You are on page 1of 51

Clopidogrel

in Patients with
Cerebrovascular
Disease
Part 2: Clinical Evidence

Clopidogrel:
a Unique Antiplatelet Agent

Mode of Action of Clopidogrel1

CLOPIDOGREL

C
ADP
ADP

GPllb/llla

Activation

(Fibrinogen receptor)

ASA
ASA

COX
TXA2

COX (cyclo-oxygenase)
ADP (adenosine diphosphate)
TxA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996; 101: 199209.

Collagen thrombin
TXA2

Effects of ADP-Receptor Activation


ADP / ATP

P2X1

P2Y1

P2Y12

Gq coupled
Cation influx
Ca2+

No effect on
fibrinogen
receptor

Calcium mobilization

Ca2+

Platelet shape change


Transient aggregation

Gi2 coupled
cAMP

Fibrinogen receptor activation


Thromboxane A2 generation

Sustained aggregation response

Adapted from Savi P et al. Biochem Biophys Res Commun 2001; 283: 37983, and Ferguson JJ. The Physiology of
Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice.
London: Martin Dunitz; 2000: pp.1535.

A Loading Dose of Clopidogrel Provides


Rapid and Full Effect by 3 Hours1
Healthy Volunteers

Mean inhibition (%)

100

80

60
40

*
*

Clopidogrel
75 mg

20

Clopidogrel
300 mg

0
-20

1.5

24

27

48

(n = 20/group)

Time (hours)
*p < 0.002 vs clopidogrel 75 mg
1. Data on file, Sanofi-Synthlabo, 1999, internal report PDY 3494.

Effects of Clopidogrel on a Key


Inflammatory Modulator (CD40L)1
Effects ex vivo in healthy volunteers
0.5
CD40L (Mn X)

0.4

Control
ADP, 30M

0.3
0.2

0.1
0
Control

1. Hermann A et al. Platelets 2001; 12: 7482.

ASA

Clopidogrel

Clopidogrel
plus ASA

*p < 0.05 versus ADP-stimulated controls

DNA synthesis (x fold increase)

Effects of Clopidogrel on Platelet-Dependent


Mitogenesis of Smooth Muscle Cells1,2
40
30
20

10

0
Control

ASA

Clopidogrel

Clopidogrel
plus ASA

*p < 0,05 versus control


1. Hermann A et al. Thromb Res 2002; 105: 1735. 2. Hermann A et al. Arch Pharmacol 2001;
363(suppl 4): 442.

Effects of Clopidogrel plus ASA vs Extended-Release


Dipyridamole plus ASA on Total Platelet and Fibrin Deposition1
7

p < 0.0001
ratio [CI 95%]
0.325 [0.21; 0.51]

6
5
4
3
2
1
0

Total Fibrin Deposition


7

Total fibrin deposition (ug/cm)

Total platelet deposition (Tera/m)

Total Platelet Deposition

p < 0.0001
ratio [CI 95%]
0.424 [0.33; 0.55]

6
5
4
3
2
1
0

Dipyridamole
plus ASA

Clopidogrel
plus ASA

Day 10

Dipyridamole
plus ASA

Clopidogrel
plus ASA

Day 10

Clopidogrel plus ASA was significantly more effective in inhibiting total


deposition of platelets (67% reduction) and of fibrin (58% reduction)
Cadroy Y , Circulation 2002, 106 (19) : II -181, 908

Current Clinical Evidence


with Clopidogrel

Current Clinical Evidence with clopidogrel


More than 35,000 patients in different studies1

Study

Patients

Maximum
follow-up

Number of
patients

Published in

CAPRIE2

Ischemic stroke, MI or PAD

36 months

19,185

Lancet, 1996

CLASSICS3

Coronary stenting

6 weeks

1,020

Circulation, 2000

CREDO4

PCI

12 months

2,116

JAMA, 2002

12 months

12,562

N Engl J Med, 2001

12 months

2,658

Lancet, 2001

CURE5
PCI-CURE*6

1.
2.
3.
4.
5.
6.

