Cypher Endeavor Stent

CYPHER STENTCYPHER STENT

Interventional ConferenceInterventional Conference

How does it work?How does it work?

PathwayPathway

Stent DesignStent Design

Drug DiffusionDrug Diffusion

SIRIUSSIRIUS

Higher rate of incomplete stent Higher rate of incomplete stent apposition (18% vs 9%), but no apposition (18% vs 9%), but no clinical eventsclinical events

No difference in stent thrombosis No difference in stent thrombosis (0.8% in both group)(0.8% in both group)

5 yr followup5 yr followup

Pooled Analysis of 5-Year Follow-Up From 4

Randomized, Controlled CYPHER® vs. Bare-Metal

Stent Trials

The CYPHERThe CYPHER®® Stent Trials: Methodology Stent Trials: Methodology

Patient-level databases of pivotal RCTs were obtained from Patient-level databases of pivotal RCTs were obtained from Cordis Corporation by the Cardiovascular Research Cordis Corporation by the Cardiovascular Research Foundation with permission for unrestricted analysesFoundation with permission for unrestricted analyses RAVEL, SIRIUS, E-SIRIUS, C-SIRIUSRAVEL, SIRIUS, E-SIRIUS, C-SIRIUS

5-year data available for all trials5-year data available for all trials

Analysis Plan (performed by M. Fahy, Sr. Biostatistician)Analysis Plan (performed by M. Fahy, Sr. Biostatistician) EndpointsEndpoints

Safety:Safety: Death (overall, cardiac, non-cardiac); MI (all, QWMI); compositesDeath (overall, cardiac, non-cardiac); MI (all, QWMI); composites Stent thrombosis: ARC definitions; per protocolStent thrombosis: ARC definitions; per protocol

Efficacy:Efficacy: TLR and TVR TLR and TVR

Survival analyses utilizedSurvival analyses utilized to maximally utilize all available FU to maximally utilize all available FU information, compared by log-rank test (exact LR if <5 events)information, compared by log-rank test (exact LR if <5 events)

Kirtane A.J., et al., TCT 2007; Oral Presentation.

Death through 5 years:Death through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*

0%

5%

10%

15%

20%

0 365 730 1095 1460 1825

DaysNumber at risk

BMS

CYPHER

870

878

857

863

843

842

824

817

795

792

694

703

* RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS

HR 1.10 [0.79,1.52]

p=0.578.9% (76)

8.2% (69)


CYPHER Stent (n=878)Bare Metal Stent (n=870)CYPHER Stent (n=878)Bare Metal Stent (n=870)

DaysNumber at risk

BMS

CYPHER

870

878

857

863

843

842

824

817

795

792

694

703

HR 1.16 [0.72,1.85]

p=0.55

4.4% (37)3.9% (32)

0%

5%

10%

15%

20%

0 365 730 1095 1460 1825

Kirtane A.J., et al., TCT 2007; Oral Presentation.* RAVEL, SIRIUS, E-SIRIUS, C-SIRIUS


Cardiac Death through 5 years:Cardiac Death through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*

DaysBMS

CYPHER

868

873

824

832

806

807

782

779

751

751

652

660

Number at risk

HR 1.15 [0.81,1.63]

p=0.44

7.9% (67)

6.8% (58)

0%

5%

10%

15%

20%

0 365 730 1095 1460 1825


Myocardial Infarction (MI) through 5 years:Myocardial Infarction (MI) through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*


DaysBMS

CYPHER

869

877

852

854

837

832

816

804

786

780

685

693

Number at risk

HR 1.54 [0.77,3.09]

p=0.22

2.4% (20)1.6% (13)

0%

5%

10%

15%

20%

0 365 730 1095 1460 1825


Q-wave MI through 5 years:Q-wave MI through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*


DaysNumber at risk

BMS

CYPHER

868

873

824

832

806

807

782

779

751

751

652

660

HR 1.12 [0.88,1.45]

p=0.36

15.1% (130)

13.6% (115)

0%

5%

10%

15%

20%

0 365 730 1095 1460 1825


Death or MI through 5 years:Death or MI through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*


DaysNumber at risk

BMS

CYPHER

868

873

824

832

806

807

782

779

751

751

652

660

HR 1.13 [0.84,1.51]

p=0.4311.1% (94)9.8% (83)

0%

5%

10%

15%

20%

0 365 730 1095 1460 1825


Cardiac Death or MI through 5 years:Cardiac Death or MI through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*


DaysNumber at risk

BMS

CYPHER

870

878

853

858

839

836

820

811

791

785

690

697

Protocol ST Definitions do not count ST after intervening TLR

HR 2.19 [0.76,6.32]

p=0.131.3% (11)

0.6% (5)

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 365 730 1095 1460 1825

6 vs. 0, p=0.02After 1 yearAfter 1 year


Protocol-defined ST through 5 years:Protocol-defined ST through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*



DaysNumber at risk

BMS

CYPHER

870

878

853

859

838

837

818

811

789

784

688

695

HR 1.62 [0.67,3.91]

p=0.28 1.6% (13)

1.0% (8)

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 365 730 1095 1460 1825



ARC Definite ST through 5 years:ARC Definite ST through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*


0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 365 730 1095 1460 1825

DaysNumber at risk

BMS

CYPHER

870

878

848

858

834

835

813

809

784

783

683

694

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

0 365 730 1095 1460 1825

DaysNumber at risk

BMS

CYPHER

870

878

848

858

834

835

813

809

784

783

683

694

HR 0.99 [0.51,1.95]

p=0.99 2.1% (17)2.0% (17)



