EuroSTAR II EuroSTAR II The European Randomized The European Randomized
CoStarCoStar™ Trial: Trial:Cobalt-Chromium Paclitaxel-eluting Stent Cobalt-Chromium Paclitaxel-eluting Stent
vs. identical BMSvs. identical BMS
EuroSTAR II EuroSTAR II The European Randomized The European Randomized
CoStarCoStar™ Trial: Trial:Cobalt-Chromium Paclitaxel-eluting Stent Cobalt-Chromium Paclitaxel-eluting Stent
vs. identical BMSvs. identical BMS
Sigmund Silber, MD, FACC, FESC
Cardiology Practice and HospitalMunich, Germany
DisclosureEuroSTAR IIEuroSTAR II
Consulting fees and honoraria from various companies,Consulting fees and honoraria from various companies,No stocks or patents, no conflict of interest related to this presentationNo stocks or patents, no conflict of interest related to this presentation
CoStar™ Stent Platform
UniStar™ Cobalt
Chromium stent
platform
PLGA
Bioresorbable
polymer
Paclit
axel
EuroSTAR IIEuroSTAR II
No residual polymer following tissue removal at 180 days
CoStar™ Resorbable Polymer- Animal Data
Explant In-vivo porcine model
EuroSTAR IIEuroSTAR II
CoStar™ Stent Design
Bridge Elements ReservoirsDuctile Hinges
Alternating hexagonal pattern
EuroSTAR IIEuroSTAR II
CoStar™ Stent Design
Bridge Elements ReservoirsDuctile Hinges
Alternating hexagonal pattern
EuroSTAR IIEuroSTAR II
highly deliverable
CoStar™ Stent Design
Bridge Elements Reservoirs
Avoid possible cracking of polymer
EuroSTAR IIEuroSTAR II
Ductile Hinges
The Power of Reservoir Technology
Single DrugStructure
Multiple DrugStructures
Drug Delivery ReservoirsDrug Delivery Reservoirs
Bi-Directional Uni-Directional
Single Adjacent
EuroSTAR IIEuroSTAR II
Objective:• To compare the the CoStar™ Paclitaxel-
Eluting Coronary Stent System to the same stent without a drug or polymer.
• Dose: 10 µg / 30 days (in-vitro)
EuroSTAR II TrialProspective, Multi-Center, Randomized, Study of the CoStar™ Paclitaxel-eluting Coronary Stent System in Patients with De Novo Lesions of Native Coronary Arteries
EuroSTAR II TrialProspective, Multi-Center, Randomized, Study of the CoStar™ Paclitaxel-eluting Coronary Stent System in Patients with De Novo Lesions of Native Coronary Arteries
EuroSTAR IIEuroSTAR II
Study AdministrationEuroSTAR IIEuroSTAR II
Principal Investigator:Principal Investigator:Prof. Dr. S. Silber, MunichProf. Dr. S. Silber, Munich, Germany, Germany
Data Coordinating Center:Data Coordinating Center:DATATRAK Deutschland GmbHDATATRAK Deutschland GmbHBonn, GermanyBonn, Germany
Steering Committee:Steering Committee:Prof. Dr. S. Silber, MunichProf. Dr. S. Silber, Munich, Germany, GermanyDr. Suryapranata, Zwolle, NetherlandsDr. Suryapranata, Zwolle, NetherlandsDr. B. Chevalier, Saint-Denis, FranceDr. B. Chevalier, Saint-Denis, France
QCA Core Lab:QCA Core Lab:
Bio-Imaging TechnologiesBio-Imaging Technologies
Leiden, The NetherlandsLeiden, The Netherlands
