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

Otsuka F et al. Eur Heart J 2015;36:2147–2159 Neoatherosclerosis may be the common final denominator in many cases of late DES failure, and is not decreasing in prevalence P=NS 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 Sirolimus Zotarolimus Everolimus Biolimus A9 20 40 60 80 100 % ±2.8% (valid for all drugs test) 12 mo in-stent LL ~0.17 mm (n=31) Potential Advantages: Rapid drug transfer to vessel wall (98% within one month2) Avoid possible polymer-related adverse effects Safe to shorten DAPT? Data on file at Biosensors Intl Tada et al. Circ Cardiovasc Interv 2010;3;174-183 8

Leaders Free: Primary Efficacy Endpoint (Clinically-Driven TLR) 12 DCS (n=1221) BMS (n=1211) 9.8% 9 CD-TLR (%) 6 5.1% 3 P < 0.001 90 180 270 390 Days Number at Risk DCS BMS 1221 1211 1167 1131 1130 1072 1098 1034 1053 984 Urban P et al. NEJM 2015;373:2038-47 9

Leaders Free: Components of the Safety Endpoint (1-year) 10 5 6 7 % p = 0.19 p = 0.01 p = 0.70 4.2 6.1 2.0 5.3 8.9 2.2 Cardiac death MI ST (def /prob) 9 8 4 3 2 1 DCS (n=1221) BMS (n=1211) Urban P et al. NEJM 2015;373:2038-47 10

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) Cobalt alloy Tantalum Drug 20 um Evolution of the Continuous Sinusoid Technology and Core Wire Technology using a tri-layer wire Drug elutes through natural diffusion via direct interaction with the vessel wall Fluid (extracellular fluid and serum elements) fills inner lumen Drug solubilizes and diffuses with the concentration gradient (high to low) Controlled and sustained elution profile Elution is controlled through drug formulation, drug load, number of holes and size of holes Drug diffuses into the tissue resulting in a uniform tissue response throughout stented area Extended elution similar to current durable polymer DES

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 Evolution of the Continuous Sinusoid Technology and Core Wire Technology using a tri-layer wire Drug elutes through natural diffusion via direct interaction with the vessel wall Fluid (extracellular fluid and serum elements) fills inner lumen Drug solubilizes and diffuses with the concentration gradient (high to low) Controlled and sustained elution profile Elution is controlled through drug formulation, drug load, number of holes and size of holes Drug diffuses into the tissue resulting in a uniform tissue response throughout stented area Extended elution similar to current 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 100 100 75 75 % Label Claim (100 % = 96µg) 50 % Label Claim (100 % = 88µg) 50 25 25 N = 6 stents per time point (2 stents/animal) Historical control1: 30 60 90 120 30 60 90 Time (days) Time (days) 1 Perkins LE. et al. J Interv Cardiol. 2009;22:S28–S41 13

DFS: Radial Force and Radio-opacity Stent Radiopacity Contrast (Avg of 6 measures ± SD) P=0.05 P=0.90 Nicolas Foin, TCT 2015

RevElution Study 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 9 Month Cohort N=50 24 Month Cohort N=50 OCT Subgroup N=30 1 mo OCT Subgroup N=15 3 mo OCT Subgroup N=15 9 mo Angio/IVUS/OCT N=30 OCT Subgroup N=30 2 mo OCT Subgroup N=15 6 mo OCT Subgroup N=15 24 mo Angio/IVUS/OCT N=20 N=20 9 mo Angio/IVUS N=20 24 mo Angio/IVUS N=20 Principal investigators: Alex Abizaid, Steve Worthley Study chair: Gregg W Stone

RevElution: In-stent Late Loss at 9 Mo 100 80 60 40 20 Percent of lesions (%) –0.5 0.0 0.5 1.0 1.5 2.0 2.5 In-stent Late Loss (mm) 0.36 ± 0.52 0.26 ± 0.28 DFS (n=49 lesions) US Resolute ZES historical control (n=93 lesions) Pnon-inferiority <0.001 Speaker note: the major difference is the absence of the rightward tail – meaning fewer bad results, likely due to elimination of issues with polymer inconsistency Worthley S et al. JACC Int 2017:on-line

RevElution: 9 Month QCA and IVUS QCA (49 lesions) In-stent In-segment RVD (mm) 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  Binary restenosis rate (%) 0% 0%  IVUS (49 lesions) In-segment Neointimal hyperplasia volume (mm3) 14.81 ± 8.96 Volume obstruction (%) 9.8 ± 5.6 Stent malapposition (%)   - Post-procedure 12.5% - Persistent at 9 months 4.1% - Late-acquired 0% Worthley S et al. JACC Int 2017:on-line

RevElution: OCT at 1, 3 and 9 Months Covered Struts per lesion, median % Malapposed Struts per lesion, median % % P<0.001 P=0.001 % P=0.03 P=0.08 1M 9M 3M 9M 1M 9M 3M 9M 1M OCT Cohort 3M OCT Cohort 1M OCT Cohort 3M OCT Cohort IQR 84.8 - 93.2 97.9 -99.8 90.3 - 97.2 98.3 - 100 Mean 89.3 ± 6.3 98.1 ± 2.7 92.9 ± 6.0 98.8 ± 2.0 IQR 0 - 2.3 0 - 0 0 - 7.0 Mean 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 Case 20001-007 OCT images of 3.0 x 26 mm DFS stent in the mid LAD presented serially at post-procedure, 1-month, and 9-month follow-up. OCT images were taken from matched positions along the treated segment, and are presented from distal (left) to proximal (right). The position of matched OCT cross-sections along the stented segment is indicated in millimeters at the bottom of the image. At post-procedure, 2.90% of the struts were malapposed. At 1 month, a favorable healing profile was observed, with 91.4% of all struts already covered, and only 0.80% persisting malapposed. At 9 months, all struts are virtually covered (98.8%) with no malapposed struts. 1.2 mm 10.6 mm 18.8 mm 25.0 mm 9-month follow-up: 98.8% strut coverage; 0% malapposed struts Worthley S et al. JACC Int 2017:on-line

RevElution: 9-Month Cinical Outcomes - in 48/50 pts - % Events (%) 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