Bioabsorbable StentsBioabsorbable StentsRon Waksman, MD, FACC, FSCAIRon Waksman, MD, FACC, FSCAI

Professor of Medicine, Georgetown University,Professor of Medicine, Georgetown University,Associate Chief of Cardiology, Associate Chief of Cardiology,

Washington Hospital Center, Washington DCWashington Hospital Center, Washington DC

Why absorbable stents?Why absorbable stents?

•• Short duration of Short duration of Plavix Plavix post stentingpost stenting•• Avoid chronic Avoid chronic inflammatory processesinflammatory processes•• Problem of reProblem of re--intervention with intervention with traditional traditional

techniquestechniques•• Ability of the vessel to perform Ability of the vessel to perform positive remodelingpositive remodeling•• Peripheral application: no longer Peripheral application: no longer crushingcrushing issue issue

after absorptionafter absorption•• CT and MRCT and MR –– (follow up) (follow up) compatibilitycompatibility

Why permanent stents? Vessel scaffolding is necessary only for a certain, limited

time, than the permanent implant has no known advantage

Company Picture Polymer/Drug Features

Bioabsorbable Vascular

Solutions (BVS)

[Guidant]

All biodegradable polymers (PLLA)

with everolimus

Igaki-Tamai

Self expanding and

balloon expandable

designs.

Zig-zag design which is deployed using a heated balloon

FIH Trial with 50 patients

Poly (DTE carbonate) with iodine on the backbone to make the stent radio opaque

Design do not require

heat to expand the stent…by ratchet links

PLLA; Transilast

RevaMedical

BiotronikMg Alloy Balloon expanding stent

with a delivery catheter

Bioabsorbable Stent ProgramsBioabsorbable Stent Programs

IgakiIgaki--Tamai PLLA Bioabsorbable Stent Tamai PLLA Bioabsorbable Stent 4 Years Follow4 Years Follow--upup

•• 63 lesions in 50 patients, 84 stents 63 lesions in 50 patients, 84 stents •• Non drugNon drug--eluting stenteluting stent•• Four year followFour year follow--up data up data

demonstrated no demonstrated no unusual findingsunusual findings

Long Term (4Long Term (4--year results)year results)DeathDeath 1/50 (2.0%)1/50 (2.0%)QMIQMI 1/50** (2.0%)1/50** (2.0%)CABGCABG 00Stent Thrombosis Stent Thrombosis 1/50** (2.0%)1/50** (2.0%)TLRTLR 9/50 (18.0%) 9/50 (18.0%) ** = same patient** = same patient

Hideo Tamai CCT 2004.

6 mo 12/60 (20%)6 mo 12/60 (20%) 6/50 (12%)6/50 (12%)12 mo 9/53 (17%)12 mo 9/53 (17%) 7/50 (14%)7/50 (14%)48 mo 48 mo 9/50 (18%)9/50 (18%)

Behaves similar to bare metal stents

Repeat PCIABRR***

Per LesionPer LesionRestenosis & TLR RatesRestenosis & TLR Rates

RestenosisRestenosis TLRTLR

18.018.0

12.712.7

00

1010

2020

1212--monthmonth

19.019.0

14.014.0

00

1010

2020

≤≤ 1212--monthmonth

(%)(%) (%)(%)

505099

636388

505077

424288

66--monthmonth

20.020.0

11.111.1

60601212

636377

22.422.4

12.012.0

≤≤ 66--monthmonth505066

49491111

3030 3030

Per PatientPer Patient

Serial Changes in Stent CSA Serial Changes in Stent CSA and Neointimal Area (IVUS)and Neointimal Area (IVUS)

postpost 3 months3 months 6 months6 months0.00.0

㎟㎟

6.06.0

8.08.0

10.010.0

8.768.76

2.632.63

7.617.61

12 months12 months

n.s.n.s.

9.129.12

n=30n=30

2.02.0

4.04.0

8.868.86

2.512.51

stent CSAstent CSA

neointimal areaneointimal area

p<0.05p<0.05 n.s.n.s.

