Innovation in Cardiovascular Interventions. New DES, Scaffolds and other Devices Have Angioplasty Results Improved

Transcription

1 Innovation in Cardiovascular Interventions New DES, Scaffolds and other Devices Have Angioplasty Results Improved Alexandra Lansky, MD Yale University School of Medicine University College of London

2 DES Evolution to Thinner Strut Thickness 1 st Generation 2 nd Generation 3 rd Generation 4 th Generation Cypher Stent TAXUS Express Stent TAXUS Liberté Stent Endeavor Stent Xience V and Xience Prime Stents ION / TAXUS Element Stent PROMUS Element Stent SYNERGY Stent current benchmark for lowest strut thickness μm ( ) μm ( ) μm ( ) μm ( ) μm ( ) μm ( ) μm ( ) μm ( ) Coating Thickness: 12.6 µm 19.6 µm 4.8 µm 7.8 µm Stainless Steel Cobalt Alloys Platinum Chromium Reported strut thicknesses are for 3.0mm diameter

3 Promus Element Xience V Drug-eluting Stents: 2 nd Generation H O O O O O O O HO N O H O O O O O H O O Everolimus Drug VDF + HFP copolymer Polymer Vision Stent O O O O O HO N O H O O O O O Everolimus VDF + HFP copolymer Element (Ion)

4 SPIRIT II, III, IV and COMPARE trials Pooled database analysis (n=6,789) MACE (Cardiac Death, MI, ID-TLR) Cardiac Death, MI, Ischemic TLR (%) 15 EES (n=4,247) PES (n=2,542) HR: 0.64 [0.54, 0.75] P< % 11.1% 7.3% 5 4.4% 0 Number at risk XIENCE TAXUS Time in Months Kereiakes DJ et al. EuroIntervention 2011:7:74-83

5 SPIRIT II, III, IV and COMPARE trials Pooled database analysis (n=6,789) Stent thrombosis (ARC definite/probable) Stent thrombosis ARC def or prob (%) 3 2 EES (n=4,247) PES (n=2,542) HR: 0.30 [0.19, 0.47] p< % 1 0.7% 0 Number at risk XIENCE TAXUS Time in Months Kereiakes DJ et al. EuroIntervention 2011:7:74-83

6 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 Acute Subacute Late Vision 2.6% Xience V 0.9% p = Definite ST was reduced with Xience V from 1.9% to 0.5%, p=0.01 Sabate M et al. Lancet 2012

7 TLF (%) PLATINUM: Target Lesion Failure 4-Year Follow-up (Primary Endpoint at 1 Year) CoCr-EES (N=749) PtCr-EES (N=758) HR [95% CI] = 0.86 [0.60, 1.24] P = % 7.4% Primary Endpoint No. at risk CoCr-EES PtCr-EES Treatment Group PROMUS Element 0-4Y Months Since Index Procedure PROMUS 0-4Y Kereiakes DJ et al. JACC 2014;63 (12):2905-4

8 Resolute Endeavor Drug-eluting Stents: 2 nd Generation Zotarolimus Phosphorylcholine Driver Drug Polymer Stent Hydrophilic Hydrophobic Zotarolimus BioLinx Driver

9 Endeavor II Trial 1197 pts randomized to E-ZES vs. BMS 9 month outcomes E-ZES (n=592) BMS (n=591) TVF (1 EP) 7.9% 15.1% P mm - Death 1,2% 0.5% MI 2.7% 3.9% TLR 4.6% 11.8% TVR 5.6% 12.5% < Stent thrombosis 0.5% 1.2% 0.22 In-segment binary restenosis E-ZES: 13.2% BMS: 35.0% P< Fajadet J et al. Circulation. 2006;114:

10 PROTECT Study Design Largest RCT and first powered for ST Real-world patients N=8709 Single and multiple coronary artery lesions No limitations on number of lesions/vessels Endeavor ZES 1:1 Randomization 196 sites world wide in 5 continents Cypher SES Clinical endpoints 30d 6mo 12mo 18mo 24mo 30mo 3yr 4yr 5yr 3-12 months of aspirin and clopidogrel Primary endpoint: ARC definite or probable ST at 3 years Powered for a 40% reduction with ZES Camenzind E et al. Lancet 2012

