DCB - New Tool for managing Recurrent ISR in Full Metal Jackets

Peripheral Arterial Disease Critical limb ischemia admits (9) 64 year old woman with a history of PVD s/p attempted bypass grafting and multiple PVI (42 LE angiogram 32 PVI/stent placements) who presented from clinic with worsening claudication symptoms. Her ABI showed a significant decrease in L 0.8-->0.28. Her R side also trended down; 0.41-->0.31. She had pain in both legs, but it is worse on the left side. PAST MEDICAL HISTORY Peripheral Arterial Disease Critical limb ischemia admits (9) Hypertension Hypercholesterolemia Blood clots Breast CA Rt Spigelian hernia Completed tamoxifen 5 years of therapy april 2013 Completed chemotherapy for march 2008 Cough Leg pain 00

Taking Colace 100 MG Capsule 1 capsule as needed BID CURRENT MEDICATIONS Taking Colace 100 MG Capsule 1 capsule as needed BID Taking Pletal 100 MG Tablet 1 tablet 30 minutes before or 2 Taking Gabapentin 300 MG Capsule 1 capsule Twice a day Taking ASA & Plavix 75 MG Tablet 1 tablet Once a day Taking Lipitor 80 MG Tablet 1 tablet Once a day Taking Librium 25mg 1 tablet twice daily Taking Pantoprazole Sodium 20 MG Tablet Taking Lisinopril 2.5 MG Taking Metoprolol Tartrate 25 MG Tablet Taking Oxycodone-Acetaminophen 5-325 MG Tablet 1 tablet as 00

Diagnostic RLE peripheral angiogram 2008/06/12 PVI HISTORY PTA/Stent Lt SFA 2008/08/18 Diagnostic RLE peripheral angiogram 2008/06/12 Thrombolysis/Thrombectomy Rt SFA 2008/06/11 TPA infusion Rt SFA 2008/04/03 PTA/Stent Rt SFA; PTA/Stent Rt distal SFA; Thrombectomy Rt SFA/popliteal junction 2008/04/01 PTA/Stent Rt SFA; PTA/Stent Rt profunda femoral; PTA /Stent Rt popliteal artery; PTA/Stent Rt anterior tibia 2008/02/26 Bilateral AFRO 2008/02/01 PTA/tPA/Stent BM Lt SFA 2010/05/27 PTA/Stent Lt SFA; PTA Lt common femoral art; PTA Lt profunda femoral art 2009/10/26 PTA Rt common femoral artery 2009/10/16 PTA/Arthrectomy Rt profunda femoral artery; PTA/Arthrectomy Rt common femoral artery 2009/08/05 PTA Lt SFA 2009/07/16 RLL angiogram 9/2011 00

PTA/Stent Lt SFA; PTA Lt common femoral art; PTA Lt profunda PTA Rt common femoral artery 2009/10/16 PTA/Arthrectomy Rt profunda femoral artery 2011/08/05 PTA Lt SFA 9/2011 Last Intervention: 03/2015 - Successful PVI of the left external iliac artery. TASC type A with a 20mmHg translesional gradient POBA followed by self-expanding stent placement - Successful PVI of the right SFA. TASC type D POBA - non-flow limiting dissection 00

Ann Vasc Surg. 2011 Jan;25(1):127-31. doi: 10.1016/j.avsg.2010.11.001. Full metal jacket stenting of the superficial femoral artery: a retrospective review. Shah PS1, Hingorani A, Ascher E, Shiferson A, Gopal K, Jung D, Marks N, Jacob T. The technique of long segment stenting of the superficial femoral artery (SFA) has been associated with poorer short- and long-term results. The full metal jacket (FMJ) stenting is typically described as long segment continuous stenting of a vessel segment. Initially, this technique was described in percutaneous coronary interventions. However, until recently, FMJ of the SFA has not been studied. We examined our experience with FMJ of the SFA to evaluate the outcomes and the safety of this technique.

Left lower extremity: - Left CIA has mild disease - Left EIA has 60 -70 % (20 mm gradient with pull back - EIA/CFA stent is totally occluded - SFA stents occluded - Pop stents occluded - reconstitution BTK in the popliteal - AT has 80 % ostial - PT has severe ISR - Peroneal is occluded in the prox and reconstitutes distally

Left lower extremity: - Left CIA has mild disease - Left EIA has 60 -70 % (20 mm gradient with pull back - EIA/CFA stent is totally occluded - SFA stents occluded - Pop stents occluded - reconstitution BTK in the popliteal - AT has 80 % ostial - PT has severe ISR - Peroneal is occluded in the prox and reconstitutes distally

Right lower extremity: - Right CIA has mild disease - Right EIA has severe (80 % stenosis) - Right CFA has severe ISR - SFA proximal has severe ISR 00

