Clopidogrel in ACS: Overview Investigator, TIMI Study Group Associate Physician, Cardiovascular...

Clopidogrel in ACS:Clopidogrel in ACS:OverviewOverview

Investigator, TIMI Study GroupAssociate Physician, Cardiovascular Division, BWH

Assistant Professor of Medicine, Harvard Medical School

Marc S. Sabatine, MD, MPHMarc S. Sabatine, MD, MPH

Clopidogrel: Mechanism

ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Adapted from Schafer AI. Am J Med. 1996;101:199-209.

CollagenThrombin

TXA2

ADP Receptor (P2YADP Receptor (P2Y1212))

TXATXA22

ADP

ADPADP

GP IIb/IIIaGP IIb/IIIareceptorreceptor

Activation

COX

Clopidogrel

Ticlopidine

Fibrinogen

Clopidogrel in NSTE ACS: CURE

CURE. NEJM 2001;345:494-502

12,563 Pts, GP IIb/IIIa & early invasive approach discouraged

RR 0.80, p<0.001

Clopidogrel(9.3%)

Placebo(11.4%)

CV

Dea

th,

MI,

Str

oke

Months of follow-up

0 3 6 9 120.0

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Yusuf S et al. Circulation 2003;107:966-972

CURE: Very Early Efficacy of Clopidogrel in NSTE ACS

Hours After Randomization

0.0

0.005

0.010

0.015

0.020

0.025

0 2 4 6 8 10 12 14 16 18 20 22 24

P=.003

Placebo+ Aspirin(n=6303)

Clopidogrel+ Aspirin(n=6259)

34%Relative RiskReduction

CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours

Cu

mu

lati

ve H

aza

rd R

ate

Fox et al. Fox et al. Circulation.Circulation. 2004;110:1202-1208. 2004;110:1202-1208.

Medical Rx GroupMedical Rx Group

PlaceboPlacebo

ClopidogrelClopidogrelRR: 0.80 (0.69-0.92)RR: 0.80 (0.69-0.92)

0.200.20

44

0.150.15

0.100.10

0.050.05

0.00.0100100 200200 300300

ClopidogrelClopidogrel

0.200.20

44

0.150.15

0.100.10

0.050.05

0.00.0100100 200200 300300

PCI GroupPCI Group

PlaceboPlacebo

RR: 0.72 (0.57-0.90)RR: 0.72 (0.57-0.90)

0.200.20

44

0.150.15

0.100.10

0.050.05

0.00.0100100 200200 300300

CABG GroupCABG GroupPlaceboPlacebo


RR: 0.89 (0.71-1.11)RR: 0.89 (0.71-1.11)

CURE: Benefit by RevascularizationC

VD

/MI/S

tro

ke

CV

D/M

I/Str

oke

CV

D/M

I/Str

oke

CURE Safety Results

1.8 2.22.7 2.4

5.0

2.22.8

3.7

5.1

8.5

0

2

4

6

8

10

12

Life-Threatening

Trans 2U Major Minor Any

Eve

nt

Rat

e (%

)

Placebo

Clopidogrel

RR 1.38(95% CI 1.13-1.67)

P=0.001

NEJM 2001;345:494-502

Clopidogrel in STEMI

Fibrinolytic, ASA, Heparin

Clopidogrel300 mg + 75 mg qd

Coronary Angiogram(2-8 days)

Primary endpoint:Occludedartery (TIMI Flow Grade 0/1)or D/MI by timeof angio

randomize

Placebo

Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours

StudyDrug

30-day clinical follow-up

Open-labelclopidogrelper MD in

both groups

ClopidogrelClopidogrel in STEMI in STEMI

15.0

21.7

0

5

10

15

20

25

Oc

clu

de

d A

rte

ry o

r D

ea

th/M

I (

%)

PlaceboPlaceboClopidogrelClopidogrel

36% P<0.0001

36% P<0.0001

Sabatine MS et al. NEJM 2005; 352: 1179

days

CV

Dea

th, M

I, o

r U

rg R

evas

c (%

)C

V D

eath

, MI,

or

Urg

Rev

asc

(%)

05

1015

0 5 10 15 20 25 30

PlaceboPlacebo


Odds Ratio 0.80Odds Ratio 0.80(95% CI 0.65-0.97)(95% CI 0.65-0.97)

P=0.026P=0.026

20%20%20%20%

BleedingBleeding

OutcomeOutcome Clopidogrel Clopidogrel (%)(%)

Placebo Placebo (%)(%)

P valueP value

Through angiographyThrough angiography

TIMI major TIMI major (Hgb (Hgb >5 g/dL or ICH) >5 g/dL or ICH) 1.31.3 1.11.1 NSNS

