Siegburg / Stanford
BMS and DES Thrombosis
Differences among DES
Eberhard Grube MDFSCAI, FACC
HELIOS Heart Center Siegburg, Siegburg, GermanyStanford University, School of Medicine, CA, USAHospital Israelita Albert Einstein, São Paulo, Brazil
SCAI 30th Annual Scientific SessionsOrlando/Fla
Siegburg / Stanford
BMS and DES Thrombosis
Differences in DESEberhard Grube MD, FSCAI
The following relationships exist related to this presentation:
Grant support (GS), consultant (C), speakers bureau (SB), stock options (SO), equity interest (EI):
Boston Scientific: GS, C, SBCordis: C, SBBiosenors: GS, C, SB, EIAbbott: C, SB, Medtronic: C, SB
Off label use of products will be discussed in this presentation.
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Contributing FactorsHonda Y et al., Circulation, 2003, 8;108(1):2-5
Stent factorsDesign/Length
PolymerSurfaceDrugs
Patient factorsGene polymorphism
LV functionACS
Lesion factorsVessel sizeThrombus
Plaque characteristics
Blood factorsCoagulation activity
Platelet inhibition
Procedural factorsResidual dissection
Incomplete stent appositionAntithrombotic/anticoagulation therapy
STENT THROMBOSIS
AntiplateletTreatment
ResistanceDrug-drug interactionDuration of therapy
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Contributing FactorsHonda Y et al., Circulation, 2003, 8;108(1):2-5
Patient factorsGene polymorphism
LV functionACS
Lesion factorsVessel sizeThrombus
Plaque characteristics
Blood factorsCoagulation activity
Platelet inhibition
Procedural factorsResidual dissection
Incomplete stent appositionAntithrombotic/anticoagulation therapy
STENT THROMBOSIS
AntiplateletTreatment
ResistanceDrug-drug interactionDuration of therapy
Stent factorsDesign/Length
PolymerSurfaceDrugs
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TAXUS
TAXUS
Polyolefin derivative Polyolefin derivative PaclitaxelPaclitaxel ExpressExpress22
DrugDrug PolymerPolymer StentStentCYPHER
CYPHER
PEVA + PBMA blendPEVA + PBMA blendSirolimusSirolimus BX VelocityBX Velocity
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Localized Hypersensitivity Related to Sirolimus Eluting Stent
Marked Chronic Inflammation and Medial Destruction
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Inflammation in DES
Conclusions:
• DES delays arterial healing and promotes inflammation
Compared to SES, PES induce greater:
• Fibrin deposition
• Medial cell loss
• WBC Infiltration
• Late Neointimal Hyperplasia
Overlapping SES vs PES
Finn, A. V. et al. Circulation 2005;112:270-278
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Overlapping SES vs PESOverlapping SES vs PESBMS PESSESBMS
Overlap Overlap
Conclusions:• BMS showed far greater endothelialization than DES• Lack of coverage highlighted in areas of overlap• Less surface coverage by endothelial cells in PES than SES
DES Delayed Endothelialization
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REALITY
0,6
1,6
0,4
1,7
0,4
1,8
0,0
0,5
1,0
1,5
2,0
2,5
Intention-to-Treat Per-Protocol Actually-Treated*
CYPHER® TAXUS™
0,6
1,6
0,4
1,7
0,4
1,8
0,0
0,5
1,0
1,5
2,0
2,5
Intention-to-Treat Per-Protocol Actually-Treated*
CYPHER® TAXUS™