Right lower extremity: - Right CIA has mild disease - Right EIA has severe (80 % stenosis) - Right CFA has severe ISR - SFA proximal has severe ISR (mid and distal angiography not done) Left lower extremity: - Left CIA has mild disease - Left EIA has 60 -70 % (20 mm gradient with pull back - EIA/CFA stent is totally occluded - SFA stents occluded - Pop stents occluded - reconstitution BTK in the popliteal - AT has 80 % ostial - PT has severe ISR - Peroneal is occluded in the prox and reconstitutes distally 00

Any Ideas Heavy Stent load Recurrent presentation 9 years of multiple procedures Morbidity Significant ISR

DRUG COATED BALLONS:

LIMITATIONS OF POBA,BMS & DES Balloon angioplasty - elastic recoil and restenosis caused by cellular proliferation are major drawbacks of angioplasty. Stenting, which could tackle dissections and eliminate elastic recoil, became the next model of intervention but was limited by stent thrombosis and increased neointimal hyperplasia, leading to in-stent restenosis. Drug-eluting stents significantly attenuate the cellularity and reduce the need for repeat revascularization; however, late stent thrombosis, dependency on prolonged dual antiplatelet therapy, and continued restenosis led to a quest for new treatment modalities

Elastic recoil & negative remodeling

MEHANISMS OF RESTENOSIS Recoiling and remodelling Neointimal hyperplasia

ANGIOGRAPHIC RESTENOSIS & CLASSIFICATION Diameter stenosis > 50% Type I focal <10 mm in length IA articulation or gap IB margin IC focal body ID multifocal Type 2 diffuse >10 mm intrastent Type 3 proliferative >10 mm extending beyond stent margins Type 4 total occlusion: restenotic lesions with TIMI flow grade of 0

MEHANISMS OF RESTENOSIS Stent implantation causes arterial injury Initiate inflammation Platform material used is cobalt chromium Lower nickel content than 316L stainless steel Migration of smooth muscle cells Activated smooth muscle cells to advance from G1 phase to S phase Smooth muscle cell proliferation and extracellular matrix formation

Int J Cardiol. 2005 Oct 10;104(3):319-25. The impact of metallic allergy on stent implantation: metal allergy and recurrence of in-stent restenosis. Iijima R1, Ikari Y, Amiya E, Tanimoto S, Nakazawa G, Kyono H, Hatori M, Miyazawa A, Nakayama T, Aoki J, Nakajima H, Hara K. Abstract BACKGROUND: Relation between metallic allergy and in-stent restenosis (ISR) has been inconclusive. We hypothesized that mechanism of restenosis is different between initial stent implantation and dilatation for ISR. Thus, we studied metallic allergy and restenosis in these two different situations separately. METHODS AND RESULTS: We performed follow-up angiography and patch test for metallic allergy in a total of 174 stented consecutive patients, 109 patients (63%) for restudy of initial stent implantation and 65 patients (37%) for restudy of treatment following ISR. The positive rate of patch test in initial stent implantation was not significantly different between with or without restenosis (10% vs. 9%; p=ns). Whereas, following dilatation of ISR, the incidence of positive patch test was significantly higher in patients with recurrence of restenosis than those without the recurrence (39% vs. 12%; p=0.02). Multivariate analysis revealed that the positive patch test (Odd Ratio 4.39, p=0.02) and diffuse typed ISR (Odd Ratio 3.68, p=0.03) were significant predictors of recurrent restenosis. CONCLUSIONS: Metal allergy does not have any correlation with the restenosis after initial stent implantation. However, metal allergy is frequently observed in patients with recurrence of ISR. Metal allergy may contribute to a mechanism in the repeat recurrence of ISR, but not to restenosis after initial stent implantation.

lesions in the superficial femoral artery & below knee Rationale for the development of DEB derives mainly from the limitations of DES. Nonstent-based local drug delivery using DEB maintains the antiproliferative properties of DES, but without the limitations of DES. in torturous vessels In treatment of ISR in small vessels lesions in the superficial femoral artery & below knee In long diffuse calcified lesions (which can result in stent fracture) in bifurcated lesions when scaffolding obstructs major side branches

ISSUES WITH SFA/POP RESTENOSIS PTA - High rate of restenosis (40 – 60%) BMS - ISR – 30-50% (RESILIENT TRIAL) DES - Same Issue (SIROCCO II TRIAL) Long lesions, complex morphology, frequent multi level Low flow rates Calcification Uneven delivery of local drug Stent fracture Polymer induced inflammation Constant bio-mechanical pressure due to body movement

Paclitaxel with Spacer which was iopromide History of DEB INVENTORS 1979 – Professor Speck invented contrast agent Ultravist (iopromide) 2001 – Both Prof. Speck and Prof. Scheller introduced Ultravist / Paclitaxel Paccocath balloon Paclitaxel with Spacer which was iopromide Paccocath Balloon B. Braun Cotavance Balloon MEDRAD

Paclitaxel Paclitaxel was identified as the primary drug for DEB because of its rapid uptake and prolonged retention due to its strong lipophilic nature. DEB technology demonstrated safety and efficacy in preclinical and in randomized clinical trials for patients with in-stent restenosis Local Dose: 300 – 600 µg (100 – 200 µg in DES) which is 300 times less compare to systemic administration. Immediate Release Short acting exposure No Polymers Cytotoxic which inhibits G2 phase of Mitosis Spacer / Excipient which facilitates local delivery

