Evolving Role of Drug-Eluting Stents In Complex SFA - Majestic Trial Data

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1 Evolving Role of Drug-Eluting Stents In Complex SFA - Majestic Trial Data Ralf Langhoff, MD Center for Vascular Medicine Berlin-Wilmersdorf St. Gertrauden Hospital Charité, CC11 Academic Teaching Hospitals Charité Berlin

2 Stents used in DCB studies Stents are utilized in DCB studies Longer mean lesion length is correlated with higher provisional stenting rate FEMPAC 1 PACIFIER 2 THUNDER 3 IT Registry 4 IN.PACT SFA 5 Bad Krozingen 6 Leipzig Registry 7 Illumenate FIH 8 In.PACT Global Reg 9 In.PACT Global LL 10 (15-25 mm) In.PACT Global LL 10 (>25 mm) Provisional Stenting in Randomized Controlled Trials may not be representative of actual stenting in studies due to study design Results from different trials are not directly comparable. Information provided for educational purposes. 1 Werk M et al. Circulation 2008; 2 Werk et al. Circ Cardiovasc Interv 2012; 3 Tepe G et al. N Engl J Med 2008; 4 icari A Et al. J Am Coll Cardiol Intv 2012; 5 Tepe et al. Circulation 2015; 6 Zeller T et al. J Endovasc Therapy 2014; 7 Schmidt A. LINC 2013; 8 Schroeder H et al. Catheter Cardiovasc Interv 2015; 9 Laird J. Endovacsular Today Feb Ansel G. TCT 2015.

3 Stents used in Real World DCB studies Real world DCB studies show higher rates of provisional stenting than those observed in Randomized Controlled Trials IT Registry 1 Bad Krozingen 2 Leipzig Registry 3 In.PACT Global Reg 4 In.PACT Global LL 5 (15-25 mm) In.PACT Global LL 5 (>25 mm) Results from different trials are not directly comparable. Information provided for educational purposes. 1 Micari A Et al. J Am Coll Cardiol Intv 2012; 2 Zeller T et al. J Endovasc Therapy 2014; 3 Schmidt A. LINC 2013; 4 Laird J. Endovacsular Today Feb 2015; 5 Ansel G. TCT 2015.

4 Effect of Occlusions in DCB outcomes Higher rate of baseline occlusive lesions corresponded with higher TLR rates at 1 year PACIFIER 1 THUNDER 2 IT Registry 3 IN.PACT SFA 4 Bad Krozingen 5 Leipzig Registry 6 Illumenate FIH 7 In.PACT Global Reg 8 Results from different trials are not directly comparable. Information provided for educational purposes. 1 Werk et al. Circ Cardiovasc Interv 2012; 2 Tepe G et al. N Engl J Med 2008; 3 Micari A Et al. J Am Coll Cardiol Intv 2012; 4 Tepe G et al. Circulation 2015; 5 Zeller T et al. J Endovasc Therapy 2014; 6 Schmidt A. LINC 2013; Schroeder H et al. Catheter Cardiovasc Interv 2015; 8 Laird J. Endovacsular Today Feb 2015.

5 Considerations for DCB vs DES in PAD Severe calcium Consider initial adjunctive atherectomy and/or DES Predilate to assess vessel response Uncoated balloon angioplasty Predilatation Successful predilatation Residual stenosis, dissection, or recoil DCB/DES Scaffold (DES)

6 Severe calcification DCB and Stent studies Severe calcification and TLR rates in DCB and Stent studies Drug Coated Balloons 1-6 Bare Metal Stents 7-11 Drug Coated Stents 12 Drug Eluting Stents 13 1 Micari A Et al. J Am Coll Cardiol Intv 2012; 2 Tepe G et al. Circulation 2015; 3 Zeller T et al. J Endovasc Therapy 2014; 4 Schroeder H et al. Catheter Cardiovasc Interv 2015; 5 Laird J. Endovacsular Today Feb 2015; 6 Ansel G. TCT 2015; 7 Matsumura et al. J of Vasc Surg. Jul 2013; ; 11 Powell, R. Charing Cross 2015; 12 Dake MD et al. Circ Cardiovasc Interv 2011; 13 Müller-Hülsbeck, S. VIVA 2015.

7 Severe calcification DCB and Stent studies Severe calcification was more prevalent in stenting studies Severe calcification did not have a negative effect on TLR rate in the MAJESTIC study DCB studies Stent studies Drug Coated Balloons 1-6 Bare Metal Stents 7-11 Drug Coated Stents 12 Drug Eluting Stents 13 MAJESTIC Results from different trials are not directly comparable. Information provided for educational purposes. 1 Micari A Et al. J Am Coll Cardiol Intv 2012; 2 Tepe G et al. Circulation 2015; 3 Zeller T et al. J Endovasc Therapy 2014; 4 Schroeder H et al. Catheter Cardiovasc Interv 2015; 5 Laird J. Endovacsular Today Feb 2015; 6 Ansel G. TCT 2015; 7 Matsumura et al. J of Vasc Surg. Jul 2013; ; 11 Powell, R. Charing Cross 2015; 12 Dake MD et al. Circ Cardiovasc Interv 2011; 13 Müller-Hülsbeck, S. VIVA 2015.

