Coronary Stents: Past, Present, Future

Transcription

1 Coronary Stents: Past, Present, Future Michael C Kim, MD FACC Director Cath Lab and IC Lenox Hill Heart and Vascular Institute Northwell Health IC AN DEC 2016 Page 1

2 1st-Generation DES was not ideal for healing Thick struts Thick, durable coating (~15 µm) High drug dose High polymer load Th Uncovered struts Virmani, CRT 2014 Th Hypersensitivity reaction üuncovered struts ühypersensitivity ümalapposition ülate stent thrombosis üneoatherosclerosis Th Malapposition from excessive fibrin deposition Th Neoatherosclerosis IC AN DEC 2016 Page 2

3 Bioabsorbable Scaffolds and Polymers become of Interest DAPT duration becomes major concern as VLST becomes a new and important condition It appears the 1 st generation polymers are the culprit If no stent remains in the coronary, then there should be no VLST. Or if the drug eluting polymer dissolves, perhaps this will rid of the issue IC AN DEC 2016 Page 3

4 Contemporary DES Platforms Strut and Coating Thickness In Perspective Durable Polymer Coated Bioabsorbable Polymer Coated Xience CoCr-EES Resolute Biomatrix Nobori Ultimaster SYNERGY MiStent Orsiro Promus PtCr-EES CoNi-ZES 316L-BES 316L- BES CoCr-SES PtCr-EES CoCr-SES CoCr-SES Strut thickness 81 µm µm µm µm µm µm µm µm Polymer PVDF BioLINX PLA PLA PDLLA + PCL PLGA PLGA PLLA Probio* Distribution / thickness Conformal 7-8µm / side Conformal 6µm / side Abluminal 10 µm Abluminal 20 µm Abluminal 15 µm Abluminal 4 µm Conformal 5 µm / 15 µm Conformal 3.5 µm / 7.5 µm *silicon carbide IC AN DEC 2016 Page 4

5 Event rates persist beyond 1 year with current PERMANENT Polymer DES Resolute All Comers 5-year TLF TLF (target Lesion Failure) is defined as cardiac death, TVMI, of clinically driven TLR. Presented by Stephan Windecker, MD PCR IC AN DEC 2016 Page 5

6 SYNERGY Stent Technology Design Platinum Chromium Platform 74μm (0.0029in) strut thickness Visibility Strength Flexibility Conformability Recoil Everolimus-Eluting 100μg/cm 2 3 month release time Ultrathin Abluminal Coating Bioabsorbable Polymer Coating (PLGA) Abluminal 4µm thick 85:15 ratio <4 month absorption time IC AN DEC 2016 Page 6

7 How may an abluminally coated bioabsorbable polymer DES be optimal for healing? Uncoated surface on luminal side to promote cell coverage and adhesion Vessel Lumen Freedom from long-term polymer exposure once coating is absorbed Strut Arterial Wall Targeted drug delivery reduces risk of restenosis and inflammation IC AN DEC 2016 Page 7

8 SYNERGY Stent Synchronous Drug Release & Polymer Absorption Preclinical evaluation in porcine model Everolimus Arterial Tissue Concentration ng/mg Everolimus Mass Remaining PLGA Mass Remaining Limit of Quantitation (LOQ) Wilson, G. J., et al. Cathet. Cardiovasc. Intervent. doi: /ccd IC AN DEC 2016 Page 8

9 Impact of Strut Thickness on Thrombogenicity Thicker Struts Associated with Increased Acute Thrombogenicity 157 µm Thick Strut DES BVS 120 µm Biomatrix Thin Strut DES 74 µm SYNERGY Thrombus formation assessed by immunofluorescence staining for platelet marker CD61 after 1 hour in ex-vivo pig AV shunt model Koppara, et al., Circ Cardiovasc Int 2015; Modified from Koskinas et al. J Am Coll Cardiol 2012;59: IC AN DEC 2016 Page 9

