P rospective evaluation of A ll - comer pe R cutaneous c A roti D revascularization I n symptomatic and increased - risk asymptomatic carotid artery stenosis using C G uard M icronet - covered embolic prevention stent sy

P rospective evaluation of A ll - comer pe R cutaneous c A roti D revascularization I n symptomatic and increased - risk asymptomatic carotid artery stenosis using C G uard M icronet - covered embolic prevention stent system : The PARADIGM Study Jagiellonian University Dept. of Cardiac & Vascular Diseases John Paul II Hospital , Krakow , Poland P. MUSIALEK 1 , A. MAZUREK 1 , M. TRYSTULA 2 , A. BORRATYNSKA 3 , M. URBANCZYK 3 , A. LESNIAK - SOBELGA 1 , P. BANYS 3 , A. BRZYCHCZY 2 , L. PARTYKA 4 , K. ZMUDKA 5 , P. PODOLEC 1 (1) Dept Cardiac and Vascular Diseases, Jagiellonian University & John Paul II Hospital, (2) Dept Vascular Surgery, John Paul II Hospital; (3) John Paul II Hospital, Krakow; (4) Krakow Cardiovascular Research Institute (KCRI); (5) Dept Interventional Cardiology, Jagiellonian University & John Paul II Hospital, Krakow, POLAND

P rospective evaluation of A ll - comer pe R cutaneous c A roti D revascularization I n symptomatic and increased - risk asymptomatic carotid artery stenosis using C G uard M icronet - covered embolic prevention stent system : The PARADIGM Study Jagiellonian University Dept. of Cardiac & Vascular Diseases John Paul II Hospital , Krakow , Poland P. MUSIALEK 1 , A. MAZUREK 1 , M. TRYSTULA 2 , A. BORRATYNSKA 3 , M. URBANCZYK 3 , A. LESNIAK - SOBELGA 1 , P. BANYS 3 , A. BRZYCHCZY 2 , L. PARTYKA 4 , K. ZMUDKA 5 , P. PODOLEC 1 (1) Dept Cardiac and Vascular Diseases, Jagiellonian University & John Paul II Hospital, (2) Dept Vascular Surgery, John Paul II Hospital; (3) John Paul II Hospital, Krakow; (4) Krakow Cardiovascular Research Institute (KCRI); (5) Dept Interventional Cardiology, Jagiellonian University & John Paul II Hospital, Krakow, POLAND

P rospective evaluation of A ll - comer pe R cutaneous c A roti D revascularization I n symptomatic and increased - risk asymptomatic carotid artery stenosis using C G uard M icronet - covered embolic prevention stent system : The PARADIGM Study Jagiellonian University Dept. of Cardiac & Vascular Diseases John Paul II Hospital , Krakow , Poland P. MUSIALEK 1 , A. MAZUREK 1 , M. TRYSTULA 2 , A. BORRATYNSKA 3 , M. URBANCZYK 3 , A. LESNIAK - SOBELGA 1 , P. BANYS 3 , A. BRZYCHCZY 2 , L. PARTYKA 4 , K. ZMUDKA 5 , P. PODOLEC 1 (1) Dept Cardiac and Vascular Diseases, Jagiellonian University & John Paul II Hospital, (2) Dept Vascular Surgery, John Paul II Hospital; (3) John Paul II Hospital, Krakow; (4) Krakow Cardiovascular Research Institute (KCRI); (5) Dept Interventional Cardiology, Jagiellonian University & John Paul II Hospital, Krakow, POLAND

P rospective evaluation of A ll - comer pe R cutaneous c A roti D revascularization I n symptomatic and increased - risk asymptomatic carotid artery stenosis using C G uard M icronet - covered embolic prevention stent system : The PARADIGM Study Jagiellonian University Dept. of Cardiac & Vascular Diseases John Paul II Hospital , Krakow , Poland P. MUSIALEK 1 , A. MAZUREK 1 , M. TRYSTULA 2 , A. BORRATYNSKA 3 , M. URBANCZYK 3 , A. LESNIAK - SOBELGA 1 , P. BANYS 3 , A. BRZYCHCZY 2 , L. PARTYKA 4 , K. ZMUDKA 5 , P. PODOLEC 1 (1) Dept Cardiac and Vascular Diseases, Jagiellonian University & John Paul II Hospital, (2) Dept Vascular Surgery, John Paul II Hospital; (3) John Paul II Hospital, Krakow; (4) Krakow Cardiovascular Research Institute (KCRI); (5) Dept Interventional Cardiology, Jagiellonian University & John Paul II Hospital, Krakow, POLAND

Potential conflicts of interest Speaker's name: Piotr Musialek I have the following potential conflicts of interest to report: Consult ing / Research Support / Speaker Bureau ABBOTT VASCULAR Balton Ltd InspireMD MEDTRONIC NB. Research in this presentation is not industry - funded

