The (Potential) Role of Drug Eluting Balloons in BTK Interventions Thomas Zeller, MD

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., Covidien, 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., Covidien, Gore & Associates, Abbott Vascular, Medtronic, Spectranetics, Terumo, TriReme, Volcano

DEB are not yet indicated in clinical routine Further Research needed! Why?

Conflicting Evidence DEBATE BTK vs. IN.PACT Deep Journal of the American College of Cardiology 2014. 64;15:1568-76 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. 2013 Aug 6;128(6):615-21 T. Zeller LINC 2014 & Zeller et al. JACC 2014

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

IN.PACT DEEP vs. CLI literature Lowest Restenosis, TLR and Major Amputation in both arms IN.PACT DEEP [1] Rocha-Singh KJ et al. Catheter Cardiovasc Interv. 2012 Nov 15;80(6):1042-51; [2] Bosiers M LINC 2011; [3] Zeller T. LINC 2011; [4] Scheinert LINC 2011 «amputations» [1] Lejay A et al. Acta Chir Belg. 2009; [2] Romiti M et al. J Vasc Surg. 2008; [3] Adam DJ et al. Lancet. 2005; [4] Rocha-Singh KJ et al. Catheter Cardiovasc Interv. 2012; [5] Scheinert D et al. JACC 2012; [6] Iida et al. EJVEVS 2012

DCB-BTK Evidence: DCB vs. DES 50-patients (CLI + IC) RCT of IN.PACT Amphirion vs. DES Lesion length: 14.8 (DCB) vs. 12.7 (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)

DEB-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

Why do we need deb in btk interventions?

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

Ferraresi R, LINC 2016

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? DEB are the optimal treatment tool for long BTK lesions an din particular foot arteries

Why do we need deb in btk interventions? Because Patency matters!

Ferraresi R, LINC 2016

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. 2013 Aug 6;128(6):615-21

Ulcer Healing & Ambulation and Vessel Patency

Vermassen F, LINC 2016

Vermassen F, LINC 2016

Background of Pedal Artery Interventions Due to the small vessel diameters and extensive external forces exposed to the distal tibial and pedal arteries stents in particular DES are no option for improving durability of the procedure. Thus, DEB is an interesting choice.

Wound Healing & Preserved Pedal Arch

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

DEB in BTK Interventions Summary I Early DCB-BTK evidence showed high promise for IN.PACT Amphirion to reduce restenosis and reintervention rates at 3 and 12 months vs. PTA Significantly higher restenosis rates reported for IN.PACT Amphirion vs. DES vs. in BTK lesions with length 1315 cm Inpact Deep is the largest BTK-CLI Trial completed to date Failed to demonstrate superior treatment effect of IN.PACT Amphirion vs. PTA Met primary safety endpoint; safety signal detected with a trend toward higher major amputation rate in the DCB arm No significant difference primary patency with Passeo 18 Lux DEB vs. PTA at 12-month FU underpowered study No difference in amputation rates No major differences in hard clinical outcomes across all studies between any DCB and control

DEB in BTK Interventions Summary II Further research on the efficacy of DEB in tibial arteries is mandatory 1. step: Due to potential safety concerns regarding the cytotoxic drug paclitaxel efficacy studies should include claudicants only, no wounds Angiographic primary endpoint, e.g. LLL, binary restenosis 2. step: clinical endpoint driven CLI study after confirmation of biological efficacy of paclitaxel eluting DEB in tibial arteries Alternative exipients resulting in higher drug uptake of paclitaxel Reduction of overall drug dose (paclitaxel) Alternative antiproliferative, non-toxic drugs in CLI patients “Limus” drugs

DEB in BTK Interventions Summary III For foot arteries and distal tibial arteries DEB need a coronary balloon like profile DEB coating must be hydrophilic High friction of the drug coating in small & calcified arteries The combination of atherectomy and DEB should be considered in calcified BTK lesions To reduce friction To reduce recoil To potentially improve drug uptake / wall persistance