Data Safety Monitoring Committee /Data Safety Monitoring Committee /
Clinical Events CommitteeClinical Events Committee
Dr. Marcus Lins, Kiel, GermanyDr. Marcus Lins, Kiel, Germany
Prof. Dr. Blanchard, FranceProf. Dr. Blanchard, France
Jan Bart Hak, Netherlands (Chairman)Jan Bart Hak, Netherlands (Chairman)
Sponsor:Sponsor:BIOTRONIK GmbH & Co. KGBIOTRONIK GmbH & Co. KG
Study DesignStudy Design
Prospective, Randomized, Multi-Center European Study Prospective, Randomized, Multi-Center European Study Lesions Lesions 25 mm in length, 2.5 – 3.5 mm diameter 25 mm in length, 2.5 – 3.5 mm diameter
303 Patients at 18 Centers303 Patients at 18 Centers
UniStarUniStar™™ Coronary Stent Coronary Stent(Control Group) (Control Group)
N = 151N = 151
CoStar CoStar ™™ Paclitaxel-eluting Stent Paclitaxel-eluting Stent
N = 152N = 152
Randomized 1:1Randomized 1:1
Antiplatelet Therapy: Antiplatelet Therapy: Clopidogrel 300 mg loading dose, 75 mg QD for Clopidogrel 300 mg loading dose, 75 mg QD for 6 months 6 monthsAspirin 100 mg QD for 6 months, and daily ASA indefinitelyAspirin 100 mg QD for 6 months, and daily ASA indefinitely
EuroSTAR IIEuroSTAR II
Study Endpoints
Primary• In-segment binary angiographic restenosis at 8 months
Secondary• Angiographic Endpoints
– In-stent late lumen loss at 8 months– In-stent and in-lesion minimum lumen diameter
(MLD)• Clinical Endpoints
– MACE at 30 days and 8 months– Target lesion revascularization (TLR) and target
vessel revascularization (TVR) at 8 months
EuroSTAR IIEuroSTAR II
Statistical Assumptions
• Assumptions:– 5% in treatment group– 15% in control group = 0.05 and = 0.2
• 110 patients needed to provide 80% power to detect a difference in the primary endpoint of in-segment binary restenosis
• A total of 150 patients will be needed in each group due to an assumed 25% lost to follow-up
EuroSTAR IIEuroSTAR II
Key Inclusion Criteria
• Up to two discrete de-novo lesions in two native coronary arteries
• Stenosis between 50-99% (visual estimate)
• Reference vessel diameter (RVD) 2.5 – 3.5 mm
• Lesion length 25 mm
• TIMI flow 1 or higher
EuroSTAR IIEuroSTAR II
Study InvestigatorsStudy Investigators
Investigator Investigator Site Name and LocationSite Name and Location
Prof. Dr. D. AndresenProf. Dr. D. Andresen Vivantes Klinikum Am Urban, Berlin, DVivantes Klinikum Am Urban, Berlin, D Prof. Dr. S. BehrensProf. Dr. S. Behrens Vivantes GmbH Reinickendorf, Berlin, DVivantes GmbH Reinickendorf, Berlin, D Prof. Dr. H. DariusProf. Dr. H. Darius Vivantes Klinikum NeukVivantes Klinikum Neukölln, ölln, Berlin, D Berlin, D Prof. Dr. H. D. GlogarProf. Dr. H. D. Glogar AHK, Wien, AAHK, Wien, A Dr. S. HoffmannDr. S. Hoffmann Vivantes Friedrichshain, Berlin, DVivantes Friedrichshain, Berlin, D Dr. M. JereczekDr. M. Jereczek Vivantes Klinikum Spandau, Berlin, DVivantes Klinikum Spandau, Berlin, D Prof. Dr. A. JeronProf. Dr. A. Jeron PD Dr. B. Lauer, PD Dr. B. Lauer,