CAS: State - of - the - art and horizon

CAS (and CEA) are - and will remain - emboli - generating procedures

2/3 CAS neuro events ( stroke , TIA) are POST - procedural n = 3179 consecutive CAS patients

FREE CELL AREA drives CAS neurologic adverse events ( and majority are those during stent healing ! )

J. Schofer, P. Musialek et al. TCT 2014 CAS using conventional carotid stents in high - risk lesions

current best - in - class Hybrid stent current best - in - class Closed - cell stent

J. Schofer, P. Musialek et al. TCT 2014 CAS using conventional carotid stents in high - risk lesions

CGuard embolic prevention system P Musialek @ ePCR 2015

CGuardtm Carotid Embolic Prevention System System specifications Stent type Nitinol - self expanding Micronet aperture size 150 - 180 ; m Guidewire 0.014" Sizes - Diameter - Length 6 - 10mm 20 - 60mm CE Mark - March 2014

Objective to evaluate feasibility and outcome of routine anti - embolic stent system use in unselected, consecutive patients referred for carotid revascularization ( all - comer ' study ) .

Methods : academic cardio - vascular centre investigator - initiated study not industry - funded all - comer patient inclusion ( six month referral sample ) all referrals tracked routine consultation and management pathways qualitative and quantitative lesion & stent evaluation investigator - independent neurological and angiographic evaluation , and external study data verification PARADIGM . . . . . . . .

Methods : The CAS Procedure EPD use mandatory ; EPD selection according to the Tailored CAS' algorithm Liberal postdilatation accepted in order to maximize potential for endovascular full reconstruction ' ( minimizing residual stenosis ) NB. 1. DWI evidence of effective MicroNet prevention against cerebral embolization (CARENET/PROFI) 2. Residual stenosis after CAS as independent predictor of in - stent restenosis Van Laanen J et al. J Cardiovasc Surg 2008 Cosottini M et al. Stroke Res 2010 Musialek P et al. J Endovasc Ther 2010 Wasser K et al. J Neurol 2012 . . . Pieniazek P, Musialek P et al. J Endovasc Ther 2008;15:249 - 62. Cremonesi A et al. EuroInervention 2009;5:589 - 98. Pieniazek P, Musialek P et al. J Endovasc Ther 2009;16:744 - 51. * *

CARENET vs PROFI : DW - MRI analysis K. Bijuklic et al. JACC , 2012;59 :1383 - 9. DW - MRI analysis @ 48 hours Filter - protected CAS procedures J. Schofer, P. Musialek et al. JACC Intv 2015 (in press) 34.6 87.1 0 10 20 30 40 50 60 70 80 90 100 INCIDENCE new ipsilateral lesions (%) n=27 n=31 Conventional Carotid stent CGuard

CGuard embolic prevention system P Musialek @ ePCR 2015

CARENET vs PROFI : DW - MRI analysis DW - MRI analysis @ 48 hours Filter - protected CAS procedures n=27 n=31 0.04 0.59 -0.1 6E-16 0.1 0.2 0.3 0.4 0.5 0.6 Conventional Carotid stent (hybrid) V O L U M E new ipsilateral lesions (mL) J. Schofer, P. Musialek et al. JACC Intv 2015 (in press) K. Bijuklic et al. JACC , 2012;59 :1383 - 9. CGuard

Endpoints : feasibility of endovascular Tx in unselected referrals device success ( able to deliver + implant + <30% DS) procedure success ( device success w/o clinical compl .) clinical efficacy : MACNE ( death / stroke /MI ) in - stent velocities (Duplex) PARADIGM . . . . . ( external neurologist , external non - invasive cardiologist ) - 24 - 48h - 30 days - 12 months - up to 5y using the study device in otherwise routine practice

PARADIGM . . ASYMPTOMATIC patients treated interventionally only if at stroke risk established lesion - level increased - risk crieria used : - thrombus - containing - tight , near - occlusive - documented progressive - irregular and/ or ulcerated - contralteral ICA occlusion / stroke - asymptomatic ipsilateral brain infarct AbuRahma A et al. Ann Surg . 2003;238:551 - 562. Ballotta E et al. J Vasc Surg 2007;45:516 - 522. Kakkos SK et al. (ACSRS) J Vasc Surg. 2009;49:902 - 909. Lovett JK et al. Circulation 2004;110:2190 - 97 Nicolaides AN et al. J Vasc Surg 2010;52:1486 - 96. Taussky P et al. Neurosurg Focus 2011;31:6 - 17.

PARADIGM: investigator - independent external angiographic analysis Methods ( cont'd ) external study data verification external statistical analysis . . .