11 ARC Definite / Probable ST PROTECT Primary Endpoint Definite or probable stent thrombosis to 3 years 5% 4% 3% 2% 1% Endeavor ZES (N = 4357) Cypher SES (N = 4352) HR [95%CI = 0.81 [ ] P= % 1.42% 0% Time After Initial Procedure (Years) Patients at Risk E-ZES C-SES Camenzind E et al. Lancet 2012

12 PROTECT Primary Endpoint Definite or probable stent thrombosis to 3 years Endeavor ZES (n = 4181) Cypher SES (n = 4159) P = 0.60 P = 0.02 P<0.001 Early (0-30 days) Late (1-12 months) Very late (1-3 years) Camenzind E et al. Lancet 2012

13 Rate (%) PROTECT Secondary Endpoints - 3 years - Endeavor ZES (n = 4181) Cypher SES (n = 4159) P = 0.03 P = 0.76 P = 0.21 P< Death MI TLR TVR Camenzind E et al. Lancet 2012

14 Cumulative Incidence of Events RESOLUTE All-Comers: TLF (Cardiac Death, TV-MI or clinically-driven TLR) 20% 15% R-ZES (n=1,140) EES (n=1,152) 95% CI = 0.6% [-2.0%, 3.2%] P = % 11.2% 10.7% 5% 0% Days after Initial Procedure Silber S et al. Lancet. 2011;377:1241-7

15 TVF (%) TWENTE (n=1,387) Target Vessel Failure at 2-Year Follow-up Xience V (n=692) Resolute (n=695) 20 P = % 10.9% Follow-up (days) Tandjung K et al. J Am Coll Cardiol 2013;61:

16 Stent Thrombosis Network Meta-analysis ARC Definite ST at 30 days 49 RCTs, 50,844 pts 30-day definite stent thrombosis* Odds Ratio [95%] CoCr-EES vs BMS 0.21 ( ) CoCr-EES vs PES 0.27 ( ) CoCr-EES vs SES 0.40 ( ) CoCr-EES vs End-ZES 0.22 ( ) CoCr-EES vs Res-ZES 0.07 ( ) PtCr-EES vs BMS 0.06 ( ) PtCr-EES vs PES 0.07 ( ) PtCr-EES vs End-ZES 0.06 ( ) PtCr-EES vs Res-ZES 0.02 ( ) SES vs BMS 0.54 ( ) Favors Stent 1 Favors Stent 2 Palmerini T et al. Lancet 2012:On-line

17 Stent Thrombosis Network Meta-analysis ARC Definite ST at 1 year 49 RCTs, 50,844 pts 1-year definite stent thrombosis* Odds Ratio [95%] CoCr-EES vs BMS CoCr-EES vs PES CoCr-EES vs SES CoCr-EES vs Res-ZES CoCr-EES vs End-ZES SES vs BMS End-ZES vs SES 0.23 ( ) 0.28 ( ) 0.41 ( ) 0.14 ( ) 0.21 ( ) 0.57 ( ) 1.92 ( ) Favors Stent 1 Favors Stent 2 Palmerini T et al. Lancet 2012:On-line

18 TLF (%) SPIRIT III: Target Lesion years 30% 25% 20% 15% 10% 5% 0% Number at risk XIENCE V (n=669) TAXUS Express (n=332) 1-year HR 0.56 [0.34, 0.90] p= % Δ3.8% 5.4% 5-year HR 0.64 [0.46, 0.89] p= % Δ6.3% 12.7% Months XIENCE V TAXUS TLF = cardiac death, target vessel MI, or ischemic-driven TLR ~1.8%/yr event rate after year 1 Stone GW et al. JACC 2011

19 SPIRIT IV: Target Lesion years Target lesion failure (%) Number at risk XIENCE V (n=2,458) TAXUS Express (n=1,229) HR [95%CI] = 0.61 [0.46, 0.81] p= % Δ 2.7% 4.0% HR [95%CI] = 0.71 [0.56, 0.90] p=0.004 HR [95%CI] = 0.78 [0.63, 0.97] p= % Δ 2.5% Months XIENCE V TAXUS TLF = cardiac death, target vessel MI, or ischemic-driven TLR Stone GW et al. JACC % ~2.6%/yr event rate after year 1