2.332.33p<0.05p<0.05 p<0.05p<0.05 n.s.n.s.

prepre postpost 3Mo3Mo

6Mo6Mo

MLD=0.76MLD=0.76 MLD=2.83MLD=2.83 MLD=2.59MLD=2.59

MLD=2.79MLD=2.7912Mo12Mo

MLD=2.98MLD=2.9818Mo18Mo

MLD=2.75MLD=2.75

IgakiIgaki--TamaiTamai PLLA Bioabsorbable PLLA Bioabsorbable Self expanding stent for the SFASelf expanding stent for the SFA

BVS Fully Bioabsorbable Drug Eluting StentBVS Fully Bioabsorbable Drug Eluting Stent

BVS Bioabsorbable Stent Platform

Everolimus

ML VISION®

Balloon SDS

ChampionTM

Bioabsorbable Polymeric Drug

Release

Poly Lactic Acid Poly Lactic Acid Bioabsorbable PolymerBioabsorbable PolymerPoly Lactic Acid (PLA)Poly Lactic Acid (PLA)•• PLA safely used in numerous PLA safely used in numerous

medical applications since medical applications since the 1960sthe 1960s

Approx. 200 products made from PLA or Approx. 200 products made from PLA or coco--polymer containing PLApolymer containing PLA

•• Breaks down to lactic acid, a natural metaboliteBreaks down to lactic acid, a natural metabolite•• BVS stent has a tailored bioabsorption rateBVS stent has a tailored bioabsorption rate•• Fully bioabsorbed Fully bioabsorbed –– no drug left behindno drug left behind

Data on file at Guidant.

Bioabsorbable Everolimus Eluting Bioabsorbable Everolimus Eluting Coronary Stent SurfaceCoronary Stent Surface

Coated

Uncoated

Photos on file at Guidant.

Representative Photomicrographs (10x): Representative Photomicrographs (10x): Porcine Coronary StudiesPorcine Coronary Studies

28 Day 90 Day90 Day 180 Day180 Day

BVS

CYPHER®

Photos on file at Guidant.Pipeline DES products are currently in development at Guidant. Not available for sale.

•• PeriproceduralPeriprocedural Rx: Rx: Heparin Heparin

•• Target vessel: RCATarget vessel: RCA•• BVS stent 3.0/12mmBVS stent 3.0/12mm•• OCT imagingOCT imaging

Strut

OCT catheter

Strut dimension0.52mmX0.10mm

BVS Intracoronary, BVS Intracoronary, InIn--vivovivoOCT ImagingOCT Imaging

REVA Bioresorbable StentREVA Bioresorbable Stent

•• Fully bioresorbable coronary stent systemFully bioresorbable coronary stent system•• Integral bioresorbable drugIntegral bioresorbable drug--elution coatingelution coating•• PaclitaxelPaclitaxel--elutingeluting

Slide & Lock DesignSlide & Lock Design

Design Enables MaterialDesign Enables Material•• Expansion based upon sliding, Expansion based upon sliding,

locking parts rather than material locking parts rather than material deformationdeformation

Facilitates the use of polymersFacilitates the use of polymers

Enables PerformanceEnables PerformanceNegligible recoilNegligible recoilComparable radial strength & Comparable radial strength & flexibilityflexibilityEquivalent sizing to current Equivalent sizing to current metal stentsmetal stentsStandard balloon deploymentStandard balloon deployment

Close-up of Slide & Lock Mechanism

7.35 mm Bend Radius

Mg Alloy Bioabsorbable Stent

Metalic stents provide temporary scaffolding, that will Disappear at 60-90 days after deployment and may reduce restenosis! and will be compatible with cardiac imaging MRI or CT

MetalicMetalic stents provide stents provide temporary scaffolding, that temporary scaffolding, that will will DisappearDisappear at 60at 60--90 days 90 days aafter deployment and may fter deployment and may reduce restenosis! and will be reduce restenosis! and will be compatible with cardiac compatible with cardiac imaging MRI or CTimaging MRI or CT

Magnesium Based Alloys –Bioabsorbable Stents

InIn--vivo results animal trialsvivo results animal trials

Quick endotheliasation and gradual Quick endotheliasation and gradual absorptionabsorption

procedure → +/- 10 days → +/- 30 days → +/- 60 days

Stent immediately after implant

Ingrowth stent in vessel wall

Gradual absorption Mg-alloy by vessel wall

• IVUS

• MR

Magnesium Stent: VisibilityMagnesium Stent: Visibility

316L Mg alloy

0

10

20

30

40

50

C E D

Properties Properties BiocompatibilityBiocompatibility

Proliferation (BrdU) test of aterial hSMC and hEC in eluates.Heublein, et al., MHH

Proliferation / % (316L)