10 EVOLVE Trial Design and Methods Patients with de novo native coronary lesions 28 mm in length, RVD 2.25 mm 3.5, %DS>50% (excluded LM disease, CTO, AMI or recent MI) Randomized 1:1:1 at 29 sites (Europe, Australia, New Zealand) PROMUS Element N=98 SYNERGY N=94 SYNERGY ½ Dose N=99 Single-blind, noninferiority design Primary Clinical Endpoint: TLF (TV-CD, TV-MI, or TLR) at 30 days Primary Angiographic Endpoint: In-stent late loss at 6 months Per protocol patients were treated with clopidogrel, ticlopidine or prasugrel for at least 6 months following the index procedure Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362 IC AN DEC 2016 Page 10

11 EVOLVE Trial Key Results 6 Months 5 Years mm P=0.19 P= Late Loss 0.13 Patients, % P= P= TLF 0 0 ST (Def/Prob) 0 PROMUS Element (n=98) SYNERGY (n=94) SYNERGY Half Dose (n=99) Meredith et al. J Am Coll Cardiol. 2012; 59 (15):1362.; Presented by Meredith at EuroPCR Intent-to-treat; P values are versus PROMUS Element (Fisher exact test) IC AN DEC 2016 Page 11

12 Late Events with Permanent vs. Bioabsorbable Polymer DES 5-year Death/MI/TVR in EVOLVE Trial Death/MI/TVR (%) 20 0 Protocol-required angiogram 0 SYNERGY vs PE HR 0.79 [0.33, 1.89] P=0.60 SYNERGY ½ vs PE HR 1.28 [0.60, 2.74] P= Numbers at risk PE SYNERGY SYNERGY ½ Dose 15.6% 12.3% 9.8% 4 5 Years Safety Population; KM Event Rate; log-rank P values. Presented by Meredith at EuroPCR IC AN DEC 2016 Page 12

13 The LEADERS trial demonstrates that benefits of bioabsorbable polymer may become evident long-term Serruys, et al. JACC Vol. 6, No. 8, IC AN DEC 2016 Page 13

14 EVOLVE II Pivotal Trial Design Patients with 3 native coronary artery lesions in 2 major epicardial vessels; lesion length 34 mm, RVD 2.25 mm 4.0, %DS 50<100 (excluded LM disease, CTO, SVG, ISR or recent STEMI) Randomized Cohort (RCT) PROMUS Element Plus N= global sites SYNERGY N=846 RCT Design Multicenter noninferiority trial Pivotal, single-blind, 1:1 randomization Primary Endpoint: TLF (CD, TV-MI, or TLR) at 12 mo Follow-up through 5 years PK Substudy SYNERGY N=21 Diabetes Substudy SYNERGY N=203 DAPT (ASA + clopidogrel, ticlopidine, prasugrel, ticagrelor) 6 months or longer as tolerated Kereiakes, et al. Circ Cardiovasc Interv. 2015;8:e DOI: /CIRCINTERVENTIONS IC AN DEC 2016 Page 14

15 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% 0 No. at risk PE SYNERGY Months ITT Population; Patients who did not receive a study stent were censored at 1 year; KM Event Rates; log-rank P values Presented by KereiakesACC 2016 IC AN DEC 2016 Page 15

16 EVOLVE II TLF and Components at 2 years Event Rate (%) PROMUS Element Plus SYNERGY P=0.57 P=0.35 P=0.89 P= Components of TLF TLF Cardiac Death TV-MI TLR ITT Population; Patients who did not receive a study stent were censored at 1 year; KM Event Rates; Per protocol spontaneous MI is defined as rise and/or fall of cardiac biomarkers with 1 value >99th percentile of the URL + evidence of myocardial ischemia. Peri-PCI MI is defined as 1 of the following: i) biomarker elevations within 48 hours of PCI (based on CK-MB >3X URL), ii) new pathological Q waves, or iii) autopsy evidence of acute MI Presented by KereiakesACC 2016 IC AN DEC 2016 Page 16

17 EVOLVE II Stent Thrombosis at 2 years Definite/Probable : ITT Population Acute ( 1 d) Subacute (2-30 d) Late (30 d 1 y) Very Late (1 2 y) PROMUS Element Plus SYNERGY N=2 (Definite) N=5 (2 Definite/3 Probable) N=1 (Prob) N=1 (Def) 0.8% (N=6) 0.4% (N=3) P=0.31 No definite ST in the SYNERGY arm after 24 hours Presented by KereiakesACC 2016 IC AN DEC 2016 Page 17