PP=0.0723=0.0723 PP=0.0333=0.0333 PP=0.0196=0.0196
111144 111133 121233
% of % of PatientsPatients
Stent Thrombosis (Acute + Subacute)
Per protocol analysis: CYPHERPer protocol analysis: CYPHER ®® 0.4, TAXUS0.4, TAXUS™™ 1.7: P=0.0331.7: P=0.033* 1 patient randomized to CYPHER* 1 patient randomized to CYPHER ®® actually treated with a TAXUSactually treated with a TAXUS ™™ stentstent
Stent Thrombosis: DES vs. BMSPer Protocol Analysis
Mauri L et al. N Engl J Med 2007;356:1020-9
1.3
0.5
0.2
0.6
0.8
0.5
0.10.2
0
0.5
1
1.5
2
OverallST
Early ST Late ST VeryLate ST
PES (N=1,400) BMS (N=1,397)
P=0.24
TAXUS I, II, IV, VEvents to 4 Years (N=2,797)
RAVEL, SIRIUS, E-SIRIUS, C-SIRIUSEvents to 4 Years (N=1,748)
%
1.2
0.5
0.1
0.60.6
0.1
0.5
0.00
0.5
1
1.5
2
OverallST
Early ST Late ST VeryLate ST
SES (N=878) BMS (N=870)
%
P=0.20
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Time after Initial Procedure (years)Time after Initial Procedure (years)
TAXUS I, II, IV, VTAXUS I, II, IV, V--SRSR
(N=2,797)(N=2,797)
00 11 22 33 44
TAXUS Stent (N=1,400)
Bare Metal Stent (N=1,397)
p=0.2499.2% (10)
98.7% (16)
6 vs.1, p=0.057 log-rank
After 1 yearAfter 1 year
Time after Initial Procedure (years)Time after Initial Procedure (years)
00 11 22 33 44
RAVEL, SIRIUS, ERAVEL, SIRIUS, E--SIRIUS, and CSIRIUS, and C--SIRIUSSIRIUS
(N=1,748)(N=1,748)
CYPHER Stent (N=870)
Bare Metal Stent (N=878)
P=0.2099.4% (5)
98.8% (10)
5 vs.0,p=0.025 log-rank
After 1 yearAfter 1 year
+0.48%
CRF analysis presented by Dr. Gregg Stone and Dr. Martin Leon, TCT 2006. TAXUS Stent data presented by Dr. Don Baim, December 7, 2006. TAXUS 4-year meta-analysis includes
TAXUS I (5 yr), II-SR cohort I (4 yr), IV (4 yr), V (2 yr) (N=2,797). The safety and effectiveness of the TAXUS®Stent have not been established in patients for longer than 12 months.
FDA Requested Analysis (Commercial TAXUS ® Stent SR Only)Freedom From (Protocol) Stent Thrombosis
+ 0.57%
95
96
97
98
99
100
95
96
97
98
99
100
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Different Definitions of Stent Thrombosis
0.57%
(5/878)
0.45%
(6/1401)“Confirmed”
(Angiographically)
“Presumed”(Sudden death within 30 days
or MI without angiographic confirmation)
TAXUS Trials(TAXUS I, II-SR, IV, V*)
(to 3 years)
Cypher Trials(RAVEL, SIRIUS, E&C-SIRIUS*)
(to 4 years)
1.03%
(9/878)1.00%
(10/1401)Total Reported
Thrombosis
?%
0.46%
(4/878)0.19%
(7/1401)SAT (1 - 30 days)
?%
Late ST (>30 days)
0.08%1/1401
• *TAXUS I 3-year data presented at TCT 2004 by Dr. E berhard Grube. TAXUS II 2-year data presented at TC T 2004 by Dr. Antonio Colombo. TAXUS IV 2-year data presented at TCT 2004 by Dr. Gregg W. Stone. TAXUS V 9-month data pr esented at ACC 2005 by Dr. Gregg W. Stone. RAVEL 4- year data presented at PCR 2005 by Dr. J. Eduardo S ousa. SIRIUS 3-year data presented at ACC 2005 by Dr. Martin B. Le on. E-Sirius 3-year data presented at ESC 2005 by D r. Vieter Legrand. C-SIRIUS presented at ACC 2003 b y Dr. Erick Schampaert.
Included per Protocol Protocol does not include “Presumed”Protocol does not include “Presumed”
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Pooled Meta-Analysis
Mauri et al. N Engl J Med 2007;356:1020-9.