UniversitUniversitätsklinik, Regensburg, Dätsklinik, Regensburg, D Zentralklinik, Bad Berka, DZentralklinik, Bad Berka, D
Dr. K. M. J. MarquesDr. K. M. J. Marques Vu Medisch Centrum, Amsterdam, NLVu Medisch Centrum, Amsterdam, NL Prof. Dr. C. NienaberProf. Dr. C. Nienaber UniversitUniversitätsklinik, Rostock, Dätsklinik, Rostock, D Prof. Dr. G. RichardtProf. Dr. G. Richardt Kliniken GmbH, Bad Segeberg, DKliniken GmbH, Bad Segeberg, D Prof. Dr. S. SilberProf. Dr. S. Silber Cardiology Practice and Hospital, Munich, DCardiology Practice and Hospital, Munich, D Dr. T. SlagboomDr. T. Slagboom OLVG Amsterdam, NLOLVG Amsterdam, NL Dr. H. SuryapranataDr. H. Suryapranata Isala Klinicken Zwolle, NLIsala Klinicken Zwolle, NL Dr. M. J. SuttorpDr. M. J. Suttorp Antonius Zh Nieuwegein, NLAntonius Zh Nieuwegein, NL Prof. Dr. W. VoelkerProf. Dr. W. Voelker UniversitUniversitätsklinik, Würzburg, Dätsklinik, Würzburg, D Dr. M. WiemerDr. M. Wiemer Herzzentrum NRW, Bad Oeynhausen, DHerzzentrum NRW, Bad Oeynhausen, D Dr. B. WitzenbichlerDr. B. Witzenbichler Campus Benjamin Franklin, Berlin , DCampus Benjamin Franklin, Berlin , D
EuroSTAR IIEuroSTAR II
Study InvestigatorsStudy Investigators
Investigator Investigator Site Name and LocationSite Name and Location
Prof. Dr. D. AndresenProf. Dr. D. Andresen Vivantes Klinikum Am Urban, Berlin, DVivantes Klinikum Am Urban, Berlin, D Prof. Dr. S. BehrensProf. Dr. S. Behrens Vivantes GmbH Reinickendorf, Berlin, DVivantes GmbH Reinickendorf, Berlin, D Prof. Dr. H. DariusProf. Dr. H. Darius Vivantes Klinikum NeukVivantes Klinikum Neukölln, ölln, Berlin, D Berlin, D Prof. Dr. H. D. GlogarProf. Dr. H. D. Glogar AHK, Wien, AAHK, Wien, A Dr. S. HoffmannDr. S. Hoffmann Vivantes Friedrichshain, Berlin, DVivantes Friedrichshain, Berlin, D Dr. M. JereczekDr. M. Jereczek Vivantes Klinikum Spandau, Berlin, DVivantes Klinikum Spandau, Berlin, D Prof. Dr. A. JeronProf. Dr. A. Jeron PD Dr. B. Lauer, PD Dr. B. Lauer,
UniversitUniversitätsklinik, Regensburg, Dätsklinik, Regensburg, D Zentralklinik, Bad Berka, DZentralklinik, Bad Berka, D
Dr. K. M. J. MarquesDr. K. M. J. Marques Vu Medisch Centrum, Amsterdam, NLVu Medisch Centrum, Amsterdam, NL Prof. Dr. C. NienaberProf. Dr. C. Nienaber UniversitUniversitätsklinik, Rostock, Dätsklinik, Rostock, D Prof. Dr. G. RichardtProf. Dr. G. Richardt Kliniken GmbH, Bad Segeberg, DKliniken GmbH, Bad Segeberg, D Prof. Dr. S. SilberProf. Dr. S. Silber Cardiology Practice and Hospital, Munich, DCardiology Practice and Hospital, Munich, D Dr. T. SlagboomDr. T. Slagboom OLVG Amsterdam, NLOLVG Amsterdam, NL Dr. H. SuryapranataDr. H. Suryapranata Isala Klinicken Zwolle, NLIsala Klinicken Zwolle, NL Dr. M. J. SuttorpDr. M. J. Suttorp Antonius Zh Nieuwegein, NLAntonius Zh Nieuwegein, NL Prof. Dr. W. VoelkerProf. Dr. W. Voelker UniversitUniversitätsklinik, Würzburg, Dätsklinik, Würzburg, D Dr. M. WiemerDr. M. Wiemer Herzzentrum NRW, Bad Oeynhausen, DHerzzentrum NRW, Bad Oeynhausen, D Dr. B. WitzenbichlerDr. B. Witzenbichler Campus Benjamin Franklin, Berlin , DCampus Benjamin Franklin, Berlin , D