Reduced Proliferation of SMCs & ECs

α-actin straining after 35dHeublein, et al., MHH

Alloy E

Reference

Alloy

hSMChEC

Structural IntegrityStructural Integrity

Testing after 3 days of implantation (minipig)

Stent structure is completely intact

Micro CT and Light optical microscope images of Mg-stents 3 days after

implantation

HistologyHistology && MorphometryMorphometry

00.5

11.5

22.5

33.5

28 d 56 d

Area / mm2

Neointima

p = 0.258, n.s.

p = 0.002

7 10 10

Mean neointima in minipig coronary arteries adjusted for injury score and media reference (ANCOVA)Heublein, et al., MHH

Harvested after

Control

Mg Alloy

Mg Alloy

Control

EvG straining 56dHeublein, et al., MHH

Control

MgAlloy

Control and Mg – minipig coronary arteries; 8 weeks fu

LAD

Cx

LAD

RCA

Cx

RCA

RCA

LAD

Cx

RCA

Cx

Cx

Cx

RCA

RCA

RCA

Mg versus Control at 30 daysMg versus Control at 30 days

Conrtol L316Mg

Neointimal Thickness of Neointimal Thickness of AMS Decreases in MinipigAMS Decreases in Minipig

n=33

0.67

0.440.37 0.39

0.79 0.78 0.80

0.67

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

1 Month 3 Months 6 Months 12 Months

[mm]

Neointima AMS Neointima Control

AMSAMS--Animal Study, 6 months follow upAnimal Study, 6 months follow upHistological FindingsHistological Findings

Animal 1, RCA pos.2, (HE 25x magnification)

HE = hematoxylin-eosin staining; EvG = Elastica van Giesson staining

Animal 1, RCA pos.4, (HE 25x magnification) Animal 26, RCA pos.2 (EvG 25x magnification)

Animal 15, LAD pos.2, (EvG 63x magnification) Animal 15, RCA pos.2, (EvG 63x magnification) Animal 1, RCA pos.4, (EvG 63x magnification)

PROGRESS AMS I Clinical PROGRESS AMS I Clinical Study Study

MarchMarch 20062006Late Late BreakingBreaking TrialsTrials ACCACC

Preliminary Data Analysis

PROGRESS AMS PROGRESS AMS –– OverviewOverview

To evaluate the clinical feasibility of the To evaluate the clinical feasibility of the Absorbable Metal Stent in the Absorbable Metal Stent in the treatment of a single treatment of a single de novode novo lesion in lesion in a native coronary arterya native coronary artery

PurposePurpose

Prospective, multiProspective, multi--center, consecutive, center, consecutive, nonnon--randomized FIM (First In Man randomized FIM (First In Man ––coronary) studycoronary) study

DesignDesign

The study included 63 patients at 8 The study included 63 patients at 8 international clinical sitesinternational clinical sitesPatientsPatients

PROGRESS AMS PROGRESS AMS –– HypothesisHypothesis

The PROGRESSThe PROGRESS--AMS study designed to AMS study designed to yield first data on the clinical safety and yield first data on the clinical safety and efficacy of the absorbable metal stent in efficacy of the absorbable metal stent in the coronary artery applicationthe coronary artery application

Primary HypothesisPrimary HypothesisTo demonstrate feasibility and safety being To demonstrate feasibility and safety being in the range of currently available stent in the range of currently available stent systems. With MACE rate after 4 months systems. With MACE rate after 4 months <30<30 % (max. 18 events)% (max. 18 events)

PROGRESS AMS PROGRESS AMS –– Primary EndpointPrimary Endpoint

The primary endpoint of PROGRESSThe primary endpoint of PROGRESS--AMS isAMS is

Major Adverse Cardiac Events (MACE) Major Adverse Cardiac Events (MACE) at 4 months at 4 months defined asdefined as

Cardiac deathCardiac deathNonfatal myocardial infarctionNonfatal myocardial infarctionIschemia driven TLRIschemia driven TLR

Early primary endpoint as basis for starting Early primary endpoint as basis for starting subsequent clinical trials with Absorbable subsequent clinical trials with Absorbable Metal StentMetal Stent

PRELIMINARY RESULTS PRELIMINARY RESULTS DemographicsDemographics

1/631/631.61.6Prior CVA, % (n)Prior CVA, % (n)6/636/639.59.5Unstable Angina, % (n)Unstable Angina, % (n)26/6326/6341.341.3Prior MI, % (n)Prior MI, % (n)

3/633/634.84.8Insulin Dependent, % (n)Insulin Dependent, % (n)