ARC Definite/Probable ST through 5 years:ARC Definite/Probable ST through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*



DaysNumber at risk

BMS

CYPHER

870

877

680

827

659

797

632

766

603

732

518

645

HR 0.35 [0.27,0.45]

p<0.0001

9.6% (80)

23.9% (205)

0%

5%

10%

15%

20%

25%

30%

0 365 730 1095 1460 1825


TLR through 5 years:TLR through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*



DaysNumber at risk

BMS

CYPHER

869

876

660

812

635

779

603

737

569

697

479

603

HR 0.44 [0.36,0.55]

p<0.0001

15.2% (127)

29.4% (250)

0%

5%

10%

15%

20%

25%

30%

0 365 730 1095 1460 1825



TVR through 5 years:TVR through 5 years:Pooled Analysis of 4 SES vs. BMS RCT’s*Pooled Analysis of 4 SES vs. BMS RCT’s*

From this independent, patient-level meta-analysis from the From this independent, patient-level meta-analysis from the 4 principal CYPHER4 principal CYPHER®® Stent trials it may be concluded that at Stent trials it may be concluded that at 5-year follow-up of patients with single de novo native 5-year follow-up of patients with single de novo native coronary lesions 2.5 – 3.5 mm in diameter and ≤30 mm in coronary lesions 2.5 – 3.5 mm in diameter and ≤30 mm in length, polymer-based sirolimus-eluting stents compared to length, polymer-based sirolimus-eluting stents compared to otherwise equivalent bare metal stents result in:otherwise equivalent bare metal stents result in: No significant increase in stent thrombosisNo significant increase in stent thrombosis

No significant increase in late stent thrombosis by ARC definitionsNo significant increase in late stent thrombosis by ARC definitions

No significant differences in death or myocardial infarction at any No significant differences in death or myocardial infarction at any time periodtime period

Sustained reduction in target lesion and target vessel Sustained reduction in target lesion and target vessel revascularizationrevascularization


On-Label CYPHEROn-Label CYPHER®® Stent Trials: Stent Trials:Conclusions through 5-year Follow-upConclusions through 5-year Follow-up

SES in AMISES in AMI

TYPHOON STUDYTYPHOON STUDY

SES in DMSES in DM

SES in small VesselSES in small Vessel

MVDMVD

Cypher vs TaxusCypher vs Taxus

All type: SES vs PES All type: SES vs PES all comersall comers

All type: SES vs PESAll type: SES vs PESall comersall comers

SES vs PESSES vs PESDM patientsDM patients

SES vs PESSES vs PESIn-stent restenosisIn-stent restenosis

SES vs PESSES vs PESlong lesionslong lesions

Meta-analysis: SES vs PESMeta-analysis: SES vs PES16 trials16 trials

Couple of precautionsCouple of precautions

Plavix?: follow up after 6 month of plavix

JACC-Meta Analysis for ST JACC-Meta Analysis for ST ’06’06

9-12 month follow-up9-12 month follow-up

DES vs BMS : MORTALITY/MI DES vs BMS : MORTALITY/MI benefit?????benefit?????

Comprehensive Meta-Analysis Comprehensive Meta-Analysis

of DES vs. BMS Randomized of DES vs. BMS Randomized

Trials and RegistriesTrials and Registries

Ajay J. Kirtane, M.D., S.M.Ajay J. Kirtane, M.D., S.M. Gregg W. Stone, M.D.Gregg W. Stone, M.D.

All-Cause Mortality: All RCTsAll-Cause Mortality: All RCTs

I-V Overall (I-squared = 0.0%, p = 0.918)

BASKET (SES only)

TAXUS II

HAAMU-STENTSeville

Ortolani et al

TAXUS IV

E-SIRIUS

Study ID

DIABETES

PRISON II

STRATEGY

RAVEL

SES-SMART

TAXUS V

Typhoon

MISSION!

SCORPIUSSESAMI

D+L Overall

Passion

C-SIRIUS

Pache et al

SIRIUS

0.97 (0.81, 1.15)

0.82 (0.37, 1.84)

1.61 (0.57, 4.53)

2.00 (0.63, 6.38)1.35 (0.23, 7.78)

2.00 (0.19, 21.38)

0.89 (0.63, 1.25)

1.08 (0.25, 2.24)

ES (95% CI)

1.44 (0.48, 4.33)

0.50 (0.09, 2.67)

0.84 (0.36, 1.96)

1.75 (0.73, 4.16)

0.21 (0.02, 1.71)

0.97 (0.57, 1.65)

1.01 (0.38, 2.65)

0.48 (0.09, 2.59)

1.28 (0.35, 4.61)0.43 (0.11, 1.63)

0.97 (0.81, 1.15)

0.70 (0.36, 1.36)

0.68 (0.11, 4.04)

1.40 (0.45, 4.35)

1.02 (0.67, 1.54)

100.00

4.80

2.87

2.301.00

0.55

26.29

2.57

(I-V)

2.55

1.07

4.30

4.08

0.62

10.92

3.27

1.09

Weight

1.861.70

6.99

0.95

2.40

17.82

%

0.97 (0.81, 1.15)

0.82 (0.37, 1.84)

1.61 (0.57, 4.53)

2.00 (0.63, 6.38)1.35 (0.23, 7.78)

2.00 (0.19, 21.38)

0.89 (0.63, 1.25)

1.08 (0.25, 2.24)

ES (95% CI)

1.44 (0.48, 4.33)

0.50 (0.09, 2.67)

0.84 (0.36, 1.96)

1.75 (0.73, 4.16)

