C.R.E.D.O. C lopidogrel for the R eduction of E vents D uring O bservation

C.R.E.D.O.Clopidogrel for the Reduction of Events

During Observation

Multicenter Multinational (USA, Canada) Prospective Multicenter Multinational (USA, Canada) Prospective Randomized Double Blind Placebo Controlled TrialRandomized Double Blind Placebo Controlled Trial

From Steinhubl et al, JAMA 2002;228:2411-20From Steinhubl et al, JAMA 2002;228:2411-20

C.R.E.D.O.Aim of the Study

Safety and efficacy of a loading dose of Safety and efficacy of a loading dose of Clopidogrel prior to elective PCIClopidogrel prior to elective PCI

Safety and efficacy of 1 Year vs 1 Month Safety and efficacy of 1 Year vs 1 Month combined treatment with Clopidogrel 75 mg + combined treatment with Clopidogrel 75 mg + ASA after elective PCIASA after elective PCI

C.R.E.D.O.Inclusion Criteria

Pts with symptomatic CAD scheduled for PCI Pts with symptomatic CAD scheduled for PCI without contraindications to antithrombotic or without contraindications to antithrombotic or antiplatelet treatment or stent implantation and antiplatelet treatment or stent implantation and with no ST segment elevation within 24 hrs or with no ST segment elevation within 24 hrs or planned staged procedures or recent (<7 days) planned staged procedures or recent (<7 days) administration of GP IIb-IIIa inhibitors, administration of GP IIb-IIIa inhibitors, clopidogrel or thrombolytics clopidogrel or thrombolytics

3-24 hrs before PCI3-24 hrs before PCI3-24 hrs before PCI3-24 hrs before PCI

28 Days and 1 Year Clinical Follow-Up28 Days and 1 Year Clinical Follow-Up28 Days and 1 Year Clinical Follow-Up28 Days and 1 Year Clinical Follow-Up

GP IIb-IIIa Inhib. (mainly Abciximab) on prespecified or Bail-out Indications

GP IIb-IIIa Inhib. (mainly Abciximab) on prespecified or Bail-out Indications

Clopidogrel 75 mg + ASA 325 mg for 1 Month

Clopidogrel 75 mg + ASA 325 mg for 1 Month

75 mg Clopidogrel +

ASA 325 mg for 1 Year

75 mg Clopidogrel +


Placebo+


Placebo+


300 mg Clopidogrel Loading Dose+

ASA 325 mg

300 mg Clopidogrel Loading Dose+

ASA 325 mg

Placebo+

ASA 325 mg

Placebo+

ASA 325 mg

C.R.E.D.O.

C.R.E.D.O.Outcomes

At 28 Days Death, MI, Urgent TVR in the per At 28 Days Death, MI, Urgent TVR in the per protocol population (all pts undergoing PCI) with protocol population (all pts undergoing PCI) with prespecified secondary analysis of pts receiving prespecified secondary analysis of pts receiving clopidogrel loading dose or placebo <6 hrs or clopidogrel loading dose or placebo <6 hrs or >>6 6 hrs before PCIhrs before PCI

At 1 Year Death, MI, Stroke with prespecified At 1 Year Death, MI, Stroke with prespecified secondary endpoints of TVRsecondary endpoints of TVR

Power Calculation based on a Power Calculation based on a Retrospective Analysis of 2450 Pts in the EPISTENT trial: 28 Days Events

13.4%13.4%

No Ticlopidine Ticlopidine ExpectedNo Ticlopidine Ticlopidine Expected Pre-PTCA Pre-PTCA for Clopid. LoadingPre-PTCA Pre-PTCA for Clopid. Loading(expected placebo) (expected placebo) Dose + 1 Year Dose + 1 Year

7.5%7.5%8.9%8.9%

From Steinhubl et al, JACC 1998;32:1366-70From Steinhubl et al, JACC 1998;32:1366-70

C.R.E.D.O.

P<0.01P<0.01

Age (yrs) 61+5 62+7 NS

Male Sex (%) 70.7% 72.1% NS

Diabetes (%) 27.5% 25.4% NS

Statins (%) 53.6% 57.5% p=0.07

Ca++ Chan. Block. (%) 25.5% 29.4% p=0.08

MI 14.3 13.1Indication (%) UAP 52.5 53.1 NS

SA 32.8 32.8

PTCA 85.6 86.2Treatment (%) Medical 8.3 7.6 NS

CABG 3.9 4.0

Clinical Characteristics (I)Clinical Characteristics (I)C.R.E.D.O.

