Disclaimer This slide kit presents data to support the rationale for the use of the ADP-receptor antagonist clopidogrel in approved and non-approved indications

DisclaimerDisclaimer

This slide kit presents data to support the rationale for This slide kit presents data to support the rationale for the use of the ADP-receptor antagonist clopidogrel in the use of the ADP-receptor antagonist clopidogrel in approved and non-approved indications approved and non-approved indications

The slide kit has been prepared for medical and The slide kit has been prepared for medical and scientific purposes, and cannot be considered as an scientific purposes, and cannot be considered as an inducement to use clopidogrel in non-registered inducement to use clopidogrel in non-registered indications indications

Neither Sanofi-Synthelabo nor Bristol-Myers Squibb Neither Sanofi-Synthelabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing inconsistent with that described in the full prescribing informationinformation

The CREDO TrialThe CREDO TrialCClopidogrel for the lopidogrel for the RReduction of eduction of EEventsvents

DDuring uring OObservationbservation

CClopidogrel for thelopidogrel for the RReduction of eduction of EEventsvents DDuring uring OObservationbservation

Steering CommitteeSteering Committee

Chair: Eric J.Topol, MDChair: Eric J.Topol, MD

Principal InvestigatorPrincipal Investigator

Steven R. Steinhubl, MDSteven R. Steinhubl, MD

The CREDO TrialThe CREDO Trial

Within 24 hoursWithin 24 hours

Incidence: 0.6%Incidence: 0.6%11

Acute Thrombosis

Subacute Thrombosis

Death

or MI

Within 4 weeksWithin 4 weeks

Incidence: 0.5%-5.7%Incidence: 0.5%-5.7%11

1 year1 year

Incidence: 15.8%Incidence: 15.8%22

11Mak K-H et al. Mak K-H et al. J Am Coll CardiolJ Am Coll Cardiol. 1996;27:494-503.. 1996;27:494-503. 22Steinhubl S et al. Steinhubl S et al. CirculationCirculation. 1999;100:18 (suppl): I-380. Abstract 1993.. 1999;100:18 (suppl): I-380. Abstract 1993.

Complications of Stent PlacementComplications of Stent Placement

Complications of Atherothrombotic DiseaseComplications of Atherothrombotic Disease

Early and Long-Term Risk of Ischemic EventsEarly and Long-Term Risk of Ischemic Events

Platelet Activation After PCIPlatelet Activation After PCI

00

1010

2020

3030

DaysDays

Placebo, No PretxPlacebo, No Pretx

Placebo + PretxPlacebo + Pretx

Abcix + PretxAbcix + Pretx

Abcix, No PretxAbcix, No Pretx

19.5%19.5%20.7%20.7%20.9%20.9%

28.5%28.5%

00 100100 200200 300300 365365

Pretx= Pre-treatmentPretx= Pre-treatmentSteinhubl S. Data presented at 1999 AHA Meeting, Atlanta, GA.Steinhubl S. Data presented at 1999 AHA Meeting, Atlanta, GA.

Risk of Death, MI, or Revascularization at 1 Year Follow-UpRisk of Death, MI, or Revascularization at 1 Year Follow-Up

% D

eath

, MI,

Tar

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Ves

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% D

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, MI,

Tar

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Ves

sel

Rev

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Rev

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EPISTENT: Importance of Pre-Treatment EPISTENT: Importance of Pre-Treatment with ADP-Receptor Antagonistswith ADP-Receptor Antagonists

††up to 12 months up to 12 months ‡‡plus ASA and other standard therapiesplus ASA and other standard therapies

Composite of CV-death or MI from randomization to end of follow-upComposite of CV-death or MI from randomization to end of follow-up††

Mehta et al. Mehta et al. Lancet. Lancet. 2001;358:527-533.2001;358:527-533.

