Drug Eluting Balloon in peripheral artery disease

Drug Eluting Balloon in peripheral artery disease Alessandro Furgieri MD Cardiovascular Department ICC Istituto Clinico Cardiologico Casal Palocco (RM) - Italy

CLI Overview and Challenges

Critical Limb Ischemia Critical Limb Ischemia: chronic ischemic rest pain, ulcers or gangrene attributable to objectively proven arterial occlusive disease. The term CLI implies chronicity and is to be distinguished from acute limb ischemia Ankle pressure < 50 mm Hg Toe pressure < 30 mm Hg TcpO2 < 30 mm Hg Norgren et al. TASC II, Eur J Vasc Endovasc Surg 33, 2007

Relevance of the problem CLI in Europe Critical Limb Ischemia (CLI) 2 million patients in Europe 150,000 amputations/year Mean age > 69 years 63% - 91% diabetic patients Mortality > 60 % @ 3 years Coppi, G.; EVC 2004

CLI: a Major Epidemic a) 100.000 limb amputation/year in US b) 1 limb lost every 30 sec in w/w c) Less than 1/2 (49%) of the patients that eventually received a primary amputation had any diagnostic evaluation prior to their amputation International Working Group of Diabetic Foot - www.iwgdf.org Boulton et al. The global burden of diabetic foot disease, The Lancet, Volume 366 Issue: 9498, (2005), pp. 1719-24 Allie et al. EuroIntervention May 2005

Relevance of the problem CLI in First Key Procedure # Patients with Lesion Assessment USA Total # Patients in Pathway Group Percent of Patients Receiving Lesion Assessment Before First Key Procedure Amputation 138 281 49% Bypass 67 96 70% PTA 33 40 83% Total 238 417 57% Less than 1/2 (49%) of the patients that eventually received a primary amputation had any diagnostic evaluation prior to their amputation! Not even a simple ABI! Allie et al. Eurointervention May 2005

CLI Natural Evolution 54% mortality, 46% amputation at 1y for untreated CLI Lepäntalo et al: EJVES 1996;11 (2): 153-157

CLI Natural Evolution diabetes neuropathy trauma, deformity ulcer 1 million one mil. major amputations ww p/y gangrene lack of healing infection

CLI Multidisciplinary Therapy awareness and prevention Early Diagnosis Treatment WOUND CARE 1. Debridement 2. Off-loading 3. Antibiotics 4. Skin Graft 5. Rehabilitation 6. Best Medical Therapy REVASCULARIZATION

Clinical Variables and Revascularization Strategies affecting CLI Outcomes

Clinical Variables Affecting CLI Diabetes and diffuse disease Outcomes Predominance of BTK lesions (74% of all lower limb lesions) Prevalence of diffuse disease with long stenosis and occlusions (66% occlusions, 50% occlusions >10 cm) 70% BTK: 74% of 2893 lesions from 417 consecutive CLI diabetic subjects with ischemic foot ulcer 60% 16% < 10 cm 50% 40% 30% 20% 44% 50% > 10 cm 10% 1% 8% 14% 36% 11% 27% 1% Graziani et al. Vascular Involvement in Diabetic Subjects with Ischemic Foot Ulcer: a New Morphologic Categorization of Disease Severity Eur J Vasc Endovasc Surg 33, 453 460 (2007) 0% Stenosis Occlusions

Wounds Clinical Variables Affecting CLI Lack of proper assessment / reporting of wound healing from the literature, however...: 1. Not all wounds are even 2. Not all wounds are ischemic 3. Wound assessment (depth, ischemic vs. non-ischemic, infected vs. non- infected...) and treatment is a key contributor factor for limb salvage Outcomes Wound healing time 6 months Complete 6m healing rate < 50% Lavery et al. The Journal of Foot and Ankle Surgery 35(6):528-531, 1996 1. Xcell Trial Rocha Sing 2011 2. Soderstrom, et al; Journal of Vascular Surgery 2009 3. Soderstrom, et al; Eur J Vasc Endovasc Surg 2008 4. Hoffman, et al; Eur J Vasc Endovasc Surg 2007 5. Chung, et al; Journal of Vascular Surgery 2006

Wounds Clinical Variables Affecting CLI Outcomes Increased mortality and amputation is associated with ischemic foot ulcers Moulik PKet al: Amputation and mortality in diabetic foot ulcers stratified by etiology Diabetes care 26;491-494, 2003

