Definitive Therapies – How to Optimize DCB Outcomes: Lessons from the European Trials Prof. Thomas Zeller Department Angiology University Heart-Center Freiburg - Bad Krozingen Bad Krozingen , Germany

Faculty Disclosure Thomas Zeller, MD For the 12 months preceding this presentation, I disclose the following types of financial relationships: Honoraria received from: Abbott Vascular, Angioslide, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Cordis Corp., Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme, VIVA Physicians Consulted for: Abbott Vascular, Bard Peripheral Vascular, Boston Scientific Corp., Cook Medical, Gore & Associates, Medtronic, Spectranetics Research, clinical trial, or drug study funds received from: 480 biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Cordis Corp., Gore & Associates, Abbott Vascular, Medtronic, Spectranetics, Terumo, TriReme, Volcano

Drug-Coated Balloons Benefits Limitations More uniform drug delivery than drug-eluting stents Native vessel maintained Reduced requirement for DAPT (if stents are avoided) Re-interventions are less challenging than in-stent-restenosis Limitations Procedural effectiveness, same as POBA Recoil Calcium Dissections Lesion length Increasing bail-out stent rate with increasing lesion length Increases cost May negatively affect procedural outcomes 3 |

Calcium May Present a Challenge Only 20% of Paclitaxel transfers into the vessel wall1 Calcification can increase the loss of anti-proliferative drug and impair uptake2 Medial calcification is common in patients with diabetes and chronic kidney disease3 Kelsch et al. Invest Radiol 2011 Schnorr Expert Rev Med Device 10(1), 105-114 (2013) Jude et al. Diabetic Medicine 27,4-14 (2010)

Impact of Calcium Barrier to optimal dilatation Barrier to optimal drug absorption Underestimated by angiography Key cause of severe dissections Bilateral / circumferential calcium ranked as most severe by different calcium grading systems Highly prevalent in: Elderlies Diabetics Kidney disease Fanelli F et al. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol. 2014 Aug;37(4):898-907 Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv. 2014 May 1;83(6):E212-20 Fitzgerald PJ et al. Contribution of localized calcium deposits to dissection after angioplasty. Circulation. 1992; 86(1):64-70 Shanahan M et al. Medial Localization of Mineralization-Regulating Proteins in Association With Mönckeberg's Sclerosis : Evidence for Smooth Muscle Cell -Mediated Vascular Calcification. Circulation. 1999;100:2168-2176 Moe SM, Chen NX. Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2008 Feb;19(2):213-6 Bertoni AG, Kramer H, Watson K, Post WS. Diabetes and Clinical and Subclinical CVD. Glob Heart. 2016 Sep;11(3):337-342

DCB and Calcium (Fanelli et al. Cardiovasc Intervent Radiol. 2014) Calcium: potential barrier to optimal drug absorption Circumferential distribution strongest influencing factor N=60 SFA lesions  6 cm (de-novo) CTO: 31.7% DCB with standard pre-dilatation a = <3 cm; b = >3cm Calcium evaluation by CTA (circumf.) and DSA (longitud.) Fanelli F, Cannavale A, Gazzetti M, Lucatelli P, Wlderk A, Cirelli C, d'Adamo A, Salvatori FM. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol. 2014 Aug;37(4):898-907 Courtesy M. Landini

DCB and Calcium (Tepe et al. J Endovasc Ther. 20151 ) Not length, nor location but bilateral Calcium distribution observed as strongest predictor of outcome N=91 (retrospective) SFA lesions  5.7 cm Restenotic: 45.1% CTO: 33.0% 6-month LLL (primary endpoint) by Angio Core lab adjudication Tepe G, Beschorner U, Ruether C, Fischer I, Pfaffinger P, Noory E, Zeller T. Drug-Eluting Balloon Therapy for Femoropopliteal Occlusive Disease: Predictors of Outcome With a Special Emphasis on Calcium. J Endovasc Ther. 2015 Oct;22(5):727-33 Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: Prevalence, mechanism, detection and clinical implications. Catheter Cardiovasc Interv. 2014;83:E212-220.

SFA-Stent Deployment Evaluation Stent Compression - Leipzig Data Angio AP projection Angio LAO projection Traditional laser cut slotted tube nitinol stent in a calcified lesion in 2 different views showing significant stent compression % MLD 15% % MLD 42%

Impaired Primary Patency due to Residual Stenosis following BMS Bausback Y et al. JEVT2014

DCB and Stenting (Tepe et al. J Endovasc Ther. 2015 ) Stents may not necessarily improve DCB results N=91 (retrospective) SFA lesions  5.7 cm Restenotic: 45.1% CTO: 33.0% 6-month LLL (primary endpoint) by Angio Core lab adjudication Tepe G, Beschorner U, Ruether C, Fischer I, Pfaffinger P, Noory E, Zeller T. Drug-Eluting Balloon Therapy for Femoropopliteal Occlusive Disease: Predictors of Outcome With a Special Emphasis on Calcium. J Endovasc Ther. 2015 Oct;22(5):727-33