PlaceboPlacebo‡‡ ClopidogrelClopidogrel‡‡

0.150.15

0.100.10

0.050.05

0.00.00 100100 200200 300300 400400

Days of follow-upDays of follow-up

12.6%12.6%

8.8%8.8%

P P = 0.002= 0.002N = 2658N = 2658

Cu

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azar

d R

ate

Cu

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d R

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31%31%Relative RiskRelative Risk

ReductionReduction

PCI-CURE – Long-Term Efficacy PCI-CURE – Long-Term Efficacy of Clopidogrelof Clopidogrel

TVR= Target Vessel RevascularizationTVR= Target Vessel Revascularization

11Steinhubl S, Ellis S, Wolski K, et al. Steinhubl S, Ellis S, Wolski K, et al. Circulation.Circulation. 2001;103:1403. 2001;103:1403. 22O’Shea, JC, Buller CE, Cantor WJ, et al. O’Shea, JC, Buller CE, Cantor WJ, et al. JAMA.JAMA. 2002;287 (5):618 – 21. 2002;287 (5):618 – 21.33Moliterno DJ, Yakubov SJ, DiBattiste PM, et al. Moliterno DJ, Yakubov SJ, DiBattiste PM, et al. Lancet. Lancet. 2002;360:355 – 360.2002;360:355 – 360.

--14.3%14.3%6.0%6.0%Abciximab + stentAbciximab + stent

--14.8%14.8%7.6%7.6%

TARGETTARGET33

Tirofiban + stentTirofiban + stent

17.5%17.5%14.2%14.2%6.9%6.9%

ESPRITESPRIT22

Eptifibatide + stentEptifibatide + stent

19.5%19.5%- - 5.3%5.3%

EPISTENTEPISTENT11

Abciximab + stentAbciximab + stent

1 Year1 Year6 Months6 Months30 Days30 Days

Event Rates in Active Compound ArmEvent Rates in Active Compound ArmSTUDYSTUDY & Treatment & Treatment

Death / MI / TVRDeath / MI / TVR

Outcomes After Stenting: Outcomes After Stenting: 30 Days - 1 Year30 Days - 1 Year

Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al. JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.

CREDO Study RationaleCREDO Study Rationale

Need for early pre-treatmentNeed for early pre-treatment

– clopidogrel loading dose provides early benefit clopidogrel loading dose provides early benefit

– this early benefit is enhanced if a loading dose is given this early benefit is enhanced if a loading dose is given pre-procedurepre-procedure

Need for long-term treatmentNeed for long-term treatment

– patients undergoing PCI remain at high-risk for long-term patients undergoing PCI remain at high-risk for long-term cardiac eventscardiac events

• there is an increased incidence of death, MI, and there is an increased incidence of death, MI, and revascularization at 1 and 3-year following PCI (revascularization at 1 and 3-year following PCI (15%)15%)

• high event rates represent the ongoing process of high event rates represent the ongoing process of atherothrombosis elsewhere in coronary vasculature atherothrombosis elsewhere in coronary vasculature

– there is also a need for reducing thrombotic events in other there is also a need for reducing thrombotic events in other arterial beds (cerebrovascular and peripheral)arterial beds (cerebrovascular and peripheral)

UTVR= Urgent Target Vessel RevascularizationUTVR= Urgent Target Vessel Revascularization


CREDO ObjectivesCREDO Objectives

ObjectivesObjectives

– to evaluate the long-term effect of prolonged (1 year) to evaluate the long-term effect of prolonged (1 year) therapy with clopidogrel plus ASA and other standard therapy with clopidogrel plus ASA and other standard therapies, for reducing the composite endpoint therapies, for reducing the composite endpoint of MI, stroke, and death in patients undergoing urgent of MI, stroke, and death in patients undergoing urgent or elective PCI, with or without stentor elective PCI, with or without stent

– to evaluate the effect of pre-treatment with a clopidogrel to evaluate the effect of pre-treatment with a clopidogrel 300 mg loading dose on the composite of death (all-cause), 300 mg loading dose on the composite of death (all-cause), MI (Q- or non-Q-wave), or urgent target vessel MI (Q- or non-Q-wave), or urgent target vessel revascularization (UTVR) at Day 28, in patients who revascularization (UTVR) at Day 28, in patients who underwent PCI, with or without stentunderwent PCI, with or without stent