EuroSTAR IIEuroSTAR II
18 Sites in 3 European States
UniStarUniStarn = 151n = 151
CoStarCoStarn = 152n = 152
Age, yearsAge, years 65.7 65.7 ± 9.4± 9.4 64.4 64.4 ± 9.2± 9.2 Male, %Male, % 68.968.9 74.374.3 Angina, %Angina, % 87.487.4 84.284.2 Stable Angina, % Stable Angina, % 74.274.2 77.377.3 Prior MI, %Prior MI, % 27.227.2 27.027.0 Prior CABG, %Prior CABG, % 8.68.6 2.02.0 Prior PCI, %Prior PCI, % 31.131.1 36.836.8 History of Stroke or TIA, %History of Stroke or TIA, % 2.72.7 4.614.61 Diabetes Melitus, %Diabetes Melitus, % 22.522.5 26.326.3 Insulin Dependent, %Insulin Dependent, % 41.241.2 37.537.5 History of Smoking, %History of Smoking, % 42.442.4 46.746.7 History of Hyperlipidemia, %History of Hyperlipidemia, % 61.661.6 61.261.2 History of Hypertension, %History of Hypertension, % 72.272.2 65.865.8 LVEF, %LVEF, % 61.1 61.1 ± 12.9± 12.9 62.2 62.2 ± 13.0± 13.0
EuroSTAR IIEuroSTAR IIDemographics and Clinical Characteristics
QCA Analysis QCA Analysis
UniStarUniStar CoStarCoStar p-valuep-value
Pre-Procedure:Pre-Procedure:
RVD, mmRVD, mm 2.73 2.73 ± 0.48± 0.48 2.74 2.74 ± 0.51± 0.51 NSNS
Lesion Length, mmLesion Length, mm 15.16 15.16 ± 7.69± 7.69 15.12 15.12 ± 7.58± 7.58 NSNS
MLD, mmMLD, mm 1.05 1.05 ± 0.30± 0.30 1.12 1.12 ± 0.37± 0.37 NSNS
% DS, mm% DS, mm 60.93 60.93 ± 10.45± 10.45 59.41 59.41 ± 0.51± 0.51 NSNS
8-Month Follow-up:8-Month Follow-up:
MLD In-stent, mmMLD In-stent, mm 1.77 1.77 ± 0.57± 0.57 2.16 2.16 ± 0.65± 0.65 <0.0001<0.0001
MLD In-segment, mmMLD In-segment, mm 1.69 1.69 ± 0.52± 0.52 1.99 1.99 ± 0.66± 0.66 0.00040.0004
% DS In-stent% DS In-stent 36.95 36.95 ± 16.93± 16.93 23.79 23.79 ± 16.33± 16.33 <0.0001<0.0001
% DS In-segment% DS In-segment 39.56 39.56 ± 15.04± 15.04 30.18 30.18 ± 17.39± 17.39 <0.0001<0.0001
EuroSTAR IIEuroSTAR II
28.2 30.3
9.1
17.6
0
10
20
30
40
50
In-Stent Restenosis In-Segment Restenosis
Bin
ary
Res
ten
osi
s (%
)
UniStar CoStar
8-Month Binary Angiographic Restenosis
29/10329/103 12/13212/132 22/12522/12527/8927/89
Primary EndpointPrimary Endpoint
41.9% Reduction41.9% Reduction
EuroSTAR IIEuroSTAR II
p=0.0002 p=0.0327
0.0
0.5
1.0
1.5
2.0
In-Stent Late Loss In-Segment Late Loss
Lat
e L
oss
(m
m)
UniStar CoStar
Late Loss at 8 MonthsEuroSTAR IIEuroSTAR II
0.81 ± 0.49
0.41 ± 0.480.64 ± 0.49
0.29 ± 0.50
p<0.0001
p<0.0001
0.00.7 0.7 0.7 0.7
2.0
0.0 0.00.7
0.0 0.00.7
0
2
4
6
8
10
CardiacDeath
Q-MI Non-Q-MI TVR TLR MACE
MA
CE
(%
)
UniStar (n=151) CoStar (n=152)
MACE at 30-DaysEuroSTAR IIEuroSTAR II