SFA 12-Month Primary Patency PTA, BMS, DES and DEF LE Sub-analyses by Lesion Length SIROCCO6 FAST1 THUNDER4 RESILIENT3 Zilver 2 SUPERB8 Zilver2 COMPLETE5 VIBRANT7 (BMS arm) DURABILITY II9 1. Krankenberg et al. Circulation. 2007; 5. Laird, ISET 2012 2. Dake et al. Circ Cardiovasc Interv. 2011 6. Duda et al. J Endovasc Ther 2006 3. Laird et al. Circ Cardiovasc Interv. 2010 7. Ansel, VIVA 2010 4. Tepe et al. NEJM 2008;358:689-99 8. Rosenfield VIVA 2012 9. Matsumura ISET 2012

IN.PACT GLOBAL LONG LESIONs IMAGING COHORT (≥15 CM) Primary Patency in non-stented subgroup Primary Patency by Lesion Length Subgroup analysis is intended to show outcomes in subjects receiving provisional stenting relative to the entire long lesion imaging cohort. Primary patency by Kaplan-Meier analysis at Day 360 is 92.5% in subjects who were treated with DCB alone vs 91.1% for the entire long lesion cohort. 13 PCR Perrpheral Istanbul2015 | IN.PACT Global Complex Lesions| November 28, 2015

DAART = Directional Atherectomy + Anti-Restenotic Therapy Mechanically re-canalize the vessel without overstretch Remove the perfusion barrier Reduce the likelihood of bail-out stenting and preserve the native vessel Treating calcified lesions with directional atherectomy prior to DCB inflation could increase the effectiveness of the treatment by Mechanically re-canalize the vessel without overstretch Remove the perfusion barrier Reduce the likelihood of bail-out stenting and preserve the native vessel 14 |

DEFINITIVE Ca++ demonstrated calcified disease can be treated with DA and embolic protection 2 Bail-out stent rate: 4.1% Flow-limiting dissection rate: 1.5% Achieved maximal lumen gain 1 1 -The DEFINITIVE Ca++ demonstrated calcified disease can be treated with DA and embolic protection -DEFINITIVE Ca++ was a 30-day study designed to evaluate the safety and effectiveness of DA paired with embolic protection to treat moderate to severely calcified lesions- core lab and CEC adjudicated data -The bail-out stent rate was 4.1% and the flow-limiting dissection rate was 1.5% -And, substantial lumen was gained by the DA device 15 | 1. Roberts Cath Cardiovasc Interven 84:236-244(2014) 2. Data on file

Cioppa et al. CV Revasc. Med. 2012 Jul-Aug:219-23. Published DAART Data Procedure Results < 30% residual stenosis achieved in all cases No procedure-related AEs Bail-out stenting rate: 6.5% (2) 1 Year Results Primary Patency (via duplex) = 90% (27/30) Freedom from MAE 87% (26/80) Authors’ Conclusion: DA and DCB may represent a potential alternative strategy for the treatment of femoro-popliteal severely calcified lesions. These very promising data and the considered hypothesis have to be confirmed in a multicenter randomized trial. Cioppa et al. CV Revasc. Med. 2012 Jul-Aug:219-23.

DEFINITIVE AR 1-Year Outcomes

DEF AR – The Value of Luminal Gain

DEFINITIVE AR Case Example: DAART Arm Sub-optimal Debulking Baseline 59% residual stenosis Post atherectomy 001-015- Dr. Rastan De novo, 8.7cm lesion, severe ca++, TASC B (per core lab) Distal SFA/pop with good run-off- over 80% stenosis, 11/12 cm lesion- had some non-focal mixed ca++ at pre and post DA Good collaterals pre and post Post-DA: an area around 35 with some residual stenosis- pre was 83%, post was 59% residual stenosis First DCB inflated 30cm-43cm –second balloon 27-31 cm –site of DCB overlap is 30-31cm Post image- around 31 and 31, and 34-35.5 there is some residual stenosis – had a residual stenosis ~27% at 37cm 12- month angio- collateral starts at 31cm- occlusion starts just below collateral –could there be some mechanical stimulus causing CTO occluded 31-~ 43- no ruler on image Mode of failure: two tight areas of stenosis, one was ~ 31- don’t know exact points of DA, post- DA ~ 35, area was ~ 59% stenosed- two DCB used 27-43- overlap at 30/31- tight area at 31/32 post-procedure- at months, occluded at 31/32 based on collateral, right down to the collateral

