Clopidogrel in ACS:

Overview

Marc S. Sabatine, MD, MPH

Investigator, TIMI Study Group

Associate Physician, Cardiovascular Division, BWH
Assistant Professor of Medicine, Harvard Medical School
 Clopidogrel: Mechanism
Clopidogrel ADP Receptor (P2Y12)

Ticlopidine ADP

ADP
GP IIb/IIIa
receptor
Collagen
Activation Thrombin
TXA2
Fibrinogen COX
TXA2

ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.

Adapted from Schafer AI. Am J Med. 1996;101:199-209.
 Clopidogrel in NSTE ACS: CURE
12,563 Pts, GP IIb/IIIa & early invasive approach discouraged

0.14
Placebo
0.12 (11.4%)
CV Death, MI, Stroke

0.10
Clopidogrel
0.08 (9.3%)

0.06
RR 0.80, p<0.001
0.04

0.02

0.0
0 3 6 9 12
Months of follow-up

CURE. NEJM 2001;345:494-502

 CURE: Very Early Efficacy of
Clopidogrel in NSTE ACS
CV Death, MI, Stroke, Severe Ischemia
0.025 Within First 24 Hours
Cumulative Hazard Rate

0.020 34%
Relative
Placebo Risk
0.015
+ Aspirin Reduction
(n=6303)
0.010
P=.003
Clopidogrel
0.005 + Aspirin
(n=6259)
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24
Hours After Randomization

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

 CURE: Benefit by Revascularization
Medical Rx Group PCI Group
0.20 0.20

CVD/MI/Stroke
Placebo
CVD/MI/Stroke

0.15 0.15
Placebo
0.10 0.10 Clopidogrel
0.05
Clopidogrel
0.05
RR: 0.80 (0.69-0.92) RR: 0.72 (0.57-0.90)
0.0 0.0
4 100 200 300 4 100 200 300

CABG Group
0.20 Placebo
CVD/MI/Stroke

0.15
Clopidogrel
0.10

0.05
RR: 0.89 (0.71-1.11)
0.0
4 100 200 300

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

CURE Safety Results

RR 1.38
(95% CI 1.13-1.67)
P=0.001

NEJM 2001;345:494-502
 Clopidogrel in STEMI
Double-blind, randomized, placebo-controlled trial in
3491 patients, age 18-75 yrs with STEMI < 12 hours

Fibrinolytic, ASA, Heparin

randomize

Clopidogrel
Placebo
300 mg + 75 mg qd
Study
Drug Primary endpoint:
Coronary Angiogram Occluded
(2-8 days) artery (TIMI Flow
Grade 0/1)
Open-label
clopidogrel or D/MI by time
per MD in of angio
both groups 30-day clinical follow-up
 Clopidogrel in STEMI

15
36%
36% Placebo

CV Death, MI, or Urg Revasc (%)

P<0.0001 20%
P<0.0001
Clopidogrel

10
5
Odds Ratio 0.80
(95% CI 0.65-0.97)
P=0.026
0

0 5 10 15 20 25 30
Clopidogrel Placebo days

Sabatine MS et al. NEJM 2005; 352: 1179

 Bleeding

Outcome Clopidogrel Placebo P value

(%) (%)
Through angiography
TIMI major (Hgb >5 g/dL or ICH) 1.3 1.1 NS
TIMI minor (Hgb 3-5 g/dL) 1.0 0.5 NS
Intracranial hemorrhage 0.5 0.7 NS
Through 30 days
TIMI major 1.9 1.7 NS
In those undergoing CABG 7.5 7.2 NS
CABG w/in 5 d of study med 9.1 7.9 NS
TIMI minor 1.6 0.9 NS
Sabatine MS et al. NEJM 2005; 352: 1179
COMMIT: Clopidogrel (75 mg qd) in STEMI
45,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)
Placebo (10.1%) Placebo (8.1%)

9 7
8
Clopidogrel Clopidogrel (7.5%)
Death, MI, Stroke (%)

(9.3%) 6
7

Mortality (%)
5
6

5 9% relative risk 4 7% relative risk

reduction (P=.002) reduction (P=.03)
4
3
3
2
2

1 1

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

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

COMMIT: Major bleed in hospital
Type Clopidogrel Placebo

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

Cerebral
Fatal 3940
Non-fatal 1615
Non-cerebral
Fatal 3637
Non-fatal 4636

Any major bleed 134 124

(0.58%) (0.54%)

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.
STARS CREDO
Leon et al. NEJM 1998; 339: 1665. Steinhubl et al. JAMA. 2002; 288: 2411.
Aspirin
12 Placebo
11.5%
+ ASA
Aspirin + warfarin 10

Death/MI/stroke 8 8.5%
P=0.001 6 Clopidogrel
+ ASA
4
Aspirin + ticlopidine
2 27% RRR
P = 0.02
0
0 3 6 9 12
Months after PCI
PCI
PCI-CLARITY Design