0.21 (0.02, 1.71)

0.97 (0.57, 1.65)

1.01 (0.38, 2.65)

0.48 (0.09, 2.59)

1.28 (0.35, 4.61)0.43 (0.11, 1.63)

0.97 (0.81, 1.15)

0.70 (0.36, 1.36)

0.68 (0.11, 4.04)

1.40 (0.45, 4.35)

1.02 (0.67, 1.54)

100.00

4.80

2.87

2.301.00

0.55

26.29

2.57

(I-V)

2.55

1.07

4.30

4.08

0.62

10.92

3.27

1.09

Weight

1.861.70

6.99

0.95

2.40

17.82

%

1.1 1 10

8,867 patients, 21 trials8,867 patients, 21 trials

Favors BMS

Estimate (95% CI) Weight (%)

0.97 (0.81,1.15)0.97 (0.81,1.15), p=0.72

Random Effects*Fixed Effects (I2=0.0%)

Favors DES

Mean f/u 2.9 yrs

Ajay J. Kirtane and Gregg W. Stone, 2008

All-Cause Mortality: RCTs (On-Label)All-Cause Mortality: RCTs (On-Label)


Ortolani et al

TAXUS V - Simple

D+L Overall

TAXUS IV

Pache et al

C-SIRIUS

E-SIRIUS

SIRIUS

TAXUS II

Study ID

RAVEL

SCORPIUS

1.05 (0.84, 1.30)

2.00 (0.19, 21.38)

1.09 (0.53, 2.22)

1.05 (0.84, 1.30)

0.89 (0.63, 1.25)

1.40 (0.45, 4.35)

0.68 (0.11, 4.04)

1.08 (0.25, 2.24)

1.02 (0.67, 1.54)

1.61 (0.57, 4.53)

ES (95% CI)

1.75 (0.73, 4.16)

1.28 (0.35, 4.61)

100.00

0.85

9.20

40.20

3.67

%

1.45

3.93

27.25

4.39

(I-V)

6.23

2.84

Weight

1.1 1 10


Favors DES Favors BMS


1.05 (0.84,1.30)

1.05 (0.84,1.30), p=0.69

Random Effects

*Fixed Effects (I2=0.0%)

Mean f/u 4.0 yrs


All-Cause Mortality: RCT’s (Off-Label)All-Cause Mortality: RCT’s (Off-Label)


HAAMU-STENT

Passion

PRISON II

MISSION!

DIABETES

BASKET (SES only)

Seville

D+L Overall

SES-SMART

STRATEGY

TAXUS V - complex

Study ID

SESAMI

Typhoon

0.84 (0.62, 1.13)

2.00 (0.63, 6.38)

0.70 (0.36, 1.36)

0.50 (0.09, 2.67)

0.48 (0.09, 2.59)

1.44 (0.48, 4.33)

0.82 (0.37, 1.84)

1.35 (0.23, 7.78)

0.84 (0.62, 1.13)

0.21 (0.02, 1.71)

0.84 (0.36, 1.96)

0.84 (0.38, 1.84)

ES (95% CI)

0.43 (0.11, 1.63)

1.01 (0.38, 2.65)

100.00

6.64

20.16

Weight

3.10

3.16

7.36

13.84

%

2.87

1.80

12.40

14.32

(I-V)

4.90

9.44

1.1 1 10




0.84 (0.62,1.13)

0.84 (0.62,1.13), p=0.24

Random Effects


Mean f/u 1.5 yrs


All-Cause Mortality: All RegistriesAll-Cause Mortality: All Registries

NOTE: Weights are from random effects analysis

D+L Overall (I-squared = 70.1%, p = 0.000)

Ontario (matched)Germany Metabolic Syndrome

GHOST (adjusted)

RESTEMARTS II (from RCT)

ACUITY (from RCT)

Western Denmark (adjusted)

STENT (adjusted)Massachusetts (matched)

Cedars Acute MI

I-V Overall

NHLBI (on label, adjusted)

Wake Forest (adjusted)

DEScover (unadjusted)

Multicenter SVG (adjusted)

MIDAS (adjusted)

Liverpool (matched)

ERACI III (from RCT)

SCAAR (adjusted)Asan Korea (adjusted)

Study ID

Melbourne

McMaster STEMI (adjusted)

REAL (adjusted)

Mayo FFR SubstudyItalian Diabetic Multivessel (adjusted)

Washington Hosp Center (matched)Rotterdam Off-Label

NHLBI (off label, adjusted)

NY State (adjusted, unmatched)

0.80 (0.72, 0.88)

0.71 (0.59, 0.84) 1.47 (0.65, 3.35)

0.55 (0.36, 0.83)

0.73 (0.51, 1.05) 0.74 (0.41, 1.35)

0.63 (0.49, 0.82)

1.00 (0.86, 1.17)

0.69 (0.55, 0.87) 0.79 (0.71, 0.89)

0.82 (0.37, 1.83)

0.83 (0.79, 0.86)

1.47 (0.87, 2.48)

0.72 (0.55, 0.95)

0.53 (0.35, 0.80)

1.33 (0.47, 3.76)

0.66 (0.59, 0.74)

0.45 (0.24, 0.84)

1.18 (0.54, 2.58)

1.03 (0.94, 1.14) 0.60 (0.46, 0.79)

ES (95% CI)

0.67 (0.23, 1.94)

0.17 (0.03, 0.97)

0.83 (0.70, 0.98)

1.00 (0.21, 4.75) 1.22 (0.36, 4.10)

1.16 (0.78, 1.75) 0.98 (0.85, 1.13)

