Stent 4th Generation SYNERGY™ Stent current benchmark for lowest strut thickness 0.140 μm (0.0055” ) 0.132 μm (0.0052”) Stainless Steel 0.096 μm (0.0038”) 0.091 μm (0.0036”) Cobalt Alloys 0.081 μm (0.0032”) 0.081 μm (0.0032”) 0.081 μm (0.0032”) 0.074 μm (0.0029”) Platinum Chromium Drug Eluting Stent ­Pre UC Davis Post 1 Year DES: Technological Advancement Meta-­‐Analysis of DES vs. BMS with 180,749 patients 22 RCTs (9,470 patients) randomized to DES or BMS and followed for ≥1 year DES resulted in: Non-­Significant 3% Reduction in Mortality HR 0.97 (0.81,1.15) Significant Non-­Significant 55% Reduction in TVR 6% Reduction in MI HR 0.94 (0.79,1.13) HR 0.45 (0.37,0.54) 30 Registries (171,279 patients) treated with DES or BMS and followed for ≥1 year DES resulted in: Significant Significant Significant 20% Reduction in Mortality 11% Reduction in MI 55% Reduction in TVR HR 0.80 (0.72,0.88) HR 0.89 (0.80-­0.98) HR 0.53 (0.47-­0.61) Issues with Drug Eluting Stents Longer Duration DAPT New Disease Definitions Emerge • In-Stent Restenosis - ISR • Acute Stent Thrombosis - AST • Sub-acute Stent Thrombosis – SST • Late Stent Thrombosis – LST • Very Late Stent Thrombosis – VLST Impact of Second Generation DES in ST Cumulative incidence (%) The Bern Rotterdam Cohort Extended – ARC Definite ST 5 EES vs. S ES Hazard Ratio* = 0.41, 95% CI 0.27–0.62, P<0.0001 EES v s. PES Hazard Ratio* = 0.33, 95% CI 0.23-­‐0.48, P <0.0001 4 Paclitaxel Stent 4.4% 3 Sirolimus Stent 2.9% 2 1 Everolimus Stent 1.4% 0 0 No. at risk PES SES EES 4214 3784 4135 6 12 18 24 30 Months after index PCI 36 3797 3569 3793 2905 3404 2604 1880 2521 1041 Raber, L. et al, data presented at the ESC 2011 42 48 686 1734 208 Compensatory Expansive Remodeling of EEM IT PIT + FA 1Y 5Y BL - Lumen Reduction Late acquired malapposition Lumen Reduction Struts Metallic Struts SE2935049 Rev. A Information contained herein intended for healthcare professionals from outside the US only. “Caged” (Stented) Vessel Lumen Reduction by Intrastent Growth of tissue Ruptured intra-­‐ stent plaque - Trends in PCI: Improvement in Patient Outcomes with the Opportunity for Further Advances Balloon Angioplasty Bare metal Stent Drug Eluting Stent Decade 1980s 1990s 2000s Acute Success rate 70-­85% >95% >95% Restenosis 40-­45% 20-­30% <10% Early Thrombosis <30 days 3-­5% 1-­2% 1-­2% Late Thrombosis >30 days NA <0.5% 1-­2% Very Late Thrombosis (>1y) NA ≈0% 1-­2% Metallic Stents § Permanent rigid scaffold § Interferes with shear stress § Interferes with late luminal enlargement § Interferes with compensatory expansive remodeling § Loss of physiologic response § Vessel distortion – lack of conformability § Compromises CT Angiography The 4th Revolution in Coronary Intervention Bioresorbable Vascular Scaffold BVS (Everolimus) ART BTI Amaranth Elixir Orbus REVA Biotronik Bioresorbable Scaffold – Rationale and Goals Rationale: Vessel scaffolding is only needed transiently* Goal: Revascularize the vessel like a metallic DES, then resorb naturally into the body. Potential benefits: § Restoration of natural physiologic vasomotor function in some patients § Enable vascular remodeling and tissue adaptation § Elimination of chronic sources of vessel irritation and sources for chronic inflammation § Possibly avoid current challenges with leaving a metal implant behind § Potentially reduce the need for prolonged DAPT § No permanent implant to complicate future interventions and re-­interventions, particularly in younger patients § Non-­invasive imaging with MSCT or MRA without ‘blooming artifact’ *Serruys PW, et al., Circulation 1988;; 77: 361. Serial s tudy s uggesting v essels s tabilize 