Νεότερα DES stents. Δεδοµένα εφαρµογής των και προοπτικές

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1 Νεότερα DES stents. Δεδοµένα εφαρµογής των και προοπτικές Δηµήτρης Γ. Σιώνης Αιµοδυναµικό Τµήµα Επεµβατικής Καρδιολογίας Σισµανόγλειο-Αµ. Φλέµιγκ ΓΝ Αθήνα

2 Δήλωση συµφερόντων None for the presentation Potential conflicts of interest Institutional research grant : Elpen, Sanofi, Boehringer Ing Honoraria : Medtronic, Sanofi

3 1 st -Generation DES was not ideal for healing Thick struts Thick, durable coating (~15 µm) High drug dose High polymer load Uncovered struts Hypersensitivity Malapposition Late stent thrombosis Neoatherosclerosis Th Th Th Th Uncovered struts Hypersensitivity reaction Malapposition from excessive fibrin deposition Neoatherosclerosis Virmani, CRT 2014

4 2 nd gen DES perm polymer: Improved efficacy and safety Data from Spirit II,III,IV and COMPARE trials (6789)

5 Event rates persist beyond 1 year with 2 nd gen PERMANENT Polymer DES TLF Rate (%) RESOLUTE All Comers Resolute ZES (N=1140) Xience V EES (N=1152) Primary endpoint Pnon-inferiority < % 8.2% Log rank P= % 16.3% Years 2% event rate per year Windecker PCR 2014

6 Etiology of metallic stents events Within 1 year Early thrombosis and restenosis Early DAPT discontinuation Suboptimal implantation (under expansion, malapposition, geographic miss, edge dissections) Longitudinal stent deformation Strut fracture Polymer defects or stripping during delivery Inflammation/hypersensitivity from the polymer/drug Non responsiveness to drug Beyond 1 year Very late thrombosis and restenosis Uncovered struts (thrombosis) Abnormal shear stress from protruding struts and/or loss of cyclic strain relief Strut fracture Persistent stimulation of SMC s from adherent fibrin and/or loss of normal vessel curvature Chronic inflammation due to late foreign body reactions and polymer hypersensitivity Positive remodeling with strut malapposition Neoatherosclerosis

7 Approaches to improve Next Generation metallic DES outcome Deliverable, Visible, Trackable Conformable No Stent Thrombosis Short DAPT duration Low TLR, Low Clinical Symptom Recurrence Improved Stent Delivery System Stent Material Thinner Struts Modified Stent Geometry Enhanced side-branch access Surface Coating Facilitating re-endothelialization Polymer facilitating endothelialization Durable, but more biocompatible Reduced Polymer Load Abluminal Polymer No Polymer Bioabsorbable Polymer Reduced Drug Load Less/no effect on endothelial function

8 Approaches to improve early and late DES outcomes Metallic DES with thinner struts

9 Thin Struts Restenosis and Thrombosis 1. ISAR STEREO 1, Circulation ISAR STEREO 2 JACC Kolandaivelu et al Circulation 2011

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12 Approaches to improve early and late DES outcomes Metallic DES polymer-free Metallic DES with bioabsorbable polymers Bioresorbable scaffolds (BRS)

13 HYPOTHESIS: Polymers play a role in phenomena observed with DES ANEURYSMS, HYPERSENSITIVITY, LATE RESTENOSIS, LISA VASO- CONSTRICTION a INCREASED INFLAMMATION b PRO- THROMBOGENIC b DELAYED HEALING c Decreased Endothelial Function Illustration based on Beckmann JA et al. JAMA. 2002;287(19): and Roesen P et al. Exp Clin Endocrinol Diabetes. 2001;109(supp 12):S474-S486. a Tongi et al. Int J Cardiol. 2007;120:212. b Joner et al. J Am Coll Cardiol. 2006;48: c Awata et al. ACC

14 Polymer Free Design Types 1.Bioactive agent in pure form, impregnated in porus surface or stent body Nano/micro can use metal sieve structure to control release kinetics Macro or wells-diffusion depends primarily on pharmacokinetic properties of the agent 2.Bioactive agents dissolved in a non-polymeric biodegradable carrier. On surface of stent In a nano-micro structure Biosensors Translumina Setagon Medronic Ziscoat 3.Bioactive agent attached to stent surface Covalent bonding Chemical precipitation or crystalization on stent surface Amazonia PAX

15 Urban F et al, NEJM 2015 Leaders Free trial Age>75 years OAC planned after PCI Baseline Hb <11g/dl or transfusion prior 4 weeks Planned major surgery Cancer diagnosed or treated <3 years Creatinine clearance <40ml/min Hospital admission for bleeding during past year Thrombocytopenia (< /mm3) Any prior intra-cerebral bleed Any stroke during the past year Severe liver disease NSAID or steroids planned after PCI Anticipated poor DAPT compliance for other medical reason Primary Efficacy Endpoint Clinically Driven TLR Primary Safety Endpoint Cardiac Death, MI, ST