– to evaluate the safety of clopidogrel, specifically the to evaluate the safety of clopidogrel, specifically the frequency of major bleeding events and early frequency of major bleeding events and early discontinuation of study drugdiscontinuation of study drug


CREDO EndpointsCREDO Endpoints

28 Day Endpoint28 Day Endpoint

– first occurrence of any component up to first occurrence of any component up to 28 days of the composite of:28 days of the composite of:

• death, MI, or UTVRdeath, MI, or UTVR 1 Year Endpoint1 Year Endpoint

– first occurrence of any component up to first occurrence of any component up to 1 year of the composite of: 1 year of the composite of:

• death, MI, or strokedeath, MI, or stroke

Clo

pid

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Clo

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Arm

Arm

Pla

ceb

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Pla

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o

Arm

Arm

†† Plus other standard therapiesPlus other standard therapies* Both groups received clopidogrel 75 mg + ASA 325 mg at time of procedure* Both groups received clopidogrel 75 mg + ASA 325 mg at time of procedure

PCI*PCI* 28 Days28 Days

Placebo + Placebo + ASAASA†† (325 mg) (325 mg)

Pre-treatmentPre-treatment3-24 h before PCI3-24 h before PCI

Clopidogrel 300 mgClopidogrel 300 mg+ ASA+ ASA†† (325 mg) (325 mg)

Clopidogrel 75 mg QDClopidogrel 75 mg QD+ ASA+ ASA†† 325 mg QD 325 mg QD

Clopidogrel 75 mg QDClopidogrel 75 mg QD+ ASA+ ASA†† 325 mg QD 325 mg QD

RR

12 Months12 Months


Placebo QDPlacebo QD+ ASA+ ASA†† (81-325 mg) QD (81-325 mg) QD

Clopidogrel 75 mg QDClopidogrel 75 mg QD+ ASA+ ASA†† (81-325 mg) QD (81-325 mg) QD

Overall Study Design Overall Study Design


Inclusion CriteriaInclusion Criteria

Patients aged > 21 yearsPatients aged > 21 years

– able to provide informed consentable to provide informed consent

– agree to comply with protocol-specified proceduresagree to comply with protocol-specified procedures Presenting with symptomatic CADPresenting with symptomatic CAD

– with objective evidence of ischemia, e.g.:with objective evidence of ischemia, e.g.:

• symptoms of angina pectoris or symptoms of angina pectoris or

• positive stress test or positive stress test or

• dynamic ECG changesdynamic ECG changes

– referred for elective or urgent PCIreferred for elective or urgent PCI

– candidate for either conventional angioplasty and/or primary candidate for either conventional angioplasty and/or primary intracoronary stent implantation intracoronary stent implantation


Exclusion CriteriaExclusion Criteria

Active internal bleeding or hx of hemorrhagic diathesisActive internal bleeding or hx of hemorrhagic diathesis

>50% stenosis of the left main coronary artery>50% stenosis of the left main coronary artery

Coronary anatomy not amenable to stent placementCoronary anatomy not amenable to stent placement

Planned staged interventional procedurePlanned staged interventional procedure

Failed PCI within 2 weeksFailed PCI within 2 weeks

Q-wave MI within 24 hoursQ-wave MI within 24 hours

Serum Creatinine Serum Creatinine 3.0 mg/dl3.0 mg/dl

ALT/AST >3x ULNALT/AST >3x ULN

IV GPIIb/IIIa antagonist within 7 daysIV GPIIb/IIIa antagonist within 7 days

Need for long-term anticoagulant or NSAID useNeed for long-term anticoagulant or NSAID use

Contraindications to antithrombotic/antiplatelet therapyContraindications to antithrombotic/antiplatelet therapy

n=2,116n=2,116

PP n=900PP n=900 PP n=915PP n=915

Clopidogrel pre-treatment Clopidogrel pre-treatment (loading dose 300 mg) (loading dose 300 mg) ++

clopidogrel long-term clopidogrel long-term (1 year)(1 year)

No pre-treatment No pre-treatment ++ clopidogrel short-term clopidogrel short-term