18 Current Status of Bioabsorbable Polymer vs Pt/Co Cr Stent No definitive evidence of benefits over current generation drug eluting polymer stents Clear cut improvement in deliverability Must be careful about stripping stent off polymer. Keep stent dry and open valve entering guide catheter. EVOLVE DAPT study currently evaluating efficacy of 3 mos DAPT in patients with high risk of bleeding and low ischemic risk. Resolute zotarolimus stent already has CE mark for 1 mos DAPT in Europe in low risk elective patients. Head to head independent OCT trial showed no difference in stent coverage between Resolute and Synergy. IC AN DEC 2016 Page 18

19 Absorb Bioresorbable Vascular Scaffold System Bioresorbable Scaffold Bioresorbable Coating Everolimus XIENCE V Delivery System l l l Poly (L-lactide) (PLLA) Based on proven MULTI-LINK pattern Naturally resorbed, fully metabolized* l l Poly (D,L-lactide) (PDLLA) Naturally resorbed, fully metabolized l Similar dose density and release rate to the XIENCE family of products l World-class deliverability All illustrations are artists renditions *Except for platinum markers See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 19 of 131

20 Degradation vs. Vessel Healing Revascularization Restoration Resorption Drug Elution Support Mass Resorption Months Platelet Deposition Leukocyte Recruitment SMC Proliferation and Migration Matrix Deposition Re-endothelialization Vascular Function Forrester JS, et al., J. Am. Coll. Cardiol. 1991; 17: 758. Oberhauser JP, et al., EuroInterv. 2009; 5: F15. See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 20 of 131

21 Mechanical Conditioning Gradual disappearance of supportive structure Vessel recovers the ability to respond to physiologic stimuli Shear stress, pulsatility & cyclic strain Tissue adaptation* Structure and functionality* Tissues in the body require physiologic stress to maintain normal structure and function European Heart Journal, 2011, doi: /eurheartj/ehr384. *Histology images are from porcine animal models, Cohort A device. See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 21 of 131

22 Absorb TM Clinical Results ABSORB III Study Design Objective Design US Pivotal Trial Prospective, single blind, randomized 2:1 Absorb vs. XIENCE, in 2000 patients, (+200 patients in Imaging Cohort), up to 220 sites (predominantly US) Absorb XIENCE Clinical Follow-Up (Months) QOL (PRO) (n= 2000) Imaging Cohort (n = +200) Angio/IVUS or Angio/OCT Primary Endpoints Powered Secondary Endpoints Target Lesion Failure at 1 year, powered for non-inferiority in 2000 clinical follow-up subjects Powered secondary endpoints of angina, all revascularization and ischemic driven target vessel revascularization at 1 year test for superiority of Absorb to XIENCE (n = 2000) Nitrate-induced vasomotion at 3y by QCA, superiority of Absorb to XIENCE (n = 200) MLA change from post-procedure to 3 y by IVUS, superiority of Absorb to XIENCE (n = 150) Diabetic subgroup to support diabetic indication of Absorb See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 22 of 131

23 Absorb TM Clinical Results ABSORB III Patient and Lesion Characteristics % Absorb N=1,322 patients XIENCE N=686 patients P-Value All Diabetes Prior PCI Stable Angina Unstable Angina B2/C Lesions Lesion Length (mm) RVD < Kereiakes, D., TCT 2015 See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 23 of 131

24 Absorb TM Clinical Results ABSORB III Met Primary Endpoint: Non-Inferior to XIENCE in 1-Year TLF (ITT) ITT Population n / N % Difference (95% CI) P NI Absorb 102 / XIENCE 41 / (-0.5, 3.9) Non-inferiority Margin = 4.5% % Difference (Absorb - XIENCE) Ellis SG et al. N Engl J Med. 2015;373: See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 24 of 131

