Fundamentals of Drug-Eluting Stents

Andrew Holden MBCHB, FRANZCR, EBIR, ONZM

Director of Interventional Radiology

Auckland Hospital, Auckland, New Zealand

Disclosures: Dr. Andrew Holden

• Dr. Holden is a Medical Advisory Board Member for Medtronic, Boston Scientific, and Gore

• Dr. Holden is a Clinical Investigator for Medtronic, Boston Scientific, Gore, Abbott, Cagent, Endologix, Intact Vascular, Shockwave, Bard, Cook, Endospan, Intervene, Spectranetics, TriReme, Merit, Reflow, Terumo, Surmodics

• No other relevant disclosures

Iida, O. et al. Cath and Cardiov Intv. 2011; 78:611–617. Kimura T, et al. N Engl J Med 1996;334:561–567.

Clinical Probability of Restenosis Following SFA Stenting : The problem

Timing of SFA restenosis is longer than coronary stenting, which predominantly occurs within 6 months after stentingFactors for restenosis in the SFA include the number of runoff vessels, severity of lower limb ischemia, and length of diseased segments

Restenosis following nitinol stenting in the SFA peaks at ~12 months

Sustained Drug Release to cover restenosis peak

• Drug release from the Eluvia system is sustained over time

o >90% of drug is released at 1 year

• Drug release coincides with the restenotic cascade

Based on pre-clinical PK analysis. Data on file at Boston Scientific.

*Dake MD, et al. J Vasc Interv Radiol. 2011;22(5):603-610.

*

Polymer Selection: PVDF-HFP on PBMA*

Biocompatible

PROMUS polymer:

PBMA-PVDF

• Extensive pre-clinical studies

• 20k clinical patients studied

• Over 10M worldwide implants

Durable

Durable coating during

deployment/fatigue testing

Tunable

Time

Dru

g R

elea

se

Ability To Tune Drug Release

Dep

loy

Forc

e

BPolymer A DC E

Deployable

BSC evaluated multiple biostable & biodegradable polymers

Boston Scientific Data on File. * PVDF-HFP on PBMA = poly-vinylidene fluoride - hexafluoropropylene on poly n-butyl methacrylate

Polymer in SE stent needs to be deployable

Eluvia Dual-Layer Coating Design• Active Polymer Layer (PTX, PVDF-HFP*) – a fluorinated polymer that Controls

Release of PaclitaxelDiffusion-controlled low-dose elution over time

• 0.167µg PTx/mm2 stent surface area• Primer Layer (PBMA)– Promotes Adhesion of Active Layer to Stent• Conformal Coating for Both Layers

Stent

PBMA Primer Layer

Paclitaxel/PVDF-HFP Active Layer

Boston Scientific Data on File. * PVDF-HFP on PBMA = poly-vinylidene fluoride - hexafluoropropylene on poly n-butyl methacrylate

• Familial hypercholesterolemic swine model of femoral restenosis

• Fluoropolymer-coated paclitaxel eluting stent (Eluvia) vs polymer-free paclitaxel-coated stent vs bare metal stent

• 30 days- Quantitative vascular angiography and optical coherence tomography

• 90 days- Histological evaluation

Gasior P, et al. Circ Cardiovasc Interv. 2017 May;10(5). pii: e004450.

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FP-PES:PES:BMS Preclinical Study

BMS, bare metal stent; FP-PES, fluoropolymer-paclitaxel eluting stent; OCT, oprical cohoerence tomography; PES, paclitaxel eluting stent

OCT and Corresponding Histology at 90 days – fluoropolymer based Paclitaxel Eluting Stent

Eluvia DES Zilver DES

Preclinical results may not necessarily be indicative of clinical performance.Gasior P, et al. Circ Cardiovasc Interv. 2017 May;10(5). pii: e004450.

ELUVIA DES

ZILVER DCS

Kaluza, G. LINC 2016. The testing was performed by or on behalf of BSC. Data on File.

Preclinical results may not necessarily be indicative of clinical performance.

DES:DES Preclinical Thrombogenicity

Human blood flow loop• 4.0x40 mm stents- ELUVIA, ZILVER PTX• 60 min flow duration• Stents rinsed and removed from tubing• Stents imaged* • Stents assayed for CD31 (platelets), D-dimer (fibrin)

and lactate dehydrogenase (total cell accumulation)

ZILVER

D-dimer(μg per stent)

Lactate dehydrogenase(Absorbance per stent)

N=4 per group Mean ± SEM

Platelet Accumulation(ng CD31 per stent)

ELUVIA ZILVERELUVIA ZILVERELUVIA

*Stents were paired in the flow loops. Comparisons not dependent on the amount of

drug released from each. Differences due to the stent designs and/or surfaces.

