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What’s New with Metallic DES? Gregg W. Stone, MD Columbia University Medical Center NewYork-Presbyterian Hospital Cardiovascular Research Foundation Disclosures • None 2017: Why do we Need Better Stents? • To further eliminate early and late stent thrombosis and restenosis • To reduce dependency on long-term DAPT • To improve lifelong prognosis Principal Causes of Adverse Events with Current Metallic DES • Early and late inflammatory and hypersensitivity reactions to the drug or polymer • Polymer irregularities that result in inconsistent drug delivery or serve as a nidus for thrombus • Mechanical issues: Strut fracture >> longitudinal deformation Polymer Integrity Issues in FDA Approved DES c/o Renu Virmani Neoatherosclerosis may be the common final denominator in many cases of late DES failure, and is not decreasing in prevalence Autopsy series SES PES EES 40 35 P=NS 35% 29% 30 25 20 19% 15 10 5 0 Neoatherosclerosis Otsuka F et al. Eur Heart J 2015;36:2147–2159 Polymer-Free Metallic Stents • Once the drug is eluted, a BMS is left behind • Potential advantages More uniform drug delivery Removes nidus for thrombosis No adverse polymer reactions Potentially more rapid healing and shorter mandatory duration of DAPT • Potential disadvantages Difficult to control drug dose and elution rate BioFreedom Drug Coated Stent (DCS) 120 um thick stainless steel stent Selectively micro-structured surface holds drug in abluminal surface structures Biolimus A9 is 10x more lipophilic than sirolimus1 100 80 60 % 40 20 0 12 mo in-stent LL ~0.17 mm (n=31) Sirolimus Zotarolimus Everolimus Biolimus A9 ±2.8% (valid for all drugs test) Potential Advantages: • Rapid drug transfer to vessel wall (98% within one month2) • Avoid possible polymer-related adverse effects • Safe to shorten DAPT? 1. Data on file at Biosensors Intl 2. Tada et al. Circ Cardiovasc Interv 2010;3;174-183 Leaders Free: Primary Efficacy Endpoint (Clinically-Driven TLR) 12 DCS (n=1221) CD-TLR (%) BMS (n=1211) 9.8% 9 6 5.1% 3 P < 0.001 0 0 90 180 Days 270 390 1221 1211 1167 1131 1130 1072 1098 1034 1053 984 Number at Risk DCS BMS Urban P et al. NEJM 2015;373:2038-47 Leaders Free: Components of the Safety Endpoint (1-year) 10 8.9 9 DCS (n=1221) BMS (n=1211) 8 7 6.1 6 % 5 5.3 4.2 4 3 2.0 2.2 2 1 0 Cardiac death MI ST (def /prob) p = 0.19 p = 0.01 p = 0.70 Urban P et al. NEJM 2015;373:2038-47 Drug-Filled Stent: Concept DFS is made from a polymer-free tri-layer wire Outer cobalt alloy layer for strength Middle tantalum layer for radiopacity Inner layer core material is removed and becomes a lumen that is filled with drug (sirolimus) 20 um Drug Tantalum Cobalt alloy Drug-Filled Stent: Concept Sirolimus is protected and contained inside the stent (drug density ~1.1 μg/mm2, based on circumferential outer stent surface area) Drug is released through multiple laser-drilled holes on the abluminal side of the stent (average 5/strut, fenestration diameter 16 - 25 μm, median 20 μm) Drug elution is controlled and sustained through natural diffusion via direct interaction with the vessel wall; the elution profile is similar to durable polymer DES Drug fills/coats inner lumen Drug elutes through abluminal holes Results in uniform drug distribution to tissue DFS: Pharmacokinetic Analysis % Eluted from Explanted DFS % Eluted from Explanted Xience 100 % Label Claim (100 % = 88µg) % Label Claim (100 % = 96µg) 100 75 50 25 N = 6 stents per time point (2 stents/animal) 0 75 50 25 Historical control1: 0 0 30 60 Time (days) 1 90 0 30 60 90 Time (days) Perkins LE. et al. J Interv Cardiol. 