DISCLOSURE Peter A. Schneider Enter patients in studies sponsored - PDF document

DCB-what is the appropriate role in the management of fem-pop disease in 2019? Peter A. Schneider, MD Division of Vascular and Endovascular Surgery University of California, San Francisco DISCLOSURE Peter A. Schneider Enter patients in studies sponsored by: Gore, Cordis, Medtronic, Silk Road, Bard, NIH, Limflow Consultant: Silk Road, Surmodics, Profusa Scientific Advisory Board: Abbott, Medtronic, Boston Scientific, CSI Chief Medical Officer: Intact Vascular, Cagent National co-PI: Roadster 2, Scaffold, Confidence, IN.PACT I believe that drug delivery has been a major step forward for patients with SFA disease 1 | [footer text here]

SFA Disease 2013 SFA Lesion CFA disease Open Pop-trifur dis Surgery Endo failure Or hybrid Really bad runoff TASC A/B TASC C TASC D Standard PTA Primary stent Limb salvage Claudication Atherectomy or stent-graft (Focal, no-stent zone) (Esp. if occlusion) Bypass, Stent Bypass in good or stent-graft Surgical candidates Selective stent Femoral-popliteal Disease: PTA and Stents PTA Stent RCT Data: PTA vs Stent RCTs Resilient 12-month Primary Patency FACT 4EVER Durability Stents Astron Vienna Vienna-3 PTA TASC A/B Lesion length (cm) 2 | [footer text here]

Probability of Restenosis with Bare Metal Stents Restenosis after SFA stenting peaks at 12 months We would like to make the “peak” flatter and push it out to a longer time frame. • Timing of SFA restenosis is longer compared to coronary stenting, which predominantly occurs within 6 months. • Factors for restenosis in the SFA include the number of runoff vessels, severity of lower limb ischemia, and length of diseased segments. Iida, O. et al. Cath and Cardiov Intv. 2011; 78:611–617. Kimura T, et al. N Engl J Med 1996;334:561–567. Drug Eluting Coronary Stents in the US Reduction in TLR Adoption of DES Jonas et al, Cathet Cardiovasc Interv, 2007 3 | [footer text here]

IMPORTANCE OF DRUG “RESERVOIRS” PACLITAXEL RESERVOIR SFA: Late Lumen Loss PACLITAXEL 6 Different Paclitaxel DCB Preparations RESERVOIR 5 PACLITAXEL RESERVOIR Solid-phase paclitaxel embeds in vessel wall, creating “reservoirs” of drug that are sustained over time. Advance Paccocath Lutonix Passeo In.Pact Stellarex PTX PTX 3 µg/mm 2 PTX 2 µg/mm 2 PTX 3.5 µg/mm 2 PTX 2.0 µg/mm 2 18 Lux + Ultravist + Polysorbate + Urea PTX 3.0 µg/mm 2 PEG PTX 3.0 µg/mm 2 & Sorbitol NO Excipient + BTHC 1. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi JP, Claussen CD, Oldenburg A, Scheller B, Speck U. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008 Feb 14;358(7):689-99 2. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, Hosten N, Hamm B, Speck U, Ricke J. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation. 2008 Sep 23;118(13):1358-65 3. Scheinert D, Duda S, Zeller T, Krankenberg H, Ricke J, Bosiers M, Tepe G, Naisbitt S, Rosenfield K. The LEVANT I (Lutonix paclitaxel-coated balloon for the prevention of femoropopliteal restenosis) trial for femoropopliteal revascularization: first-in- human randomized trial of low-dose drug-coated balloon versus uncoated balloon angioplasty. JACC Cardiovasc Interv. 2014 Jan;7(1):10-9 4. Scheinert D, Schulte KL, Zeller T, Lammer J, Tepe G. Paclitaxel-Releasing Balloon in Femoropopliteal Lesions Using a BTHC Excipient: Twelve-Month Results From the BIOLUX P-I Randomized Trial. J Endovasc Ther. 2015 Feb;22(1):14-21 5. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, Eschenbach G, Hartmann H, Lange C, Schnorr B, Stiepani H, Zoccai GB, Hänninen EL. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv. 2012 Dec;5(6):831-40 6. D.Scheinert – LINC 2013 oral presentation 7. Schroeder H, Meyer DR, Lux B, Ruecker F, Martorana M, Duda S. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: Outcomes from the ILLUMENATE first-in-human study. Catheter Cardiovasc Interv. 2015 Feb 23 7 Angiogram at 6 months: substantially less loss of lumen size 12 Month Patency IN.PACT SFA RCTs of DCB vs PTA Lyden, TCT 2016 Tepe et al. Circ 2015;131:495 Illumenate 73.7% DCB 82.3% @ day 365 @ day 410 PTA 70.9% @ day 365 50.4% Rosenfield et al. NEJM 2015;373:145 @ day 410 Kaplan/Meier' 100 90 DCB 80 Levant Free 70 from 60 Primary PTA Patency 50 Event (%) 40 30 Survival % 20 Tim e Lutonix DCB Standard PTA P-valu e 10 365 day s 73 . 5% 56 . 8% 0 . 001 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Months from Randomization Date Proportions-based difference was 65.2% for DCB vs. 52.6% for standard PTA � 12.6% difference 4 | [footer text here]