0.94 (0.64, 1.38)

0.84 (0.72, 0.97)

100.00

5.981.15

3.09

3.631.92

Weight

4.87

6.29

5.256.80

1.20

2.31

4.66

3.13

0.76

6.80

1.78

%

1.25

6.984.70

(D+L)

0.73

0.29

6.10

0.360.57

3.216.44

3.40

6.35

1.1 1 10

161,232 patients, 28 registries161,232 patients, 28 registries

Favors BMS


0.80 (0.72,0.88), p<0.0010.83 (0.79,0.86)

Favors DES

*Random Effects (I2=70.1%)Fixed Effects

Mean f/u 2.5 yrs


MI: All RCTsMI: All RCTs8,850 patients, 20 trials8,850 patients, 20 trials

D+L Overall (I-squared = 3.0%, p = 0.420)I-V Overall

SCORPIUS

TAXUS II

PRISON II

TAXUS V

Passion

STRATEGY

MISSION!

Typhoon

SIRIUS

TAXUS IV

BASKET (All)

RAVEL

Ortolani et alDIABETES

HAAMU-STENT

Study ID

E-SIRIUS

SES-SMART

SCANDSTENT

SESAMI

C-SIRIUS

1.1 1 10


SESAMI

Passion

C-SIRIUS

RAVEL

TAXUS IV

TAXUS V

SCORPIUS

SIRIUS

DIABETES

MISSION!

E-SIRIUS

SCANDSTENT

Study ID

Ortolani et al

SES-SMARTSTRATEGY

HAAMU-STENT

BASKET (All)

Typhoon

TAXUS II

PRISON II

D+L Overall

0.94 (0.79, 1.13)

1.00 (0.20, 4.88)

0.83 (0.26, 2.69)

0.59 (0.14, 2.47)

1.24 (0.49, 3.14)

0.99 (0.66, 1.48)

1.27 (0.79, 2.04)

0.82 (0.23, 2.95)

0.96 (0.59, 1.55)

0.60 (0.20, 1.50)

0.62 (0.28, 1.39)

1.94 (0.93, 4.02)

0.33 (0.09, 1.18)

ES (95% CI)

1.50 (0.26, 8.61)

0.16 (0.04, 0.67)0.82 (0.31, 2.40)

0.25 (0.03, 2.19)

1.15 (0.64, 2.08)

0.80 (0.22, 2.97)

0.63 (0.23, 1.72)

0.83 (0.26, 2.64)

0.94 (0.78, 1.13)

100.00

1.29

2.40

1.59

3.80

20.13

Weight

14.59

2.02

14.07

3.23

5.11

6.13

%

1.98

(I-V)

1.07

1.653.13

0.71

9.45

1.94

3.24

2.44

1.1 1 10


0.94 (0.78,1.13)0.94 (0.79,1.13), p=0.54


Random Effects*Fixed Effects (I2=3.0%)


Mean f/u 2.9 yrs

MI: RCTs (On Label)MI: RCTs (On Label)


RAVEL

Study ID

D+L Overall

SIRIUS

E-SIRIUS

TAXUS II

TAXUS IV

C-SIRIUS

TAXUS V - Simple

SCORPIUS

Ortolani et al

1.03 (0.81, 1.30)

1.24 (0.49, 3.14)

ES (95% CI)

1.03 (0.81, 1.30)

0.96 (0.59, 1.55)

1.94 (0.93, 4.02)

0.63 (0.23, 1.72)

0.99 (0.66, 1.48)

0.59 (0.14, 2.47)

0.98 (0.52, 1.81)

0.82 (0.23, 2.95)

1.50 (0.26, 8.61)

100.00

6.29

(I-V)

23.26

%

10.13

5.36

33.28

2.63

13.95

Weight

3.33

1.77

1.1 1 10




1.03 (0.81,1.30)

1.03 (0.81,1.30), p=0.82

Random Effects



Mean f/u 4.4 yrs

MI: RCT’s (Off Label)MI: RCT’s (Off Label)4,532 patients, 12 trials4,532 patients, 12 trials

1.1 1 10


SCANDSTENT

HAAMU-STENT

Typhoon

D+L Overall

SES-SMART

PRISON II

TAXUS V - complex

Passion

Study ID

STRATEGY

MISSION!

SESAMI

BASKET (All)

DIABETES

0.83 (0.62, 1.10)

0.33 (0.09, 1.18)

0.25 (0.03, 2.19)

0.80 (0.22, 2.97)

0.77 (0.54, 1.10)

0.16 (0.04, 0.67)

0.83 (0.26, 2.64)

1.84 (0.86, 3.94)

0.83 (0.26, 2.69)

ES (95% CI)

0.82 (0.31, 2.40)

0.62 (0.28, 1.39)

1.00 (0.20, 4.88)

1.15 (0.64, 2.08)

0.60 (0.20, 1.50)

100.00

5.08

1.83

4.97

4.24

Weight

6.26

%

14.52

6.16

(I-V)

8.03

13.11

3.30

24.22

8.29

1.1 1 10



SCANDSTENT

HAAMU-STENT

Typhoon

D+L Overall

SES-SMART

PRISON II

TAXUS V - complex

Passion

Study ID

STRATEGY

MISSION!

