Cobalt-Chromium Paclitaxel-eluting Stent vs. 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

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

[email protected]

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


CoStar™ Stent Design

Bridge Elements ReservoirsDuctile Hinges

Alternating hexagonal pattern



Bridge Elements ReservoirsDuctile Hinges

Alternating hexagonal pattern


highly deliverable


Bridge Elements Reservoirs

Avoid possible cracking of polymer


Ductile Hinges

The Power of Reservoir Technology

Single DrugStructure

Multiple DrugStructures

Drug Delivery ReservoirsDrug Delivery Reservoirs

Bi-Directional Uni-Directional

Single Adjacent


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


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


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


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


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


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


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


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


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


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

(%

)


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


0.70.00.0 0.0

0

2

4

6

8

10

Subacute Late

Ste

nt

Th

rom

bo

sis

(%)


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




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


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


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 ?




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


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


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.


Cobalt-Chromium Paclitaxel-eluting Stent vs. identical BMS

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