25 Absorb TM Clinical Results ABSORB III One Year Clinical Results % Absorb N=1,322 patients XIENCE N=686 patients P-Value TLF Cardiac Death TV-MI ID-TLR Def/Prob ST All Revascularization ID-TVR Kereiakes, D., TCT 2015 See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 25 of 131

26 Absorb TM Clinical Results ABSORB III One Year Definite/Probable ST Results OUTCOMES BY QCA RVD YEAR ST IN VERY SMALL VESSELS IMPACT OF POST-DILATATION AND PRESSURE 1-Year Events (%) 20% 15% 10% 5% 0% RVD <2.25 mm (median 2.09 mm) Absorb 12.9% 8.3% 4.6% 1.5% RVD 2.25 mm (median 2.74 mm) XIENCE 6.7% 5.5% 0.9% 0.6% TLF ST TLF ST Stent Thrombosis (%) 12% 9% 6% 3% 0% 4.6% 1.5% RVD <2.25 mm Absorb 8.1% XIENCE 2.5% 3.1% 1.9% 0.0% 0.0% # Events: Absorb (n / N) 11 / / 74 5 / / 105 # Risk: XIENCE (n / N) 2 / / 79 0 / 15 0 / 36 Kereiakes, D., TCT 2015 See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 26 of 131

27 ADOPTION OF OPTIMAL IMPLANTATION TECHNIQUES REDUCED ST EVENTS WITHIN LARGE, REAL-WORLD REGISTRIES Medical Science Inserted this slide from AP OUS Absorb PCR Eblast 1. C. Hamm, GABI-R EuroPCR 2016; 2. B. Cortese, RAI Registry EuroPCR 2016; 3. Puricel, S. et al. J Am Coll Cardiol. 2016; 67(8):921-31; 4. T. Gori, 4 Cities Registry, EuroPCR See Important Safety Information referenced within. Not to be reproduced, distributed or excerpted Abbott. All rights reserved. SE Rev A 27 of 131

28 P S P OBJECTIVES OBJECTIVE Prepare lesion to receive scaffold Facilitate delivery Enable full expansion of pre-dilatation balloon to facilitate full scaffold expansion OBJECTIVE Accurately size the vessel Select appropriate scaffold for best fit OBJECTIVE Achieve <10% final residual stenosis Ensure full strut apposition PRESCRIBE DAPT In ABSORB III all patients were maintained on DAPT for a minimum of 12 months. Risks versus benefits should be considered for each patient, including judgment regarding risk of antiplatelet therapy. Antiplatelet therapy should be used per ACC/AHA guidelines, information from the ABSORB family of clinical trials, current literature on DES and scaffolds, and the specific needs of individual patients. Wright, RS, et al., Circulation. 2011; 123: / Wijns, W, et al., European Heart Journal. 2010; 31: / Levine, GN, et al., Circulation. 2011; 124: / Steg, PG, et al., European Heart Journal. 2012; 33: / O Gara, PT, et al., Circulation. 2012; 127: e368-e425. See Important Safety Information referenced within Abbott. All rights reserved. SE Rev. A 28 of 31

29 P PREPARE THE LESION PREPARE VESSEL TO RECEIVE SCAFFOLD ENABLE FULL SCAFFOLD EXPANSION PRE-DILATATION NC Balloon: Use a non-compliant pre-dilatation balloon 1:1 balloon-to-artery ratio: This aids in determining vessel size FULL EXPANSION OF THE PRE-DILATATION BALLOON 20-40%: Achieve a residual stenosis between 20% and 40% after pre-dilatation 2nd Inflation: Confirm vessel prep is optimal by re-inflating balloon to nominal pressure If there is no waist, continue to scaffold deployment; if there is a waist, do additional vessel preparation Consider the use of cutting/scoring balloon, Rotablator ä, CSI, or Laser to achieve the same 20-40% residual stenosis in resistant lesions Note: It is imperative to do a thorough lesion prep up front; unlike a metallic stent, the scaffold will not score the plaque during high pressure post-dilatation. See Important Safety Information referenced within Abbott. All rights reserved. SE Rev. A 29 of 31

