SCRIPPS CLINIC

Stent Safety: Fear Not Stent Safety: Fear Not

Paul S.Teirstein, MDChief of CardiologyDirector of Interventional CardiologyScripps Clinic

Disclosures:Cordis, Boston, Medtronic: Research Grants

Consultant

Speakers Bureau

Shepherd Scienti Equity

Renu Vermani gives informed consent to a DES patient

Source: Millennium Research Group

Influence of Clinical Trials Results andPerception:DES Penetration in the US

89.3% 89.0%87.9% 87.8% 88.0% 87.7%

86.1%

72.8%70.4% 70.2%

66.8%65.2% 64.8%

67.9%

85.9%83.9%

80.1%

76.9%

68.0%

60.0%

65.0%

70.0%

75.0%

80.0%

85.0%

90.0%

95.0%

BASKET LATE Trial ESC

conference

FDA Panel Meeting

COURAGE

SCRIPPS CLINIC

DES Penetration in the USin the US

68.1% 67.9%66.8%

65.2% 64.8%63.8%

62.6%

66.9%

62.1%61.1% 61.7%

62.7%

64.3%

55%

57%

59%

61%

63%

65%

67%

69%

71%

73%

75%

Mar 07 Apr May

Ju

n Jul

Aug

Sep

Oct Nov

Dec

Jan 0

8Feb

Mar

9.5% increase

Source: Millennium Research Group

Lagerqvist et al, NEJM 2007

DES pts = 13,738

Bare metal pts = 6,033

Lagerqvist et al, NEJM 2007

Lagerqvist et al, NEJM 2007

DES pts = 13,738

Bare metal pts = 6,033

Stent Thrombosis!

What a difference a year makes!

SCAARUCR

SWEDEN2007

0 1 2 3 4

0.00

0.05

0.10

0.15

2003-2005, Adjusted

Time (years)

Cum

ulat

ive

risk

of d

eath

BMSDES

BMS 18769 18136 17948 16109 13401 10326 7158 3970 1179DES 12015 11705 11559 9020 6181 3844 2153 847 115

RR: 1.03 (0.94, 1.14)

Adjusted DeathTotal cohort

N=35 262

0 1 2 3 4

0.00

0.05

0.10

0.15

2003-2005

Time (years)

Cum

ulat

ive

risk

of d

eath

BMSDES

BMS 12556 12185 12061 10837 9001 6920 4824 2697 783DES 6381 6237 6161 4844 3280 2038 1140 462 58

RR: 0.95 (0.83, 1.1)

One stent cohort

N=18 937

2003 – 2005 data: One more year of patients and follow-up. Mortality is no longer higher for DES

DES and Clinical Outcomes: The Mega-Meta Analysis

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

AllAll--Cause Mortality: All RCTsCause 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

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)

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

2.55

1.07

4.30

4.08

0.62

10.92

3.27

1.09

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)

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

2.55

1.07

4.30

4.08

0.62

10.92

3.27

1.09

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 yrsAjay J. Kirtane and Gregg W. Stone, 2008

NOTE: Weights are from random effects analysis

D+L Overall (I-squared = 70.9%, p = 0.000)

Asan Korea (adjusted)

SMART

Melbourne

Massachusetts (matched)

Washington Hosp Center (matched)

Multicenter SVG (adjusted)

I-V Overall

Rotterdam Off-Label

STENT (adjusted)

ACUITY (from RCT)

REAL (adjusted)

Liverpool (matched)

Wake Forest (adjusted)

Mayo FFR Substudy

Cedars Acute MI

GHOST (adjusted)

Sussex ElderlyERACI III (from RCT)

NY State (adjusted, unmatched)

Ontario (matched)

MIDAS (adjusted)

RESTEM

McMaster STEMI (adjusted)

Germany Metabolic Syndrome

Western Denmark (adjusted)

ARTS II (from RCT)

DEScover (unadjusted)

Northern New England (adjusted)