Cheng Y, Montero-Baker M, et al. LINC, 2018. Preclinical results may not necessarily be indicative of clinical performance.

Vascular Healing Response of 3 Contemporary StentsFamilial Hypercholesterolemic Swine Model

Conclusion: “Eluvia had a better anti-restenoticeffect and less injury in the presence of clear paclitaxel effects when compared with the Superaand EverFlex stents”

Amorphous CoatingCrystalline Coating

Crystalline Amorphous

Particles Released +++ ++

Uniform Coating ++ +++

Drug Transfer to Vessel +++ +++

Drug Retention vs. Time +++ +

Biological Effectiveness +++ ++

Vascular Toxicity +++ ++

Impact on Biological Performance

Paclitaxel Formulation Types (DCB)

Granada JF, et al. Open Heart. 2014;1(1):e000117. Tesfamariam B. J Control Release. 2016 ;238:149-156.

• Crystalline PTX ideal properties for DCB – embeds in vessel wall acting as a micro-reservoir for diffusion and release

• Amorphous PTX can be used in DES as a polymer acts as a reservoir for controlled diffusion

Polymer Controls Localized Drug Release and Vessel Wall Diffusion

≠ Drug Coated Stent

≠ Drug Coated Balloon + Bare Metal Stent

Boston Scientific Data on File.

Eluvia Differs from Peripheral Paclitaxel-Coated Technologies

aSimulated use in a tortuous vessel model under clinically relevant flow conditions.

Device sizes for particulates testing: 6mmx120mm stents, 6mmx80mm balloons. BSC Data on file.

Data from ELUVIA, Zilver PTX, Lutonix, Stellarex and IN.PACT DFUs. Abbreviations: DCB, drug-coated balloon; DES, drug-eluting stent.

Paclitaxel-Eluting Paclitaxel-Coated

ELUVIA DESZilver PTX

Stent

DCB

IN.PACT Lutonix Stellarex

Biostable Polymer ✓

Excipient ✓ ✓ ✓

Amorphous Coating Morphology

✓ ✓

Paclitaxel Dose Density(µg/mm2)

0.167 3 3.5 2 2

Total Dose(6 mm x 120 mm)

409 µg 1103 µg 8448 µg 4500 µg 4721 µg

Diffusion-Controlled Elution ✓

Particulate Countsa

(≥10µm size)1381 11,928 567,432 210,320 193,968

• Only device with a polymer to elute drug over time

• Low dose density and low total dose

IMPERIALPharmacokinetics Sub-study (N=13)

• All patients treated with Eluvia

• Plasma paclitaxel unquantifiable (<1 ng/mL) in all 13 patients at 30 minutes post-implantation

Plasma paclitaxel measured at 10 min, 30 min, and 1, 2, 3, 4, 6, 12, 24, 48 hours post-implant.

Gray WA, Lancet 2018

Paclitaxel-Eluting Coronary Stent Design and Clinical Use are Applicable to Eluvia DES

• Atherosclerotic disease is systemic, affecting coronary and peripheral arteries

• Response to injury (restenosis) phases are the same in peripheral and coronary vascular beds

• Paclitaxel anti-restenotic mechanism of action on vessels is the same

Forrester JS, et al. J Am Coll Cardiol. 1991;17(3):758-69

Coronary paclitaxel-eluting stent data inform the safety

profiles of paclitaxel and Eluvia DES

Eluvia DES and Coronary DES Design Principles

Abbreviations: DES, drug-eluting stent; PVDF-HFP, poly(vinylidene fluoride-co-hexafluoropropylene. SIBS, poly(styrene-block-isobutylene-block-styrene).

Stent sizes for total dose: ELUVIA DES 6.0 mm x 40 mm. Coronary 4.0 mm x 38 mm.

ELUVIA DESPaclitaxel-Eluting

Stents(TAXUS)

Everolimus-Eluting Stents

(PROMUS/XIENCE)

Vasculature Peripheral Coronary

Biostable Polymer ✓ (PVDF-HFP) ✓ (SIBS) ✓ (PVDF-HFP)

Amorphous Coating Morphology ✓ ✓ ✓

Paclitaxel ✓ ✓

Low Dose ✓ ✓ ✓

Total Dose on Stent 135 µg 282 µg 242 µg

Diffusion-Controlled Elution ✓ ✓ ✓

Stone GW, et al. JACC Cardiovasc Interv. 2011;4(5):530-542.

Cumulative event rate data on file. Abbreviations: BMS, bare metal stent; PTx, paclitaxel.