Clopidogrel Loading Dose+ Clopidogrel 1 Year

N= 1053


N= 1053

Placebo Loading Dose+ Clopidogrel 1 Mo

N= 1063


N= 1063

Received >1 Stent (%) 89.7 88.3 NS

Total Stent Length (mm) 24.4 23.5 NS

GP IIb-IIIa Antag. (%) 47.4% 43.3%

p=0.08


N= 900


N= 900


N= 915


N= 915

Clinical Characteristics (II)Clinical Characteristics (II)C.R.E.D.O.

C.R.E.D.O.Death, MI and Urgent TVR at 28 DaysDeath, MI and Urgent TVR at 28 Days

Com

bin

e d E

nd

Po i

nt

Oc c

ur r

enc e

(%

)C

omb

ine d

En

dP

o in

t O

c cu

rre n

c e (

%)

1010

-18.5%-18.5%

Clopid. No LoadingClopid. No LoadingClopid. LoadingClopid. Loading

0 Days 7 14 21 28 0 Days 7 14 21 28 00

44

66

88

22

8.3%8.3%

6.8%6.8%

NSNS

C.R.E.D.O.Death, MI and Urgent TVR at 28 DaysDeath, MI and Urgent TVR at 28 Days

Com

bin

e d E

nd

Po i

nt

Oc c

ur r

enc e

(%

)C

omb

ine d

En

dP

o in

t O

c cu

rre n

c e (

%)

1010

-38.6%-38.6%

0 Days 7 14 21 28 0 Days 7 14 21 28 00

44

66

88

22

P=0.051P=0.051

Clopid. No LoadingClopid. No LoadingClopid. < 6 Hrs LoadingClopid. < 6 Hrs LoadingClopid. Clopid. >> 6 Hrs 6 Hrs

C.R.E.D.O.Death, MI, Urgent TVR at 28 DaysDeath, MI, Urgent TVR at 28 Days

C.R.E.D.O.Death, MI and Stroke at 1 YearDeath, MI and Stroke at 1 Year

Com

bin

e d E

nd

Po i

nt

Oc c

ur r

enc e

(%

)C

omb

ine d

En

dP

o in

t O

c cu

rre n

c e (

%)

0 3 6 9 12 Mths 0 3 6 9 12 Mths

00

55

1010

1515

-26%-26%

Clopid. 1 MthClopid. 1 MthClopid. 1 YearClopid. 1 Year

10.5%10.5%

8.5%8.5%

P=.02P=.02

C.R.E.D.O.Death, MI, Stroke at 1 Year in Key SubgroupsDeath, MI, Stroke at 1 Year in Key Subgroups

0 1/2 4 24 48 Hrs0 1/2 4 24 48 Hrs

Death MI Stroke TVRDeath MI Stroke TVR

1.71.7

1 Month Clopidogrel

2.32.3

6.76.7

8.48.4

0.90.9 0.90.9

13.113.1 13.613.6

1 Year Clopidogrel1 Year Primary and Secondary Prespecified EndPoints1 Year Primary and Secondary Prespecified EndPoints

C.R.E.D.O.

28 Days 1 Year28 Days 1 Year

4.84.8

1 Month Clopidogrel

P = 0.07

Loading Dose-1 Year ClopidogrelMajor BleedingsMajor Bleedings

P = 0.24

C.R.E.D.O.

3.83.8

8.88.8

6.76.7

More than ½ of major procedural bleedings due to CABGMore than ½ of major procedural bleedings due to CABG

C.R.E.D.O.Conclusions

Prolongation of treatment with an ADP Prolongation of treatment with an ADP inhibitor such as clopidogrel beyond 1 month inhibitor such as clopidogrel beyond 1 month after PCIreduces the incidence of death/MI at 1 after PCIreduces the incidence of death/MI at 1 yearyear

There is a strong trend to reduction of There is a strong trend to reduction of death/MI/urgent TVR at 28 daysdeath/MI/urgent TVR at 28 days after a loading after a loading dose of 300 mg of clopidogrel administered at dose of 300 mg of clopidogrel administered at least 6 hrs before PCIleast 6 hrs before PCI

C.R.E.D.O.Questions and Criticisms

Did pretreatment interfere with long-term Did pretreatment interfere with long-term results?results?

Did the poor compliance to long-term Did the poor compliance to long-term treatment with clopidogrel (only 63/61% of pts treatment with clopidogrel (only 63/61% of pts took the study drug) modify results? Can we took the study drug) modify results? Can we improve it?improve it?