(28 days)(28 days)

ITT = Intent-to-Treat: All randomized patients (PP patients + patients who did not undergo PCI) ITT = Intent-to-Treat: All randomized patients (PP patients + patients who did not undergo PCI)

PP = Per Protocol: All patients who underwent PCI after randomizationPP = Per Protocol: All patients who underwent PCI after randomization


ITT n=1,063ITT n=1,063ITT n=1,053ITT n=1,053

Per-Protocol and Intent-to-Treat Per-Protocol and Intent-to-Treat PopulationsPopulations

* Plus ASA and other standard therapies* Plus ASA and other standard therapies


Clopidogrel* Clopidogrel* Placebo*Placebo*(n=1,053)(n=1,053) (n=1,063)(n=1,063)

Age (mean, yearsAge (mean, yearsSD) SD) 61.5 61.5 11.211.2 61.8 61.8 11 11

Female (%)Female (%) 29.329.3 27.9 27.9

Diabetes (%) Diabetes (%) 27.527.5 25.425.4

Hyperlipidemia (%)Hyperlipidemia (%) 75.775.7 76.276.2

Hypertension (%)Hypertension (%) 67.467.4 69.669.6

Family history of premature CAD (%)Family history of premature CAD (%) 41.541.5 42.942.9

Prior MI (%)Prior MI (%) 33.533.5 34.434.4

Prior Stroke (%)Prior Stroke (%) 6.46.4 7.07.0

Prior PAD (%)Prior PAD (%) 9.79.7 10.310.3

Baseline Characteristics Baseline Characteristics

Chronic Medication at BaselineChronic Medication at Baseline

Clopidogrel* Clopidogrel* Placebo*Placebo* (n=1,053)(n=1,053) (n=1,063)(n=1,063)

Aspirin (%) Aspirin (%) 29.929.9 29.629.6

Beta-Blockers (%)Beta-Blockers (%) 63.163.1 65.5 65.5

Statin (%) Statin (%) 53.653.6 57.557.5

ACE-I (%)ACE-I (%) 33.033.0 34.234.2

CCB (%)CCB (%) 25.525.5 29.429.4

* Plus ASA and other standard therapies* Plus ASA and other standard therapies Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al. JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.

Clopidogrel* Clopidogrel* Placebo* Placebo* (n=900)(n=900)†† (n=915)(n=915)††

IV GPIIb/IIIa Antagonist Use (%) IV GPIIb/IIIa Antagonist Use (%) 47.4 47.4 43.343.3

Pre-Specified (%) Pre-Specified (%) 24.124.1 22.7 22.7

Bail-Out (%) Bail-Out (%) 23.323.3 20.620.6

* Plus ASA and other standard therapies * Plus ASA and other standard therapies †† PP=Per-ProtocolPP=Per-Protocol


During the Period of Initial PCIDuring the Period of Initial PCI

Use of IV GPIIb/IIIa AntagonistsUse of IV GPIIb/IIIa Antagonists

Clopidogrel*Clopidogrel* Placebo*Placebo*(n=1,053)(n=1,053) (n=1,063)(n=1,063)

Unstable angina (%) Unstable angina (%) 52.552.5 53.153.1

Recent MI (%) Recent MI (%) 14.314.3 13.113.1

Stable angina or other (%) Stable angina or other (%) 32.832.8 32.832.8



Clinical Diagnosis Requiring PCIClinical Diagnosis Requiring PCI

MI, Stroke, or Death – ITT PopulationMI, Stroke, or Death – ITT Population



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Months From RandomizationMonths From Randomization

27% RRR27% RRRP=0.02P=0.02

Placebo*Placebo*Clopidogrel*Clopidogrel*

00

55

1010

1515

8.5%8.5%

11.5%11.5%

00 33 66 99 1212

Long-Term (1 Year) Benefits of Long-Term (1 Year) Benefits of Clopidogrel in PCI PatientsClopidogrel in PCI Patients

Clopidogrel*Clopidogrel* Placebo*Placebo*EndpointsEndpoints (n=1053)(n=1053) (n=1063)(n=1063) RRRRRR 95% CI95% CI