MACE defined as composite of TVR, new Q- or non-Q-wave MI attributed to target vessel, or cardiac death attributed to target vessel
p=NS for all comparisons
0.7 0.7 1.3
29.1 27.8 29.8
0.0 0.7 2.6
17.815.1
19.7
0
10
20
30
40
50
CardiacDeath
Q-MI Non-Q-MI TVR TLR MACE
MA
CE
(%
)
UniStar (n=151) CoStar (n=152)
MACE at 8 Months EuroSTAR IIEuroSTAR II
p=0.0214 p=0.0079 p=0.0465
p=NS p=NS p=NS
Stent Thrombosis: Definitions per Protocol
• Subacute:– Abrupt vessel closure of the treatment site that
results in clinical manifestations of ischemia and occlusion occurring after the patient left the cath lab but with 30 days of index procedure
• MI attributed to target vessel• ACS with angiographic evidence of thrombus• Death within 30 days that cannot be attributed to
other obvious cause• Late:
– MI attributable to the target vessel, with angiographic documentation or thrombus or total occlusion at the target lesion 31-120 days post-procedure
EuroSTAR IIEuroSTAR II
0.70.00.0 0.0
0
2
4
6
8
10
Subacute Late
Ste
nt
Th
rom
bo
sis
(%)
UniStar (n=151) CoStar (n=152)
Stent Thrombosis EuroSTAR IIEuroSTAR II
p=NS for all comparisons
The four Studies with the Cobalt-Chromium CoStar™ Stent
releasing Paclitaxel 10µg/30 days (in-vitro) The four Studies with the Cobalt-Chromium CoStar™ Stent
releasing Paclitaxel 10µg/30 days (in-vitro)
COSTAR ICOSTAR I COSTAR IICOSTAR II EUROSTAR IEUROSTAR I EUROSTAR IIEUROSTAR II
Principal InvestigatorPrincipal InvestigatorU. KaulU. Kaul
IndiaIndia
M. W. KrucoffM. W. Krucoff
USAUSA
K. D. DawkinsK. D. Dawkins
UKUK
S. SilberS. Silber
GermanyGermany
Study DesignStudy Design RegistryRegistryRandomizedRandomized
vs. Taxusvs. Taxus RegistryRegistryRandomizedRandomized
vs. BMSvs. BMS
Patients (Paclitaxel)Patients (Paclitaxel) n = 40n = 40 n = 989n = 989 n = 145n = 145 n = 152n = 152
RVD, mmRVD, mm 2.46 2.46 ± 0.41± 0.41 2.77 2.77 ± 0.47± 0.47 2.62 2.62 ± 0.54± 0.54 2.74 2.74 ± 0.51± 0.51
Lesion Length, mmLesion Length, mm 15.94 15.94 ± ?± ? 15.35 15.35 ± 6.48± 6.48 10.9 10.9 ± 5.19± 5.19 15.12 15.12 ± 7.58± 7.58
6 - 8 Months Angiographic Results:6 - 8 Months Angiographic Results:
In-Segment RR, %In-Segment RR, % 0,00,0 16.9 (18.7)16.9 (18.7) 5.85.8 17.617.6
In-Stent Late Loss, mmIn-Stent Late Loss, mm 0,55 ± 0,380,55 ± 0,38 0.62 (0.64)0.62 (0.64) 0.28 ± 0.420.28 ± 0.42 0.41 ± 0.48
8 - 12 Months Clinical Results:8 - 12 Months Clinical Results:
TLR, %TLR, % 1.81.8 6.66.6 2.82.8 15.115.1
MACE, %MACE, % 7.57.5 11.011.0 8.38.3 19.719.7
Stent Thrombosis, %Stent Thrombosis, % 00 0.60.6 0.70.7 00
The four Studies with the Cobalt-Chromium CoStar™ Stent
releasing Paclitaxel 10µg/30 days (in-vitro) The four Studies with the Cobalt-Chromium CoStar™ Stent
releasing Paclitaxel 10µg/30 days (in-vitro)
COSTAR IICOSTAR II EUROSTAR IIEUROSTAR II
Principal InvestigatorPrincipal Investigator M. W. KrucoffM. W. Krucoff