20 Etiology of metallic stent events beyond 1 yr Very late thrombosis and restenosis Possible causes 1.Uncovered stent struts (thrombosis) 2.Persistent stimulation of SMCs, from adherent fibrin and/or loss of normal vessel curvature 3.Abnormal shear stress from protruding struts and/or loss of cyclic strain relief (compliance mismatch) 4.Chronic inflammation due to late foreign body reactions and polymer hypersensitivity 5.Positive remodeling with strut malapposition 6.Strut fracture 7.Neoatherosclerosis

21 Neoatherosclerosis: Transformation of Neointimal Hyperplasia to Necrotic Core in BMS and DES 6-mo Taxus %NC 8% %DC 2% 9-mo Taxus %NC 28% %DC 8% 22-mo Taxus %NC 39% %DC 20% 48-mo BMS %NC 40% %DC 25% 57-mo BMS %NC 57% %DC 15% Kang SJ et al. AJC 2010;106:

22 TCFA Development in Neointimal Hyperplasia Is More Common with DES than BMS, occurs earlier, and can rupture causing stent thrombosis and occlusion Nakazawa G et al. J Am Coll Cardiol 2011;57:

23 Three Approaches to Improve Late DES Outcomes 1. Metallic DES with bioabsorbable polymers 2. Metallic DES, polymer-free 3. Bioresorbable scaffolds (BRS)

24 Stent thrombosis (%) Stent thrombosis (%) Meta-analysis of Bioresorbable Polymer DES: ISAR-TEST 3, ISAR-TEST 4, and LEADERS at 4 yrs ,062 randomized pts assigned to bioresorbable polymer eluting sirolimus or biolimus A (2,388) or Cypher (1,704) Definite Stent Thrombosis 0 0 Durable polymer 0.02 [0.47, 1.38] P=0.43 HR [95%CI] = 0.56 [0.35, 0.90] P=0.015 Biodegradable polymer 0.22 [0.08, 0.61] P= % 1.3% Years Years BP DP ISAR-TEST 3 1/202 2/202 ISAR-TEST 4 9/ /652 LEADERS 20/857 32/850 Overall 30/2358 Test for heterogeneity P=0.84 Test for inconsistency 1 2 =0% Test for overall effect z 2 =2.43 (P=0.015) HR (95% CI) 0.47 (0.04, 5.04) 0.45 (0.18, 1.12) 0.62 (0.35, 1.08) 44/ (0.35, 0.90) 0.1 Favors BP HR 10 Favors DP Stefanini GG et al. EHJ 2012;33:

25 Abluminal Bioabsorbable Polymer SYNERGY Stent (BSC) Abluminal bioabsorbable polymer (PLGA) 3-4 um thick Thin PtCr stent (74 81 um) PLGA bioabsorbable polymer + everolimus on abluminal side of stent Coating weight on 16 mm stent ~200 µg (vs ~685 µg for Xience / Promus) Everolimus elutes over ~3 months (similar to Xience / Promus) PLG undetectable by ~4 months, leaving behind a BMS

26 Late loss, mm Target lesion failure, % 291 Pts Randomized to Promus Element vs. Synergy vs Synergy ½ dose Primary Endpoints Late Loss at 6 Months TLF at 30 Days P=0.19 P= P=0.49 P= PROMUS Element SYNERGY SYNERGY ½ Dose PROMUS Element 1.1 SYNERGY 3.1 SYNERGY ½ Dose Meredith I et al. JACC 2012;59:

27 EVOLVE II Study Design SYNERGY Stent Pivotal Trial 2,006 pts with native coronary lesions 34 mm in length, RVD 2.25 mm - 4.0, %DS 50% Up to 3 lesions in 2 vessels (excludes LM disease, CTO, ISR, STEMI) Randomized cohort (RCT) PROMUS Element N=842 Up to 160 global sites Enrollment Complete SYNERGY N=842 RCT Design Multicenter noninferiority trial Single-blind, 1:1 randomization Primary Endpoint: TLF at 12 mo Follow-up: 30d, 6m, 12m, 18m and annual 2-5 yrs PK Substudy SYNERGY N=20-30 Diabetes Substudy SYNERGY N=

28 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

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

30 Bioresorbable Vascular Scaffold A new paradigm providing temporary vessel support and then allow the physiology to recover and evolve naturally.