SESAMI

BASKET (All)

DIABETES

0.83 (0.62, 1.10)

0.33 (0.09, 1.18)

0.25 (0.03, 2.19)

0.80 (0.22, 2.97)

0.77 (0.54, 1.10)

0.16 (0.04, 0.67)

0.83 (0.26, 2.64)

1.84 (0.86, 3.94)

0.83 (0.26, 2.69)

ES (95% CI)

0.82 (0.31, 2.40)

0.62 (0.28, 1.39)

1.00 (0.20, 4.88)

1.15 (0.64, 2.08)

0.60 (0.20, 1.50)

100.00

5.08

1.83

4.97

4.24

Weight

6.26

%

14.52

6.16

(I-V)

8.03

13.11

3.30

24.22

8.29

1.1 1 10


0.77 (0.54,1.10)

0.83 (0.62,1.10), p=0.19

Random Effects



Mean f/u 1.5 yrs

MI: All RegistriesMI: All Registries



ACUITY (from RCT)

Melbourne

ARTS II (from RCT)

Asan Korea (adjusted)

Ontario (matched)

Study ID

NHLBI (on label, adjusted)

Washington Hosp Center (matched)

STENT (adjusted)



Germany Metabolic Syndrome

NHLBI (off label, adjusted)

Western Denmark (adjusted)

GHOST (adjusted)

SCAAR (adjusted)

REAL (adjusted)

RESTEM

DEScover (unadjusted)

Brazil Large Vessels

Cedars Acute MI

Massachusetts (matched)

Italian Diabetic Multivessel (adjusted)

I-V Overall

Mayo FFR Substudy


0.89 (0.80, 0.98)

1.07 (0.91, 1.25)

1.00 (0.39, 2.58)

0.53 (0.32, 0.88)

0.66 (0.42, 1.05)

1.10 (0.91, 1.32)

ES (95% CI)

0.71 (0.47, 1.05)

0.51 (0.29, 0.88)

0.69 (0.52, 0.92)

2.30 (0.91, 5.96)

0.84 (0.60, 1.18)

0.23 (0.07, 0.78)

0.71 (0.50, 1.00)

1.29 (1.06, 1.57)

1.12 (0.74, 1.70)

1.01 (0.91, 1.11)

0.92 (0.76, 1.11)

0.80 (0.52, 1.23)

0.69 (0.40, 1.18)

1.50 (0.25, 8.90)

0.25 (0.06, 1.16)

0.92 (0.83, 1.02)

1.02 (0.46, 2.25)

0.96 (0.91, 1.01)

0.67 (0.12, 3.84)

0.28 (0.04, 1.71)

100.00

8.90

1.10

3.09

3.55

8.26

(D+L)

4.21

2.69

6.10

1.11

5.15

0.70

5.01

Weight

%

8.02

4.03

10.17

8.18

3.86

2.80

0.33

0.48

10.10

1.50

0.35

0.30

0.89 (0.80, 0.98)

1.07 (0.91, 1.25)

1.00 (0.39, 2.58)

0.53 (0.32, 0.88)

0.66 (0.42, 1.05)

1.10 (0.91, 1.32)

ES (95% CI)

0.71 (0.47, 1.05)

0.51 (0.29, 0.88)

0.69 (0.52, 0.92)

2.30 (0.91, 5.96)

0.84 (0.60, 1.18)

0.23 (0.07, 0.78)

0.71 (0.50, 1.00)

1.29 (1.06, 1.57)

1.12 (0.74, 1.70)

1.01 (0.91, 1.11)

0.92 (0.76, 1.11)

0.80 (0.52, 1.23)

0.69 (0.40, 1.18)

1.50 (0.25, 8.90)

0.25 (0.06, 1.16)

0.92 (0.83, 1.02)

1.02 (0.46, 2.25)

0.96 (0.91, 1.01)

0.67 (0.12, 3.84)

0.28 (0.04, 1.71)

100.00

8.90

1.10

3.09

3.55

8.26

(D+L)

4.21

2.69

6.10

1.11

5.15

0.70

5.01

Weight

%

8.02

4.03

10.17

8.18

3.86

2.80

0.33

0.48

10.10

1.50

0.35

0.30

1.1 1 10




0.89 (0.80,0.98), p=0.023 0.96 (0.91,1.01)


*MI is QWMI in Washington Hospital Center, RESTEM

Ajay J. Kirtane and Gregg W. Stone, 2008Mean f/u 2.5 yrs

TVR: All RCTsTVR: All RCTs



Pache et al

Study ID

HAAMU-STENT

C-SIRIUS

Typhoon

STRATEGY

SIRIUS

SCANDSTENT

TAXUS II

PRISON II

TAXUS IV

E-SIRIUS

MISSION!

Ortolani et al

SESAMI

I-V Overall

TAXUS V

RAVEL

0.45 (0.37, 0.54)

0.38 (0.23, 0.64)

ES (95% CI)

0.33 (0.09, 1.19)

0.30 (0.10, 0.93)

0.42 (0.25, 0.69)

0.34 (0.16, 0.77)

0.48 (0.37, 0.62)

0.17 (0.09, 0.33)

0.61 (0.35, 1.08)

0.37 (0.19, 0.69)

0.57 (0.45, 0.72)

0.35 (0.21, 0.56)

0.38 (0.17, 0.85)

0.58 (0.25, 1.36)

0.36 (0.17, 0.79)

0.51 (0.45, 0.57)

0.77 (0.60, 0.98)

0.51 (0.25, 1.04)

100.00

7.14

(D+L)

1.91

2.45

7.20

4.22

11.51

5.44

%

6.44

5.49

11.94

Weight

7.45

4.08

3.78

4.36

11.75

4.83

1.1 1 10



Estimate (95% CI)Weight (%)

0.45 (0.37,0.54), p<0.0010.51 (0.45,0.57)