Revascularization Strategies Affecting CLI Outcomes Targets in BTK PTA: complete vs. selected revascularization 1. The most important factor affecting Limb Salvage is the number of patent arteries post-pta [1;2] 1. 1 vessel better than 0 2. 2-3 vessels better than 1 3. Tibials better than peroneal 2. Direct revascularization (distal bypass) of the angiosome specific to the anatomy of the wound leads to a higher rate of healing and limb salvage [3] 3. Trade-off between driven by 1) procedural time and cost, and 2) technical access / success in treating the angiosome specific vessel 1. Peregrin et al. PTA of Infrapopliteal Arteries: Long-term Clinical Follow-up and Analysis of Factors Influencing Clinical Outcome Cardiovasc Intervent Radiol (2010) 33:720 725 2. Faglia et al. When is a technically successful peripheral angioplasty effective in preventing above-the-ankle amputation in diabetic patients with critical limb ischaemia Diabet Med. 2007 Aug;24(8):823-9 3. Neville et al. Revascularization of a Specific Angiosome for Limb Salvage: Does the Target Artery Matter? Ann Vasc Surg 2009; 23: 367-373

Revascularization Strategies Affecting CLI Outcomes Wound Related Artery: Detection and Treatment Anterior Tibial Angiosome Anterior Tibial Artery (ATA) becomes the dorsalis pedis artery that supplies the dorsum of the foot Peroneal Angiosome Peroneal Artery (PA) supplies the lateral border of the ankle and the outside of the heel. Two branches of the PA supply the anterolateral part of the ankle and the hind foot: the anterior perforating branch to the anterolateral part of the upper ankle and the calcaneal branch to the plantar aspect of the heel Foot Angiosomes Posterior Tibial Angiosome Posterior Tibial Artery (PTA) supplies the plantar aspect of the toes, the web spaces between the toes, the sole of the foot, and the inside of the heel. Three main branches of the PTA supply distinct portions of the sole: the calcaneal branch to the heel, the medial plantar artery to the instep, and the lateral plantar artery to the lateral midfoot and the forefoot Iida et al. Catheterization and Cardiovascular Interventions 75:830 836 (2010) Nevil et al. Ann Vasc Surg 2009

Clinical Variables Affecting CLI Outcomes Wound Related Artery: Detection and Treatment Angiosome based revascularization drives success feeding artery flow to the site of ulceration successfully acquired feeding artery flow to the site of ulceration NOT acquired RC and Nr of of Angiosomes: RC4 1 Angiosome, RC5 1 2 Angiosomes, RC6 > 1 Angiosome Iida et al. Importance of the Angiosome Concept for Endovascular Therapy in Patients with Critical Limb Ischemia - Catheterization and Cardiovascular Interventions 75:830 836 (2010)

BTK Vessel Patency: Clinical Relevance NO 1:1 correlation between patency and limb salvage NO 1:1 correlation between patency and wound healing Kudo T et al. JVS 2005;41:423-435 Pomposelli, et al. J Vasc Surg, 37; 2003

BTK Vessel Patency: Clinical Relevance Podiatrists, Vasc.Surgeons and the philosophy of cross-referral Philosophy of crossreferral: the sigmoid curve represents the probability of healing based on toe pressures. When a patient is referred to a multidisciplinary team, the vascular team treats wounds that are profoundly ischemic, with the goal of improving flow and pushing the wound up the curve. Conversely, when flow is adequate, the podiatry team manages wound healing, offloading, reconstruction, and prevention. Patients falling in the middle of the curve are frequently managed simultaneously by combined efforts. Rogers LC, Armstrong DL: Podiatry Care, Chapter 113, Rutherford's Vascular Surgery, 7th Edition, Cronenwett JL, Johnston KW, editors, Elsevier Inc, 2010

Significance of Patency in BTK-CLI and Solutions for Improvement

CLI Stage Clinical Variables Affecting CLI Outcomes Rutheford Class at baseline determines outcome Rocha Sing Xcell Trial oral presentation LINC 2011

