1. What is the Data for DCB in BTK & What Next?
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, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Cordis Corp., Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme
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. Most DCBs have shown a biologic effect in femoro-popliteal lesions
6-month Late Lumen Loss from 8 DCB Technologies
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 Feb 14;358(7):689-99
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 Sep 23;118(13):
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 Jan;7(1):10-9
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 Feb;22(1):14-21
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 Dec;5(6):831-40
D.Scheinert - Advance 18 PTX Study - LINC 2013 oral presentation
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 Aug;86(2):278-86
T.Albrecht – Preliminary angiographic and clinical 6-month results of the CONSEQUENT trial - LINC 2016 oral presentation
W.Guo - AcoArt I First Prospective, Randomized, Multicenter Clinical Trial for the Use of the Orchid DCB in Femoropopliteal Artery Disease - LINC 2016 oral presentation

4. Evidence from DEB Trials Long-term Freedom from TLR
Significant and sustained TLR reduction up to 5 years
FEMPAC 2Y
THUNDER 5Y

5. Context view: 4 RCTs, 3 DCBs
1-year Primary Patency
Complex
Patient Population
similar patient characteristics
p=0.002
p<0.001
p<0.001
p<0.001
PTA
PTA
PTA
PTA
Stellarex
(ptx 2 µg/mm2)
In.Pact
(ptx 3.5 µg/mm2)
Lutonix
(ptx 2 µg/mm2) *
Corelab adjudicated (VascCore Core laboratory - Boston, MA, USA) Duplex derived Primary Patency based on 2.5 PSVR threshold. ‡ day 365; † day 360
S.Lyden - ILLUMENATE Pivotal Stellarex DCB IDE Study 12-month Results - oral presentation, TCT 2016
M.Brodmann - ILLUMENATE European Randomized Clinical Trial: 12-month Final Results from the Stellarex DCB – oral presentation, AMP 2016
Tepe G et al. IN.PACT SFA Trial Investigators.. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation G.Tepe, Charing Cross 2014 oral presentation + P. Krishnan, DCB show superior 3-year outcomes vs. PTA: results from In.Pact SFA randomized trial - oral presentation, VIVA 2016
K.Rosenfield et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med 2015

6. DCB are not yet indicated in clinical routine in BTK lesions
Further Research needed!
Why?

7. Conflicting Evidence DEBATE BTK vs. IN.PACT Deep
Journal of the American College of Cardiology ;15:
Drug-Eluting Balloon Versus
Standard Balloon Angioplasty for
Infrapopliteal Arterial Revascularization in Critical Limb Ischemia
12 Month Results From the IN.PACT DEEP Randomized Trial
Thomas Zeller, Iris Baumgartner, Dierk Scheinert, Marianne Brodmann, Marc Bosiers, Antonio Micari, Patrick Peeters, Frank Vermassen, Mario Landini, David B. Snead, K. Craig Kent, Krishna J. Rocha-Singh, IN.PACT DEEP Trial Investigators
Circulation
Drug-Eluting Balloon in peripherAl inTErvention for Below The Knee Angioplasty Evaluation (DEBATE-BTK): A Randomized Trial in Diabetic Patients with Critical Limb Ischemia
Single-Center Randomized Trial
132 Patients
CLI: 100%, Diabetes: 100%
Average lesion length: 13 cm
CTO: 80%
IN.PACT™ Amphirion™ vs. PTA ™
Liistro F et al. Drug-eluting balloon in peripheral intervention for below the knee angioplasty evaluation (DEBATE-BTK): a randomized trial in diabetic patients with critical limb ischemia. Circulation Aug 6;128(6):615-21
T. Zeller LINC 2014 & Zeller et al. JACC 2014

8. Binary Restenosis (BR) and Clinically Driven TLR (CD-TLR)
IN.PACT Deep
12-month Freedom from Major Amputation, Binary Restenosis Rate, TLR Rate & LLL
12-month
Binary Restenosis (BR) and
Clinically Driven TLR (CD-TLR)
12-month
Late Lumen Loss
0.605
± 0.775
0.616
± 0.781
Zeller T. et al. JACC 2014