30 S SIZE APPROPRIATELY ACCURATELY SIZE THE VESSEL IMAGING RECOMMENDED Use Imaging for First Experience (IVUS, OCT or QCA): Imaging recommended for first Absorb ä cases for eye recalibration and accuracy in sizing Absorb scaffold Sizing Variability: Sizing accuracy can vary by 0.3 mm depending on imaging modality used Recognize the risk of under/over-estimating vessel size by visual estimation Actual Size OCT IVUS QCA Visual Estimate 3.0 mm 3.0 mm 3.1 mm 2.8 mm mm Most Accurate Over-Estimates Under-Estimates ENSURE SIZING ACCURACY Nitro: Use standard dose of intracoronary nitroglycerin prior to determining RVD Size While Preparing the Lesion: Inter/Intra-Observer Variability Margin of Error* Use the inflated NC 1:1 pre-dilatation balloon size in the lesion to more accurately size the vessel * Margin of error estimates based on resolution for each imaging modality: Resolution of OCT and IVUS: Bezerra, H.G., J Am Coll Cardiol.: Cardiovasc Interv. 2009; 2: Resolution of QCA: Dahm, J. and van Buuren, F. Int J Vasc Med Offset and variability of visual estimate: data on file at Abbott Vascular. See Important Safety Information referenced within Abbott. All rights reserved. SE Rev. A 30 of 31

31 P POST-DILATE OBJECTIVE: FULL SCAFFOLD EXPANSION Achieve <10% Final Residual Stenosis / Ensure Complete Apposition ACHIEVE FULL EXPANSION DO NOT LEAVE SCAFFOLD UNDER-EXPANDED Use High-Pressure: High pressure dilatation (>16 atm) with an NC balloon up to 0.5 mm larger than the nominal scaffold diameter can safely be utilized to optimize scaffold expansion <10% Final Residual Stenosis: Essential to fully expand scaffold, achieving <10% final residual diameter stenosis in treated segment Short NC Balloon as needed: If residual stenosis is present, then consider using a short non-compliant balloon that is up to mm larger than the nominal scaffold diameter (i.e. use a 3.5 mm non-compliant balloon with a 3.0 mm scaffold) Pay Attention to Expansion Limits: Do not post-dilate the scaffold beyond its maximum expansion limit (+0.5 mm above nominal scaffold diameter) to avoid potentially damaging the scaffold NC Post-Dilatation Balloon Size Recommendation: Sub-optimal result should be post-dilated See Important Safety Information referenced within. Images from ABSORB Cohort B Abbott. All rights reserved. SE Rev. A 31 of 31

32 P POST-DILATE OBJECTIVE: FULL SCAFFOLD EXPANSION Achieve <10% Final Residual Stenosis / Ensure Complete Apposition ASSESSING STRUT APPOSITION Scaffold struts are not visible on fluoroscopy or cineangiography Only IVUS or OCT will allow for visualization of struts and assessment of strut apposition When crossing a newly deployed scaffold with devices such as imaging catheters, exercise care to avoid disrupting the scaffold geometry High pressure (>16 atm) post-dilatation with a noncompliant balloon up to 0.5 mm larger than the nominal scaffold diameter should routinely be performed unless intracoronary imaging shows complete scaffold expansion and full strut apposition Malapposition cannot be detected by angiography and is shown here using OCT. Images from ABSORB Cohort B. See Important Safety Information referenced within Abbott. All rights reserved. SE Rev. A 32 of 31

33 WHERE ARE WE IN 2017 Current 3 rd generation stents are the safest, most deliverable to date. VLST is essentially an obsolete concept I feel confident using Resolute, Promus Premier, or Xience that 6 mos DAPT is more than enough to ensure safety in all patients EVOLVE DAPT study will hopefully bring 3 mos DAPT into the mainstream in the USA. Can we get away with only 1 mos DAPT as Resolute is approved for in Europe? Not there yet in USA I see no real compelling role for ABSORB stent to be used in its current form. More time, money for stent and for pre and post deployment, and imaging should be required for optimal results. Time will tell if late events decrease with the Synergy stent or if the 2 nd generation ABSORB stent can become more deliverable. See Important Safety Information referenced within Abbott. All rights reserved. SE Rev. A 33