15/6315/63

41/6341/6339/6339/6330/6330/63

11/6311/6344/6344/6369.869.8Males, % (n)Males, % (n)

23.823.8Prior PCI, % (n)Prior PCI, % (n)

65.165.1Hypertension , % (n)Hypertension , % (n)61.961.9Hypercholesterolemia, % (n)Hypercholesterolemia, % (n)47.647.6Smoking History, % (n)Smoking History, % (n)

17.417.4Diabetes, % (n)Diabetes, % (n)

61.3 61.3 ±± 9.5 9.5 Age, yrsAge, yrs

PRELIMINARY RESULTSPRELIMINARY RESULTS

38.138.123.823.8

00

00

00

23.823.8

%%

24241515

00

00

00

1515

nn

0000

00

00

00

00

%%

0000

00

00

00

00

nn

0000

00

00

00

00

nn

00QQ--wave MI (new wave MI (new patholpathol. . QQ--waves with CK or CKwaves with CK or CK--MB elevated)MB elevated)

00Non Q wave MI (CK 2 Non Q wave MI (CK 2 times above normal with times above normal with CKCK--MB elevated) MB elevated)

00Ischemic Driven TLRIschemic Driven TLR00TLR (Any)TLR (Any)

%%

00DeathDeath

00MACE (Cardiac death, MACE (Cardiac death, nonfatal MI, ischemia nonfatal MI, ischemia driven TLR)driven TLR)

In Hospital In Hospital EventsEvents

3030--Day Day EventsEvents

44--Month Month EventsEvents

Stent not Stent not visiblevisible, , butbut optimal optimal vesselvessel lumenlumenopacificationopacification

Multislice CT (16 row) imaging of coronary arteries

PRELIMINARY RESULTS PRELIMINARY RESULTS –– QCA Brief QCA Brief SummarySummary

31//57 (54.4%)31//57 (54.4%)Binary Restenosis (%)Binary Restenosis (%)1.37 1.37 ±± 0.520.52MLD, mmMLD, mm

2.46 2.46 ±± 0.370.37MLD POST, mmMLD POST, mm12.4 12.4 ±± 5.6 5.6 Diameter Stenosis (%) PostDiameter Stenosis (%) Post

1.09 1.09 ±± 0.510.51Late Loss, mmLate Loss, mm

48.2 48.2 ±± 17.217.2Diameter Stenosis (%)Diameter Stenosis (%)N = 57 lesionsN = 57 lesionsFOLLOWFOLLOW--UP QCA at 4 monthsUP QCA at 4 months

N = 60 lesionsN = 60 lesions

All TLR Preliminary SummaryAll TLR Preliminary Summary

Occurence of TLR

0

20

40

60

80

100

0 30 60 90 120 150 180 210 240 270 300 330

Days Post Intervention

TLR

Occ

uren

ce

4-m

on

thA

NG

IO

IVUS of Heavily IVUS of Heavily Calcified RCACalcified RCA (Pre)(Pre)

Lesion @ severe narrowing

Distal Reference

Proximal Reference

Bonnier Waksman, Eindhoven May 21, 2004

Proximal StentFull expansion after Full expansion after

second proximal stentsecond proximal stent

Bonnier Waksman, Eindhoven May 21, 2004

IVUS at FollowIVUS at Follow--upup

ConclusionsConclusionsThe FIM coronary study showed:The FIM coronary study showed:•• FeasibilityFeasibility•• Safety: no death, no MI, no stent thrombosisSafety: no death, no MI, no stent thrombosis•• The study met the primary endpoint < 30% of MACEThe study met the primary endpoint < 30% of MACE•• The Absorbable Metal Stent (AMS):The Absorbable Metal Stent (AMS):

•• The AMS technology platform is proven The AMS technology platform is proven •• Was successfully delivered to the lesion (100% Was successfully delivered to the lesion (100%

device success)device success)•• Was MRI / CT compatibleWas MRI / CT compatible•• Was absorbed as intendedWas absorbed as intended

Absorbable Metal Stent Platform:

• Fully absorbable platform

• Proven biocompatibility throughout the entire absorption process*

• Effective scaffolding properties**

* = Animal data available at Biotronik / ** = In vitro data available at Biotronik

Controlled Drug Eluting Stent Design:

• Precise drug release kinetic and direction

• Resorbable polymer with minimal tissue/polymer contact area

• Protected non-deforming reservoirs

Outlook - Drug eluting absorbable metal stent

Complete occlusion of the left pulmonary artery Complete occlusion of the left pulmonary artery after deafter de--banding and closure of the arterial duct banding and closure of the arterial duct with a clip (the device with three markers is for with a clip (the device with three markers is for

calibration purposes)calibration purposes)

Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

Crossing the stenosis with a guide wire Crossing the stenosis with a guide wire angiography revealed reperfusionangiography revealed reperfusion

Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

Implantation procedure of Mg Stent Implantation procedure of Mg Stent 3.0/10mm with a contrast filled balloon 3.0/10mm with a contrast filled balloon

catheter catheter

Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

At one week follow up after Mg Stent the At one week follow up after Mg Stent the left lung was reperfusedleft lung was reperfused

Peter Zartner, M. D., Pediatric CardiologyUniversity of Erlangen-Nuremberg, Germany

•• 20 CLI patients (Rutherford 420 CLI patients (Rutherford 4--5) with BTK 5) with BTK pathologypathology

1. Improving inflow limiting ATK lesions1. Improving inflow limiting ATK lesions

2. Lekton Mg implant if short (max 30mm) BTK 2. Lekton Mg implant if short (max 30mm) BTK stenoses stenoses •• Suboptimal angiographic result after PTA Suboptimal angiographic result after PTA

–– ≥≥50% stenosis post50% stenosis post--treatmenttreatment•• At the physicianAt the physician’’s discretions discretion

–– flowflow--limiting dissectionlimiting dissection–– threatened or acute closurethreatened or acute closure

•• Implants performed between December Implants performed between December ‘‘03 03 ––January January ‘‘0404

FIM details Below The KneeFIM details Below The Knee

•• MaleMale 1010 50%50%•• FemaleFemale 1010 50%50%

•• Average age Average age 76 yrs (59 76 yrs (59 -- 96)96)

•• Clinical vascular statusClinical vascular status

Rutherford Class IVRutherford Class IV 99 45%45%Rutherford Class VRutherford Class V 1111 55%55%

Patient demographicsPatient demographics (N=20)(N=20)

Lesion descriptionLesion description (N=20)(N=20)

•• Average lesion lengthAverage lesion length 11 mm (2 mm 11 mm (2 mm –– 20 mm)20 mm)

•• Average vessel diameterAverage vessel diameter 2.7mm (2.5 mm 2.7mm (2.5 mm –– 3 3 mm)mm)

•• Average stenosisAverage stenosis 84 % 84 % (75% (75% –– 95%)95%)

•• DissectionDissection 00 0%0%

•• UlcerationUlceration 11 5%5%

•• ThrombusThrombus 33 15%15%

•• CalcificationCalcification 1414 70%70%

High Patency Rate Below The KneeHigh Patency Rate Below The Knee

0

20

40

60

80

100

0 100 200 300 400

••Primary Clinical PatencyPrimary Clinical Patency

••TimeTime••(Days)(Days)

Bosiers M, Dendermonde, Belgium; Peeters P, Bonheiden, Belgium

• 3M 89.5%• 6M 84.2%• 9M 78.9%• 12M 72.4%

•• 3M3M 89.5%89.5%•• 6M6M 84.2%84.2%•• 9M9M 78.9%78.9%•• 12M 72.412M 72.4%%

94.7% Limb Salvage After One Year94.7% Limb Salvage After One Year

0

20

40

60

80

100

0 100 200 300 400

••Limb Salvage RateLimb Salvage Rate

••TimeTime••(Days)(Days)

Bosiers M, Dendermonde, Belgium; Peeters P, Bonheiden, Belgium

•• 3M3M 100.0%100.0%•• 6M6M 94.7%94.7%•• 9M9M 94.7%94.7%•• 12M 94.712M 94.7%%

Bioabsorbable Stents Future DirectionsBioabsorbable Stents Future Directions

Main challengesMain challenges•• Rate of degradationRate of degradation•• Time to complete degradationTime to complete degradation•• Radial force and elimination of recoilRadial force and elimination of recoil•• Bioabsorbable DESBioabsorbable DESFuture ApplicationsFuture Applications•• Coronary, Workhorse stent Vulnerable Coronary, Workhorse stent Vulnerable

PlaquePlaque•• Peripheral, SFA, tibialPeripheral, SFA, tibial•• Pediatric pulmonary Pediatric pulmonary coarctationcoarctation of aorta of aorta

biliarybiliary, etc., etc.