BTK Vessel Patency: Clinical Relevance 1) Baseline RC, 2) wound type and stage, 3) revascularization Strategy, 4) proper wound care are all key contributing factors to limb salvage Multidisciplinary close surveillance with secondary intervention is mandatory Vessel patency remains necessary but not sufficient for wound healing and limb salvage Vessel patency is necessary at least to the extent of time required for ischemic wounds to heal

Role of DES in BTK-CLI DES have shown to significantly decrease restenosis vs PTA and BMS in short / focal lesions BTK DEB are available in short length to address short lesions without stents Length of BTK treated lesion (R.Ferraresi - EuroPCR 2011)

ACHILLES: Study Flowchart Total PatientPopulation n = 200 1:1 randomization CYPHER SELECT PLUS n = 99 patients n = 113 lesions Stent(s) implantented (99patients) Stents/patient: 1.8 on avg. Balloon Angioplasty n = 101 patients n = 115 lesions PTA (93 patients) Cross over the Stent (8 patient) 12 months follow-up: Pts. comp. clinical f/u: n=74 (74.7%) -Deceased (n = 11) -Whithdrew consent (n = 4) -Lost to FU (n = 10) Lesions eval. Angio ff/u : n=67 (59.3%) 12 months follow-up: Pts. Comp. clinical f/u: n=80 (79.2%) Deceased (n =12) Whithdrew consent (n = 3) Lost to FU (n = 6 Lesions eval. angio f/u : n=74 (64.3%)

ACHILLES: Patient Demographics - ITT CYPHER SELECT Plus (99 Patients) PTA (101 Patients) P-value Age, years 72.4 ± 9.4 74.3 ± 8.2 0.117 Male, % 67.7 75.2 0.274 History of CAD, % 45.5 44.6 1.000 History of PVD, % 66.7 63.4 0.685 Diabetes, % 64.6 64.4 1.000 Hyperlipidemia, % 77.6 68.3 0.154 Hypertension, % 89.9 91.1 0.813 Smoker, % 38.4 26.3 0.094

ACHILLES: Lesion Characteristics - ITT CYPHER SELECT Plus PTA (115 LESIONS) P-value Total Lesion Llength, mm 26.9 ± 20.9 26.8 ± 21.3 0.990 Total Occlusion, % 81.3 75.4 0.334 Total Lenghth of Occlusion, mm Reference Vessel Diameter, mm 6.7 ± 19.3 11. 0 ± 22.4 0.135 2.6 ± 0.5 2.6 ± 0.6 0.991 Restenotic Lesions, % 5.3 1.8 0.171 Calcification (moderate,severe), % 15.1 15.2 1.000

DES in Below The Knee

Angioplasty of Tibial Arteries Pre PTA Post PTA 2/200mm - balloon

IN.PACT DEB with FreePac Coating Technology IN.PACT Medtronic DEB balloon line Paclitaxel Molecule Urea Spacer Molecule Freepac proprietary hydrophilic drug coating formulation separates Paclitaxel molecules balances hydrophilic and lipophilic properties facilitates Paclitaxel elution into the vessel wall biocompatible hydrophilic naturally-occurring high degree of transfer efficiency

Leipzig DEB-BTK Registry Results and Interpretation

IN.PACT BTK Registry - Leipzig Dierk Scheinert, Andrej Schmidt Center of Vascular Medicine Angiology and Vascular Surgery Park Hospital Leipzig, Germany IN.PACT DEB in real world BTK complex lesions Study type Prospective single center, single arm, investigator initiated study Objective Assess IN.PACT Amphirion efficacy for the treatment of long BTK lesions occlusions Population Symptomatic patients with CLI or severe claudication Eligibility At least one lesion BTK 80 mm Primary Endpoint 3 month restenosis rate Nr of patients 104 / 109 limbs A.Schmidt et al. submitted

IN.PACT BTK Registry Leipzig (angio-subgroup) DEB (angio subgroup) # patients / limbs 74 / 79 Male gender 51 (68.9%) mean age (y) 73.5 ± 9.3 DEB (angio subgroup) 3m Ang. FU Restenosis (>50%) 27.4% Full-segment Resten. 10% diabetics 54 (73%) Restenosis Length 64 mm Renal insuff. 34 (45.9%) RC 3 16 (20.3%) RC 4 14 (17.7%) RC 5 49 (62%) RC 6 0 (0%) avg lesion length 173 ± 87 mm 12m Clinical FU Deaths 16.3% Limb Salvage 95.6% Clinical Improvement (1) 91.2% (2) Compl. wound healing 74.2% TLR 17.3% Tot occlusions 61.9% (1) clinical improvement = reduction in size and/or depth of ulceration or improvement of rest-pain

