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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
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00
00
00
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0000
00
00
00
00
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0000
00
00
00
00
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0000
00
00
00
00
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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.