3491 Patients Randomized

into CLARITY-TIMI 28

1752 assigned clopidogrel

1739 assigned placebo
300 mg 75 mg/d

(CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT)

A n g i o g r a p h y
Open-label
clopidogrel w/ 933 underwent PCI 930 underwent PCI
loading dose during index hosp. during index hosp.
recommended

30-day clinical follow-up

PCI CV Death, MI, or Stroke
8
following PCI

Odds Ratio 0.54

(95% CI 0.35-0.85) No Pretreatment 6.2%
Percentage with outcome (%)

P=0.008
6

46%
4

Clopidogrel 3.6%
Pretreatment
2

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

0

0 10 20 30
Days post PCI
Meta-Analysis of Clopidogrel Pretreatment
MI before PCI (%)
Clopidogrel No Favors Favors
Pretreatment No Pretreatment
Trial Pretreatment Pretreatment

PCI-CURE 3.6 5.1

OR 0.67
CREDO n/a n/a P=0.005
0.25 0.5 1.0 2.0
CV Death or MI after4.0
PCI (%) OR (95% CI)
PCI-CLARITY 6.1

Overall 3.7 5.5

Clopidogrel No OR 0.71
Trial Pretreatment Pretreatment P=0.004
PCI-CURE 2.9 4.4
Sabatine MS et al. JAMA 2005;294:1224-32
0.25 0.5 1.0 2.0
OR (95% CI)
 Efficacy of Clopidogrel PreRx by GPI Use
Without GPI
Favors Favors
Trial Clopi PreRx No PreRx PreRx No PreRx
PCI-CURE 27/1039 (2.6) 39/988 (3.9)
CREDO 26/473 (5.5) 34/519 (6.6)
OR 0.72
PCI-CLARITY 22/639 (3.4) 30/615 (4.9) (0.53-0.98)
OVERALL 75/2151 (3.5) 103/2122 (4.9) P=0.03
0.25 0.5 1.0 2.0
OR (95% CI)
With GPI P=0.85 for
heterogeneity
Trial Clopi PreRx No PreRx by GPI use

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

CREDO 29/427 (6.8) 32/396 (8.1)
OR 0.69
PCI-CLARITY 12/288 (4.2) 28/310 (9.0) (0.47-1.00)
(0.47-1.00)
OVERALL 55/989 (5.6) 83/1063 (7.8) P=0.05
0.25 0.5 1.0 2.0
Sabatine MS et al. AHJ in press. OR (95% CI)
Clopidogrel for High Atherothrombotic Risk and
Ischemic Stabilization, Management, and
Avoidance (CHARISMA): Study Design
N=15,603
Clopidogrel
Patients 45 years 75 mg once daily
or older who are Aspirin 75-162 mg once daily (n=7600)
at high risk of
atherothrombotic
events
R Double-blind treatment up to 1,040 primary efficacy events occur*

Aspirin 75162 mg once daily

)
te
Placebo

da
y sit
1 tab once

d
ud vi
en
vis nth

vis nth

st y
*Event-driven trial: vis nth Visits every daily

d ud
o
it

primary efficacy (n=7600)

it

xe st
o

6 months
it
m

(fi al
1-

3-

outcome of vascular
6-

(12 m, 18 m),

n
Fi
death, MI, stroke and intermediate
phone calls
in between
R = randomization. (15 m, 21m)

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

 Overall Population: Primary Efficacy Outcome
(CV Death, MI, or Stroke)
Placebo + ASA
8 7.3%
Cumulative event rate (%)

Clopidogrel + ASA
6.8%
6

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

2 p=0.22

0
0 6 12 18 24 30
Months since randomization

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

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 analysis

ICH= Intracranial Hemorrhage

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

 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)
(Pinteraction=0.045)

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)

0.4 0.6 0.8 1.2 1.4 1.6

Clopidogrel Better Placebo Better

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

 Primary Endpoint (CV Death, MI, or Stroke)
in Patients with Previous MI, IS, or PAD
CAPRIE-like Cohort
10 N=9,478 Placebo + ASA
Primary outcome event rate (%)

8.8%
8 Clopidogrel + ASA
7.3%

4
RRR: 17.1 % [95% CI: 4.4%, 28.1%]
2 p=0.01

0
0 6 12 18 24 30
Months since randomization

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

300 mg upstream in INV strategy I

ACC/AHA 300 mg upstream + GPI in INV IIa
UA/ 2007
300 mg ASAP in CONS strategy I
NSTEMI
ESC 2007 300 mg immediately in all patients I

STEMI ACC/AHA
75 mg in all patients I
(non 1 300 mg load if age <75 yrs IIa
2007
PCI)
ACC/AHA/
SCAI 2005
300 mg 6 hrs before PCI I
PCI
ESC 2005 300 mg 6 hrs before PCI I