IN.PACT BTK Registry - Leipzig vs historical PTA cohort (A.Schmidt et al. Cath. and Cardiovasc. Interventions 2010) DEB (angio subgroup) PTA* (historical group) # patients / limbs 74 / 79 58 / 62 Male gender 51 (68.9%) 38 (65.5%) DEB (angio subgroup) PTA* (historical group) 3m Angiographic FU Restenosis (>50%) 27.4% 69% mean age (y) 73.5 ± 9.3 70.5 ± 8.08 diabetics 54 (73%) 52 (89.7%) Renal insuff. 34 (45.9%) 30 (51.7%) RC 3 16 (20.3%) 0 (0%) RC 4 14 (17.7%) 16 (25.8%) RC 5 49 (62%) 46 (74.2%) RC 6 0 (0%) 0 (0%) avg lesion length 173 ± 87 mm 183 ± 75 mm Full-segment Resten. 10% 56% Restenosis Length 64 mm 155 mm 12m Clinical FU 15m Clinical FU Deaths 16.3% 10.5% Limb Salvage 95.6% 100% Clinical Improvement (1) 91.2% 76.5% Compl. wound healing 74.2% 78.6% TLR 17.3% 50% Tot occlusions 61.9% 64.9% (1) clinical improvement = reduction in size and/or depth of ulceration or improvement of rest-pain

Leipzig Experience with IN.PACT Amphirion

Leipzig Experience with IN.PACT Amphirion

IN.PACT BTK Registry - Leipzig Most distal lesions appear to perform worst 3-month Restenosis Rate. by treated site APop (P3) Tibialis prox Tibialis mid Tibialis dist foot Nr treated segments 11 54 45 37 13 Restenosis Rate (>50%) 9.1% 9.3% 20% 18.9% 38.5% Restenosis developed proportionally to the distality of the treated segment with a 38.5% rate in the foot arteries

IN.PACT BTK Registry - Leipzig DEB usage for treating real world long BTK lesions and occlusions: Remarkably low (27.4%) shown in the primary endpoint of 3- month Angiographic Restenosis Rate Very low restenosis burden (10% full segment restenosis) and reintervention rate at 12 m (17.3%) While lesion specific outcomes appear notably better vs historical PTA cohorts, no meaningful differences were detectable in the hard clinical endpoints of amputation free survival and wound healing Properly designed head-to-head DEB-PTA trials with a parallel careful control of the full span of variables concurring to clinical outcome (ie. wound care) would be warrented

DEB SFA Italian Registry Hypothesis Drug Eluting Balloon can reduce Femoral-popliteal restenosis in alternative to Stenting Study Device Paclitaxel molecule Urea Spacer molecule IN.PACT Admiral - Medtronic Freepac - proprietary hydrophilic drug coating formulation separates Paclitaxel molecules balances hydrophilic and lipophilic properties facilitates Paclitaxel elution into the vessel wall

DEB SFA Italian Registry Investigator Initiated multicenter registry to assess the benefit of DEB for the treatment of femoro-popliteal arterial disease in patients with claudication and rest pain 105 patients enrolled from July 2009 to May 2010 across 6 Italian Sites: Montevergine Cl. (Mercogliano) Paolo Rubino 32 Villa Maria Eleonora (Palermo) Antonio Micari 28 Città di Lecce (Lecce) Fausto Castriota 19 Villa Antea (Bari) Alfredo Marchese 10 Villa Maria Cecilia (Cotignola) Alberto Cremonesi 9 Villa Azzurra (Rapallo) Paolo Pantaleo 7 105

Endpoints and Key Eligibility Criteria Primary Endpoint: 1-year Primary Patency Secondary Assessments: ABI, RC, WIQ, ACD, QoL at 3, 6, 12, 24 months Key Inclusions RC 2-3-4 Reference vessel diameter 3-7 mm Lesions and/or occlusions 15 cm 1 crural vessel run-off either preexisting or successfully established Adequate in-flow Key Exclusions In Stent restenosis Aneurism in the target vessel Acute thrombus in the target limb Failure to cross the Target Lesion with a guide wire Use of alternative therapies (e.g. atherectomy, cutting balloon, laser, radiation therapy, cryoplasty, )