SCAAR (adjusted)

Italian Diabetic Multivessel (adjusted)

NHLBI (off label, adjusted)NHLBI (on label, adjusted)

0.78 (0.71, 0.86)

0.60 (0.46, 0.79)

0.59 (0.48, 0.71)

0.67 (0.23, 1.94)

0.79 (0.71, 0.89)

1.16 (0.78, 1.75)

1.33 (0.47, 3.76)

0.81 (0.78, 0.85)

0.98 (0.85, 1.13)

0.69 (0.55, 0.87)

0.63 (0.49, 0.82)

0.83 (0.70, 0.98)

0.45 (0.24, 0.84)

0.72 (0.55, 0.95)

1.00 (0.21, 4.75)

0.82 (0.37, 1.83)

0.55 (0.36, 0.83)

0.72 (0.30, 1.72)1.18 (0.54, 2.58)

0.84 (0.72, 0.97)

0.71 (0.59, 0.84)

0.66 (0.59, 0.74)

0.73 (0.51, 1.05)

0.17 (0.03, 0.97)

1.47 (0.65, 3.35)

1.00 (0.86, 1.17)

0.74 (0.41, 1.35)

0.53 (0.35, 0.80)

0.51 (0.26, 1.00)

1.03 (0.94, 1.14)

1.22 (0.36, 4.10)

0.94 (0.64, 1.38)1.47 (0.87, 2.48)

100.00

4.35

5.23

0.71

6.15

3.02

0.74

5.85

4.83

4.50

5.55

1.70

4.31

0.35

1.16

2.91

1.001.20

5.77

5.46

6.14

3.40

0.28

1.11

5.72

1.83

2.95

1.53

6.30

0.56

3.192.20

0.78 (0.71, 0.86)

0.60 (0.46, 0.79)

0.59 (0.48, 0.71)

0.67 (0.23, 1.94)

0.79 (0.71, 0.89)

1.16 (0.78, 1.75)

1.33 (0.47, 3.76)

0.81 (0.78, 0.85)

0.98 (0.85, 1.13)

0.69 (0.55, 0.87)

0.63 (0.49, 0.82)

0.83 (0.70, 0.98)

0.45 (0.24, 0.84)

0.72 (0.55, 0.95)

1.00 (0.21, 4.75)

0.82 (0.37, 1.83)

0.55 (0.36, 0.83)

0.72 (0.30, 1.72)1.18 (0.54, 2.58)

0.84 (0.72, 0.97)

0.71 (0.59, 0.84)

0.66 (0.59, 0.74)

0.73 (0.51, 1.05)

0.17 (0.03, 0.97)

1.47 (0.65, 3.35)

1.00 (0.86, 1.17)

0.74 (0.41, 1.35)

0.53 (0.35, 0.80)

0.51 (0.26, 1.00)

1.03 (0.94, 1.14)

1.22 (0.36, 4.10)

0.94 (0.64, 1.38)1.47 (0.87, 2.48)

100.00

4.35

5.23

0.71

6.15

3.02

0.74

5.85

4.83

4.50

5.55

1.70

4.31

0.35

1.16

2.91

1.001.20

5.77

5.46

6.14

3.40

0.28

1.11

5.72

1.83

2.95

1.53

6.30

0.56

3.192.20

1.1 1 10

All-Cause Mortality: All Registries169,595 patients, 31 registries

Favors BMS

Estimate (95% CI) Weight (%)

0.78 (0.71,0.86), p<0.0010.81 (0.78,0.85)

Favors DES

*Random Effects (I2=71%)Fixed Effects

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

TVR: All RCTsTVR: All RCTs

NOTE: Weights are from random effects analysis

D+L Overall (I-squared = 53.2%, p = 0.006)

Pache et al

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)

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

1.91

2.45

7.20

4.22

11.51

5.44

6.44

5.49

11.94

7.45

4.08

3.78

4.36

11.75

4.83

1.1 1 10

7,291 patients, 16 trials7,291 patients, 16 trials

Favors DES Favors BMS

Estimate (95% CI) Weight (%)

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

*Random Effects (I2=53.2%)Fixed Effects

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

SCRIPPS CLINIC

Is there a DES safety problem?

