Drug Eluting Technology in Peripheral Interventions

Drug Eluting Technology in Peripheral Interventions: 

Drug Eluting Technology in Peripheral Interventions Mr.Mohamed Omar Elfarok , M.Sc , FRCDENG ,FRCSED

Topics to be covered: 

Topics to be covered

General concept: 

General concept Drug eluting technology is new to peripheral field It contains Drug eluting balloon and Drug eluting stents We have DES both above and below the knee but with different specifications

Drugs used in this technology: 

Drugs used in this technology - Everolimus - Paclitaxel - Sirolimus - Tacrlimus - Zotarolimus -Others

Slide 5: 

Pre - PTA What is the problem with SFA stenting

Slide 6: 

Pre - PTA Post - PTA

Slide 7: 

Pre - PTA Post - PTA Follow up - 9 months Restenosis

Slide 8: 

Pre-PTA Another case of SFA lower third Stenosis :

Slide 9: 

Pre-PTA Post PTA-stenting

Slide 10: 

Pre-PTA Post PTA-stenting Follow up 22 months In-stent Restenosis

Slide 11: 

Angiography: > 50% narrowing of the luminal diameter within the recanalized segment compared with the diameter of normal segments of the artery Duplex ultrasound: PSV ratio ≥ 2.4 SFA Restenosis - Definition

Slide 12: 

SFA Restenosis - Duplex ultrasound a. SFA above the Restenosis b. SFA Restenosis c. SFA below the Restenosis PSV ratio: peak systolic velocity b peak systolic velocity a ≥ 2.4

Slide 13: 

Combined Nitinol Randomized Data

Slide 14: 

Combined Nitinol Randomized Data 1 yr SFA In-stent restenosis = 30%

Slide 15: 

SFA Restenosis - Pathophysiology Restenosis arises from neointimal formation and arterial remodelling PTA Endothelial denudation Exposure of subendothelial matrix Platelets adhesion and activation

Slide 16: 

SFA Restenosis - Pathophysiology Restenosis arises from neointimal formation and arterial remodelling PTA Endothelial denudation Exposure of subendothelial matrix Platelets adhesion and activation Platelets release mitogens (thromboxane A2, serotonin, PDGFs)

Slide 17: 

SFA Restenosis - Pathophysiology Restenosis arises from neointimal formation and arterial remodelling PTA Endothelial denudation Exposure of subendothelial matrix Platelets adhesion and activation Platelets release mitogens (thromboxane A2, serotonin, PDGFs) SMC proliferation and migration to the intima and extracellular matrix synthesis

Slide 18: 

SFA Restenosis - Pathophysiology Restenosis arises from neointimal formation and arterial remodelling PTA Endothelial denudation Exposure of subendothelial matrix Platelets adhesion and activation Platelets release mitogens (thromboxane A2, serotonin, PDGFs) SMC proliferation and migration to the intima and extracellular matrix synthesis Neointimal formation Arterial remodelling

Slide 19: 

The pathophysiology and burden of restenosis WS Weintraub Am J Cardiol 2007; 100(suppl)3k-9k.

Slide 20: 

SFA Restenosis - Pathophysiology PTA Arterial remodelling Expansive remodeling Constrictive remodeling Intimal hyperplasia RESTENOSIS R Zargham Clinical Science 2008; 114:257-264

Slide 21: 

SFA Restenosis – Prevention The reduction of restenosis after endovascular treatment in SFA is a challenge Medical therapy Devices

Slide 22: 

SFA Restenosis – Prevention: Medical Therapy Antiplatelet therapy

Slide 23: 

SFA Restenosis – Prevention: Medical Therapy Antiplatelet therapy Cilostazol LMWH Cholesterol-lowering agents AT1 receptor blockers

Slide 24: 

SFA Restenosis - Pathophysiology Restenosis arises from neointimal formation and arterial remodelling PTA Endothelial denudation Exposure of subendothelial matrix Platelets adhesion and activation Platelets release mitogens (thromboxane A2, serotonin, PDGFs) SMC proliferation and migration to the intima and extracellular matrix synthesis Neointimal formation Arterial remodelling Antiplatelets Cilostazol

Slide 25: 

SFA Restenosis – Prevention: Devices Drug-eluting stent Drug-eluting balloon Cryoplasty Cutting balloon Irradiation (endovascular brachytherapy or external beam irradiation) Mechanical barrier

Slide 26: 

SFA Restenosis – Prevention: Devices Drug-eluting stent Drug-eluting balloon Cryoplasty Cutting balloon Irradiation (endovascular brachytherapy or external beam irradiation) Mechanical barrier

Slide 27: 

Inhibit proliferation and migration of vascular smooth muscle cells SFA Restenosis – Prevention with Devices: Drug eluting stent