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2229 patients after successful DES implantation 2229 patients after successful DES implantation
PESPES1167 pts1167 pts
2223 stents 2223 stents
SATSAT4 (0.4%)4 (0.4%)
SATSAT10 (0.9%)10 (0.9%)
LSTLST5 (0.5%)5 (0.5%)
LSTLST10 (0.9%)10 (0.9%)
Total SESTotal SES9 (0.9%) 9 (0.9%)
Total PESTotal PES20 (1.7%)20 (1.7%)
9.3 9.3 ±±±±±±±± 5.6 months 5.6 months Total DES 29/2229 Total DES 29/2229 (1.3%)(1.3%)
P=0.5P=0.5
P=0.3P=0.3
P=0.09P=0.09
10.2 10.2 ±±±±±±±± 4.44.4 mm 7.9 7.9 ±±±±±±±± 3.63.6 mm
Stent Thrombosis after DES
SESSES1062 pts 1062 pts
2272 stents 2272 stents
Iakovou et al, JAMA 2006
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Solutions to Avoid Stent ThrombosisSolutions to Avoid Stent Thrombosis
Improved SAFETYImproved SAFETYImproved SAFETY
Optimal Stent DesignOptimal Stent Design
Drug DurationDrug Duration Optimal Procedural ResultOptimal Procedural Result
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DES on the US Market – Forecast
TAXUS® Liberté™
2007 2008
JNJ
BSC
ABT
As of January, 2007. TAXUS, Liberté and PROMUS are trademarks of Boston Scientific Corporation or its affiliates. PROMUS Stent is a private-labeled XIENCE™ V Everolimus Eluting Coronary
Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE is a trademark of Abbott Laboratories group of companies. Cypher, Cypher-Mini and Cypher-Max
are trademarks of Cordis Corporation. CoStar is a registered trademark of Conor Medsystems Inc. Endeavor is a trademark of Medtronic Vascular, Inc. Caution- TAXUS Liberté, TAXUS Atom,
TAXUS 4.0mm, PROMUS, Xience V, Endeavor, CoStar, Cypher Mini and Max are investigational devices. Not currently available for sale in the US.
PROMUS™
Xience™ V
MDT
Endeavor®
Cypher® \ CoStar®
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EfficacySafety
Device Introduction
Generation of Evidence after Device IntroductionGeneration of Evidence after Device Introduction
FIM Pivotal Post approval studies
Early Safety
To assess stent thrombosis differences one needs large patient populations as well as
long-term follow-up
Siegburg / Stanford
1 yr 2 yrs 3 yrs 5 yrs4 yrs
TAXUS II (n=536)TAXUS IV (n=1314)TAXUS V (n=1156)TAXUS VI (n=448)RAVEL (n=238)SIRIUS (n=1058)E-SIRIUS (n=352)C-SIRIUS (n=100)ENDEAVOR I (n=100)ENDEAVOR II (n=1197)ENDEAVOR III (n=436)
~3,500 patients
~1,800 patients
~1,700 patients
Colombo et al. Circulation. 2003;108:788; Stone et al. N Engl Med. 2004;350:221; Stone et al. JAMA. 2005;294:1215; Dawkins et al. Circulation. 2005;112:3306; Morice et al. N Engl J Med.
2002;346:1773; Moses et al. N Engl J Med. 2003;349:1315; Schofer et al. Lancet. 2003;3362:1093; Schampaert et al. JACC. 43:1110; Dr. Meredith, EuroPCR 2006; Dr. Kandzari, ACC 2006; Dr.
Serruys, ESC 2006. Dr. Stone, ACC 2007
SPIRIT I (n=54)
SPIRIT II (n=300)~ 1334 patients
TAXUS I (n=61)
Currently Available Drug-Eluting Stent Pivotal Clinical Trial Data
SPIRIT III (n=980)
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Endeavor Shows More CompleteEndothelization than Cypher and Taxus
0
25
50
75
100
Mean % Endothel
Cypher
Taxus
Endeavor
% of Struts Endothelialized
Virmani et. al; PCR 2006
CypherCypher TaxusTaxus EndeavorEndeavor
Rabbit model at 21 days
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Defined as angiographic thrombus or subacute closur e within the stented vessel at the time of the clin ically driven angiographicrestudy for documented ischaemia (chest pain and ECG changes). Any death not attributed to a non-cardi ac cause within the first 30 days is considered a surrogate for stent t hrombosis in the absence of documented angiographic stent patency .
