1. 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

2. 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

3. 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 |

4. 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), (2013)
Jude et al. Diabetic Medicine 27,4-14 (2010)

5. 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 Aug;37(4):
Rocha-Singh KJ, Zeller T, Jaff MR. Peripheral arterial calcification: prevalence, mechanism, detection, and clinical implications. Catheter Cardiovasc Interv 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:
Moe SM, Chen NX. Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol Feb;19(2):213-6
Bertoni AG, Kramer H, Watson K, Post WS. Diabetes and Clinical and Subclinical CVD. Glob Heart Sep;11(3):

7. 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 Aug;37(4):
Courtesy M. Landini

8. 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 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:E

9. 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%

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

11. 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 Oct;22(5):727-33

12. 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 Duda et al. J Endovasc Ther 2006
3. Laird et al. Circ Cardiovasc Interv Ansel, VIVA 2010
4. Tepe et al. NEJM 2008;358: Rosenfield VIVA 2012
9. Matsumura ISET 2012

13. 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

14. 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 |

15. DEFINITIVE Ca++ demonstrated calcified disease can be treated with DA and embolic protection2
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: (2014) 2. Data on file

16. 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 Jul-Aug:

17. DEFINITIVE AR
1-Year Outcomes

18. DEF AR – The Value of Luminal Gain

19. DEFINITIVE AR Case Example: DAART Arm Sub-optimal Debulking
Baseline
59% residual stenosis
Post atherectomy
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 cm –site of DCB overlap is 30-31cm
Post image- around 31 and 31, and 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 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

20. DEFINITIVE AR Case Example: DAART Arm - Sub-optimal Debulking
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 cm –site of DCB overlap is 30-31cm
Post image- around 31 and 31, and 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 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

21. 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
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 cm –site of DCB overlap is 30-31cm
Post image- around 31 and 31, and 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 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

22. 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

25. | 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

26. | 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

27. 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

28. 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