Study Flow Chart (1) 97 carotid stenosis patient referrals ( external >> internal ) *Dept. of Cardiac & Vascular Dieases , John Paul II Hospital , Krakow , Poland; 10.2014 - 03.2015 *

Study Flow Chart (1) 97 carotid stenosis patient referrals ( external >> internal ) Neuro - Vascular Team Neurologist Interventional Angiologist Vascular Surgeon Cardiologist *Dept. of Cardiac & Vascular Dieases , John Paul II Hospital , Krakow , Poland; 10.2014 - 03.2015 * . . . . Gupta K et al. A multispecialty consensus - based approach to carotid revascularization. J Invasive Cardiol . 2014;26:123 - 7. Tomai F et al. Carotid artery revascularization selected by consensus of a cardiovascular team. EuroIntervention 2014;9:1294 - 300. Kole MK et al. A multidisciplinary carotid revascularization board. Surg Neurol Int. 2012;3:117.

Study Flow Chart (1) 97 carotid stenosis patient referrals ( external >> internal ) Neuro - Vascular Team for carotid revascularization 73 patients NOT for carotid revascularization 24 patients Neurologist Interventional Angiologist Vascular Surgeon Cardiologist n= 19: l esion increased risk and/ or severity criteria not met n = 2: ICA totally occluded on verification n = 2: ICA functionally occlded + h/o prior ipsil . large infarct with hemorrhagic transformation n = 1: severe haemodynamic instability (ICA stenosis a sympt .) *Dept. of Cardiac & Vascular Dieases , John Paul II Hospital , Krakow , Poland; 10.2014 - 03.2015 * . . . . Gupta K et al. A multispecialty consensus - based approach to carotid revascularization. J Invasive Cardiol . 2014;26:123 - 7. Tomai F et al. Carotid artery revascularization selected by consensus of a cardiovascular team. EuroIntervention 2014;9:1294 - 300. Kole MK et al. A multidisciplinary carotid revascularization board. Surg Neurol Int. 2012;3:117.

Study Flow Chart (2) 73 Patients for carotid revascularization CAS in n= 67 Patients ( bilateral in 3) CEA in n= 5 Patients CAS + CEA in n= 1 Patient (LICA - CEA and RICA - CAS) (92%) (1%) (7%) n = 1 eGRF 14 => no contrast n = 1 extreme access tortuousity n = 1 severe aortic valve disease + calcific LICA ( AVR + CEA ) n = 1 floating thrombus in CCA n = 1 ICA diameter <2.0 mm + contralat . occlusion hybrid management

Study Flow Chart (2) 73 Patients for carotid revascularization CAS in n= 67 Patients ( bilateral in 3) CEA in n= 5 Patients CAS + CEA in n= 1 Patient (LICA - CEA and RICA - CAS) (92%) (1%) (7%) n = 1 eGRF 14 => no contrast n = 1 extreme access tortuousity n = 1 severe aortic valve disease + calcific LICA ( AVR + CEA ) n = 1 floating thrombus in CCA n = 1 ICA diameter <2.0 mm + contralat . occlusion hybrid management 71 ICAs treated endovascularly in 68 patients

Clinical characteristics of study patients (n=68) age , mean SD ( min - max ) 69 7 ( 55 - 83 ) male, % (n) 66 % (45) symptomatic, % (n) symptomatic 14 days, % (n) acutely symptomatic (emergent CAS) , % (n) 53 % (36) 28 % (19) 9 % (6) index lesion (CAS) , % (n) RICA LICA RICA+LICA 52 % (35) 44 % (30) 4% ( 3) CAD, % (n) 65 % (44) h/of MI, % (n) 27 % ( 18) CABG or PCI in the past, % (n) 38 % (26) PCI as bridge to CAS, % (n) 16 % (11) AFib (h/o or chronic), % (n) 6% (4) diabetes, % (n) 35 % (24) h/o neck or chest radiotherapy, % (n) 4% (3)

Percutaneous treatment 100% using the intended MicroNet - covered embolic prevention stent system CGuard ( ie , no other stents used during the study period) PARADIGM: Results (1) Transient Dopamine infusion 1 9 % (n=14) Device success 100% Debris in EPD 18% ( n=13 ) Procedure success 100% Access site complications 0% ( n=0 ) V ascular plug closure 45% (n=32) . . . . . . .