MI, Stroke, deathMI, Stroke, death 8.58.5 11.511.5 26.926.9 (3.9,44.4)(3.9,44.4)

MI, deathMI, death†† 7.97.9 10.410.4 24.024.0 (-0.9,42.7)(-0.9,42.7)

DeathDeath†† 1.71.7 2.32.3 24.624.6 (-38.9,59.1)(-38.9,59.1)

MIMI†† 6.76.7 8.48.4 20.820.8 (-8.4,44.2)(-8.4,44.2)

StrokeStroke†† 0.90.9 0.90.9 10.010.0 (-21.3,24.0)(-21.3,24.0)


† † The study was not powered to detect a treatment effect with clopidogrel in individual components The study was not powered to detect a treatment effect with clopidogrel in individual components of the composite endpoint. of the composite endpoint.


% of patients with events% of patients with events

Long-Term (1 Year) Benefits of Long-Term (1 Year) Benefits of ClopidogrelClopidogrel


0.60.6 0.80.8 1.01.0 1.21.2

IV GP IIb/IIIa Inhibitor UseIV GP IIb/IIIa Inhibitor Use YesYes (N=826) (N=826) NoNo (N=1289)(N=1289)ACSACS YesYes (N=1407)(N=1407) NoNo (N=694)(N=694)DiabetesDiabetes YesYes (N=560)(N=560) NoNo (N=1556)(N=1556)StentStent YesYes (N=1616)(N=1616) NoNo (N=500)(N=500)MaleMale (N=1510)(N=1510)FemaleFemale (N=606)(N=606)

OverallOverall (N=2116)(N=2116)

28.828.8 26.526.5

27.627.6 22.722.7

11.211.2 32.832.8

28.828.8 19.019.0 24.524.5 32.132.1

26.926.9

0.40.4Hazard ratio (95% CI)Hazard ratio (95% CI)

Placebo*Placebo*BetterBetter

Clopidogrel*Clopidogrel*BetterBetter RRRRRR

(52.4 to -6.5)(52.4 to -6.5)(49.3 to -6.6)(49.3 to -6.6)

(47.8 to -0.4)(47.8 to -0.4)(53.2 to -27.6)(53.2 to -27.6)

(46.2 to -46.8)(46.2 to -46.8)(51.6 to 6.8)(51.6 to 6.8)

(47.4 to 3.6)(47.4 to 3.6)(57.0 to -52.6)(57.0 to -52.6)(45.5 to -4.6)(45.5 to -4.6)

(58.9 to -12.1)(58.9 to -12.1)

(44.3 to 3.9)(44.3 to 3.9)

95% CI95% CI


SubgroupSubgroup

Consistent Long-Term Benefit of Consistent Long-Term Benefit of Clopidogrel: MI, Stroke, or Death Clopidogrel: MI, Stroke, or Death at 1 Yearat 1 Year


1 Year Results:1 Year Results:ConclusionsConclusions

Clopidogrel plus aspirin and other standard therapy Clopidogrel plus aspirin and other standard therapy demonstrated a 27% RRR (p=0.02) in the combined endpoint demonstrated a 27% RRR (p=0.02) in the combined endpoint of MI, stroke, and death compared to placebo plus aspirinof MI, stroke, and death compared to placebo plus aspirin

The benefit was consistent in all patient subgroups The benefit was consistent in all patient subgroups evaluatedevaluated

In the CREDO trial patients received standard In the CREDO trial patients received standard of care in the US:of care in the US:

– almost half of patients received IV GP IIb/IIIa antagonists, almost half of patients received IV GP IIb/IIIa antagonists, and clopidogrel showed an incremental benefit on top of IV and clopidogrel showed an incremental benefit on top of IV GP IIb/IIIa therapyGP IIb/IIIa therapy

– short time to PCI: 3 to 24 hours (per protocol); short time to PCI: 3 to 24 hours (per protocol); mean = 9.8 hoursmean = 9.8 hours

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Days From RandomizationDays From Randomization

No-PT - Placebo*No-PT - Placebo*

PT- Clopidogrel*PT- Clopidogrel*

00

55

1010

00 77 1414 2121 2828

PT = Pre-treatmentPT = Pre-treatment

*Plus ASA and other standard therapies*Plus ASA and other standard therapies

Death, MI, UTVR- PP PopulationDeath, MI, UTVR- PP Population

18.5% 18.5% RRRRRR

P=0.23P=0.23

99

88

11

44

33

22

77

66

8.3%8.3%

6.8%6.8%

Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al.

JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.

Early Effects of Pre-treatment with Early Effects of Pre-treatment with Clopidogrel – 28 Day ResultsClopidogrel – 28 Day Results

0.40.4 0.60.6 0.80.8 1.01.0 1.21.2

Hazard ratio (95% CI)Hazard ratio (95% CI)

3 to <6 hrs3 to <6 hrs 7.97.9 7.07.0 893 893

6 to 24 hr6 to 24 hr 5.85.8 9.4 9.4 851 851

RRR -13.4RRR -13.4P=NSP=NS

RRR 38.6RRR 38.6P=0.05P=0.05

RRR 18.5RRR 18.5P=0.23P=0.23Overall CREDO ResultsOverall CREDO Results

NN PT-Clopidogrel*PT-Clopidogrel* No-PT*No-PT*

Events (%)Events (%)No-PTNo-PTBetterBetter

PT-ClopidogrelPT-ClopidogrelBetterBetter

PT= Pre-treatmentPT= Pre-treatment



Effect of Timing of Loading Dose:Effect of Timing of Loading Dose:28 Day Endpoint - Death, MI, UTVR28 Day Endpoint - Death, MI, UTVR


Day 28 Results:Day 28 Results:ConclusionsConclusions

Pre-treatment with a clopidogrel loading dose Pre-treatment with a clopidogrel loading dose (300 mg) provided a favorable trend towards a (300 mg) provided a favorable trend towards a reduction in the composite of MI, death, and reduction in the composite of MI, death, and UTVR (18.5% RRR, p=0.23) UTVR (18.5% RRR, p=0.23)

Data suggest a greater benefit (RRR=38.6%, Data suggest a greater benefit (RRR=38.6%, p=0.05) when a clopidogrel loading dose was p=0.05) when a clopidogrel loading dose was given given 6 hours prior to PCI6 hours prior to PCI

The benefit of clopidogrel was incremental to the The benefit of clopidogrel was incremental to the use of IV GP IIb/IIIa antagonists, with a use of IV GP IIb/IIIa antagonists, with a favorable safety profilefavorable safety profile


Incremental Benefit of Treatment with Incremental Benefit of Treatment with Clopidogrel from 29 Days to 1 YearClopidogrel from 29 Days to 1 Year

In the ITT analysis, a 19.7% RRR was obtained In the ITT analysis, a 19.7% RRR was obtained for the reduction of the combined endpoint of for the reduction of the combined endpoint of death, MI, and stroke at 28 days with death, MI, and stroke at 28 days with pre-treatment of clopidogrelpre-treatment of clopidogrel

Continued treatment with clopidogrel from day Continued treatment with clopidogrel from day 29 to 1 year was associated with a further 37.4% 29 to 1 year was associated with a further 37.4% RRR (p=0.04) for the combined endpoint of RRR (p=0.04) for the combined endpoint of death, MI, and strokedeath, MI, and stroke

* Plus ASA and other standard therapies* Plus ASA and other standard therapies †† 101 patients underwent CABG in the clopidogrel group101 patients underwent CABG in the clopidogrel group‡‡ 99 patients underwent CABG in the placebo group99 patients underwent CABG in the placebo groupITT=Intent-To-Treat populationITT=Intent-To-Treat population


881717 Non-CABGNon-CABG

55556464 CABGCABG

0.120.1263 (5.9%)63 (5.9%)‡‡81 (7.7%)81 (7.7%)††ProceduralProcedural

0.280.288 (0.8%)8 (0.8%)13 (1.2%)13 (1.2%)Non-proceduralNon-procedural

0.070.0771 (6.7%)71 (6.7%)93 (8.8%)93 (8.8%)AnyAny

P-valueP-valuePlacebo* Placebo* (n=1,063)(n=1,063)