Unstable angina or NQWMI


CURE patients undergoing PCI

Bhatt D, Topol E. Nature Rev (Drug Dis) 2003; 3: 1528


CAPRIE Steering Committee. Lancet 1996; 348: 13291339
Bertrand NE et al. Circulation 2000; 102: 624629
Steinhubl S et al. JAMA 2002; 288(19): 2411242
The CURE Trial Investigators. N Engl J Med 2001; 345: 494502
Mehta SR et al. Lancet 2001; 358: 527533

* PCI-CURE is a sub-study of the CURE study

CAPRIE Trial: Design1


Objective: to compare the efficacy and safety of
clopidogrel 75 mg with active control ASA 325 mg
Double-blind, randomized, prospective trial
Multicenter (384 centers in 16 countries)
Follow-up of 19,185 patients from 1 to 3 years with:
Ischemic atherothrombotic stroke
Myocardial infarction (MI)
Peripheral arterial disease

Combined primary endpoint: cluster of ischemic


stroke, MI, and vascular death
1. CAPRIE Steering Committee. Lancet 1996; 348: 132939.

CAPRIE: Long-Term Efficacy of


Clopidogrel versus ASA1
Cumulative Event Rate
(Myocardial Infarction, Ischemic Stroke or Vascular Death)
ASA

Overall
relative
risk
Clopidogrel reduction

16

Cumulative event rate (%)

8.7% *

12

p = 0.043, n = 19,185
0
0

12

15

18

21

24

Months of follow-up
ASA = acetylsalicylic acid MI = myocardial infarction *Intention to treat analysis
1.CAPRIE Steering Committee. Lancet 1996; 348: 13291339.
2. Antiplatelet Trialists' Collaboration. BMJ 2002; 324: 7186.

27

30

33

36

CAPRIE: Clopidogrel Reduces


Hospitalizations* Compared with ASA
Cumulative event rate:
Re-hospitalization for ischemia* or bleeding**1

Cumulative event rate (%)

20

9.1%
Relative
risk
reduction

ASA

Event rate per year


15

P=0.018

ASA
8.85%

10

Clopidogrel

8.03%
Clopidogrel

p = 0.018

0
0
ASA = acetylsalicylic acid

10

15

20

25

Months of follow-up

* Transient ischemic attack, angina pectoris, peripheral arterial disease


** Gastrointestinal, central nervous system or other bleeding
1. Bhatt et al. Am Heart J 2000; 140: 6773

30

35

CAPRIE: Amplified Benefit of Clopidogrel


in Patients with Higher Vascular Risk13
Events Prevented/1,000 Patients/Year over ASA

Event rate*/1000 patients


(average follow-up, 2 years)

300
250
200
152
150

1
1

200

2
8

238

3
4
204

172

141

100
50
0
All CAPRIE patients
(n=19,825)

Prior history of any Prior history of major


ischemic event acute event (MI or stroke)3
(n=8,854)
(n=4,496)

*Event rate of myocardial infarction, ischemic stroke, or vascular death


1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Jarvis B, Simpson K. Drugs
2000; 60: 34777. 3. Ringleb PA et al. Eur Heart J 1999; 20: 666.

ASA
Clopidogrel

CAPRIE: Amplified Benefit of Clopidogrel


in Patients with Diabetes1,2
Events Prevented/1,000 Patients/Year over ASA

Event rate*/1000 patients/year

250
200
150

137

1
1

177

2
1

215

3
8
177

156

ASA
Clopidogrel

126

100
50
0
All CAPRIE patients

Diabetes

Diabetes treated with


insulin

*Event rate of myocardial infarction, stroke, vascular death, or hospitalization


1. Bhatt DL et al. Am Heart J 2000; 140: 6773. 2. Jarvis B, Simpson K. Drugs 2000; 60: 34777.

CURE: Design1
Objective: to evaluate the early and long-term efficacy and safety
of clopidogrel (300/75 mg) on top of standard therapy (including
ASA)
Double-blind, randomized, prospective trial
Multicenter (482 centers in 28 countries)
Follow-up of 12,562 patients from 3 months to 1 year with acute
coronary syndromes (without ST segment elevation)
Primary endpoint: first occurrence of any component of the
cluster of:
cardiovascular death
myocardial infarction
stroke (ischemic, hemorrhagic, or of uncertain type)

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.