31 BioResorbable Scaffolds Scaffold Compromise is thicker struts (>130 μm ) 157 μm μm 130 μm 150 μm

32 Potentials of Fully Bioresorbable Coronary Scaffolds Ormiston J et al. Circ Cardiovasc Interv 2012;5: Late Lumen Enlargement

33 Long-term Mechanical Differences between Scaffolds and Metallic Stent Metallic Stent Scaffold Baseline At 6 months scaffold begins to resorb 1 year At 1 year, the vessel is no longer mechanically constrained Caging inhibits natural vessel movement and remodeling Restoration of vascular physiology Restoration of cellular response Restoration of vasomotion and positive remodeling

34 Late Loss with Absorb Cohort B vs. Xience V Cumulative frequency distribution (mm) 6 month (SPIRIT II): 0.17 ± 0.32 mm (N=97) 24 month (SPIRIT II): 0.33 ± 0.37 mm (N=97) 6 month (Cohort B): 0.19 ± 0.18 mm (N=42) 24 month (Cohort B): 0.27 ± 0.20 mm (N=38) Late loss (mm) Claessen BE et al. Circ CV Int. 2009;2: Serruys PW. ESC 2012

35 ABSORB II 1-Year Patient Flowchart Intent To Treat N=501 1 subject consent withdrawn Absorb BVS N=335 Baseline Xience N=166 N= day N=166 3 subjects consent withdrawn 1 subject died N= day N=165 2 subjects consent withdrawn 1 subject consent withdrawn N=329 (98.2%) 1-year N=164 (98.8%)

36 ABSORB II: Clinical Outcomes Cumulative incidence in percentage Absorb 335 pts Xience 166 pts p value Target Lesion Failure 4.8 % 3.0 % 0.35 Cardiac death 0 % 0 % 1.00 Target vessel MI 4.2 % 1.2 % 0.07 Clinically indicated TLR 1.2 % 1.8 % 0.69 All TLR 1.2 % 1.8 % 0.69 MACE 7.3 % 9.1 % All death 0 % 0.6 % All MI 4.5 % 1.2 % All revascularization 3.6 % 7.3 %

37 ABSORB II: Definite scaffold/stent thrombosis Cumulative incidence in percentage Absorb 335 pts Xience 166 pts p value Definite scaffold/stent thrombosis Acute (0-1 day) 0.3 (1pt) 0.0 NS Sub-acute (2 30 days) 0.3 (1pt) 0.0 NS Late ( days) NS Probable scaffold/stent thrombosis Acute (0-1 day) NS Sub-acute (2 30 days) NS Late ( days) 0.3 (1pt) 0.0 NS

38 GHOST Registry Centers ElisabethKrankenhaus, Essen C. Naber S. Pyxaras Royal Brompton Hospital, London C. Di Mario A. Mattesini University of Giessen, Giessen H. Nef Medizinische Klinik, Mainz T. Gori Uniwersytet Medyczny, Poznan M. Lesiak A. Araszkiewicz San Raffaele Hospital and Emocolumbus Clinic, Milan A. Colombo A. Lateeb Klinikum Großhadern, Munich J. Mehilli S. G. Di Dio Hospital, Agrigento G. Caramanno S. Geraci Ferrarotto Hospital, Catania C. Tamburino (PI) D. Capodanno (co-pi) P. Capranzano

39 Angiographic Clinical GHOST: All Comers *Compared to ABSORB II eligibility (Diletti et al. Am Heart J. 2012;164:654-63)

40 Ghost: 6-Month Outcomes * TLF** TVF ST defin/prob CV Death All Death TV MI Any MI ID TLR ID TVR

41 GHOST: Scaffold Thrombosis 1.5% There were 20 cases of angiographically confirmed ST and three of probable ST. 70% occurred in the first month after PCI, at a median of 5 days, suggesting the need for scrupulous lesion selection and PCI techniques when using BVS Intravascular imaging was performed in only 9 of 23 patients who experienced ST 20 of 23 patients were on DAPT at the time of ST ST rates were numerically higher when more experience was accumulated and more complex patients were treated

42 Conclusions: Current and future directions in stenting Current DES have improved safety and efficacy profiles in ACS and stable CAD compared to first generation devices By limiting polymer, polymer-free systems, or fully bioresorbable scaffolds, will likely further reduce stent thrombosis and improve late outcomes If BRS reduce very late events from 1-5 years and/or stabilize or regress plaque, this will be transformative