Clopidogrel* Clopidogrel* (n=1,053)(n=1,053)Major BleedingMajor Bleeding

Safety Outcomes: Major Bleeding Safety Outcomes: Major Bleeding Events One-Year Results ITTEvents One-Year Results ITT

0.340.347 (1.3%)7 (1.3%)11 (2.3%)11 (2.3%) No (n=991)No (n=991)

>0.99>0.999 (2.3%)9 (2.3%)9 (2.1%)9 (2.1%) Yes (n=823)Yes (n=823)

IV GP IIb/IIIa use – IV GP IIb/IIIa use –

(PPP only)(PPP only)

0.120.1236 (3.4%)36 (3.4%)‡‡50 (4.7%)50 (4.7%)††ProceduralProcedural

0.370.374 (0.4%)4 (0.4%)1 (0.1%)1 (0.1%)Non-proceduralNon-procedural

0.240.2440 (3.8%)40 (3.8%)51 (4.8%)51 (4.8%)AnyAny

P-valueP-valueNo No

pre-treatment* pre-treatment* (n=1,063)(n=1,063)

Pre-treatmentPre-treatmentwith clopidogrel* with clopidogrel*

(n=1,053)(n=1,053)Major BleedingMajor Bleeding

* Plus ASA and other standard therapies* Plus ASA and other standard therapies †† 101 patients underwent CABG in the clopidogrel group101 patients underwent CABG in the clopidogrel group‡‡ 99 patients underwent CABG in the placebo group99 patients underwent CABG in the placebo groupITT=Intent-To-Treat populationITT=Intent-To-Treat populationPPP= Per Protocol populationPPP= Per Protocol population


Safety Outcomes: Major Bleeding Safety Outcomes: Major Bleeding Events 28 Days ITT ResultsEvents 28 Days ITT Results



Overall Safety Outcomes: Overall Safety Outcomes: Conclusions at 1 YearConclusions at 1 Year

When clopidogrel was continued for a full year When clopidogrel was continued for a full year there was no statistically significant increase in there was no statistically significant increase in major bleeding (8.8% clopidogrel* vs. 6.7% major bleeding (8.8% clopidogrel* vs. 6.7% placebo*, p=0.07)placebo*, p=0.07)

Minor bleedings rates were comparable (5.3% Minor bleedings rates were comparable (5.3% clopidogrel* vs. 5.6% placebo*, p=0.84)clopidogrel* vs. 5.6% placebo*, p=0.84)

No fatal bleeds or intracranial hemorrhages No fatal bleeds or intracranial hemorrhages were observedwere observed



CREDO - General ConclusionsCREDO - General Conclusions

Long-term results at 1 year demonstrate that clopidogrel* Long-term results at 1 year demonstrate that clopidogrel* provided a 27% RRR (p=0.02) in the combined endpoint provided a 27% RRR (p=0.02) in the combined endpoint of MI, stroke, and deathof MI, stroke, and death

The results indicate an increased benefit of pre-treatment The results indicate an increased benefit of pre-treatment with clopidogrel ³6 hrs prior to PCI (RRR 38%, p=0.05)with clopidogrel ³6 hrs prior to PCI (RRR 38%, p=0.05)

Clopidogrel* provided incremental benefit between Day Clopidogrel* provided incremental benefit between Day 29 and 1 year (37.4% RRR, p=0.04)29 and 1 year (37.4% RRR, p=0.04)

In the CREDO trial patients received standard of care in In the CREDO trial patients received standard of care in the USthe US

The benefit was consistent through all patient subgroups The benefit was consistent through all patient subgroups evaluated and independent of the background therapy evaluated and independent of the background therapy including ASA, with a favorable safety profileincluding ASA, with a favorable safety profile

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Disclaimer This slide kit presents data to support the rationale for the use of the ADP-receptor antagonist clopidogrel in approved and non-approved indications