TIMI minor TIMI minor (Hgb (Hgb 3-5 g/dL) 3-5 g/dL) 1.01.0 0.50.5 NSNS

Intracranial hemorrhageIntracranial hemorrhage 0.50.5 0.70.7 NSNS

Through 30 daysThrough 30 days

TIMI majorTIMI major 1.91.9 1.71.7 NSNS

In those undergoing CABGIn those undergoing CABG 7.57.5 7.27.2 NSNS

CABG w/in 5 d of study medCABG w/in 5 d of study med 9.19.1 7.97.9 NSNS

TIMI minorTIMI minor 1.61.6 0.90.9 NSNSSabatine MS et al. NEJM 2005; 352: 1179

COMMIT: Clopidogrel (75 mg qd) in STEMI

9% relative risk reduction (P=.002)

Placebo (10.1%)

Clopidogrel (9.3%)

Days

Dea

th,

MI,

Str

oke

(%

)

9

8

7

6

5

4

3

2

1

00

Mo

rtal

ity

(%)

Days

Placebo (8.1%)

Clopidogrel (7.5%)

7% relative risk reduction (P=.03)

7

6

5

4

3

2

1

07 14 21 28 0 7 14 21 28

COMMIT Collaborative Group. Lancet. 2005;366:1607.

45,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)

Type Clopidogrel Placebo

(n=22,958) (n=22,891)

CerebralFatal 39 40

Non-fatal 16 15

Non-cerebralFatal 36 37Non-fatal 46 36

Any major bleed 134 124 (0.58%) (0.54%)

COMMIT: Major bleed in hospital

Chen Z et al. Lancet 2005;366:1607-21.

PCI – Rx following PCI

Following percutaneous coronary intervention (PCI), treatment with ADP receptor blockers such as ticlopidine or clopidogrel reduces thrombotic & ischemic complications.

Aspirin

Aspirin + warfarin

Aspirin + ticlopidine

P=0.001

CREDOSteinhubl et al. JAMA. 2002; 288: 2411.

12

10

8

6

4

2

0

STARSLeon et al. NEJM 1998; 339: 1665.

0 3 6 9 12Months after PCI

11.5%

8.5%

Placebo + ASA

Clopidogrel + ASA

27% RRRP = 0.02

Dea

th/M

I/s

tro

ke

PCI – PCI-CLARITY Design

30-day clinical follow-up

933 underwent PCI during index hosp.

930 underwent PCIduring index hosp.

3491 Patients Randomized into CLARITY-TIMI 28

1752 assigned clopidogrel300 mg 75 mg/d

1739 assigned placebo

Open-label clopidogrel w/ loading dose

recommended

(CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT)

A n g i o g r a p h y

PCI – CV Death, MI, or StrokeCV Death, MI, or Strokefollowingfollowing PCIPCI

02

46

8

0 10 20 30Days post PCI

Per

cen

tag

e w

ith

ou

tco

me

(%) No Pretreatment – 6.2%No Pretreatment – 6.2%

Clopidogrel – 3.6%Clopidogrel – 3.6%Pretreatment Pretreatment

46%46%46%46%


P=0.008P=0.008


P=0.008P=0.008

Sabatine MS et al. JAMA 2005;294:1224-32

Clopidogrel No

Trial Pretreatment Pretreatment

PCI-CURE 3.6 5.1

CREDO n/a n/a

PCI-CLARITY 4.0 6.1

Overall 3.7 5.5

Clopidogrel NoTrial Pretreatment Pretreatment

PCI-CURE 2.9 4.4

CREDO 6.0 7.1

PCI-CLARITY 3.3 5.4

Overall 3.9 5.5

Meta-Analysis of Clopidogrel PretreatmentMeta-Analysis of Clopidogrel Pretreatment

1.00.25 2.00.5

1.00.25 2.00.5OR (95% CI)

OR (95% CI)

CV Death or MI after PCI (%)CV Death or MI after PCI (%)CV Death or MI after PCI (%)CV Death or MI after PCI (%)

MI before PCI (%)MI before PCI (%)MI before PCI (%)MI before PCI (%)

OR 0.67OR 0.67P=0.005P=0.005OR 0.67OR 0.67P=0.005P=0.005

FavorsPretreatment

FavorsNo Pretreatment

OR 0.71OR 0.71P=0.004P=0.004OR 0.71OR 0.71P=0.004P=0.004

Sabatine MS et al. JAMA 2005;294:1224-32

Trial Clopi PreRx No PreRx

PCI-CURE 27/1039 (2.6) 39/988 (3.9)

CREDO 26/473 (5.5) 34/519 (6.6)

PCI-CLARITY 22/639 (3.4) 30/615 (4.9)

OVERALL 75/2151 (3.5) 103/2122 (4.9)