16 The Drug Filled Stent-Concept (Medtronic) Drug (sirolimus) is protected and contained inside the stent Drug releases through multiple laser-drilled holes on the abluminal side of the stent Drug elution is controlled and sustained through natural diffusion via direct interaction with the vessel wall. Elution profile is similar to durable polymer DES Drug coats inner lumen Drug elutes through abluminal holes Uniform distribution in stented area

17 Case by Prof. Stephen Worthley. OCT Analysis by Daniel Chamié, MD, OCT Core Laboratory, Cardiovascular Research Center, Sao Paulo, Brazil DFS case, Early Healing of Overlapping Struts Post-Procedure Age (yrs) 60 Gender (M/ F) Diabetes (Y/N) F Y(ID) RVD (mm) 3.0 Lesion Length (mm) Lesion location 46 Mid RCA 1-Month Followup 0.6 mm 14 mm 17 mm 17.8 mm 42.2 mm

18 Approaches to improve early and late DES outcomes Metallic DES polymer-free Metallic DES with bioabsorbable polymers Bioresorbable scaffolds (BRS)

19 Vascular Response to Durable Polymers Newer generation durable polymers are still a source of inflammation, neoatherosclerosis and thrombosis risk Virmani et al TCT 2012

20 Time Course For Polymer Bioabsorption BioMime (PLLA+PLGA) SYNERGY (PLGA) Ultimaster (PLLA - CL) MiStent (PLGA) ABLUMINUS (PLA) ELIXIR DESyne BD (PLA) FIREHAWK (PLA) BIOMATRIX (PLA) NOBORI (PLA) SVELTE (Amino Acid) ORSIRO (PLLA) REAMS 2 (Mg w/pla coat) ART (PDLLA) ELIXIR DESolve (PLLA) BVS (PLLA) REVA ReZolve (Polycarb) (no drug) Time (Months) Drug Release Bioabsorbable Polymer Bioresorbable Scaffold (BRS)

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22 An abluminally coated bioabsorbable polymer DES be optimal for healing? may Uncoated surface on luminal side to promote cell coverage and adhesion Freedom from long-term polymer exposure once coating is absorbed Strut Vessel Lumen Arterial Wall Targeted drug delivery reduces risk of restenosis and inflammation

23 SYNERGY OCT Results in All Comers Patients Understanding healing from 30 Days 6 Months 30 days 3 Months 6 Months 72.2% Covered 99.3% Covered* 94.5% Covered 96.6% Covered N=30 N=37 N=22 N=20 SORT-OUT VIII PCR 2015 TIMELESS CRT 2015 De la Torre CCI % Thrombosis De la Torre CCI 2015

24 EVOLVE II TLF at 2 years PROMUS Element Plus vs SYNERGY TLF (%) Endpoint: 12 months ITT P noninferiority = years HR 1.10 [0.79, 1.52] P= % 8 6.7% 8.5% 4 6.5% No. at Months risk PE SYNERGY ITT Population; Patients who did not receive a study stent were censored at 1 year; KM Event Rates; log-rank P values Kereiakes, ACC 2016

25 3 rd generation

26 Approaches to improve early and late DES outcomes Bioresorbable scaffolds (BRS) Absence of metallic cage

27 4 th Evolution in Coronary Angioplasty Bioresorbable Scaffold Lifecycle - Polymer exposure - Drug elution to reduce risk - Drug elution complete complete of restenosis - Mechanical support to maintain - Scaffold support no longer - Mechanical support to patency required maintain patency - Natural vasomotion and positive remodeling REVASCULARIZATION RESTORATION enabled RESORPTION Scaffold Mass Drug Elution Scaffold Support Months Forrester, et al. J Am Coll Cardiol. 1991: Oberhauser, et al. EuroInterv.

28 Available and upcoming Bioresorbable Scaffolds

29 First Generation BVS The Absorb Series Everolimus/PDLLA (1:1) matrix coating 7µm Conformal coating Controlled drug release similar to Xience CoCr-EES -Impressive results of pivotal trials -Non inferior to 2 nd gen DES -First signs of safety issues in GHOST trial (2.1% thrombosis)

30 1 st gen BVS Meta-Analyses Comparison Target Lesion Failure Absorb (%) Xience (%) Odds Ratio (95% CI) P value Cassese et al, % 5.1% 1.20 [0.9, 1.6] 0.21 Stone et al, % 5.1% 1.25 [0.92, 1.70] 0.18 Myocardial Infarction Cassese et al, % 3.5% 1.36 [0.98, 1.89] 0.06 Stone et al, % 4.0% 1.34 [0.97, 1.85] 0.07 Lipinski et al, % 1.5% 2.06 [1.31, 3.22] Stent Thrombosis (def/prob) Cassese et al, % 0.5% 1.99 [1.00, 3.98] 0.05 Stone et al, % 0.6% 2.09 [0.92, 4.75] 0.08 Lipinski et al, % 0.7% 2.06 [1.07, 3.98] Absorb better Xience better Cassese, et al. The Lancet 2016; 387: Lipinski, et al. JACC Cardiovasc Interv 2016;9: Stone, et al. The Lancet 2016 [epub ahead of print].