CURE: Early and Long-Term Efficacy of


Clopidogrel
Cumulative events (MI, stroke, or cardiovascular death)

Cumulative hazard rate

0.14

20%*

Relative
risk
reduction
p = 0.00009

Placebo (+ASA)*
(n =6,303)

0.12
0.10
0.08

Clopidogrel* (+ ASA)
(n = 6,259)

0.06
0.04
0.02
0.00

Months of follow-up
*On top of standard therapy (including ASA)
1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502
2. Data on file, 2002, p73 internal CSR-EFC 3307

12

CURE : Early and Long-term Efficacy of


Clopidogrel
Primary endpoint (stroke, MI or cardiovascular death)
8%
p < 0.001

7%
6%

p < 0.001

6,3%

5,4%

5%

5,2%
4,3%

4%
3%
2%
1%
0%

0 to 30 days

Placebo (+ASA)

*On top of standard therapy (including ASA)


1. S. Yusuf, Circulation 2003; 107: 966-72

>30 days to 1 year

Clopidogrel (+ASA)

CURE: Patients with a


Previous Stroke
Event Rate
(Myocardial Infarction, Stroke, or Cardiovascular Death)
25%

Placebo (+ASA)
Clopidogrel (+ASA)

22.4%

Events (%)

20%

17.9%

15%
11.4%

10%

45*

21*

21*
11.0%

9.3%

8.9%

5%
0%

All patients
n=12,562

No previous stroke
n=12,056

*Number of events prevented/1,000 patients treated

On top of standard therapy (including ASA)


1) US Prescibing Information 2002 ; 2) Data on file, 2002, p87 internal CSR-EFC 3307.

Previous stroke
n=506

CREDO trial: Design1


Objectives:
Evaluate efficacy and safety of one year compared with one month
of clopidogrel on top of standard therapy including ASA in patients
undergoing urgent or elective percutaneous coronary intervention (PCI)
Determine the benefit of a clopidogrel loading dose prior to PCI

Methodology: Randomized, double-blind, multi-center


(99 centres US and Canada)
Population: 2,116 patients, followed for one year
Main outcomes:
One year: first occurrence of death, stroke or myocardial infarction (MI)
28 days: first occurrence of death, MI or urgent vessel revascularisation
* On top of standard therapy including acetylsalicylic acid

1. Steinhubl S et al. JAMA 2002; 288(19): 24112420


2. Steinhubl S et al. Circulation 1999; 100 (18 Suppl): I380. Abstract 1993

Combined endpoint occurrence (%)

CREDO: Long-term Efficacy of Clopidogrel *1


1-year results (Stroke, MI or death)

15

11.5%

n = 2,116

10

8.5%

27%
Relative Risk
Reduction
p = 0.02

5
Placebo (+ ASA) *
Clopidogrel (+ ASA)*

0
0

12

Months from randomization


1. Steinhubl S et al. JAMA 2002; 288(19): 24112420

* On top of standard therapy including acetylsalicylic acid


All patients received clopidogrel post-PCI up to Day 28
MI = myocardial infarction
PCI = percutaneous coronary intervention

CREDO: Consistent Efficacy Among Vascular


Endpoints including Stroke (at 1 Year)
Endpoints

% of patients with events

(combined)

Clopidogrel*

(n=1053)

(n=1063)

RRR, 95% CI

Placebo*

MI, Stroke, Death 8.5

11.5

26.9 (3.9 to 44.4)

MI, Death

7.9

10.4

24.0 (-0.9 to 42.7)

Death

1.7

2.3

24.6 (-38.9 to 59.1)

MI

6.6

8.5

21.7 (-7.1 to 42.7)

Stroke

0.9

1.1

25.0 (-77.9 to 68.4)

* On top of standard therapy including ASA


Steinhubl S, et al. JAMA, November 20, 2002 Vol 288, No 19: 2411 2420

Long-term Registry with Clopidogrel+ASA


in Cerebrovascular Patients (1)
Objective:
investigate effictiveness and safety of long-term clopidogrel
on top of ASA in patients with mild-to-moderate stroke or TIA

Design:
179 patients, who experienced their index event while
reportedly undergoing ASA therapy
18 months +/- 9.7 months
Single centre observational study

Source: RL. Levine, et al., Journal of Stroke and Cerebrovascular diseases 2003: 12, 1: 37-43

Long-term Registry with Clopidogrel+ASA


in Cerebrovascular Patients (2)
Long-term effectiveness and safety:
Low rate of vascular events compared to historical controls
(4.5%) in patients treated with the combination of C+A
No major or fatal bleeding events occurred in any patient on
combination C+A therapy
Minor bleeding in 10 of 134 patients treated with C+A (7.5%)
and 2 of 15 patients(13.3%) treated with arterial procedure,
followed by C+A

Conclusion of the authors:


Combined clopidogrel + ASA therapy appears both safe as
well as effective in this observational study
Source: R L. Levine, et al., Journal of Stroke and Cerebrovascular diseases 2003: 12, 1: 37-43