USAUSA
S. SilberS. Silber
GermanyGermany
Study DesignStudy Design RandomizedRandomized
vs. Taxusvs. Taxus RandomizedRandomized
vs. BMSvs. BMS
Patients (Paclitaxel)Patients (Paclitaxel) n = 989n = 989 n = 152n = 152
RVD, mmRVD, mm 2.77 2.77 ± 0.47± 0.47 2.74 2.74 ± 0.51± 0.51
Lesion Length, mmLesion Length, mm 15.35 15.35 ± 6.48± 6.48 15.12 15.12 ± 7.58± 7.58
6 - 8 Months Angiographic Results:6 - 8 Months Angiographic Results:
In-Segment RR, %In-Segment RR, % 16.9 (18.7)16.9 (18.7) 17.617.6
In-Stent Late Loss, mmIn-Stent Late Loss, mm 0.62 (0.64)0.62 (0.64) 0.41 ± 0.48
8 - 12 Months Clinical Results:8 - 12 Months Clinical Results:
TLR, %TLR, % 6.66.6 15.115.1
MACE, %MACE, % 11.011.0 19.719.7
Stent Thrombosis, %Stent Thrombosis, % 0.60.6 00
different release kinetics ?
The four Studies with the Cobalt-Chromium CoStar™ Stent
releasing Paclitaxel 10µg/30 days (in-vitro) The four Studies with the Cobalt-Chromium CoStar™ Stent
releasing Paclitaxel 10µg/30 days (in-vitro)
COSTAR IICOSTAR II EUROSTAR IIEUROSTAR II
Principal InvestigatorPrincipal Investigator M. W. KrucoffM. W. Krucoff
USAUSA
S. SilberS. Silber
GermanyGermany
Study DesignStudy Design RandomizedRandomized
vs. Taxusvs. Taxus RandomizedRandomized
vs. BMSvs. BMS
Patients (Paclitaxel)Patients (Paclitaxel) n = 989n = 989 n = 152n = 152
RVD, mmRVD, mm 2.77 2.77 ± 0.47± 0.47 2.74 2.74 ± 0.51± 0.51
Lesion Length, mmLesion Length, mm 15.35 15.35 ± 6.48± 6.48 15.12 15.12 ± 7.58± 7.58
6 - 8 Months Angiographic Results:6 - 8 Months Angiographic Results:
In-Segment RR, %In-Segment RR, % 16.9 (18.7)16.9 (18.7) 17.617.6
In-Stent Late Loss, %In-Stent Late Loss, % 0.62 (0.64)0.62 (0.64) 0.41 ± 0.48
8 - 12 Months Clinical Results:8 - 12 Months Clinical Results:
TLR, %TLR, % 6.66.6 15.115.1
MACE, %MACE, % 11.011.0 19.719.7
Stent Thrombosis, %Stent Thrombosis, % 0.60.6 00
Angiography routinely performed at primary angiographic endpoint of 8 months
Angiography 1 month after the primary clinical endpoint at 8 months
Conclusions• EuroSTAR II is a positive trial, having reached its primary endpoint.
• The CoStar™ Paclitaxel-eluting stent had a significantly lower angiographic restenosis rate and a significantly lower late loss than the identically designed bare UniStar™.
• With comparable vessel size and comparable lesion length in the TAXUS-IV trial, in-stent late loss of the CoStar™ Paclitaxel-eluting stent in the EuroSTAR II trial was in the range of the Taxus stent.
• TLR, TVR and MACE were also significantly reduced.
• No early or late stent thromboses were seen with the CoStar™ stent.
• The reservoir technology combined with a completely absorbable polymer offers a great potential for further development using different drugs with modifiable optimization of release kinetics, specifically taylored to the patients’ needs.
EuroSTAR IIEuroSTAR II