•Probabably NOT!•There may even be a safety advantage for some DES patient subgroups

•TVR benefit makes DES the right choice for most patients

SCRIPPS CLINIC

Do DES patients need prolonged dual antiplatelet therapy?

•Evils of dual antiplatelet therapy§Bleeding§Bruising§Cost§Need for unplanned surgery§Endless, daily, phone calls and questions from physicians and patients

2.55.3

11.6

18.9

6.1 7.5

15.8

2.8

0

5

10

15

20

25

Cardiac death MI TVR non MIrelated

MACE

6 m

onth

eve

nts

(%)

BMS DES

BASKET Trial: BASKET Trial: 18 Month18 Month MACEMACEN=836 (N=836 (All ptsAll pts with 18 month FU)with 18 month FU)

P=0.83P=0.83

Kaiser C et al. ESC 2006.Kaiser C et al. ESC 2006.

P=0.66P=0.66 P=0.05P=0.05 P=0.26P=0.26

0.8 1.30.0

1.3 1.32.6

1.2

4.14.9

1.4

0

2

4

6

8

Late stentthrombosis

Thrombosis-relatedevents

Cardiac death Non-fatal MI Death or MIEven

ts b

etw

een

6-18

mon

ths

(%) BMS DES

BASKET LATE Trial: 6-18 Mo MACEN=743 (pts with early events excluded)

P=0.01P=0.01

Pfisterer M. ACC 2006Pfisterer M. ACC 2006

P=0.04P=0.04P=0.50P=0.50 P=0.23P=0.23 P=0.09P=0.09

Kandzari.GreatWall_2007

18

Antiplatelet Therapy and DES

Eisenstein et al. JAMA 2007

Will new stent technology improve stent safety and reduce the need for

long term antiplatelet therapy?

Polymer and Drug MatrixPolymer and Drug Matrix

TissueTissue

BloodBlood

PC Basecoat PC Basecoat (≈ 1μm thick)(≈ 1μm thick)

Drug LayerDrug Layer90% Zotarolimus (1090% Zotarolimus (10μμg/mm)g/mm)10% PC10% PC (≈ 2(≈ 2--4μm thick)4μm thick)

PC Overspray PC Overspray (≈ 0.1 μm thick)(≈ 0.1 μm thick)Stent

Strut

3.0 mm Stents3.0 mm Stents500x magnification500x magnification

IllustrativeIllustrativeNot to ScaleNot to Scale

TaxusTaxusCypherCypherNew Gen New Gen DESDES

ENDEAVOR Safety ConsiderationsENDEAVOR Safety ConsiderationsDesign FeaturesDesign Features

HistopathologyHistopathology

Rapid drug elutionRapid drug elution

Stent design = reduced injury Stent design = reduced injury (rounded thin struts)(rounded thin struts)

0

25

50

75

100

0 5 10 15 20 25

% D

rug

Elut

ed

Time (Days)

65

8798 99

PC Basecoat PC Basecoat (≈ 1μm)(≈ 1μm)

Drug LayerDrug Layer90% Zotarolimus90% Zotarolimus10% PC10% PC (≈ 2(≈ 2--4μm)4μm)

Stent Strut

Biocompatible PCBiocompatible PC

SafeSafeformulationformulation

Inve

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atio

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438E

E

DES Release Profiles (in vivo)DES Release Profiles (in vivo)

Source: Medtronic Vascular Data Presentation, TCTMD; TAXUS IV SR Presentation, TCTMD; Cypher Presentation, TCTMD; Data on file at Abbott Vascular.