9. DCB-BTK - Negative Evidence: BIOLUX P II
72-patients (CLI + IC) RCT of Passeo-18 Lux vs. PTA
12-month CD-TLR Rates:
30.1% (DCB) vs. 30.6% (PTA)
(p=0.805)
12-month Loss of Primary Patency
49.2% (DCB) vs. 45.6% (PTA)
(p=0.908)
Event Rate: TLR Lesions
0.0%
20%
40%
60%
80%
100%
Time to Event (days)
365
uncoated
DRB
Event Rate: Patency loss
0.0%
20%
40%
60%
80%
100%
Time to Event (days)
365
uncoated
DCB
Amputation target extremity
Major
8/ 23.7 [12.6,42.0]
1/ 3.3[0.5,21.4]
9/ 25.8 [ 14.3, 43.9]
2/ 5.6 [1.4,20.7]
0.975
0.631
Zeller T et al., JACC CCI 2015

10. DCB-BTK Evidence: DCB vs. DES
50-patients (CLI + IC) RCT of IN.PACT Amphirion vs. DES
Lesion length: 14.8 (DCB) vs (DES) (p=0.330)
Key findings (DCB vs. DES) at 6-month:
Binary restenosis: 58% vs. 28% (p=0.0457)
LLL: 1.35±0.2 vs. 1.15±0.3 (p=0.62)
>50% restenosis length (cm): 4.3±1.6 vs. 3.6±1.5 (p=0.16)
TLR: 14.3% vs. 7.4 (p=0.21)
(P.M. Kitrou, MD, PhD – CIRSE 2013, LINC 2014)

11. Why do we need dCb in btk interventions?

12. In CLI most BTK lesions are longer than 10cm
Bare metal stents did fail to show a benefit over PTA

13. Ferraresi R, LINC 2016

14. In CLI most BTK lesions are longer than 10cm
Bare metal stents did fail to show a benefit over PTA
No dedicated DES for BTK use are yet commercially available and clinically tested
Appropriate length, at least 8cm for balloon expandable stents
Drug eluting nitinol stents not yet tested below the knee
Are stents the right choice for long distant BTK lesions extending to the foot?
DCB are the optimal treatment tool for long BTK lesions an din particular foot arteries

15. NO DCB Class Effect?! results awaited
IN.PACT DEEP failure applies to IN.PACT Amphirion only.
Each DCB stands on the merits of its own data
480-patient RCT of Lutonix DCB vs. PTA in BTK-CLI
results awaited
Marianne Brodmann LINC 2014

16. DCB in BTK Interventions What next?
Is paclitaxel the right drug for BTK interventions?

17. Paclitaxel Eluting DES vs PTA/BMS
Below the knee
Paclitaxel Eluting DES vs PTA/BMS
PADI CLI: PTA±BMS vs DES for infrapopliteal lesions
Multi-center randomized two-arm study
136 patients with 144 limbs
CLI, Rutherford 4-6
De novo stenoses or occlusions below knee joint
Vessel diameter 2-6 mm, length ≤ 90 mm
PTA±BMS or paclitaxel-DES (Taxus Liberté)
Heparin, Aspirin, Clopidogrel
Overhagen et al. Circ Cardiovasc Interv 2016

18. DCB in BTK Interventions What next?
Is paclitaxel the right drug for BTK interventions?
“Limus” eluting DCB might become the appropriate solution for long BTK lesions.

19. Below the knee DES vs PTA/BMS
Systematic Review of infrapopliteal DES: A meta-analysis of randomized controlled trials
3 RCTs with 501 patients
Achilles: DES vs PTA in CLI & IC, n=200
Destiny: DES vs BMS in CLI, n=140
Yukon-BTX: DES vs BMS in CLI & IC, n=161
Relatively short and focal infrapopliteal lesions
InfraPop: Meta-Analysis of RCT
Results at 1 year
DES
PTA/BMS P=
Primary Patency
80.0%
58.8%
<0.0001
Rutherford class improvement
79.0%
69.6%
0.045
Wound healing
76.8%
59.7%
0.04
TLR
9.9%
22.0%
0.001
Event-free survival
72.2%
57.3%
Survival
85.5%
86.6%
0.75
Amputation
6.4%
10.8%
0.11
Katsanos K et al, Cardiovasc Intervent Radiol 2013