Single Center Registry with Clopidogrel +


ASA after Carotid Stenting (1)
Population:
162 patients with severe symptomatic (>70%) or
asymptomatic (>80%) carotid artery stenosis who were not
candidates for sugical endarterectomy

Design:
Prospective, single centre observational study
all patients treated with: ASA 325mg + clopidogrel* (or
ticlopidine in some cases) + heparin IV
abciximab (bolus and infusion) in 82% of patients
4 weeks follow-up
*most patients received loading dose of 300mg clopidogrel immediately after the procedure

Source: D. Bhatt et al., J Invas Cardiol 2001: 13, 767-71

Single Center Registry with Clopidogrel +


ASA after Carotid Stenting (2)
Procedural and 30-day event rates

Clopidogrel
(n = 139)

Ticlopidine
(n = 23)

Procedural events
Stroke

Intracranial hemorrhage

Myocardial Infarction

Death

1 (PE)

Total

3 (2.2%)

2 (8.7%)

Stroke

Intracranial hemorrhage

Myocardial Infarction

Death

unclear

Total

3 (2.2%)

1 (4%)

6 (4.3%)

3 (13%)

30 days (new events)

Total (all events)*

*p = 0.03
Source: D. Bhatt et al., J Invas Cardiol 2001: 13, 767-71

PE = pulmonary embolus; MI = Myocardial Infarction

Single Center Registry with Clopidogrel +


ASA after Carotid Stenting (3)
Conclusions of the authors:
Dual antiplatelet therapy with clopidogrel plus ASA in
patients receiving carotid artery stents is associated with low
rate of events.
Furthermore, clopidogrel appears to be superior to
ticlopidine

Source: D. Bhatt et al., J Invas Cardiol 2001: 13, 767-71

CAPRIE: Favorable Safety for Clopidogrel


Compared ASA*
ASA

Clopidogrel

(n = 9,586)

(n = 9,599)

Diarrhea (severe)1
Gastritis2
Gastro-intestinal ulcer2
Gastro-intestinal hemorrhage
(severe)1

0.11%
1.32%
1.15%

0.23%
0.75%
0.68%

NS
< 0.001
0.001

0.71%

0.49%

< 0.05

Intracranial hemorrhage1

0.49%

0.35%

NS

Rash (severe)1

0.10%

0.26%

< 0.05

Neutropenia2

0.17%

0.10%

NS

Adverse experiences

*Patients with ASA intolerance were excluded

Clinically severe or resulting in early drug discontinuation


1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Harker LA et al.
Drug Safety 1999; 21: 32535.

p value

CURE: Bleeding Episodes


Event
Major bleeding1

Placebo*
(n = 6,303)

Clopidogrel*
(n = 6,259)

p value

2.7%

3.7%

0.001

Life-threatening

1.8%

2.2%

NS

Other major bleeding

0.9%

1.5%

0.002

Transfusions of 2 units
of blood1

2.2%

2.8%

0.02

Minor bleeding1

2.4%

5.1%

< 0.001

Major bleeding by
TIMI definition2

1.2%

1.1%

0.70

Major bleeding by
GUSTO definition3

1.1%

1.2%

0.48

*On top of standard therapy (including ASA)


1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Chesebro JH et al.
Circulation 1987; 76: 14254. 3. The GUSTO Investigators. N Engl J Med 1993; 329: 67382.

CURE: Life-Threatening Bleeding1


Placebo*
(n = 6,303)

Clopidogrel*
(n = 6,259)

P-value

1.8%

2.2%

NS

Fatal

0.2%

0.2%

Causing drop in
hemoglobin 5 g/dl

0.9%

0.9%

Requiring transfusion
4 units of blood

1.0%

1.2%

Causing hemorrhagic
stroke

0.1%

0.1%

Requiring surgery

0.7%

0.7%

Hypotension requiring
intropic agents

0.5%

0.5%

Event
Life-threatening bleeding

*On top of standard therapy (including ASA)


1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.