Perc

enta

ge

0

20

40

60

80

100

Time (day)0 30 60 9020 50 8010 40 70 110100 120

CYPHER®

TAXUS®

Endeavor™ XIENCE™ V

ENDEAVOR RESOLUTETM

180

Primary Endpoint: TVF at 9 monthsSecondary Endpoints: In-segment % DS at 8 months; TLR and TVR at 9

monthsDrug Therapy: ASA and Clopidogrel/Ticlid ≥6 months

Zotarolimus Dose: 10 mg per mm stent length

Primary Endpoint: TVF at 9 monthsSecondary Endpoints: In-segment % DS at 8 months; TLR and TVR at 9

monthsDrug Therapy: ASA and Clopidogrel/Ticlid ≥6 months

Zotarolimus Dose: 10 mg per mm stent length

ENDEAVOR IV – 3yr FU

Single Single De NovoDe Novo Native Coronary LesionNative Coronary LesionVessel Diameter: 2.5Vessel Diameter: 2.5––3.5 mm3.5 mm

Lesion Length: Lesion Length: ≤ ≤ 27 mm27 mmPrePre--dilatation requireddilatation required

30d 6mo 4yr3yr3yr2yr9mo 12mo8mo 5yrClinical/MACEClinical/MACE

Angiography/IVUSAngiography/IVUSQCA and IVUS QCA and IVUS

SubsetSubset(328 total = 21.2%)(328 total = 21.2%)

Clinical Trial Design Clinical Trial Design PIs: Martin B. Leon and David E. KandzariPIs: Martin B. Leon and David E. Kandzari

1:1 randomizationN = 1,548 patients

80 sitesUS

Endeavor Stent n = 774

Taxus Stentn = 774

ENDEAVOR IV – 3yr FUCD/MI to 36 months

10%

8%

6%

4%

0%

Cum

ulat

ive

Inci

denc

e of

Car

diac

Dea

th/M

I

0 90 180 270 360 450 540 630 720 810 900 990 1080

Time after Initial Procedure (days)

2%

Endeavor 773 769 754 747 734 720 706 703 697 685 673 669 666

Taxus 775 758 747 738 727 715 702 698 693 678 667 658 650

1-year HR0.66 [0.35, 1.25]

P=0.201P=0.201∆1.0%∆1.0%3.1%

2.1% 3.6%

7.1%

∆3.5%∆3.5%

3-year HR0.52 [0.32, 0.82]

P = 0.004P = 0.004

EndeavorTaxus

Values are the KM estimatesValues are the KM estimatesPP values were calculated by Log Rank Testvalues were calculated by Log Rank Test

0.1% 0.1%

0.8%0.7%

1.5%

0.0%

Rat

eR

ate

Endeavor (n=734)Taxus (n=734)

ARC DefiniteARC Definite ARC ProbableARC Probable ARC DefiniteARC DefiniteProbableProbable

n=6 n=11n=1n=5n=1

P =0.124P =0.124P =0.124P =0.124P =0.062P =0.062P =0.062P =0.062

P =0.006P =0.006P =0.006P =0.006

ENDEAVOR IV – 3yr FUARC VLAST 12-36 mos

RRR 91%RRR 91%NNT: 71NNT: 71P=0.006P=0.006

Values are the event ratesValues are the event ratesP values were calculated by Fisher Exact TestP values were calculated by Fisher Exact Test

1yr 2yr 3yr 4yr 5yr1yr 2yr 3yr 4yr 5yr

Continued Access Single Arm (n = 296) 4yrContinued Access Single Arm (n = 296) 4yrContinued Access Single Arm (n = 296) 4yrContinued Access Single Arm (n = 296) 4yrENDEAVOR II CAENDEAVOR II CA

ENDEAVOR IENDEAVOR I Single Arm FirstSingle Arm First--inin--Man (n = 100) 5yrMan (n = 100) 5yrSingle Arm FirstSingle Arm First--inin--Man (n = 100) 5yrMan (n = 100) 5yr