No All-cause Mortality Signal in Meta-analysis of Paclitaxel-eluting Stent vs BMS

5-year patient-level meta-analysis of mortality in ~2800 patients with coronary artery disease treated with paclitaxel-eluting or bare metal stent

HR: 1.08 (95%CI 0.84-1.39)

log-rank p=0.53

15%

10%

5%

0%

0 200 400 600 800 1000 1200 1400 1600 1800 2000

Days Since Procedure

Paclitaxel-Eluting Stent

BMS

Paclitaxel-Eluting Coronary Stent vs Bare Metal StentCumulative Event Rate (TAXUS I, II, IV, V)

At risk: 0 180 365 545 730 1095 1460 1825BMS 1397 1388 1370 1349 1328 1311 1262 1210

PTX-Eluting 1400 1389 1366 1345 1322 1304 1252 1192

No Difference in All-cause Mortality between Paclitaxel-eluting Stent and Bare Therapy in CLI and AFS improvement

• RCT of infrapopliteal paclitaxel-eluting stent placement to treat CLI (N=73)

• Similar survival rates for paclitaxel-eluting vs bare control through 5 years

• Paclitaxel-eluting stent treatment reduced major amputation rate by 57% at 5 years (19.3% vs 34.0%)

Abbreviations: BMS, bare metal stent; CLI, critical limb ischemia; PTA, percutaneous transluminal angioplasty.

Spreen MI, et al. J Am Heart Assoc. 2017;6(4). pii: e004877. doi: 10.1161/JAHA.116.004877.

PADI Trial 5-Year Survival

PTA-BMS

PTX-Eluting Stent

37.0% vs 37.7%

log-rank p=0.45

• 62 patients, 49% CLI

• 12-month results

• Mean lesion length 200mm

• Moderate – severe calcification in 42%; CTOs 79%

Real World Registries: Munster All-Comers Registry

Bisdas T, et al. JACC Cardiovasc Interv

• Single center audit of “real world” experience with Eluvia in femoro-popliteal intervention

• All patients had at least 2 years follow-up (treated March 2016 – October 2017)

• 51 patients (47 males, 4 females)

• 27 patients (52.9%) presented with critical limb ischemia

• Mean lesion length 105.4mm (25-270mm)

• 27 cases (52.9%) with CTOs

• Mean CTO length 90.1mm

• 26 cases (50.9%) with significant calcification (PACSS ≥ 3)

Real World Registries: Auckland All-Comers Registry

• Mean stent length 130mm (40 – 380mm)

• Concomitant ipsilateral limb intervention – 20 cases (39.2%), 17 cases tibial

• Technical success 98% (one early stent thrombosis)

• No stent fractures on follow up

1 Month 6 Months 1 Year 2 Years

Primary Patency 98.0% (50/51) 98.0% (49/50) 94.0% (47/50) 93.8% (45/48)

1 Month 6 Months 1 Year 2 Years

Freedom CD-TLR 98.0% (50/51) 98.0% (49/50) 98.0% (49/50) 93.8% (45/48)

Primary Patency

Freedom from Target Lesion Revascularization

Real World Registries: Auckland All-Comers Registry

Real World Registries: Auckland All-Comers Registry

Estimated patencies at 0.5, 1, 2, 3 years, given by the survivor function

• No aneurysmal degeneration on Duplex US to 2 years and beyond

• 2-year all cause mortality 3/51 (5.8%) – suicide, heart failure, sepsis

Real World Registries: Auckland All-Comers Registry

Auckland All-Comers Registry :

• Similar case numbers, longer follow-up

• Similar incidence CLI (Munster 49%, Auckland 53%)

• Shorter lesions but similar complexity

• No cases used after previous atherectomy or DCB angioplasty

Real World Registries: Comparisons

CaseNumbers

MiniumumF/Up

Lesion length (mm)

CTOs Mod-severe Ca2+

12-month PP

24-monthPP

AneurysmalDegeneration

Munster Registry

62 12-months 200 42% 79% 87% - 8.1%

Auckland Registry

51 24-months 105 53% 51% 94% 94% 0%

BSC PI Drug-Eluting Stent Clinical Program

IMPERIALMulticenter, Head to Head RCT 2:1(Eluvia : ZilverTMPTXTM)

N = 465 2Y follow up complete

MAJESTICMulticenter, single-arm(Eluvia)

N = 57 3Y follow up complete

EMINENTMulticenter, RCT 2:1(Eluvia : BMS)

N = 750 Enrolling

REGALMulticenter registry(Eluvia)

N = 500 Enrolling

SPORTS*Multicenter, RCT 1:1:1 (Eluvia:DCB:BMS)

N = 222 Enrolling

SAVALMulticenter, RCT 2:1(SAVAL : PTA) & single-arm

N = 201 & N = 100

Enrolling

*These investigator-sponsored studies are supported by grant funding from Boston Scientific. Boston Scientific is not responsible for the collection, analysis or reporting of these studies which remain the sole responsibility of the investigators. Information for the use in countries with applicable product registrations.SAVAL is an investigational device and not available for sale in the US. CAUTION: The law restricts these devices to sale by or on the order of a physician. Rx Only.