Index lesion qualitative characteristics (n=71 lesions) All (n=71) Symptomatic (n=37) Asymptomatic (n=34) p thrombus, % (n) 15 % (11) 24 % (9) 6% (2) 0.025 near occl./string, % (n) 21 % (15) 30 % (11) 12% (4) 0.084 proggressive*, % (n) 27 % (19) 11 % (4) 44% (15) 0.003 ulcerated, % (n) 41 % (29) 46 % (17) 35 % (12) 0.470 irregular, % (n) 72 % (51) 65 % (24) 79% (27) 0.197 contralateral occl. , % (n) 17 % (12) 22 % (8) 35% (12) 0.291 highly calcific, % (n) 23 % (16) 14 % (5) 35% (12) 0.050 asymptomatic ipsilat . brain embolization /infarct N/A N/A 32% (11) N/A * veriified imaging PARADIGM: Results (2) ICA reference diameter 4.99 0.36mm (from 4.27 to 6.02mm) Lesion length 19.9 5.8mm (from 8.19 to 30.25mm) Quantified . .

Index lesion quantitative characteristics (n=71 lesions ) All (n=71 lesions) Symptomatic n=37 Asymptomatic n=34 p Before CAS PSV, m/s 3.8 1.3 3.7 1.1 3.8 1.5 0.862 EDV, m/s 1.3 0.7 1.4 0.6 1.3 0.8 0.687 Diameter stenosis % (QA) 82 9 79 9 84 9 0.021 CAS EPD type Proximal* Distal** 35 % (25) 65 % (46) 44 % (16) 56 % (21) 26 % (9) 74 % (25) 0.092 post - dilat balloon # peak pressure, mmHg 18.4 3.4 17.5 3.6 19.2 2.9 0.037 After CAS Stent length (QA) Nominal 30 mm (min - max) Nominal 40 mm (min - max) 29.66 0.30 ( 28.73 - 30.07) 39.73 0.34 ( 38.88 - 40.22) 29.66 0.28 ( 29.02 - 30.07) 39.69 0.41 ( 38.88 - 40.22) 29.65 0.32 ( 28.73 - 30.02) 39.77 0.28 ( 39.14 - 40.04) NA Residual diam. stenosis 7 4% 5 4% 7 5% 0.257 in - stent PSV, m/s 0.70 0.28 0.66 0.29 0.74 0.27 0.266 in - stent EDV, m/s 0.17 0.07 0.17 0.07 0.18 0.07 0.457 * Emboshield (n=7); FilterWire (n=14) ; Spider (n=25) ** Gore FlowReversal (n=4) or flow reversal with MoMa (n=21); (NB. mean flow reversal time was 6min 48s, from 5min 18s to 11min 2s) # 4.5mm (n=5); 5.0mm (n=36); 5.5mm (n=29); 6.0mm (n=1); 30mm in 51 lesions; 40mm in 18 lesions (2 other lesions required two stents each) PARADIGM: Results (3)

Death/stroke/MI @ 48h 0% Death/stroke/MI @ 30d 0% PARADIGM: Results (4) . .

PARADIGM: Results (5) PSV (m/s) baseline CGuard 30 days

Death/stroke/MI @ 48h 0% Death/stroke/MI @ 30d 0% PARADIGM: Results (4) . .

>90% all - comer carotid artery stenosis patients , including >50% symptomatic presentations , can be treated endovascularly using the MicroNet - covered embolic prevention stent system CGuard use of the MicroNet - covered embolic prevention stent system enables endovascular reconstruction ' of the diseased carotid artery across a wide lesion spectrum ( from extremely tight and thrombotic to highly calcific ) in absence of periprocedual clinical complications . . . endovascular revascularization with routine use of the MicroNet - - covered embolic prevention stent system CGuard in an unselec - ted patient polulation is extremely safe procedural safety of the MicroNet - covered embolic prevention system extends throughtout the stent healing period . PARADIGM: Conclusions

CGuard 5 month follow - up CGuard Piotr Musialek @ ePCR 2015

RCCA & RICA LICA CGuard Piotr Musialek @ ePCR 2015 @ 5 months Wallstent Precise

C Guard : Endovascular Solution For All - comers 61 yo symptomatic LICA 72 yo asymptomatic RICA Piotr Musialek @ ePCR 2015 Endovascular Reconstruction of the Carotid Bifurcation

amenable to elimination with mesh Stent placement Stent relaese CAS (and CEA) are - and will remain - emboli - generating procedures P Musialek @ ePCR 2015

C Gu ard embolic prevention stent system Compatible with ALL EPD types Deliverable in hard - access anatomies Optimal visibility Reliable, predictable, and extremely precise placement No indication of foreshortening Radial strength sufficient for v. hard lesions . . . . . . Piotr Musialek @ ePCR 2015

Full respect of the carotid bifurcation anatomy - > endovascular anatomic reconstruction ' Optimal performance across all lesion subsets (including high calcium/thrombus/string) . . C Gu ard embolic prevention stent system Piotr Musialek @ ePCR 2015 The most OPEN of open - cell stent designs ' and The most CLOSED of the closed - cell designs '