Mean f/u 3.2 yrsAjay J. Kirtane and Gregg W. Stone, 2008

TVR: RCTs (On Label)TVR: RCTs (On Label)



E-SIRIUS

TAXUS IV

SIRIUS

RAVEL

I-V Overall

TAXUS II

Study ID

C-SIRIUS

TAXUS V - Simple

Ortolani et al

Pache et al

0.53 (0.43, 0.65)

0.35 (0.21, 0.56)

0.57 (0.45, 0.72)

0.48 (0.37, 0.62)

0.51 (0.25, 1.04)

0.54 (0.47, 0.62)

0.61 (0.35, 1.08)

ES (95% CI)

0.30 (0.10, 0.93)

0.91 (0.64, 1.29)

0.58 (0.25, 1.36)

0.38 (0.23, 0.64)

100.00

10.98

19.99

19.03

6.65

9.25

(D+L)

3.19

15.38

5.08

Weight

10.44

%

1.1 1 10




0.53 (0.43,0.65), p<0.001

0.54 (0.47,0.62)

*Random Effects (I2=48.8%)

Fixed Effects

Mean f/u 4.2 yrs


TVR: RCTs (Off Label)TVR: RCTs (Off Label)



Typhoon

Study ID

STRATEGY

SCANDSTENT

TAXUS V - complex

I-V Overall

HAAMU-STENT

SESAMI

MISSION!

PRISON II

0.38 (0.27, 0.52)

0.42 (0.25, 0.69)

ES (95% CI)

0.34 (0.16, 0.77)

0.17 (0.09, 0.33)

0.62 (0.44, 0.86)

0.42 (0.34, 0.52)

0.33 (0.09, 1.19)

0.36 (0.17, 0.79)

0.38 (0.17, 0.85)

0.37 (0.19, 0.69)

100.00

16.43

(D+L)

10.35

12.95

21.55

%

4.98

10.65

10.04

Weight

13.06

1.1 1 10




0.38 (0.27,0.52), p<0.001

0.42 (0.34,0.52)

*Random Effects (I2=47.8%)

Fixed Effects

Mean f/u 1.6 yrs


TVR: All RegistriesTVR: All Registries



DEScover (adjusted)



GHOST (adjusted)

Montevergine

STENT (adjusted)

Washington Hosp Center (matched)

I-V Overall

Asan Korea (adjusted)

NY State (adjusted, unmatched)

RESTEM

Ontario (matched)

Cedars Acute MI

Brazil Large Vessels

REAL (adjusted)

Multicenter SVG (adjusted)

Study ID

Mayo FFR Substudy


0.53 (0.47, 0.61)

0.58 (0.40, 0.83)

0.32 (0.05, 1.92)

0.63 (0.48, 0.83)

0.28 (0.20, 0.39)

0.51 (0.39, 0.68)

0.58 (0.47, 0.71)

0.65 (0.49, 0.85)

0.57 (0.54, 0.60)

0.32 (0.24, 0.43)

0.54 (0.50, 0.60)

0.62 (0.47, 0.80)

0.69 (0.60, 0.80)

0.22 (0.08, 0.62)

0.43 (0.17, 1.10)

0.67 (0.59, 0.76)

0.58 (0.28, 1.18)

ES (95% CI)

0.18 (0.04, 0.78)

0.58 (0.39, 0.86)

100.00

5.81

0.46

7.38

6.31

7.30

8.70

7.35

Weight

7.05

10.70

7.53

9.88

1.34

1.57

10.17

2.41

(D+L)

0.68

5.35

%

1.1 1 10



Estimate (95% CI)Weight (%)

0.53 (0.47,0.61), p<0.001 0.57 (0.54,0.60)


Mean f/u 2.2 yrs


Conclusions (1)Conclusions (1)In 22 RCTs in which 9,470 pts were randomized to DES or BMS and followed for ≥1 yr, DES resulted in:

• Non significant 3% and 6% reductions in mortality and MI respectively

• A highly significant 55% reduction in TVR

In 30 registries in which 174,302 pts were treated with either DES or BMS and followed for ≥1 yr, DES resulted in:

• A highly significant 20% reduction in mortality

• A significant 11% reduction in MI

• A highly significant 47% reduction in TVR

Final NoteFinal Note

Majority of trial at short term Majority of trial at short term followup.followup.

No randomized studies so far to look No randomized studies so far to look at mortality benefit/harm between at mortality benefit/harm between BMS and DESBMS and DES

All powered to look at TLR and re-All powered to look at TLR and re-stenosis preventions.stenosis preventions.

Final NoteFinal Note

Of course there is sign benefit for TLR (5-8% vs Of course there is sign benefit for TLR (5-8% vs 30%)30%)

This is off set with slight (p= NS) increase in This is off set with slight (p= NS) increase in late ST.late ST. This has not translated into increase mortality in This has not translated into increase mortality in

meta-analysis and registeries.meta-analysis and registeries. We still do not know optimal time for anti We still do not know optimal time for anti

platelet therapy, but at least 1 yr recommended.platelet therapy, but at least 1 yr recommended. Increase risk of ST with increasing length of Increase risk of ST with increasing length of

stentstent SES better than PESSES better than PES

Endeavor StentEndeavor Stent

Endeavor-PharmocologyEndeavor-Pharmocology

MechanismMechanism

Drug Elution

• Zotarolimus elutes completely from the PC polymer coating to the injury site by the fourteenth day post-implant

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days

Pe

rce

nt D

rug

Elu

ted

(%

)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days

Pe

rce

nt D

rug

Elu

ted

(%

)

Preclinical studies on file at Medtronic, Inc.