EIEIn=100n=100
1 2 3 12 13 14Days Post ProcedureDays Post Procedure
30 100 150 270 200 360 720
EIIEIIn=598n=598
EII CAEII CAn=296n=296
EIIIEIIIn=323n=323
= 1%
= 0.5%
= 0.0%
= 0.0%
Overall Thrombosis = 0.3%Overall Thrombosis = 0.3%
ENDEAVOR IENDEAVOR I--III Clopidogrel Therapy for III Clopidogrel Therapy for ≥≥ 3 months3 months
10801 year 2 years 3 years
Endeavor Clinical ProgramRate of Protocol Defined Stent Thrombosis by Study
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Different Definitions of Stent Thrombosis
0
0.57%
(5/878)
0.45%
(6/1401)“Confirmed”
(Angiographically)
“Presumed”(Sudden death within 30 days
or MI without angiographic confirmation)
TAXUS Trials(TAXUS I, II-SR, IV, V*)
(to 3 years)
ENDEAVOR Trials(ENDEAVOR I & II*)
(2 years)
Cypher Trials(RAVEL, SIRIUS, E&C-SIRIUS*)
(to 4 years)
1.03%
(9/878)1.00%
(10/1401)Total Reported
Thrombosis
?%
0.6%
(4/691)
0.46%
(4/878)0.19%
(7/1401)SAT (1 - 30 days)
?%
?%
?%
Late ST (>30 days)
0.08%1/1401
0.6%
(4/691)• *TAXUS I 3-year data presented at TCT 2004 by Dr. E berhard Grube. TAXUS II 2-year data presented at TC T 2004 by Dr. Antonio Colombo. TAXUS IV 2-year data presented at TCT
2004 by Dr. Gregg W. Stone. TAXUS V 9-month data pr esented at ACC 2005 by Dr. Gregg W. Stone. RAVEL 4- year data presented at PCR 2005 by Dr. J. Eduardo S ousa. SIRIUS 3-year data presented at ACC 2005 by Dr. Martin B. Le on. E-Sirius 3-year data presented at ESC 2005 by D r. Vieter Legrand. C-SIRIUS presented at ACC 2003 b y Dr. Erick Schampaert. ENDEAVOR I data presented at ESC 2005 b y Dr. Wijns. ENDEAVOR II data presented at PCR 2005 by Dr.J. Fajadet. Data from trials that are not he ad-to-head are not intended to be comparative.
Included per Protocol Protocol does not include “Presumed”Protocol does not include “Presumed”
Cypher is registered trademarks of Cordis Corporation, Endeavor is trademarks of Medtronic Corporation, NIR® is a registered trademark of Medinol Ltd. - Jerusalem
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Examples of Next Generation Stents
2. Generation DESXience V: Everolimus – Durable PolymerBioMatrix: Biolimus – Absorbable PolymerConor: Paclitaxel – Absorbable Polymer ??ZoMaxx: Zotarolimus – Durable Polymer
Drug Combo… and many more …
Lesion Dedicated DESDevax – BifurcationsXtent – Multi-lesion
Absorbable DES
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ML VISION®
Stent Delivery System
Everolimus
ML VISION®
Platform
Durable Polymer
XIENCE V® DES Everolimus Eluting Coronary Stent System
Everolimus – Durable PolymerXience V (SPIRIT Trials)
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XIENCE V Stent Thrombosis
1.30.5Late stent thrombosis (%)(>30days)
0.00.0Early stent thrombosis (%)(<30days)
TAXUS®
77 patientsXIENCE™ V223 patientsSPIRIT II
0.00.15Late stent thrombosis (%)(>30days)
0.00.3Early stent thrombosis (%)(<30days)
TAXUS®
322 patientsXIENCE™ V658 patientsSPIRIT III
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S-Stent™ (stainless steel)
Biolimus A9™(rapamycinderivative)
BioMatrixStent
BioMatrixStent
Biolimus – Absorbable PolymerBioMatrix Stent (STEALTH Trial)
PLA PolymerAsymmetrical bioresorbablecoating
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0.160.15
0.28
0.07 0.07
0.14
0.24
0.04
0.23
0.13
0.34
0.0
0.1
0.2
0.3
0.4
Late
Los
s (m
m)
6 mos.9 mos. 8 mos. 6 mos. 8 mos.8 mos. 8 mos. 8 mos.