ENDEAVOR IIENDEAVOR II

ENDEAVOR IIIENDEAVOR IIIENDEAVOR IVENDEAVOR IV 1:1 RCT vs. Taxus1:1 RCT vs. Taxus®® (E = 773,T = 775) 3yr(E = 773,T = 775) 3yr1:1 RCT vs. Taxus1:1 RCT vs. Taxus®® (E = 773,T = 775) 3yr(E = 773,T = 775) 3yr

ENDEAVOR PKENDEAVOR PKSingle Arm (n = 99) 2yrSingle Arm (n = 99) 2yrSingle Arm (n = 99) 2yrSingle Arm (n = 99) 2yrENDEAVOR JapanENDEAVOR Japan

Premarket Safety and Efficacy Package

Endeavor Clinical Program Endeavor Clinical Program Pooled Safety and Efficacy AnalysesPooled Safety and Efficacy Analyses

1:1 RCT vs. BMS (E = 598,D = 599) PK (n = 106) 5yr1:1 RCT vs. BMS (E = 598,D = 599) PK (n = 106) 5yr1:1 RCT vs. BMS (E = 598,D = 599) PK (n = 106) 5yr1:1 RCT vs. BMS (E = 598,D = 599) PK (n = 106) 5yr

3:1 RCT vs. Cypher® (E = 323,C = 113) 3:1 RCT vs. Cypher® (E = 323,C = 113) 4yr4yr3:1 RCT vs. Cypher® (E = 323,C = 113) 3:1 RCT vs. Cypher® (E = 323,C = 113) 4yr4yr

Pharmacokinetic Study (n = 43) 3yrPharmacokinetic Study (n = 43) 3yrPharmacokinetic Study (n = 43) 3yrPharmacokinetic Study (n = 43) 3yr

Included in Pooled Safety and Efficacy Analyses Included in Pooled Safety and Efficacy Analyses (N=2132)(N=2132)

Included in Pooled Safety and Efficacy Analyses Included in Pooled Safety and Efficacy Analyses (N=2132)(N=2132)

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2008

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Page

27

27

Before 1 yearEndeavor: 0.7%Driver: 1.2%

After 1 year (VLST)Endeavor: 0.1%Driver: 0.3%

27

Endeavor Driver

Pooled Endeavor: Long-term safety

Days 0 30 270 360 720 1080 1440Endeavor 2132 2131 2114 2068 2036 1650 1087

% CI 0.0% 0.3% 0.5% 0.6% 0.7% 0.7% 0.7%Driver 596 595 587 576 570 559 543% CI 0.2% 1.2% 1.3 % 1.3% 1.3% 1.5% 1.5%

1.5%

0.7%

P = 0.071

0%

2%

4%

6%

8%

10%

0 9090 360 720 1440

ARC

Def

/Pro

b ST

180180 270270 450 540 630 810 900 990 1080 1170 13501260Days

ENDEAVOR Pooled Safety: Mauri, TCT 2008. E I (5 yr), E II (4 yr), E IICA (4 yr), E III (3 yr), E IV (2 yr) & E PK (1 yr).p-values are unadjusted for multiple comparisons. Pooled Kaplan-Meier analysis.

ARC Definite/Probable ST to 4 years

Everolimus-elutingXIENCE V

Paclitaxel-elutingTAXUS

3690 pts enrolled at 66 U.S. sitesRVD ≥2.5 mm - ≤3.75 mm; Lesion length ≤28 mm

Max. 3 lesions with a maximum of 2 per epicardial vesselPrePre--rand:rand: ASA ≥300 mg, clopidogrel ASA ≥300 mg, clopidogrel ≥300 mg load unless on chronic Rx≥300 mg load unless on chronic Rx

Randomized 2:1 XIENCE V®:TAXUS® Express2

Stratified by diabetes and presence of complex lesionsPre-dilatation mandatory

Clinical f/u only: 1, 6, 9 months and yearly for 1-5 years

Aspirin ≥80 mg QD for 5 years; clopidogrel 75mg QD for at least 12 mos (if not at high risk for bleeding)