FIRST GENERATION BALLOON Paccocath Technology Description FIRST GENERATION BALLOON Paclitaxel+Hydrophilic Spacer (iopromide)

1.) After pre-dilatation of the stenosis, the DCB is centered across the entire treated area 2.) 30 second minimum inflation transfers therapeutic dose of the drug to the endoluminal surface 3.) Paclitaxel diffuses into the arterial wall from the endoluminal surface after drug delivery 4.) Therapeutic drug levels are sustained in the artery through 30 days post treatment 5.) Drug continues to inhibit restenosis in the arterial wall while allowing the lumen to restore and re-endothelialize 6.) Evidence of pharmacological effects peaks at 90 days

Current Drug Coated Balloons on the Market Peripheral and coronary DCBs with CE Mark Company Device Name Balloon Drug Load Carrier Lutonix Moxy DCB 2 µg/mm² Non- polymeric Medrad-Possis Coatavance 3 µg/mm² iopromide Medtronic/Invatec In.Pact 3.5 µg/mm² Urea Biotronik Pantera Lux, Passeo 18 BTHC B. Braun Sequent Please Eurocor DIOR II, Freeway Shellac Aachen Resonance Elutax Unknown Blue Medical Protege

First Generation Landmark trials THUNDER TRIAL FEMPAC TRIAL

Thunder & fempac trial 6 months results No. of patients FEMPAC TRIAL THUNDER TRIAL     Uncoated 42 54     Coated 45 48 6-mo late lumen loss, mm 1.0±1.1 1.7±1.8 0.5±1.1 0.4±1.2 6-mo angiographic restenosis, % 47 44 19 17 6-mo % TLR 33 37 9 4 18–24 mo % TLR 52 20 15 6-mo major amputations 2

Follow up 18 and / or 24 Months Fempac 2 year outcome PAC Balloon Vs. Control Follow up 18 and / or 24 Months

THUNDER FIVE YEAR OUTCOME Freedom from TLR: Kaplan-Meier

Next generation trials LEVANT I PACIFIER Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoro popliteal Restenosis Trial for Femoro popliteal Revascularization Randomized Multicenter Trial Evaluating Prevention of Restenosis with Paclitaxel-Coated PTA Balloon Catheters in Stenosis or Occlusion of Femoro popliteal Arteries

LEVANT-I 6 months results

PACIFIER – 6 months Angiographic follow up DEB Control P value % Diameter Stenosis % 28.6% 40.4% 0.01 Min. Lumen Diameter mm 3.6 mm 3.0 mm 0.03 Binary Restenosis n/N (%) 4/40 (10%) 12/39 (31%) Late Lumen Loss mm -0.05 mm 0.61 mm 0.003

Metanalysis of deb randomized trials Conclusion: Consistent with statistically significant lower rate of restenosis in DEB Trials.

DEB VS DES INPACT VS ZILVER PTX Major Adverse Event DEB DES p Adjusted p N 131 97 Any TLR 19.3% (21/109) 21.5% (21/79) 0.705 0.550 Clinical Driven TLR 15.6% (17/109) 19.0% (15/79) 0.543 0.572 Loss of Patency 23.9% (26/109) 30.4% (24/79) 0.319 0.372 DEB provisional Stent rate = 18.3% Single Center Retrospective with Propensity Score analysis IN.PACT DEB vs Zilver PTX 228 Patients Mean lesion length = 19 cm

DEB VS PTA INPACT TRIAL

SUMMARY Role of DEB in SFA/POP Intervention is promising. DEB is superior to PTA in all clinical trials. Results of DEB angioplasty are comparable or better than DES. DEB are easier to use. It is COST EFFECTIVE modality for De-Novo & restenosis lesions. Compared to stents , NO anatomical Limitation. DEB preserve future percutaneous and open surgical options.

LIMITATIONS OF DEB Acute recoil Elimination of Late negative remodeling- not clear Variability of pharmacokinetics and control of dosing of drug

Back to our patient - on her 42nd arrival to cath lab – treated with DEB Successful PVI to right AT, Pop, SFA, CFA ISR using paclitaxel DCB and PVI to REIA with placement of nitninol SES. - PVI to Left Pop ISR CTOusing 4.0 balloon followed by 4.0 DCB - PVI to SFA ISR CTO (distal to prox) with 6 x 200 mm followed by 6.0 DCB - PVI to CFA with 6.0 balloon followed by 6.0 DCB - PVI to EIA using 7.0 DCB followed by placement of 8 x 60 SES. Excellent final result with brisk flow all the way to the foot. Contrast 20 c.c. and rest of angio was done using CO2 angiography.

- Excellent Results Unbelievable ABI on 11/18/2015 was 1 on the left and 0.99 on the right No Hospital admission for 9 months - We have quite a few patients with FMJ in their LE vessels and have seen great results with use of DCB in these patients.

Thank You