Strut ComparisonStrut Comparison

Low-Profile Stent and Polymer

PC basecoat (~1 μm thick)

Drug layer90% zotarolimus (10 μg/mm)10% PC (~2–3 μm thick)

PC overspray (~0.1 μm thick)

148 μm 153 μm95 μmTotal thickness

132 μm 140 μm91 μmStrut thickness16 μm 13 μm4 μm (2.7 d/1.4 p)Drug/polymerTaxus® Cypher®Endeavor

3.0-mm stents500x magnification

Illustrationsnot to scale

The Endeavor stent has thin struts and a thin polymer coating compared with other DES

Stent strut

Stent strutStent strut

Post-elution~1-μm coating of PC polymer

Taxus is a registered trademark of Boston Scientific Corporation. Cypher is a registered trademark of Cordis Corporation

PolymerPolymer

Inert polymer-does not induce Inert polymer-does not induce inflammationinflammation

Physiological polymerPhysiological polymer

Stent SummaryStent Summary

DrugDrug ZotarolimusZotarolimus

Pharmocokenetic (similar to sirolimus)Pharmocokenetic (similar to sirolimus) Mechanism (similar to sirolimus)Mechanism (similar to sirolimus)

PolymerPolymer PCPC

Dilevery systemDilevery system Driver Stent Driver Stent Significantly smaller profileSignificantly smaller profile

Endeavor Clinical Program Endeavor Clinical Program OverviewOverview

9m 2yr 3yr 9m 2yr 3yr 4yr 4yrENDEAVOR I

ENDEAVOR II

ENDEAVOR II CA

ENDEAVOR III

ENDEAVOR IVENDEAVOR IV

ENDEAVOR PK

Single Arm First-in-Man (n=100) 4yrSingle Arm First-in-Man (n=100) 4yr

1:1 RCT vs. BMS (E=598,D=599) PK (n=106) 3yr1:1 RCT vs. BMS (E=598,D=599) PK (n=106) 3yr

Continued Access Single Arm (n=296) 2yrContinued Access Single Arm (n=296) 2yr

3:1 RCT vs. Cypher® (E=323,C=113) 2yr3:1 RCT vs. Cypher® (E=323,C=113) 2yr

1:1 RCT vs.Taxus® (E=773,T=775)1:1 RCT vs.Taxus® (E=773,T=775) 12mo12mo1:1 RCT vs.Taxus® (E=773,T=775)1:1 RCT vs.Taxus® (E=773,T=775) 12mo12mo

Pharmacokinetic Study (n=43) 9moPharmacokinetic Study (n=43) 9mo

Single Arm (n=99) 9moSingle Arm (n=99) 9moENDEAVOR Japan

E-FIVE Open Label Single Arm (n=8000)Open Label Single Arm (n=8000)

US Post Approval

PROTECT 1:1 RCT vs. Cypher (E=4400,C=4400)1:1 RCT vs. Cypher (E=4400,C=4400)

Open Label Single Arm Study (n=5000)Open Label Single Arm Study (n=5000)

Proposed

Ongoing

Premarket Safety and Efficacy Package

Endeavor IVEndeavor IVPatient FlowchartPatient Flowchart

Angio F/U (8 mo)Angio F/U (8 mo)135/164135/16482.3%82.3%

Patients EnrolledPatients EnrolledN = 1548N = 1548

RandomizedRandomizedEndeavorn = 773

TaxusTaxusn = 775n = 775

Angio F/U (8 mo)144/164 87.8%

Clinical F/U(9 mo)

758/77398.1%

Clinical F/UClinical F/U

(9 mo)(9 mo)749/775 749/775 96.6%96.6%

(12 mo)749/77396.9%

(12 mo)(12 mo)741/775 741/775 95.6%95.6%

Endeavor IV Endeavor IV Primary Endpoint Result Primary Endpoint Result

at 9 monthsat 9 monthsTarget Vessel Failure

TV

F

Ra

te

P for Non-Inferiority < 0.001Δ=3.8%

TaxusTaxus(n=54/749)(n=54/749)

EndeavorEndeavor(n=50/758)(n=50/758)

7.2%7.2%6.6%6.6%

Endeavor IVEndeavor IV 8 Month QCA8 Month QCA

EndeavorEndeavor(144 pts)(144 pts)

TaxusTaxus(135 pts)(135 pts) P valueP value

RVD (mm)RVD (mm) 2.65 2.65 0.470.47 2.68 2.68 0.45 0.45 0.6350.635

MLD (mm)MLD (mm)

In-stentIn-stent 1.95 1.95 0.610.61 2.25 2.25 0.61 0.61 <0.001<0.001

In-segment% DSIn-segment% DS 1.80 1.80 0.550.55 1.98 1.98 0.56 0.56 0.0080.008

% DS% DS

In-stentIn-stent 26.41 26.41 19.7419.74

16.09 16.09 17.9917.99 <0.001<0.001

In-segmentIn-segment 32.28 32.28 17.0217.02

26.61 26.61 15.5215.52 0.0040.004

Late loss (mm)Late loss (mm)