8 DES for Peripheral Applications: Intended Clinical Benefit Minimize negative vessel remodeling and proliferative response 1 Scaffolding prevents vessel shrinkage Anti-proliferative drugs (eg, paclitaxel) counteract neointimal response to stenting Clinical trials of drug-eluting stents have shown improved stent patency following treatment of femoropopliteal 2 and belowthe-knee 3,4 lesions Prolong stent patency 1 Costa MA. Circ 2005; 2 Dake MD, et al. Circ Cardiovasc Interv. 2011; 3 Bosiers M, et al. J Vasc Surg. 2012; 4 Rastan A, et al. Eur Heart J

9 Drug Eluting Stents - Peripheral SFA BTK Zilver PTX Cook Medical Eluvia DES Boston Scientific Promus Element Plus BTK Boston Scientific Xience Prime BTK Abbott Vascular Product Image CE Mark/US Approval CE US CE US CE US CE US No Not indicated for BTK in US Stent Platform Zilver Flex Innova Promus Premier Material Nitinol Nitinol Polymer None Biostable Fluorinated Polymer Matrix Platinum Chromium Alloy Biostable Fluorinated Polymer Matrix No Cobalt Chromium Biostable Fluorinated Polymer Matrix Drug Paclitaxel Paclitaxel Everolimus Everolimus Deployment Self-expandable Self-expandable Balloon Expandable Balloon Expandable Sizes Diameter Length Diameter Length Diameter Length Diameter Length 6-8mm mm 6-7mm mm mm 12-38mm 2.5-4mm 28-38mm Cook Medical (2014). Zilver PTX Drug-Eluting Peripheral Stent Instructions for Use

10 Eluvia TM Drug-Eluting Vascular Stent System CE Mark February 2016 Innova stent platform Self-expanding nitinol Biostable polymer matrix Paclitaxel 6F Tri-axial SDS, guidewire compatible Blue Tri-Ax shaft fixed as the clear middle shaft is retracted releasing stent during deployment

11 Eluvia Drug Eluting Stent: Stent Architecture Balanced geometry designed for even stress distribution and optimal radial strength Spacing of interconnects provides balanced stress distribution for all deformation modes Width, Length and angles optimized for maximum strength Radial Force and Flexibility must be matched by excellent Fracture Resistance Stent Fracture rates in studies using the INNOVA Stent platform: SuperNOVA Study (Innova): 2.2% at 24M The MAJESTIC Study (Eluvia): 0.0% at 12M

12 The Eluvia Stent system is an investigational device, not Boston available Scientific for Data sale on in File. the European Economic Area (EEA). Eluvia Coating Design Dual Layer System Conformal coating for both layers, studied in 20k clinical patients, more than 20M ww implants Primer Layer (PBMA): Promotes Adhesion of Active Layer to Stent Active Layer (PTx, PVDF-HFP) Controls Release of Paclitaxel o 0.167µg PTx/mm 2 stent surface area PBMA Primer Layer Stent Paclitaxel/PVDF-HFP Active Layer

13 Coating Design Specifications Zilver PTX Eluvia Medicinal Substance Paclitaxel Paclitaxel Coating Design No carrier Proven PROMUS Polymer Drug/Total Dose Size Matrix 3µg/mm 2 8 x 120mm = 1112 µg 0.167µg/mm 2 7 x 150mm = 517 µg 6-8mm mm 6 & 7mm mm SEM Image 100x Boston Scientific Data on File.

14 Eluvia Drug-Eluting Vascular Stent System for SFA: MAJESTIC Clinical Study MAJESTIC Clinical Study Study Overview: MAJESTIC Device Objective Study Design Subjects Investigational Centers Follow-up Primary Endpoint Eluvia Drug-Eluting Vascular Stent System (Boston Scientific) Evaluate the performance of Eluvia DES System when treating Superficial Femoral (SFA) and/or Proximal Popliteal Artery (PPA) lesions up to 110mm in length Prospective, multicentre, single-arm, open label 57 patients with femoropopliteal artery lesions 14 sites (Europe, Australia, New Zealand) No center to enroll > 20% (11 subjects) of the total study population Baseline, Procedure 1 month, 9 months, 1 year, 2 years, 3years Primary patency of target lesion at 9 months Primary endpoint met: 9M patency of 94.4% Clinicaltrials.gov Identifier: NCT

15 MAJESTIC Study Key Eligibility Criteria Chronic lower limb ischemia defined as Rutherford categories 2, 3, or 4 De novo or restenotic lesions ( 70% stenosis) in the native SFA or proximal popliteal artery Reference vessel diameter 4-6 mm Total lesion length 30 mm and 110 mm Safety and Efficacy Core lab-adjudicated primary patency Clinical Events Committeeadjudicated MAE All-cause death (through 1M) Target limb major amputation TLR

16 Baseline Lesion Characteristics (Core Lab) Arterial Segments Ostial 0.0% Proximal 1.8% Mid 59.6% Distal 77.2% Proximal Popliteal 8.8% Length (mm) 70.8±28.1 Calcification None/Mild 21.1% Moderate 14.0% Severe 64.9% Percent Diameter Stenosis 86.3%±16.2% Occlusions 46% Minimum Lumen Diameter (mm) 0.7±0.8 Reference Vessel Diameter (mm) 5.2±0.8 Patency to Foot No Infrapopliteal Vessel Patent 5.3% 1 Vessel Patent 28.1% 2 Vessels Patent 31.6% 3 Vessels Patent 22.8% Müller-Hülsbeck, S. VIVA 2015.