Slide 28: 

Drug Eluting stents in the Infrainguinal Circulation Machan L Techniques in Vascular and Interventional Radiology 2004; 7:28-32 Active Agents used in stent coating to prevent Restenosis Drugs Active Agents Immunosoppressive drugs Sirolimus ( rapamycin ) Everolimus ABT-578 FK506 ( tacrolimus ) Mycophenolic Acid Antiproliferative Drugs Paclitaxel Angiopeptin Tyrosine kinasi inhibitor Actinomycin D C-myc Antisense Anti-inflammatory drugs Corticosteroid Tranilast Antithrombosis Agents Heparin Inhibitors platelet aggregation Extracellular Matrix Modulators Batimastat Prohealing Agents Endothelial coating Antibodies to CD34 Nitric oxide donors VEGF 17- β -estradiol

Cost Effectiveness (coronary): 

Cost Effectiveness (coronary) DES involve higher upfront cost and extended clopidogrel use but reduce TVR compared to BMS (in coronary) Total cost of DES and BMS similar at 3 years Cost per TVR avoided with DES use was 4731$ through 1 year and 4703$ second year and 6379$ third year Even considering prolonged need for clopidogrel , DES remain reasonably cost –effective compared with BMS at 3 years Schafer PE ,et al. Circ Cardiovasc Qual Outcomes 2011

Zilver PTX Randomized Trial: 

Zilver PTX Randomized Trial Zilver PTX is the only DES in peripheral in EGYPT This is a 24 month update on the Trial We will concentrate on Safety and Effectiveness .

What is Zilver PTX: 

What is Zilver PTX A DES designed for SFA It had CE Marked Dual therapy stent : Mechanical supprot : Zilver Flex Stent platform Drug Coating : Paclitaxel only No polymer or binder 3 Ug.mm2 dose density

The Basic Science of Paclitaxel: 

Paclitaxel is a proven anti-proliferative drug Hydrophobic - Low water solubility = Low wash off in the bloodstream Lipophilic and protein bound = High uptake in vessel wall Permanent binding to the cell = Long- lasting effect The nature of paclitaxel combined with Cook proprietary coating process allows for polymer-free drug delivery: Maximized benefit of paclitaxel without issues associated with polymers The Basic Science of Paclitaxel

Paclitaxel is lipophilic (attracted to lipids) – since lipids are found in high concentrations in the vessel wall, a polymer is not needed for adequate delivery: 

Paclitaxel is lipophilic (attracted to lipids) – since lipids are found in high concentrations in the vessel wall, a polymer is not needed for adequate delivery

The Zilver PTX registry is a large, high-quality prospective study that shows real-world use of the product: 

The Zilver PTX registry is a large, high-quality prospective study that shows real-world use of the product

Paclitaxel is hydrophobic (does not dissolve in water) so a polymer is not needed to prevent wash off during tracking or implantation: 

Paclitaxel is hydrophobic (does not dissolve in water) so a polymer is not needed to prevent wash off during tracking or implantation

Paclitaxel is a natural substance from the bark, branches or needles of the yew tree and was originally developed as a cancer drug to stop cell proliferation: 

Paclitaxel is a natural substance from the bark, branches or needles of the yew tree and was originally developed as a cancer drug to stop cell proliferation

Zilver PTX Single –Arm Study: 

Zilver PTX Single –Arm Study Broad patient SFA lesion inclusion criteria Enrolled 787 patients (900 lesions)at 30 centers in Europe,Russia , Canada, and Korea It is the largest study to date for endovascular ttt of SFA disease Primary endpoint=Event –Free Survivial

Slide 38: 

Overview Background — Zilver PTX drug-eluting stent - Trial design - Patient demographics/lesions Zilver PTX Randomized Trial - 24-month update - Safety - Effectiveness - Primary Patency • 81.2% Zilver PTX vs. 62.7% BMS

Follow-up: 

Follow-up Clinical assessment ( ABPI,Rutherford scores,Walking scorres )at 1,6,12,24 months Site-based evaluation of primary patency by duplex ultrasound and stent integrity by x ray at 6,12 months

Physician Steering Committee: 

Physician Steering Committee Michael Dake , MD (Global Coordianting PI) Prof Dierk Scheinert ,MD. Prof Gunnar Tepe , MD. Fabrisio Fanelli , MD. Jorg Tessarek , MD.