In-stentIn-stent 0.67 0.67 0.490.49 0.42 0.42 0.50 0.50 <0.001<0.001

In-segmentIn-segment 0.36 0.36 0.470.47 0.23 0.23 0.45 0.45 0.0230.023

Endeavor IVEndeavor IVClinical Events at 12 monthsClinical Events at 12 months

EndeavorEndeavorn=749n=749

TaxusTaxusn=741n=741 P-ValueP-Value

Death (all) – % (#)Death (all) – % (#) 1.1(8)1.1(8) 1.1(8)1.1(8) 1.0001.000

CardiacCardiac 0.5 (4)0.5 (4) 0.5 (4)0.5 (4) 1.0001.000

MI (all) – % (#)MI (all) – % (#) 1.6 (12)1.6 (12) 2.6 (19)2.6 (19) 0.2080.208

Q WaveQ Wave 0.3 (2)0.3 (2) 0.1 (1)0.1 (1) 1.0001.000

Non Q waveNon Q wave 1.3 (10)1.3 (10) 2.4 (18)2.4 (18) 0.1310.131

Death (cardiac) + MI (all) – Death (cardiac) + MI (all) – % (#)% (#) 2.1 (16)2.1 (16) 3.1 (23)3.1 (23) 0.2600.260

Stent Thrombosis (all) – % Stent Thrombosis (all) – % (#)(#) 0.8 (6)0.8 (6) 0.1 (1)0.1 (1) 0.1240.124

0-30 days 0-30 days 0.4 (3)0.4 (3) 0.1 (1)0.1 (1) 0.6250.625

31-360days 31-360days 0.4* (3) 0.4* (3) 0 0 0.2500.250

TLR – % (#)TLR – % (#) 4.5 (34) 4.5 (34) 3.2 (24)3.2 (24) 0.2280.228

TVR (non-TL) – % (#)TVR (non-TL) – % (#) 2.5 (19)2.5 (19) 4.2 (31)4.2 (31) 0.0850.085

TVR – % (#)TVR – % (#) 6.3 (47)6.3 (47) 6.7 (50)6.7 (50) 0.7530.753

MACE – % (#)MACE – % (#) 6.5 (49)6.5 (49) 6.6 (49)6.6 (49) 1.0001.000

TVF – % (#)TVF – % (#) 7.7 (58)7.7 (58) 9.4 (70)9.4 (70) 0.2670.267

*Day 83, 145, 171

TaxusEndeavorFre

edo

m f

rom

TV

F

100%

85%0 30 60 90 120 150 180 210 240 270 300 330 360

Time after Initial Procedure (days)

TVFTVF 00 3030 181800

272700

363600

EndeavEndeavoror

773773 760760 737737 712712 670670

TaxusTaxus 775775 748748 721721 692692 655655

90%

95%

TVF-free 92.3% 90.6% 0.243

Endeavor Taxus P (log rank)

Endeavor IVEndeavor IVTVF Free Survival to 360 TVF Free Survival to 360

daysdays

Endeavor IVEndeavor IV Target Vessel Target Vessel

RevascularizationRevascularization

EndeavorEndeavor(41/758)(41/758)

TaxusTaxus(37/749)(37/749)


TaxusTaxus(50/741)(50/741)

P P = 0.728= 0.728

9 months9 months 12 months12 months

Rat

eR

ate

P P = 0.753= 0.753

5.4% 4.9%6.3% 6.7%

Endeavor IVEndeavor IV Target Lesion Target Lesion

RevascularizationRevascularization


TaxusTaxus(20/749)(20/749)


TaxusTaxus(24/741)(24/741)

P P = 0.154= 0.154

9 months9 months 12 months12 months

Rat

eR

ate

P P = 0.228= 0.228

4.1%

2.7%

4.5%3.2%

8.5%

3.6%3.0% 3.3%

Endeavor IV Endeavor IV TLR by Angiographic Follow-up TLR by Angiographic Follow-up

at 12 monthsat 12 monthsT

LR

R

ate

12/14112/141 4/1334/133 22/60822/608 20/60820/608

EndeavorEndeavor TaxusTaxus EndeavorEndeavor TaxusTaxus

Angiographic Follow-upAngiographic Follow-up Clinical Follow-upClinical Follow-up

P P =0.070=0.070

P P =0.875=0.875

Endeavor IV Endeavor IV TVF – Post Hoc Subgroup AnalysisTVF – Post Hoc Subgroup Analysis

Risk Ratio Risk Ratio [95% CI][95% CI] Risk RatioRisk Ratio EndeavorEndeavor TaxusTaxus P-Value P-Value

InteractionInteraction

0.760.76

1.101.10

7.9%7.9%

6.2%6.2%

8.5%8.5%

6.9%6.9%0.9600.960

Diabetes

Non-diabetes

0.820.82

1.131.13

0.810.81

7.3%7.3%

7.2%7.2%

5.5%5.5%

9.0%9.0%

6.4%6.4%

6.7%6.7%

0.4790.479

RVD

2.5mm

>2.5 <3.0mm

3.0mm

0.650.65

1.191.19

0.530.53

4.4%4.4%

8.0%8.0%

5.8%5.8%

6.8%6.8%

6.7%6.7%

11.0%11.0%

0.7350.735

Lesion Length

10mm10mm

>10 <20mm>10 <20mm

20mm20mm

1.011.01

0.950.95

6.2%6.2%

14.3%14.3%

6.2%6.2%

15.1%15.1%0.9010.901

Single Stent

Multiple Stents

0.10.1 11 1010FavorsEndeavor

FavorsTaxus

Endeavor ConclusionEndeavor Conclusion

More flexible, smaller struts (driver More flexible, smaller struts (driver stent)stent)

Similar pharmo-kenetics to CypherSimilar pharmo-kenetics to Cypher Non inferior to Cypher and Taxus for Non inferior to Cypher and Taxus for

MACEMACE But higher late loss/re-stenosisBut higher late loss/re-stenosis Possibly no last stent thrombosis????Possibly no last stent thrombosis????

Cypher Endeavor Stent

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