Baseline Demographics Nr of Patients 105 Age (y) 68 9 Gender females 20 (19.0%) males 85 (81.0%) Hypertension 90 (85.7%) Hyperlipidaemia 78 (74.3%) Diabetes Insul. dependant 51 (48.6%) 23 (45.1%) Renal insufficiency 2 (1,9%) Smoking 66 (62.8%) Coronary Artery Dis. 45 (42.9%) Carotid Artery Dis. 15 (14.3%) ABI 0.56 0.15

Baseline Lesion Characteristics Nr of lesions 114 Lesion location Prox SFA 14 (12.3%) Mid SFA 55 (48.2%) Dist SFA 33 (28.9%) Pop. 1 segment 8 (7.0%) Pop. 2 segment 4 (3.5%) Inflow Good: 100 (95.2%) Impaired: 5 (4.8%) Outflow Good: 39 (37.1%) Impaired: 66 (62.9%) Lesion type de-novo 109 (95.6%) restenotic 4 (3.5%) ISR 1 (0.9%) Calcification None 38 (33.3%) Moderate 57 (50.0%) Severe 19 (16.7%) Mean les. length Mean RVD 76.3 38.3 mm 5.2 0.6 mm % DS 92.5 8.2 Total Occlusions 34 (29.8%)

Procedural and Acute Outcome 1. Predilatation with standard undersized (-0.5 mm) PTA balloon 2. DEB dilatation with 1:1 balloon: RVD for 180 sec 3. Provisional stenting in case of flow limiting dissections and persistent residual stenosis > 50% Inflow re-established 5 (100%) Outflow re-established 66 (100%) Lesion crossing True lumen 105 (92.1%) Subintimal 9 (7.9%) pre-dilatation 113 (99.1%) DEB infl. time 181 20.4 sec Nr DEB p/lesion 135/114 = 1.18 Device Success 135 (100%) Tech. Success 121 (89.6%) Post-Dilatation 20 (17.5%) Stenting 14 (12.3%) 11 (9.6%) flow limit. dissection 3 (2.6%) persistent stenosis Residual % DS 12.2 ± 9.5%, range 0 40%

Case Example Villa Maria Eleonora Hospital pre-dilatation: Admiral 4.0-80 DEB: In.Pact Admiral 5.0-120 mm

Primary Patency 1-year Primary Patency [1] = 83.7% 2-year [2] Primary Patency [1] = 72.4% Survival from TLR, Occlusion, >50% Restenosis 1. Rates calculated on actual events (PSVR < 2.5) 2. Mean follow up time = 27± 3 months

Major Adverse Events 25,0% death amputation TLR composite 14,3% 17,5% 0,0% 9,8% 7,6% 5,6% 4,5% 2,2% 2,2% 2,2% 1,1% 1,1% 1,1% 1,0% 0,0% 0,0% 0,0% 3-month 6-month 1-year 2-year* (89 Patients) (90 Patients) (92 Patients) (98 Patients) * Mean follow up time = 27±3 months

ABI and ACD Significant improvement vs. baseline maintained at 2-year follow up ABI Walking Capacity * Mean follow up time = 27±3 months

Rutherford Class Significant improvement vs. baseline maintained at 2-year follow up * Mean follow up time = 27±3 months

Quality of Life Significant improvement vs. baseline maintained at 2-year* follow up on key functional QoL components P<0.001 P<0.001 P<0.001 P=0.497 P=0.309 * Mean follow up time = 27±3 months

DEB: where else and how to use it + Conclusions

BTK restenosis: how to stop the clock... Refractory, relapsing restenosis patency courtesy of Andrej Schmidt MD 6m after IN.PACT Amphirion : restenosis 6w (PTA) 4m (Stent) 5m (PTA) 6m (DEB) RC5 Left

Conclusions CLI is a complex multifactorial disease requiring multidisciplinary approach Vessel patency remains necessary but not sufficient for wound healing and limb salvage DEB is the only device able to treat long lesions BTK while leaving nothing behind DEB showed optimal results in SFA lesions of primary and secondary patency Early DEB data show reduction of angiographic restenosis rates and TLR Further study results are awaited to better understand the role of DEB in BTK/CLI

Thank You for your attention