Primary Investigators

Global: William A. Gray, MD

European: Stefan Müller-Hülsbeck, MD

Study Design

Head to Head RCT

(EluviaTM DES vs ZilverTMPTXTM)

Long Lesion Sub-study

(Eluvia)

Pharmacokinetic

Sub-study (Eluvia)

• 2:1 randomized

• Single-blind

• Non-inferiority trial

• Single arm

• Lesion length 140 mm-190 mm

• Single-arm

Patients

N=465

Eluvia N=309 vs

Zilver PTX N=156

N=50 N=13

InvestigationalCenters

65 study centers: US, Canada, New Zealand, Belgium, Germany, Austria, Japan

IMPERIAL Clinical Study Overview

Gray WA, Lancet 2018.

Correction to IMPERIAL 1-Year Kaplan-Meier Analysis of Primary Patency

• In the course of responding to a query on 2-year data, we identified a data correction needed in the 1-year Kaplan-Meier analysis of primary patency

• The correction does not affect efficacy, safety events, or mortality; both study arms affected equally

• Does not affect the overall number of events, primary 1-year conclusions, or subgroup analysis conclusions previously reported

• Only the timing of events in the time-to-event analysis was affected

• The Lancet and appropriate regulatory bodies have been notified and corrections are forthcoming

• All statistical programming has been independently re-validated and 2-year data are unaffected

Gray WA, LINC 2020.

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target

lesion revascularization or bypass of the target lesion, as assessed by the DUS core lab.

Kaplan-Meier Analysis of Primary Patency at 1 YearOriginal

0%

20%

40%

60%

80%

100%

Cu

mu

lati

ve E

ven

t-F

ree

(%

)

Months Since Procedure

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Log-rank

p=0.0119

Zilver PTX

79.5%

Eluvia

88.5%

Gray WA, Lancet 2018.

EluviaZilver PTX

Error bars are 95%CI.

Primary patency defined as duplex ultrasound PSVR ≤2.4, in the absence of clinically-driven target lesion

revascularization or bypass of the target lesion, as assessed by the DUS core lab. The Kaplan-Meier curve is based

on the time to event of clinically-driven TLR and/or 12-month duplex ultrasound patency failure up to 395 days.

Kaplan-Meier Analysis of Primary Patency at 1 YearCorrected

0%

20%

40%

60%

80%

100%

Cu

mu

lati

ve E

ven

t-F

ree (

%)

Months Since Procedure

0 1 2 3 4 5 6 7 8 9 10 11 12 13

Error bars are 95%CI.

Log-rank

p=0.0094

Zilver PTX

81.8%

92.1%Eluvia

EluviaZilver PTX

Correction submitted to The Lancet.Gray WA, LINC 2020.

Primary Patency at 1 YearOcclusion, Calcification, Diabetes

The Kaplan-Meier curve is based on the time to event of clinically-driven TLR and/or 12-month duplex ultrasound patency failure up to 395 days. Error bars are SE. Diabetes = Medically-treated diabetes.

Diabetes

0%

20%

40%

60%

80%

100%

Cu

mu

lati

ve E

ven

t-Fr

ee (

%)

Months Since Procedure0 2 4 6 8 10 12

Eluvia

95.2%

Zilver PTX

81.5%Log rank p=0.1228

original

corrected

Occlusion Calcification

0%

20%

40%

60%

80%

100%

Cu

mu

lati

ve E

ven

t-Fr

ee (

%)

Months Since Procedure

Log rank p=0.5220

0 2 4 6 8 10 12

original

corrected

None/Mild

91.2%

Mod/Sev

92.5%

0%

20%

40%

60%

80%

100%

Cu

mu

lati

ve E

ven

t-Fr

ee (

%)

Months Since Procedure0 2 4 6 8 10 12

original

corrected

Log rank p=0.0677

CTO

86.4%

No CTO

94.7%

Wit

hin

Elu

via

Arm

Conclusions• Polymer mediated release from Eluvia Drug Eluting Stent:

• Delivers controlled, low dose and localized paclitaxel for tissue response• Inhibits neointima, reduces thrombogenicity and maintains safety profile in pre-clinical

models• Leverages coronary DES learnings on dose and delivery and reassures on a large dataset

of 5 year mortality

• In the Auckland Hospital long-term experience confirms excellent performance of Eluvia in a real-world setting with 93.8% primary patency and freedom from CD-TLR at 2 years!

• Corrected 1-year time-to-event analysis of primary patency confirms the original effectiveness conclusion of statistically significant improvement in primary patency for patients treated with Eluvia, with no impact on safety

• Corrected subgroup analyses likewise confirm original conclusions of excellent patency rates for patients treated with Eluvia at 1 year, regardless of lesion or patient complexity