Can we reduce the excess of bleeding?Can we reduce the excess of bleeding?

ASA <100 mg 100-150 mg 150-300 mg >300 mgASA <100 mg 100-150 mg 150-300 mg >300 mg

Aspirin Dose and Bleeding Events in CUREAspirin Dose and Bleeding Events in CURE

1.921.92

From Peters et al EHJ 2002;Suppl.4:510From Peters et al EHJ 2002;Suppl.4:510

Aspirin/Clopidogrel (p=0.042)

2.822.822.242.24

3.193.19 3.323.32

4.634.63

3.773.77

4.644.64

Major or Life Threatening Bleeding EventsMajor or Life Threatening Bleeding Events

Aspirin Alone (p=0.057)

12563 Pts with non-ST Elevation ACS12563 Pts with non-ST Elevation ACS

C.R.E.D.O.Will a higher loading dose help?Will a higher loading dose help?

0

10

20

30

40

50

60

70

80

90

300 + 75

600 + 150

10 + 10 Pts pretreated with 200 mg Aspirin10 + 10 Pts pretreated with 200 mg Aspirin

0 1/2 4 24 48 Hrs0 1/2 4 24 48 HrsAD

P 2

0 μ

mo l

- in

du

ced

Ag g

reg a

t io n

AD

P 2

0 μ

mo l

- in

du

ced

Ag g

r eg a

tion

From Muller et al, Heart 2001;85:92-93From Muller et al, Heart 2001;85:92-93

C.R.E.D.O.Do we still need IIb-IIIa inhibitors in pts with Do we still need IIb-IIIa inhibitors in pts with effective clopidogrel pretreatment?effective clopidogrel pretreatment?

ISAR- REACT: after 600 mg loading dose ISAR- REACT: after 600 mg loading dose

Clopidogrel: Randomization to Abciximab or Clopidogrel: Randomization to Abciximab or

Placebo Placebo

TOPSTAR StudyTOPSTAR Study

From Bonz et al, JACC 2002;40:662-8From Bonz et al, JACC 2002;40:662-8

Prior 30 min 12 Hrs 48 HrsPrior 30 min 12 Hrs 48 Hrs

100100 100100

1010

128128

1414

1081088787

9898

% P

late

let

Fu

nct

ion

% P

late

let

Fu

nct

ion

109 Pts with 375 mg Clopidogrel and 500 mg ASA 109 Pts with 375 mg Clopidogrel and 500 mg ASA 24 Hrs before PCI 24 Hrs before PCI

Placebo bolus + 18 Hrs infusionTirofiban 10 μg + 18 Hrs Infusion

TOPSTAR StudyTOPSTAR Study

From Bonz et al, JACC 2002;40:662-8From Bonz et al, JACC 2002;40:662-8

Positive Troponin T (>0.01 Positive Troponin T (>0.01 μg/ml)

40%40%

63%63%

109 Pts with 375 mg Clopidogrel and 500 mg ASA 109 Pts with 375 mg Clopidogrel and 500 mg ASA 24 Hrs before PCI 24 Hrs before PCI

Placebo bolus + 18 Hrs infusionTirofiban 10 μg + 18 Hrs Infusion

C.R.E.D.O.Is 1 Year Treatment Enough?Is 1 Year Treatment Enough?

CHARISMA: 15000 Stable Angina Pts with 42 Mths F-UpCHARISMA: 15000 Stable Angina Pts with 42 Mths F-Up

Dea

th, M

I K

a pla

n- M

e ier

cu

m.

Dea

th, M

I K

apla

n-M

e ie r

cu

m.

Haz

ard

rat

esH

a za r

d r

ates

From Metha et al, Lancet 2001;358:527-33From Metha et al, Lancet 2001;358:527-33

2658 Pts undergoing PCI in the CURE trial2658 Pts undergoing PCI in the CURE trial

C.R.E.D.O.Questions and Criticisms

What about cost-effectiveness?What about cost-effectiveness?

Mechanism of clinical benefit? prevention of Mechanism of clinical benefit? prevention of periprocedural damage, TVR late events and periprocedural damage, TVR late events and non TVR late eventsnon TVR late events

Long-term treatment with clopidogrel advised Long-term treatment with clopidogrel advised for pts who receive drug eluting stents (3 mths for pts who receive drug eluting stents (3 mths SIRIUS, 6 mths TAXUS) SIRIUS, 6 mths TAXUS)

C.R.E.D.O. C lopidogrel for the R eduction of E vents D uring O bservation

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