Demographics and comorbidities: 

Demographics and comorbidities OverallPatients(n) 787 Age(years) 67±9 Male 73% Height(cm) 170±8 Weight(kg) 78±15 Diabetes 36% IHighCholesterol 58% Hypertension 80% Past/CurrentSmoker 80%

Zilver PTX stent Implanted: 

Zilver PTX stent Implanted Numberof Stents Implanted %of Lesions (n=900) %of Patients (n=787) 1 50% 40% 2 22% 25% 3 13% 16% 4 14% 17% >4 1% 2% Average 1.9stents perlesion 2.2stents perpatient

Stent Integrity Results: 

Stent Integrity Results Confirmed Stent Fractures through 12 months (n = 1432 stents evaluated) 1.5% (n = 22)

Safety Results: 

Safety Results Event-Free Survival: freedom from death, amputation, revascularization, or worsening Rutlierford score (by two classes or to class 5 or 6)

Effectiveness : Clinical outcomes: 

Effectiveness : Clinical outcomes

Baseline Lesion Characteristics: 

Baseline Lesion Characteristics Lesions 900 LesionLength 100±82mm DiameterStenosis 85±16% TASCClass*;A 26% B 29% C 25% D 14% Lesions>7cm 48% Lesions>15cm 22% TotalOcclusions 38% Restenosis 24% In-stentRestenosis 14%

Effectiveness and patency: 

Effectiveness and patency

Literature Comparisons: 

Literature Comparisons

Slide 49: 

Zilver PTX Randomized Trial * Prospective, multinational trial - Protocol approved by FDA, PMDA and German regulatory authorities • CEC and DSMB oversight, and imaging Core Lab analyses * Key inclusion/exclusion criteria - Rutherford classification > 2 - Reference vessel diameter 4-9 mm - Lesion length < 14 cm - De novo or restenotic lesions (no in-stent restenosis) - > 50% diameter stenosis - One lesion per limb (bilateral treatment allowed)

Slide 50: 

Zilver PTX Randomized Trial • 12-month event-free survival - Primary safety endpoint - Per patient freedom from death, amputation, target lesion revascularization, or worsening Rutherford score (by 2 classes or to class 5 or 6) • 12-month primary patency - Primary effectiveness endpoint - Per lesion patency by duplex ultrasonography, patent = PSVR < 2.0 (or angiography if available, patent = diameter stenosis < 50%) - One lesion per limb, bilateral treatment allowed • 5 year ongoing follow-up - 2, 3, 4 and 5 year patency evaluations for all stent patients and a randomly selected subset of patients with acutely successful PTA - 3 and 5 year stent radiographs

Clinical Trial Design: 

Clinical Trial Design

Slide 52: 

PTA ZilverPTX P-value Lesions 251 247 Normal-to-normallesionlength(mm) 63±41 66±39 0.35 Stenosedlesionlength(mm)�'� 53±40 54±41 0.76 Diameterstenosis(%y 78±17 80±17 0.44 Totalocclusions 25% 30% 0.20 Denovo lesions 94% 95% 0.69 Lesioncalcification� None 5% 2% <0.01* Little 38% 26% Moderate 22% 35% Severe 35% 37% Baseline Lesion Characteristics �Angiographic core lab assessment 2 Region with > 20% diameter stenosis *Statistically significant

Slide 53: 

Low Stent Fracture Rate • 546 stents implanted - 453 Zilver PTX (average of 1.5 stents per patient) - 93 Zilver BMS • X-ray core laboratory analysis of 457 stents at 12 months • Four stent fractures - No associated adverse events 0.9% stentfracture rate through 12 months (next evaluations at 3 and 5 years)

Slide 54: 

Conclusions 24-month results support sustained safety and effectiveness — Primary Zilver PTX significantly better patient safety than PTA (p < 0.01) — Primary Zilver PTX patency of 74.8% — Provisional Zilver PTX patency (81.2%) significantly higher than provisional BMS patency (62.7%, p < 0.01) - PTX coating reduces 24-month restenosis rates by 50%

Superior Results - Data: 

Zilver PTX works in the SFA (24 month data) Freedom from TLR is largely preserved thru 24 months 82% De novo lesions have better results? Freedom from TLR 87% Use of Zilver PTX the first time, why Multiple stents, Freedom from TLR in lesions > 15cm 81% Superior Results - Data

Zilver PTX - 50% fewer reinterventions!: 

Zilver PTX - 50% fewer reinterventions!

Zilver PTX - 15x fewer stent fractures!: 

Zilver PTX - 15x fewer stent fractures!

Zilver PTX - 100% polymer-free drug delivery: 

Zilver PTX - 100% polymer-free drug delivery

Zilver PTX registry data shows overall freedom from TLR is 89% at 12 months and 82% at 24 months: 

Zilver PTX registry data shows overall freedom from TLR is 89% at 12 months and 82% at 24 months

1. Superior SFA Results 2. Polymer-Free PTX Delivery 3. Proven Durable Zilver Platform: 

1. Superior SFA Results 2. Polymer-Free PTX Delivery 3. Proven Durable Zilver Platform

What about DEB: 

What about DEB Good example

Thank You!: 

Thank You!