3-­4 months f ollowing PTCA. Compensatory Expansive Remodeling of EEM - PIT FA 2Y 6M BL + Lumen Enlargement by Plaque Regression Struts Scaffolding Lumen Enlargement By Bioresorbable Scaffolding Bioresorbable Scaffold – A new treatment Paradigm for Atherosclerotic Plaque - SE2935049 Rev. B - Lumen Reduction IT Design Requirements of a Fully Bioresorbable Scaffold: Three Phases of Functionality Revascularization Restoration Resorption 0 to 3 months 3 to 12 months + ~12 months + Transition from scaffolding to d iscontinuous structure Implant is d iscontinuous and inert Performance should mimic that o f a standard DES •Good deliverability •Gradually lose radial strength •Resorb in a benign fashion •Minimum of acute recoil •Struts must be incorporated into the vessel wall (strut coverage) •Allow the vessel to respond naturally to physiological stimuli •Sufficient acute radial strength •Controlled delivery of drug to abluminal tissue •Excellent conformability •Become structurally discontinuous Bioresorbable Vascular Scaffold Components Bioresorbable Scaffold • Poly (L-­lactide) (PLLA) • Naturally resorbed, fully metabolized All illustrations are artists’ renditions Bioresorbable Coating • Poly (D,L-­lactide) (PDLLA) coating • Naturally resorbed, fully metabolized Everolimus • Similar dose density and release rate to XIENCE V XIENCE V Delivery System • World-­class deliverability Bioresorbable Polymer Everolimus/PDLLA Matrix Coating Drug/polymer matrix Polymer backbone • Thin layer • Amorphous (non-­crystalline) • 1:1 ratio of Everolimus/PDLLA matrix • Conformal coating, 2-­4 µm thick • Controlled drug release PLLA Scaffold • Semi-­crystalline • Provides device structure • Processed for required radial strength TCT 2014 13 Sep 2 014 -­ 17 Sep 2 014 , Washington, DC -­ U.S.A Five Year Angiographic Results of the ABSORB Everolimus Eluting Bioresorbable Vascular Scaffold B De Bruyne1, MD, PhD;; G.G Toth1, MD;; Y Onuma2,3, MD, PhD;; HM Garcia Garcia3, MD, PhD;; PW Serruys2, MD, PhD B 1OLV Hospital, Aalst, Belgium;; 2 Thorax Centre, Erasmus MC, Rotterdam, The Netherlands;; 3 Cardialysis BV, Rotterdam, The Netherlands on behalf of the ABSORB Cohort B Investigators Saturday September 13, 5:00 PM Results OCT ImagesOver Time Showing Complete Resorbtion of the Scaffold Struts Baseline 6 Months 2 Years 5 Years Courtesy of Dr RJ v Geuns, Rotterdam, The Netherlands Absorb Cohort B1 5 Year Results; B de Bruyne, TCT 2014 ABSORB III + IV Randomized Trials ~5,000 pts with up to 3 de novo lesions in different epicardial vessels randomized to ABSORB v XIENCE, with FU for at least 5 years, at up to 130 sites Primary ABSORB IV endpoints (superiority): 1. Angina at 1 year (n=3,000 from ABSORB IV) 2. TLF between 1 and 5 yrs (n=5,000, landmark analysis) Absorb IV PRO (baseline, 1, 3, 6, 9 months, 1, 2 and 3 years) Detailed angina CRF, + validated instruments: Seattle Angina Questionnaire (SAQ), Rose Dyspnea Scale (RDS), EuroQoL 5D (EQ5D) Detailed assessment of hospitalizations, revascularizations, MACE Detailed resource utilization and cost data through 5 years Ischemia substudy (RESOLVE): CTA, CT perfusion, CTFFR and SPECT at multiple time points PI: GW Stone Co-­‐PIs: SG Ellis, DJ Kereiakes Case Examples PATIENT 1 PATIENT 2 Case Examples PATIENT 1 PATIENT 2 Case Examples PATIENT 1 PATIENT 2 Future Directions § 2nd and 3rd generation of BVS ú Different drugs, different polymers, strut design, etc. § Drug Filled Stents ú BMS Surface ú Drug sits in a hollow core and elutes through surface holes SYNERGY™ Stent Platform Abluminal Bioabsorbable Polymer Bioabsorbable polymer (PLGA) Applied only to the abluminal surface (rollcoat) Thin strut PtCr Stent Durable Permanent Polymer + Drug 360 Around Stent Current Durable Polymer Abluminal Bioabsorbable Polymer PLGA Bioabsorbable Polymer (3 µm) + Everolimus* on Abluminal Side of Stent *2 doses of everolimus evaluated: one similar to PROMUS™ stent and one that is half the dose Presented by Ian Meredith, MBBS, PhD at TCT 2010 Study sponsored by Boston Scientific Corporation. Not for sale. See glossary for prescriptive information. Drug Filled Stent (DFS) Technology Polymer Free Drug Delivery Innovative DES Design • Essentially a BMS surface • Designed to address drug carrier issues such as: § Polymer biocompatibility § Inflammation upon polymer degradation § Surface coating durability CAUTION: Design concepts not approved for sale or clinical use Paclitaxel Coated Balloon Technology Acute Tissue Transfer of Paclitaxel University of California Davis Medical Center THANK YOU Polylactide Degradation by Hydrolysis Primary mode of degradation is by hydrolysis of ester bonds § Water preferentially penetrates amorphous regions of the polymer matrix § Hydrolysis initially results in a loss of molecular weight, but not radial strength, as the strength comes from crystalline domains § Once polymer chains are sufficiently short to diffuse from struts or become soluble, mass loss occurs § Pietrzak WS, et al. J. Craniofaxial Surg, 1997;; 2: 92-­96. Middleton JC, Tipton AJ, Biomaterials, 21 (2000) 2335-­2346. 1 Polylactide Degradation vs. Radial Support Hydrolysis occurs via random chain scission of the ester bond U U •⊗ •⊗ •⊗ •⊗ •⊗ •⊗ •⊗ •⊗ •⊗ •⊗ •⊗ •⊗ Tie chains U Hydrolysis randomly cleaves amorphous tie chains, leading to a decrease in molecular weight without altering radial strength U U U U U Support When enough tie chains are broken, the device begins losing radial strength U U U U Molecular Weight Mass Loss 1 3 6 Illustration is a rtist’s rendition. Data o n file a t A bbott V ascular. 12 18 ⊗ ⊗ ⊗ ⊗ ⊗ ⊗ 24 Mos ‘Caged’ (Stented) Vessel Delayed Healing → Stent T hrombosis? * uncovered struts1 Benign NIH Neo-­Atheroma → Stent T hrombosis? In-­Stent Restenosis Late Acquired Malapposition → Stent T hrombosis? 1. Virmani, R. CIT 2010 Design Requirements of a Fully Bioresorbable Scaffold: Aligning Device Engineering with Vascular Biology Revascularization Restoration Resorption Support Full Mass Loss & Bioresorption Everolimus Elution Mass Loss 1 3 6 Months Platelet Deposition Matrix Deposition Leukocyte Recruitment Re-­endothelialization SMC Proliferation and Migration Vascular Function Forrester J S, et al., J . Am. Coll. Cardiol. 1991;; 17: 758. Oberhauser J P, et al., EuroIntervention Suppl. 2009;; 5: F15-­F22. 2 Years Potential of a Fully Bioresorbable Vascular Scaffold Benign NIH In-­Scaffold Restenosis Expansive Remodeling Late Lumen Enlargement Plaque Regression Since struts disappear, issues related to very late persistent strut malapposition and chronically uncovered struts become irrelevant Bioresorption and vessel wall integration are a reality BL ISA incomplete stent apposition Apposed 6M Persistent ISA Late acquired ISA 2Y Resolved ISA Non Discernible Resolved ISA Non Discernible Serruys, PW, PCR, 2010 Bioresorption at jailed side branch is a real phenomenon Okamura et al., EHJ, 2010 Potential Causes for Less Angina and Ischemia with Absorb Compared to Metallic Stents Metallic Stent Absorb Baseline At 6 months, Absorb begins to resorb 1 year At 1 year, the vessel is no longer mechanically constrained • Lumen gain allows for blood flow • “Caging” inhibits natural vessel movement • Vasomotion allows the vessel to accommodate and remodeling increased flow demand