2009;22:S28–S41 120 DFS: Radial Force and Radio-opacity Stent Radial Stiffness Stent Radiopacity Contrast (3.0 mm stent, n=3) 5 P=0.05 P=0.90 4.4 4 3.6 3.5 3 2 Radiopacity contrast (arb unit) Radial Stiffness per Unit Length (N/mm per mm) 6 (Avg of 6 measures ± SD) 0.6 0.5 0.43 0.36 0.4 0.3 0.2 0.1 0.0 DFS 1 0 DFS INTEGRITY ONYX Nicolas Foin, TCT 2015 0.47 ONYX INTEGRITY RevElution Study 9 Month Cohort N=50 N = 100 at 15 sites in Australia, Brazil, Singapore 1-2 de novo native coronary lesions per pt; RVD: 2.25 mm – 3.5 mm Lesion length: ≤27 mm OCT Subgroup N=30 N=20 9 mo Angio/IVUS N=20 1 mo OCT Subgroup N=15 3 mo OCT Subgroup N=15 9 mo Angio/IVUS/OCT N=30 24 Month Cohort N=50 OCT Subgroup N=30 2 mo OCT Subgroup N=15 6 mo OCT Subgroup N=15 24 mo Angio/IVUS/OCT N=30 Principal investigators: Alex Abizaid, Steve Worthley Study chair: Gregg W Stone N=20 24 mo Angio/IVUS N=20 RevElution: In-stent Late Loss at 9 Mo Percent of lesions (%) 100 DFS US Resolute ZES historical control (n=49 lesions) (n=93 lesions) 0.26 ± 0.28 0.36 ± 0.52 80 Pnon-inferiority <0.001 60 40 20 0 –0.5 0.0 0.5 1.0 1.5 2.0 In-stent Late Loss (mm) Worthley S et al. JACC Int 2017:on-line 2.5 RevElution: 9 Month QCA and IVUS QCA (49 lesions) In-stent RVD (mm) In-segment 2.68 ± 0.39 MLD (mm) 2.30 ± 0.41 2.05 ± 0.36 % Diameter stenosis 13.7 ± 12.1 23.3 ± 8.0 Late loss (mm) 0.26 ± 0.28 0.11 ± 0.22 0% 0% Binary restenosis rate (%) IVUS (49 lesions) In-segment Neointimal hyperplasia volume (mm3) 14.81 ± 8.96 Volume obstruction (%) 9.8 ± 5.6 Stent malapposition (%) - Post-procedure - Persistent at 9 months - Late-acquired Worthley S et al. JACC Int 2017:on-line 12.5% 4.1% 0% RevElution: OCT at 1, 3 and 9 Months 100 Covered Struts Malapposed Struts per lesion, median % per lesion, median % 91.4 99.0 95.6 99.5 10 75 % P<0.001 50 P=0.001 % 5 P=0.03 P=0.08 25 0.3 0 0 1M 9M 1M OCT Cohort 3M 9M 3M OCT Cohort 0.0 1M 9M 1M OCT Cohort IQR 84.8 93.2 97.9 -99.8 90.3 97.2 98.3 100 IQR 98.1 ± 2.7 92.9 ± 6.0 98.8 ± 2.0 Mean Mean 89.3 ± 6.3 0.2 0.0 3M 9M 3M OCT Cohort 0 - 2.3 0-0 0 - 7.0 0-0 1.5 ± 2.3 0.1 ± 0.4 1.1 ± 2.2 0.3 ± 0.8 1M: n=14 patients, 17 lesions, 19 stents, 605 cross-sections and 7403 struts analyzed 3M: n=15 patients, 17 lesions, 19 stents, 651 cross-sections and 7451 struts analyzed 9M: n=25 patients, 29 lesions, 32 stents, 1102 cross-sections and 12,819 struts analyzed RevElution: Representative case Post-procedure: 2.9% malapposed struts 1-month follow-up: 91.4% strut coverage; 0.8% malapposed struts 9-month follow-up: 98.8% strut coverage; 0% malapposed struts 1.2 mm 10.6 mm 18.8 mm 25.0 mm Worthley S et al. JACC Int 2017:on-line RevElution: 9-Month Cinical Outcomes - in 48/50 pts 15 10 Events (%) % 5 2.1 2.1 0.0 0 TLF Cardiac death TV-MI 0.0 0.0 TLR Stent thrombosis (definite/probable) While undergoing a CT-guided lung biopsy for lung cancer 263 days post DFS, 1 patient developed ischemic symptoms with elevated troponin levels with no ECG changes (adjudicated as non-Q-wave MI) Worthley S et al. JACC Int 2017:on-line RevElution: Conclusions at 9 Months The drug-filled stent (DFS) is a novel polymer-free DES with sirolimus contained inside the stent and eluted through abluminal holes DFS was safe and effective with late lumen loss non-inferior to historical control, with minimal neointima hyperplasia and 0% binary restenosis at 9 months DFS implantation resulted in a high degree of early stent strut coverage and 0% late incomplete malapposition, indicative of rapid early healing The 9-mo TLF rate was low (2.1%), with no stent thrombosis Follow-up in the 2-year cohort is ongoing, and large-scale RCTs are being planned