SPIRIT IV Study Algorithm

XIENCE V 2458 pts

TAXUS1195 pts

Pvalue

Death, all 1.0% 1.3% 0.61

- Cardiac 0.4% 0.4% 1.00

- Non cardiac 0.6% 0.8% 0.52

MI, all 1.9% 3.1% 0.02

- Q-wave 0.1% 0.4% 0.13

- Non Q-wave 1.7% 2.8% 0.05

All death or MI 2.8% 4.1% 0.05

Cardiac death or MI 2.2% 3.3% 0.07

MI = Target Vessel MI + Non-Target Vessel MI Categorical data, 365 ± 28 days

Death and MI at 1 Year

Stent Thrombosis (ARC Def or Prob)

Number at risk

XIENCE V 2458 2426 2412 2388 2376

TAXUS 1229 1195 1184 1174 1166

1.06%

0.29%

Months

p=0.003

HR [95%CI] = 0.27 [0.11, 0.67]

Δ 0.77%

Sten

t thr

ombo

sis

(%)

XIENCE VTAXUS

COMPARE - Study Outline

Eligible Patients for PCI

Guide-wire passage± Predilatation

Operator blinded1:1 Randomization

Taxus Liberte Xience V

Clinical events were adjudicated by an independent CECTarget vessel revascularizations were analysed by an independent QCA core lab.

Expected MACE 9% versus 14 %

(delta 5%)Power 85%

1800 patients

Direct stenting 34 %Direct stenting 34 % “REAL WORLD”“REAL WORLD”

COMPARE Trial

AMI 25 %AMI 25 %

Calcification 34 %Calcification 34 %

Multistenting 62 %Multistenting 62 %

Ostial 19 %Ostial 19 %Thrombus 24 %Thrombus 24 % CTO 4 %CTO 4 %

NSTEMI 23 %NSTEMI 23 %

Multivessel 27 %Multivessel 27 %

Saphenous graft 2 %Saphenous graft 2 %

Bifurcation 10 %Bifurcation 10 %

Diabetes 18 % Diabetes 18 %

Chronic renal failure 3 %Chronic renal failure 3 %Left main 2 % Left main 2 %

Taxus Xience

2.6 %

0.7 %

Cum

ulat

ive

Inci

denc

e of

Eve

nts

(%)

Days Since Index Procedure

0

1

3

5

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

P = 0.002 (log-rank test)

RR = 0.26 (0.11-0.64)

2

4

COMPARE – 2ry Endpoint ResultEarly and Late Stent Thrombosis (definite & probable according ARC)

“I gotta have my Plavix”

Are we creating Plavix Are we creating Plavix Addicts?Addicts?

Data on file M

edtronic Inc.UC200802485aEE

95.6

76.3

42.7

26.3

9.9

98.7

% o

n D

APT

Post procedure 30 days 6 months 9 months

Endeavor Clinical ProgramEndeavor Clinical ProgramDual Antiplatelet Therapy Usage(average)

1 year 2 years

Before 1 yearEndeavor: 0.7%Driver: 1.2%

After 1 year (VLST)Endeavor: 0.1%Driver: 0.3%

1

Endeavor DriverEndeavor Driver

Pooled Endeavor: Reassuring long-term safety

1.5%559

0.7%16501080

1.5%1.3%1.3%1.3 %1.2%0.2%% CI543570576587595596Driver

0.7%0.7%0.6%0.5%0.3%0.0%% CI108720362068211421312132Endeavor1440720360270300Days

1.5%559

0.7%16501080

1.5%1.3%1.3%1.3 %1.2%0.2%% CI543570576587595596Driver

0.7%0.7%0.6%0.5%0.3%0.0%% CI108720362068211421312132Endeavor1440720360270300Days

1.5%

0.7%

P = 0.071

0%

2%

4%

6%

8%

10%

0 9090 360 720 1440

AR

C D

ef/P

rob

ST

180180 270270 450 540 630 810 900 990 1080 1170 13501260Days

ENDEAVOR Pooled Safety: Mauri, TCT 2008. E I (5 yr), E II (4 yr), E IICA (4 yr), E III (3 yr), E IV (2 yr) & E PK (1 yr).p-values are unadjusted for multiple comparisons. Pooled Kaplan-Meier analysis.