CURE: Relation Between Safety


and ASA Dosage1
6.0%
4.9%

Bleeding rate (%)

5.0%
4.0%
4.0%

3.5%

3.0%

2.6%

Placebo (+ASA)*

2.3%

2.0%

Clopidogrel (+ASA)*

2.0%
1.0%
0.0%

< 100 mg

100200 mg
ASA dose 75325 mg

*On top of standard therapy (including ASA)


1. Clopidogrel Prescribing Information, US, February 2002.

> 200 mg

CREDO: Safety End Points at 1 Year


Clopidogrel*

Placebo*

(n = 1,053)

(n = 1,063)

Major bleeding1
Any
Nonprocedural
Procedural

8.8%
1.2%
7.7%

6.7%
0.8%
0.68%

NS
NS
NS

Minor bleeding
Any
Nonprocedural
Procedural

5.3%
0.7%
4.7%

5.6%
0.8%
4.9%

NS
NS
NS

Adverse experiences

p value

* On top of standard therapy including acetylsalicylic acid

Source: Steinhubl S et al. JAMA 2002; 288(19): 24112420

Comparison of different
antiplatelet drugs

Antithrombotic Trialists Collaboration:


Efficacy of Single Antiplatelet Agents vs. ASA1
Antiplatelet agent

% odds reduction

p value

Dipyridamole

-2%

NS

Clopidogrel

10%

0.03

0.0

0.5

Newer antiplatelet agent better

1.0

1.5

2.0

ASA better

1. Adapted from Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

Antithrombotic Trialists Collaboration:

Efficacy of Dual Antiplatelet Therapies vs. ASA alone 1


Comparison

% odds reduction

Dipyridamole + ASA

6%

ADP-receptor antagonist* + ASA

20%

0.0

0.5

1.0

Dual antiplatelet therapy

1.5

2.0

ASA alone better

*Ticlopidine; note: CURE results not available at moment of review

1. Adapted from Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186. 2. The CURE Trial Investigators.
N Engl J Med 2001; 342: 494502. 3. Data on file, 2002: p73 internal CSR-EFC 3307.

Cochrane Review:
ADP-Receptor Antagonists vs ASA1
Cerebrovascular patients (n = 9,840)
Outcome

Odds ratio (and 95% CI)

Stroke (fatal or not)

14%

Myocardial infarction, stroke,


or vascular death

10%

0.6

0.8 1.0

ADP-blocker better

1. Hankey GJ et al. Stroke 2000; 31: 177984.

1.2

1.4

ASA better

Cochrane Review:
Dipyridamole alone vs ASA alone
(n= 3,436)
Outcome

Odds ratio (and 95% CI)

Vascular death

- 7%

Vascular events

- 2%
0.6 0.8 1.0

Dipyridamole better

1. De Schrijver, Algra, van Gijn, The Cochrane Library 2003, Issue 1

1.2

1.4

ASA alone better

Cochrane Review:
Dipyridamole+ASA vs ASA alone
n = 7,316
Outcome

Odds ratio (and 95% CI)

Vascular death

- 3%

Vascular events

10%
0.6 0.8 1.0

Dipyridamole+ASA better

1. De Schrijver, Algra, van Gijn, The Cochrane Library 2003, Issue 1

1.2

1.4

ASA alone better

Indirect Comparison of Antiplatelet Drugs:


Reduction of vascular events
Antithrombotic Trialists Collaboration Review 2
Clopidogrel

vs. ASA : 10 % RR (p=0,03)

Dipyridamole

vs. ASA : - 2% RR (NS)

Cochrane Review 1
ADP-receptor antagonist

vs. ASA : 10 % RR (p<0,05)

Dipyridamole

vs. ASA : - 2 % RR (NS)

1). De Schrijver, Algra, van Gijn, The Cochrane Library 2003, Issue 1; 2). Hankey GJ et al. Stroke 2000; 31:
177984.; Antithrombotic Trialists Collaboration. BMJ 2002; 324: 7186.

Indirect Comparison of Dual Antiplatelet Strategies:


reduction of vascular events

Antithrombotic Trialists Collaboration Review 2


Dipyridamole +ASA

Cochrane Review 1
Dipyridamole +ASA

vs. ASA : 6 % RR (NS)

vs. ASA : 10% RR (p=0.05)

Recent Major Clinical trials*


CURE4: clopidogrel +ASA

vs. Placebo +ASA : 20% RR (p<0.001)

CREDO3 : clopidogrel +ASA vs. Placebo +ASA : 27% RR (p=0.02)

*Note: results of CURE & CREDO not available at moment of reviews


1). De Schrijver, Algra, van Gijn, The Cochrane Library 2003, Issue 1; 2) Hankey GJ et al. Stroke 2000; 31: 177984.; Antithrombotic Trialists Collaboration. BMJ 2002;
324: 7186. 3) Steinhubl S et al. JAMA 2002; 288(19): 24112420 ; 4) The CURE Trial Investigators. N Engl J Med 2001; 345: 494502