TAXUS™ Stent
CYPHER™ Stent
ENDEAVOR™ Stent
XIENCE™ V Stent(PROMUS™ Stent)
In-Segment Late Loss Across Multiple Randomized Clinical Trials
ENDEAVOR III
REALITY
TAXUS IV
REALITY
SPIRIT
II
SPIRIT
I
SIRIU
S
SPIRIT
II
Data from trials that are not head-to-head are not intended to be comparative. SPIRIT is sponsored by Abbott. PROMUS Stent is a private-labeled XIENCE V Everolimus Eluting Coronary Stent System manufactured by Abbott and distributed by Boston Scientific Corporation. XIENCE is a trademark of Abbott Laboratories group of companies. PROMUS, TAXUS and Express2 are trademarks of Boston Scientific Corporation or its affiliates. Cypher is a trademark of Cordis Corp. Endeavor is a trademark of Medtronic Vascular, Inc. For products, sponsors, and publications, refer to the Clinical Trial Glossary.
6 mos.ENDEAVOR II
I
PSST 4128
8 mos.
SPIRIT
III
SPIRIT
III
8 mos.
0.09
STEALT
H
BioMATRIX ™
Stent
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STEALTH I Cumulative Hierarchical MACE
0.0%0.0%0.0%0.0%Stent thrombosis
0.0%0.0%0.0%0.0%TLR-CABG
1.3%0.0%1.3%0.0%TLR-PTCA
24 Months6 MonthsRESULTS
2.5%
0.0%
2.5%
5.0%
S-Stent
1.3%1.3%2.5%Non-Q Wave MI
5.1%3.8%2.5%MACE
1.3%0.0%0.0%Death*
1.3%1.3%0.0%Q Wave MI
BioMatrixBioMatrixS-Stent
*Death events were noncardiac: 1 diabetic foot syndrome (S-Stent) and 1 acute leukemia (BioMatrix)
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10 µg Paclitaxel With Controlled Mural Release
Conor/JnJ(CoStar)
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Discrete MicroDrop Structures (Labcoat)
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BioMatrix Freedom StentBiolimus A9 ® Drug
• Abluminal drug coating targets blood vessel walls• Small amounts are released into circulation
Bloodstream
Pure Biolimus A9 impregnated in metal stent surface
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28-DAY Porcine Histology Results
BARE Control BA9/PLA POLYMER BA9 MicroStruct.
Drug 225µg/Poly 225µg 225µg drug
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BioMatrix Freedom StentBiolimus A9 ® Drug
First-in-man: Baseline, Oct 2006
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BioMatrix Freedom StentBiolimus A9 ® DrugFirst-in-man: 6 Months Follow-up, March 2007
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The STENT Thrombosis Study
10,000 consecutive pts receiving DES at up to 12 sites
10,000 consecutive pts receiving DES 10,000 consecutive pts receiving DES at up to 12 sitesat up to 12 sites
Aspirin and Clopidogrel responsiveness evaluatedAspirin and Clopidogrel responsiveness evaluated(Accumetrics VerifyNow system)(Accumetrics VerifyNow system)
Clinical FU for 2-5 yearsClinical FU for 2Clinical FU for 2 --5 years5 years
Angiographic core lab assessment of all Angiographic core lab assessment of all stent thromboses and 1:3 matching controlsstent thromboses and 1:3 matching controls
PIs: Gregg W. Stone and Chuck SimontonPIs: Gregg W. Stone and Chuck SimontonSponsors: CRF and the Dickinson Inst.Sponsors: CRF and the Dickinson Inst.Principal study group: STENT Registry investigatorsPrincipal study group: STENT Registry investigators
Funded by grants from Boston Scientific Funded by grants from Boston Scientific (lead supporter), Accumetrics, Abbott (lead supporter), Accumetrics, Abbott
Vascular, Cordis, and MedtronicVascular, Cordis, and Medtronic
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The PROTECT Randomized Trial
Global randomized trial 8,000 patients
Endeavor vs. Cypher stent
Primary endpoint = stent thrombosisPI: W. Wijns
Sponsor: Medtronic Corp.
Siegburg / Stanford
ThankThank youyou