ARC Definite/Probable cumulative ST to 4 years

SCRIPPS CLINIC

Thienopyridine x 6 months:§ Single de novo atherosclerotic lesion with diameter stenosis 50% to 100% (includes total coronary occlusions § Lesion length ≤40 mm § Reference vessel diameter ≥2.25 mm to 4.0 mm§ Lesion not involving side-branch intended to be stented§ Ostial or non-ostial location § In-stent restenosis not treated with prior brachytherapy§ 1 or 2 vessels per patient (up to two lesions per vessel with each lesion meeting anatomic criteria above)§ Saphenous vein or arterial bypass graft

N = 900 patients treated with Endeavor stents

SCRIPPS CLINIC

Bedside Monitoring of Platelet Reactivity: Accumetrics VerifyNow Assay for Plavix responsiveness

Insert assay device Add blood sample Read result in minutes

SCRIPPS CLINIC

Patients

Plavix “resistant”

Plavix sensitive

All 6 episodes of stent thrombosis

Stent Thrombosis after DES Implantation at 6 Month Follow-up

N=321

Price MJ et al, ACC 2007

SCRIPPS CLINICSCRIPPS CLINIC4/28/2010

0.0%

5.0%

10.0%

15.0%

20.0%

0 1 2 3 4

Marcucci et alPrice et alPatti et al

N=683

N=380N=160

Increasing Risk With Greater Residual Reactivity After Clopidogrel According to VerifyNow P2Y12 AssayEvent Rates In Prospective PCI Studies Stratified By PRU Quartile

PRU Quartile (Increasing PRU)

Adapted from Price MJ, Circulation. 2009;119(19):2625-2632

Prim

ary

CV

Eve

nt ra

te

Stent Thrombosis Rates at End of StudyTritron Study

“Standard Therapy”placebo loading dose

clopidogrel 75mg +placebo/day

“Standard Therapy”placebo loading dose, then

clopidogrel 75mg +placebo/day

“Tailored Therapy”clopidogrel 600-mg*, thenclopidogrel 150-mg/day

Successful PCI with DES (with 600mg clopidogrel load) without major complication or GPIIb/IIIa use

VerifyNow P2Y12 Assay 12-24 hours post-PCI

PRU ≥ 230?

Non-Responder

Clinical Follow-up And Platelet Function Assessment at 30 days, 6M

Primary Endpoint: 6 month CV Death, Non-Fatal MI, ARC definite/prob ST

Yes No

N = 1100 N = 583

Responder

A B C

Random Selection

N = 1100

Safety Endpoint: GUSTO Moderate or Severe Bleeding

ACSRR

G R A V T A S

*total first day dose Price MJ et al, Am Heart J 2009

SCRIPPS CLINICSCRIPPS CLINIC4/28/2010

Clopidogrel, Genotype, and Clinical Outcomes in ACSTRITON Results According to Carriage of Reduced Fxn CYP2C19 Allele in ACS Patients Receiving Clopidogrel

12.1%

8.0%

P= 0.01

Carriers

Non-carriers

Reduced function allele present in 30% of population

Mega JL et al, NEJM 2009;360:354-62

SCRIPPS CLINIC

FEAR NOT

• Stent Thrombosis scare was never justified • New DES technology has significantly improved safety § Stent Thrombosis rates are lower§ Duration of dual anti-platelet requirement may shorter

• Personalized medicine - titrating anti-platelet therapy to individual’s genotype and platelet reactivity has likely further improved stent safety