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32 Possible Causes of Increased ST Rates with ABSORB Poor Lesion Preparation Thick Struts (157µm overlapping 354µm) Non-laminar Flow Inadequate Post-dilatation Malapposition Delayed Healing Fractures Proposed solutions Use in >2.5mm vessels Need for proper preparation Adequate postdilatation Avoid overlapping scaffolds Thrombosis Strut Fracture Malapposition Underexpansion Thick Struts 1 Jaguszewski, M. Eur Heart J. Feb 2015 [Epub ahead of print]. 2 Ormiston, et al. Circ Cardiovasc Interv. 2011;4: RadcliffeCardiology.com, September Sipotz, J. presented at TCT2014. Capodanno, et al. EuroIntervention 2015 Feb;10(10):

33 DESolve Bioresorbable Coronary Scaffold- elutes for 3 months absorbs in 2 years 3.4m m Hierarchical Events (n,%) 3.8m m Verheye et al, JACC Interv M (N=122) 12M (N=122) 4.0m m 24M (N=122) 4.75m m 36M (N=122) Major Adverse Cardiac Events 3.3% 5.7% 7.4% 8.2% Cardiac Death 1(0.8%) 2 (1.6%) 3 (2.5%) 4 (3.3%) Target Vessel MI Q wave Non Q wave MI 1(0.8%) 0(0,0%) 1(0.8%) 1 (0.8%) 0 (0,0%) 1 (0.8%) 1 (0.8%) 0 (0,0%) 1 (0.8%) 1 (0.8%) 0 (0,0%) 1 (0.8%) Clinically Indicated TLR 2 (1.6%) 4 (3.3%) 5 (4.1%) 5 (4.1%) Definite Stent Thrombosis 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)

34 BIOTRONIK Mg BRS Magmaris results

35 Bioresorbable Scaffolds data The Idea. the Data.. the Future Absence of Permanent Rigid Metallic Cage Preservation of targets for CABG Restoration of vasomotion Late luminal enlargement Significantly longer procedure time Significantly lower acute gain and post procedure MLD Numerically high adverse event rates even in relatively simple lesions Signal for high rates of late events More than 8 studies with >2% ST at 1 year in realworld populations Strut thickness Fracture resistance Visibility Absorption time Radial force Clinical data Future (near) BRS

36 Bioresorbable scaffolds Next Gen Absorb 120 NG Absorb 2 Magmaris BOSTON s RENUVIA Bioresorbable Scaffold Bioresorbable Microfiber Scaffold (BRMS)- MIRAGE Medtronic Mg Absorbable Scaffold Puricel et al, JACC 2016;67:

37 Conclusions Current metallic DES (either with durable or bioabsorbable polymer) have shown excellent safety and efficacy, therefore remain the default treatment for CAD either SIHD or ACS. Bioabsorbable polymer DES seem to offer advantages over durable polymer DES but are not a homogenous class Novel technologies include advantages on stent design and platform (DFS, polymer-free) may show further advantages of metallic DES. 1 st generation BRS use face problems short and long term as far as the efficacy and safety of the devices Possible overcome of these limitations can be achieved with the development of 2 nd generation BRS and the refinement of the deployment procedure Till then, the Operator is a major factor in the efficacy and safety of 1 st generation BRS, being an

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39 Stent Thrombosis at 36 months Definite ST Definite, Probable or Possible ST Orsiro Xience Prime Orsiro Xience Prime (N=298) (N=154) (N=298) (N=154) Acute (0-48h) 0 % 0 % Acute (0-48h) 0 % 0 % Subacute (48h-30d) 0 % 0 % Subacute (48h-30d) 0 % 0 % Late (>30d) 0 % 0 % Late (>30d) 0 % 0 % Very late (>12m) 0 % 0 % Very late (>12m) 0 % 0.7 % Overall 0 % 0 % Overall 0 % 0.7 %* * One possible very late ST occured in a diabetic patient in the Xience Prime arm Source: T. Slagboom, Poster, EuroPCR 2015

40 Bioresorbable Scaffolds data The Idea. the Data.. the Future Absence of Permanent Rigid Metallic Cage Restoration of vasomotion Late luminal enlargement Preservation of targets for CABG Appeal to physician/ patient Freedom from longterm polymer exposure Angina relief Significantly longer procedure time Significantly lower acute gain and post procedure MLD Numerically high adverse event rates even in relatively simple lesions Signal for high rates of late events More than 8 studies with >2% ST at 1 year in realworld populations Strut thickness Fracture resistance Visibility Absorption time Radial force Clinical data Future (near) BRS