20. Sirolimus Coated Balloon – Selution
Use of micro-reservoirs made out of biodegradable polymer intermixed with Sirolimus
Controlled and sustained drug release
Long-term distribution of Sirolimus into tissue to maintain therapeutic levels
Novel Cell Adherent Technology – CAT™
Minimizes wash-off during insertion, tracking and lesion crossing
Optimizes drug transfer to tissue during short-term balloon dilatation
© M.A. Med Alliance – 2016

21. Med Alliance SELUTION™ – PK Study
Source: Med Alliance – PK Study ( ) / Bard – Catheterization and Cardiovascular Interventions 83:132–140 (2014) / Medtronic – Presentation Melder (LINC 2012).

22. DCB in BTK Interventions What next?
Is paclitaxel the right drug for BTK interventions?
“Limus” eluting DCB might become the appropriate solution for long BTK lesions.
The vessel preparation prior to DCB angioplasty might solve the problem of early recoil as one potential failure mode of paclitaxel releasing DCB

23. Early Recoil After Balloon Angioplasty of Tibial Artery Obstructions in Patients With Critical Limb Ischemia
Frederic Baumann, MD; Jacqueline Fust; Rolf Peter Engelberger, MD; Ulrike Hügel, MD; Do-Dai Do, MD; Torsten Willenberg, MD; Iris Baumgartner, MD; Nicolas Diehm, MD.
1Department of Clinical and Interventional Angiology, Swiss Cardiovascular Center, Inselspital, University Hospital of Bern, Switzerland.
2Department of Internal Medicine, Inselspital, University Hospital of Bern, Switzerland.
3Department of General and Orthopedic Surgery, Hospital of Münsterlingen, Switzerland.
Baumann et al. J Endovasc Ther February 2014 vol. 21 no

24. Results: Author’s Conclusions:
Elastic recoil: /30 patients (97%)
Mean luminal compromise: 29%
Acute lumen gain: mm (2.00 mm mm)
Subacute lumen loss (15 min.): mm (2.00 mm mm)
Author’s Conclusions:
Early recoil is frequently observed in CLI patients undergoing tibial angioplasty and may significantly contribute to restenosis. These findings support the role of dedicated mechanical scaffolding approaches for the prevention of restenosis in tibial arteries.
Baumann et al. J Endovasc Ther February 2014 vol. 21 no

25. Prospective, randomized, multicentric study
Atherectomy and Drug-Coated Balloon Angioplasty in Treatment of Long Infrapopliteal Lesions (ADCAT-Study)
Atherectomy (Turbohawk, Medtronic) and paclitaxel-coated balloon angioplasty (Lutonix14, Bard) for treatment of long atherosclerotic BTK lesions
Prospective, randomized, multicentric study

26. Combination Therapy OPTIMIZE BTK1
Multicenter, randomized (atherectomy+DCB vs. DCB)
Target N = 50 at up to 10 EU sites
RCC 3-5, BTK lesions
Diamondback (CSI) ” DCB
Primary Endpoints:
Technical success
(< 50% residual stenosis without significant angiographic complications
Procedural success
(achievement of technical success for all target lesions treated during the index procedure)
Device success
(successful delivery and deployment of the DCB to the target lesion as described IFU)
Treatment success
(percentage of target lesions meeting technical success with <30% residual stenosis post DCB angioplasty without the use post-adjunctive treatments)
Estimated target completion date: June 2018
Clinicaltrials.gov record NCT

27. We Know… Not all lesions are the same
Above the Knee1
Below the Knee1
Mixed morphology (multiple plaque types & thrombus)
Medium to large vessels (4 - 9 mm)
Lesions more commonly calcified
Tortuous, challenging anatomy
Small vessels ( mm)
1. VIVA 2011 survey – 100 physicians surveyed.
2. Bishop et al. Ann Vasc Surg. 2008;22:

28. DCB in BTK Interventions Summary
The combination of atherectomy and DCB should be considered in calcified BTK lesions
To reduce friction
To reduce recoil
To potentially improve drug uptake / wall persistence
Alternative antiproliferative drugs such as “limus” drugs should be explored
Alternative ways of applying the drug to the adventia (Bullfrog, LIMBO study, dexamethasone)