Drug Coated Balloons and Drug-Eluting Stents Femoral-popliteal Disease PTA DES Stent DCB RCT Data: DCB/DES Stent-graft RCTs DCB RCTs Levant 2 12-month Primary Patency IN.PACT Illumenate DES RCT Zilver PTX Imperial Stent-graft RCTs Viper Vibrant Viastar Lesion length (cm) IN.PACT SFA Trial Primary Patency at 3 Years 24.4% 2 Schneider et al. Circ: Cardiovasc Interv 2018;11:e005891 5 | [footer text here]

Vessel Preparation § Lumen gain § Plaque modification, change vessel compliance § Minimize arterial wall defects § Prepare for drug delivery § Prepare for definitive therapy § Results of may help determine which definitive therapy is appropriate Technologies that Benefit Tools for Vessel Prep § Drug-coated balloon § PTA § Woven nitinol stent § Modifications of angioplasty § Bioabsorbable vasc scaffold § Atherectomy § Stent graft/covered stent § Lithoplasty § Self expanding nitinol stent - Including DES Primary Patency-DCB for Long Lesions Schmidt et al. JACC Cardiovasc Interv 2016;9;715 Lesions >15cm Mean lesion length 25cm Lesions >15cm 49.5% occlusions Primary patency at 1 year=83.2% Mean lesion length 24cm 65.3% occlusions Primary patency: 1 year= 79.2% 2 years=53.7% Micari et al. JACC Cardiovasc Interv 2016;9;950 Mean length 26cm Schmidt et al. JACC Cardiovasc Interv 2016;9;715 IN. PACT Provisional Stent 40.4% (63/156) Zilver PTX Mean lesion length 19cm LL 15-25 cm: 33.3% (33/99) 53% occlusions LL > 25 cm: 52.6% (30/57) Primary patency at 1 year: DCB= 76.1% DES= 69.6% Schneider CX 4/16 Zeller et al. J Endovasc Ther 2014;21;359 6 | [footer text here]

Drug Coated Balloons and Drug Eluting Stents Femoral-popliteal Disease PTA DES Woven nitinol Stent DCB Stent-graft Atherectomy DCB/DES for Longer Lesions 12-month Primary Patency Registries IN.PACT Global Leipzig Bad Krozingen Italy Definitive LE Superb Lesion length (cm) DCB for Long Lesions Total IN.PACT All-Subjects: Long Lesion Subgroup Freedom From CD-TLR through 12 months 20-30 cm >30 cm TASC D Lesion Length 25.24±2.96 34.75±4.17 Occluded Lesion 70.0% (142/203) 76.9% (70/91) Provisional Stent 37.1% (75/202) 50.5% (46/91) Schneider LINC 2019 7 | [footer text here]

DCB paradigm vs DES paradigm DCB DES § Dependent upon vessel prep § Stent entire lesion § No geographic miss § More severe morphologies § How much scaffolding? § Stent across healthier segments § Long lesions and occlusions § In-stent restenosis § Total paclitaxel dose SFA Disease 2019 SFA Lesion CFA disease Open Pop-trifur dis Surgery Endo failure or hybrid Really bad runoff TASC A/B TASC C/D/D+++ DCB with focal Aggressive vessel prep dissection repair Good result Bad result DCB with focal DES dissection repair as needed 8 | [footer text here]

Mortality Rates From Trials of SFA Therapy All-Cause Death at 2 Years Laird J, et al. J Am Coll Cardiol 2015: 66; 2329-38 ZILVER PTX Dake M, et al. J Am Coll Cardiol 2013: 61; 2417-27 IN.PACT Japan Presented by Iida, O. LINC 2018, Leipzig Germany Majestic Muller-Hulsbeck S, et al. Cardiovasc Interv Radiol 2017:40;1832-1838 IN.PACT Global Micari A, et al. J Am Coll Cardiol –Cardiovasc Interv 2018: 11; 945-53 SMART SES and BMS Duda et al. J Endovasc Ther 2006: 14; 701-710 LEVANT 1 Scheinert D, et al. J Am Coll Cardiol - Cardiovasc Interv 2014: 7; 10-19 Complete SE SFA Data on file. Medtronic, Inc. LEVANT 2 Lutonix IFU Durability II Rocha-Singh K, et al. Cather Cardiovasc Interv 2015 : 86; 164-170 ILLUMENATE US Presented by Mathews S, NCVH 2018, New Orleans, USA ETAP BMS Rastan A, et al. J Endovasc Ther 2015: 22; 22-27 ILLUMENATE EU Presented by Schroder H, CIRSE 2017, Copenhagen, Denmark RESILIENT BMS LifeStent IFU. Revised 2/04-16. ACOART-I Presented by Guo W, LINC 2017, Leipzig, Germany Dashed Line: Caro J, Migliaccio-Walle K, Ishak KJ and Proskorovsky I. BMC Cardiovasc Disord. 2005;5:14. CONSEQUENT Albrecht T, et al. Cardiovasc Intervent Radiol 2018: 41; 1008-14 Figure 3. Random effects forest plot of all-cause death at 4 to 5 years. Pooled point estimate was expressed as risk ratio (RR). Conclusions- — There is increased risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the lower limbs. Further investigations are urgently warranted. JAHA 2018;7:e011245 Coincidental, statistical aberration, real danger sign? What is the mechanism? 9 | [footer text here]