17 Primary Patency Rate Primary Patency*: 12 Months 12-month primary patency was 96.1% (49/51) Kaplan-Meier estimate: 96.4% 100% 80% 96.4% 60% 40% 20% 0% Months Since Index Procedure Entered Events Event Rate 0% 0% 0% 0% 0% 1.8% 3.6% 3.6% *Primary patency defined as duplex ultrasound peak systolic velocity ratio 2.5 and absence of TLR or bypass Müller-Hülsbeck, S. VIVA 2015.

18 Primary Patency Rate Patency at 12 Months: DES vs BMS Kaplan-Meier estimate for Eluvia DES: 96.4% Paclitaxel effect suggested by divergence from bare metal platform 100% 80% 60% 40% 20% MAJESTIC (Eluvia) SuperNOVA (Innova) a 0% Months Since Index Procedure Primary patency defined as duplex ultrasound peak systolic velocity ratio 2.5 (MAJESTIC) or 2.4 (SuperNOVA) and absence of TLR or bypass. a Patients who received mm length Innova stents (n=202). Results from different trials are not directly comparable. Information provided for educational purposes. Müller-Hülsbeck, S. VIVA 2015.

19 Safety Profile MAE 12-month composite MAE rate was 3.8% (2 TLR events) Overall 95% CI 12-Month MAE 3.8% [0.5%, 13.0%] All-Cause Death at 1 Month 0.0% [0.0%, 6.7%] Target Limb Major Amputation 0.0% [0.0%, 6.7%] Target Lesion Revascularization (TLR) 3.8% [0.5%, 13.0%] Stent Integrity No stent fractures observed upon angiographic core lab analysis Müller-Hülsbeck, S. VIVA 2015.

20 Diabetic Patients (n=20) Subgroup with challenging baseline medical and lesion characteristics Lesion Characteristics Arterial Segments Proximal 5% Mid 70% Distal 75% Length (mm) 77.7±20.4 Calcification None/Mild 15% Moderate 10% Severe 75% Patency to Foot No Infrapopliteal Vessel Patent 10% 1 Vessel Patent 35% Patient Characteristics Demographics Age (Years) 69.6±9.5 Male Gender 95% Medical History Smoking 90% Hyperlipidemia 85% Hypertension 85% Coronary Artery Disease 70% Peripheral Vascular Surgery 10% Other Peripheral Endovascular Interventions 35% History of Claudication 90% 2 Vessels Patent 30% 3 Vessels Patent 15% Müller-Hülsbeck, S. VIVA 2015.

21 Diabetic Patients 100% (14/14) 12-month primary patency 0% composite 12-month MAE rate Safety 12-Month MAE 0% (0/16) All-Cause Death at 1 Month 0% (0/16) Target Limb Major Amputation 0% (0/16) Target Lesion Revascularization (TLR) 0% (0/16) Müller-Hülsbeck, S. VIVA 2015.

22 KM curves for SFA DES trials Historically, SFA DES studies have demonstrated a pronounced decline in primary patency between 6 and 12M The MAJESTIC study does not show the pronounced loss of patency during this time period Müller-Hülsbeck, S. Presented at VIVA Dake et al. J Endovasc Ther Lammer et al. J Vasc Surg Duda et al. J Endovasc Ther Results from different trials are not directly comparable. Information provided for educational purposes.

23 DES Trials: Lesion Complexity and Patency 12M Patency (KM 360 days) Ca++ (%) RC 3 (%) CTO (%) L length (cm) 100,0% 96,4% 8,0 80,0% 60,0% 83,1% 5,4 7,1 7,0 6,0 5,0 4,0 40,0% 3,0 20,0% 2,0 1,0 0,0% ZILVER PTX RCT [1] MAJESTIC DES [2] N=241 N=57 Results from different trials are not directly comparable. Information provided for educational purposes. 0,0 [1] Dake MD et al. Circ Cardiovasc Interv [2] Müller-Hülsbeck, S. VIVA 2015.

24 SuperNOVA (BMS) Prospective, multicentre, single-arm, open label n = 299 (2yr follow-up complete) MAJESTIC (DES) Prospective, multicentre, single-arm, open label n= 57 (1yr follow-up complete) IMPERIAL (DES) Prospective, multicenter, RCT 2:1 (Eluvia:Zilver PTX) n = 485 (Enrolling)

25 Thank You for Your Attention! Dr. med. Ralf Langhoff Center for Vascular Medicine Berlin-Wilmersdorf St. Gertrauden-Hospital Charité, CC11 Academ. Teaching Hospital Humboldt University Berlin - Charité