DEFINITIVE AR Case Example: DAART Arm - Sub-optimal Debulking 001-015 Distal SFA/pop with good run-off- over 80% stenosis, 11/12 cm lesion- had some non-focal mixed ca++ at pre and post DA Good collaterals pre and post Post-DA: an area around 35 with some residual stenosis- pre was 83%, post was 59% residual stenosis First DCB inflated 30cm-43cm –second balloon 27-31 cm –site of DCB overlap is 30-31cm Post image- around 31 and 31, and 34-35.5 there is some residual stenosis – had a residual stenosis ~27% at 37cm 12- month angio- collateral starts at 31cm- occlusion starts just below collateral –could there be some mechanical stimulus causing CTO occluded 31-~ 43- no ruler on image Mode of failure: two tight areas of stenosis, one was ~ 31- don’t know exact points of DA, post- DA ~ 35, area was ~ 59% stenosed- two DCB used 27-43- overlap at 30/31- tight area at 31/32 post-procedure- at months, occluded at 31/32 based on collateral, right down to the collateral 34% residual stenosis Post DAART DCB Inflations

DEFINITIVE AR Case Example: DAART Arm - Sub-optimal Debulking Clinically-driven TLR 349 days post DAART procedure Occlusion begins at site of sub-optimal debulking 001-015 Distal SFA/pop with good run-off- over 80% stenosis, 11/12 cm lesion- had some non-focal mixed ca++ at pre and post DA Good collaterals pre and post Post-DA: an area around 35 with some residual stenosis- pre was 83%, post was 59% residual stenosis First DCB inflated 30cm-43cm –second balloon 27-31 cm –site of DCB overlap is 30-31cm Post image- around 31 and 31, and 34-35.5 there is some residual stenosis – had a residual stenosis ~27% at 37cm 12- month angio- collateral starts at 31cm- occlusion starts just below collateral –could there be some mechanical stimulus causing CTO occluded 31-~ 43- no ruler on image Mode of failure: two tight areas of stenosis, one was ~ 31- don’t know exact points of DA, post- DA ~ 35, area was ~ 59% stenosed- two DCB used 27-43- overlap at 30/31- tight area at 31/32 post-procedure- at months, occluded at 31/32 based on collateral, right down to the collateral

Periprocedural Complications (Per CEC) DAART (N= 48) DCB (N = 54) p-value Distal Embolization 6% (3/48) 0/54 0.101 No Intervention 1 Surgical Intervention Endovascular Intervention 2 Dissection (flow-limiting, Grade C/D) 2% (1/48) 19% (10/54) 0.009 6 4 Perforation 4% (2/48) 0.219

| For Medtronic presentation use only, do not copy or distribute Co-Principal Investigators Krishna Rocha-Singh, MD Chief Scientific Officer Prairie Heart Institute of Illinois Brian DeRubertis MD, FACS Associate Professor of Surgery UCLA Division of Vascular Surgery The REALITY Study evaluates patient outcomes with adjuctive use of Medtronic HawkOne™ or Medtronic TurboHawk ™ and Medtronic IN.PACT™ Admiral™ drug-coated balloon. The multi-center, international, prospective, single-arm study will enroll up to 250 subject at up to 15 sites. The study includes angiographic and duplex ultrasound core lab adjudication. Primary patency is assessed by duplex ultrasound at 12-months. Patients are followed up to 24 months to determine clinically driven target lesion revascularization (CD-TLR). The study is sponsored and managed by VIVA physicians with support from Medtronic through an external research project grant. | For Medtronic presentation use only, do not copy or distribute

| For Medtronic presentation use only, do not copy or distribute Co-Principal Investigators Krishna Rocha-Singh, MD Chief Scientific Officer Prairie Heart Institute of Illinois Brian DeRubertis MD, FACS Associate Professor of Surgery UCLA Division of Vascular Surgery Consent 250 subjects Goal Enrollment 150 subjects Ten U.S. Sites Lesion length 8-18cm Occlusion length 6-10cm 3 German Sites Lesion length up to 25cm | For Medtronic presentation use only, do not copy or distribute

Optimizing DCB Intervention Proposed Fem-Pop Treatment Algorithm Each femoro-popliteal lesion Pre-Dilatation with 1:1 sized balloon Flow-limit Dissection or residual stenosis >50%? Flow-limit Dissection or residual stenosis >50%? YES NO Stent YES DEB NO Directional Atherectomy

Treatment Options to Overcome DCB Limitations Summary DCB offer promising results in the treatment of femoro-popliteal lesions However, limitations exist in complex lesion morphologies such as: Severely calcified lesions Acute residual stenosis > 30% Lesion length DEFINITIVE AR resulted by trend in better outcomes in those challenging lesion subsets for the combination of DA & DEB “spot” atherectomy might be a cost effective strategy A sufficiently powered study to confirm this potential benefit is mandatory Lithoplasty offers potential advantages when combined with DCB or used as a DCB