Trial Clopi PreRx No PreRx

PCI-CURE 14/274 (5.1) 23/357 (6.4)

CREDO 29/427 (6.8) 32/396 (8.1)

PCI-CLARITY 12/288 (4.2) 28/310 (9.0)

OVERALL 55/989 (5.6) 83/1063 (7.8)

Efficacy of Clopidogrel PreRx by GPI UseEfficacy of Clopidogrel PreRx by GPI Use

1.00.25 2.00.5

1.00.25 2.00.5OR (95% CI)

OR (95% CI)

OR 0.72OR 0.72(0.53-0.98)(0.53-0.98)

P=0.03P=0.03

OR 0.72OR 0.72(0.53-0.98)(0.53-0.98)

P=0.03P=0.03

FavorsPreRx

FavorsNo PreRx

OR 0.69OR 0.69(0.47-1.00)(0.47-1.00)

P=0.05P=0.05

OR 0.69OR 0.69(0.47-1.00)(0.47-1.00)

P=0.05P=0.05

Without GPIWithout GPIWithout GPIWithout GPI

P=0.85 for P=0.85 for heterogeneityheterogeneity

by GPI useby GPI use

With GPIWith GPIWith GPIWith GPI

Sabatine MS et al. AHJ in press.

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA): Study Design

Double-blind treatment up to 1,040 primary efficacy events occur*

Aspirin 75–162 mg once daily

Clopidogrel75 mg once daily

(n=7600)

Placebo1 tab once

daily (n=7600)

Aspirin 75-162 mg once daily

Fina

l stu

dy v

isit

(fix

ed s

tudy

end

dat

e)

1-m

onth

vis

it3-

mon

th v

isit

Patients 45 years or older who are at high risk of atherothrombotic events

R = randomization.

N=15,603

R

Bhatt et al. Am Heart J. 2004;148:263

*Event-driven trial: primary efficacy outcome of vascular death, MI, stroke

Visits every 6 months(12 m, 18 m…),and intermediate phone callsin between(15 m, 21m…)

6-m

onth

vis

it

Overall Population: Primary Efficacy Outcome (CV Death, MI, or Stroke)

Bhatt DL et al. NEJM 2006;354:1706-17

Cu

mu

lati

ve e

ven

t ra

te (

%)

0

2

4

6

8

Months since randomization

0 6 12 18 24 30

Placebo + ASA 7.3%

Clopidogrel + ASA6.8%

RRR: 7.1% [95% CI: -4.5%, 17.5%]p=0.22

Overall Population: Safety Results

Clopidogrel Placebo + ASA + ASA

Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value

GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09

Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17

Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89

GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08) <0.001

*Adjudicated outcomes by intention to treat analysisICH= Intracranial Hemorrhage


CHARISMA Study: Primary Efficacy Results (CV Death, MI, or Stroke) by Prespecified Entry Category

Population RR (95% CI) P value

Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.046(n=12,153)

Multiple Risk Factors 1.20 (0.91, 1.59)0.20 (n=3284)

Overall Population 0.93 (0.83, 1.05)0.22 (n=15,603)

0.6 0.8 1.41.2

Clopidogrel Better Placebo Better

1.60.4

(Pinteraction=0.045)


Primary Endpoint (CV Death, MI, or Stroke) in Patients with Previous MI, IS, or PAD“CAPRIE-like Cohort”

RRR: 17.1 % [95% CI: 4.4%, 28.1%]p=0.01

Pri

mar

y o

utc

om

e ev

ent

rate

(%

)

0

2

4

6

8

10

Months since randomization

0 6 12 18 24 30

Clopidogrel + ASA7.3%

Placebo + ASA 8.8%

N=9,478

Bhatt DL et al. JACC 2007;49:1982

Conclusions

• Upstream clopidogrel given across the spectrum of ACS death and ischemic complications

• Treatment benefit emerges early and is comparable regardless of ultimate revasc.

• Treatment mandated in patients after stenting

• Clopidogrel pretreatment before PCI death or ischemic complications after PCI, regardless of GP IIb/IIIa use

• Long-term use not beneficial in 1° prevention; may be beneficial in 2° prevention

Clopidogrel in the Guidelines

Setting Society Recommendation Grade

UA/NSTEMI

ACC/AHA2007

300 mg upstream in INV strategy

300 mg upstream + GPI in INV

300 mg ASAP in CONS strategy

I

IIa

I

ESC 2007 300 mg immediately in all patients I

STEMI(non 1 PCI)

ACC/AHA2007

75 mg in all patients

300 mg load if age <75 yrs

I

IIa

PCI

ACC/AHA/SCAI 2005

300 mg 6 hrs before PCI I

ESC 2005 300 mg 6 hrs before PCI I

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