Clopidogrel Clinical Trials :


one of the largest clinical trial
programs ever developed

One of the Largest Clinical Trial Programs Ever Developed


More than 100,000 patients in studies with clopidogrel1

Study

Patients

Maximum
follow-up

Number of
patients

Status of study
(data expected)

CAPRIE2

Ischemic stroke, MI or PAD

36 months

19,185

Published (Lancet, 1996)

CLASSICS3

Coronary stenting

4 weeks

1,020

Published (Circulation, 2000)

CREDO4

PCI

12 months

2,116

Published (JAMA, 2002)

12 months

12,562

Published (N Engl J Med, 2001)

CURE5

Unstable angina or NQWMI

PCI-CURE*6

CURE patients undergoing PCI

12 months

2,658

Published (Lancet, 2001)

ACTIVE

Atrial fibrillation

48 months

~14,000

Ongoing (2007)

CAMPER

PAD (post-angioplasty)

30 months

~2,000

Ongoing (2006)

CARESS

Carotid stenosis

10 days

~100

Ongoing (2004)

CHARISMA

Coronary, cerebrovascular,

42 months

~15,200

Ongoing (2005)

PAD, or major risk factors


COMMIT (CCS-2)

Acute MI

4 weeks

~45,000

Ongoing (2005)

CLARITY

Acute MI

4 weeks

3,000

Ongoing (2004)

MATCH

TIA or ischemic stroke

18 months

7,601

Ongoing (2004)

1) Bhatt D, Topol E. Nature Rev (Drug Dis) 2003; 3: 1528


2) CAPRIE Steering Committee. Lancet 1996; 348: 13291339
3) Bertrand NE et al. Circulation 2000; 102: 624629
4) Steinhubl S et al. JAMA 2002; 288(19): 2411242
5) The CURE Trial Investigators. N Engl J Med 2001; 345: 494502
6) Mehta SR et al. Lancet 2001; 358: 527533

* PCI-CURE is a sub-study of the CURE study

MATCH Study
Management of ATherothrombosis with Clopidogrel in High-risk patients
with recent transient ischemic attack (TIA) or ischemic stroke (IS)

Rationale
Patients with a recent TIA or Ischemic Stroke remain at high risk
of subsequent major vascular events
Prevention of major ischemic events in high-risk patients
requires aggressive antiplatelet therapy
Synergy between clopidogrel and ASA is supported
by pre-clinical and clinical data13
Benefit of clopidogrel is amplified in high-risk patients 4

1. Makkar RR et al. Eur Heart J 1998; 19: 153846. 2. Herbert JM et al. Thromb Haemost
1998; 80: 5128. 3. Cadroy Y et al. Circulation 2000; 101: 28238. 4. Ringleb PA.
Eur Heart J 1999; 20: 666.

MATCH Objectives and Endpoint


Objectives
Evaluate clopidogrel plus ASA versus monotherapy in in patients
with a recent TIA or ischemic stroke and at high risk of recurrent
ischemic events
Evaluate safety of long-term administration of combined
clopidogrel and ASA treatment in patients with cerebrovascular
disease
Primary endpoint
First occurrence of ischemic stroke, myocardial infarction,
vascular death, or rehospitalization for an acute ischemic event
(TIA, angina or worsening of peripheral arterial disease) during
18 months of follow-up

1. Reference : http://www.strokeconference.org/abstracts/ongoing28/CTP15.pdf. Last access : 05/2003

MATCH Status
Patients recruited: 7,600 (recruitment ended since April 2002 - all
patients will be followed for 18 months)
Mean age: 66 years (range, 40-92 years)
Men: 63%/Women: 37%

Percentage (%)

100

80

68%

60

33%

40

20

14%

16%

Previous MI

Angina
pectoris

12%

Diabetes
mellitus

Previous IS

Symptomatic
PAD

Qualifying events: transient ischemic attack (22%), ischemic stroke (78%)


1. Reference : http://www.strokeconference.org/abstracts/ongoing28/CTP15.pdf. Last access : 05/2003

CARESS: Effects of Clopidogrel (+ ASA) on


Silent Cerebral Microemboli in Carotid Stenosis
Background:
Clinically, silent cerebral microemboli (MES) detected by transcranial
Doppler sonography (TCD) have been shown to be an independent
predictor of subsequent cerebrovascular event in patients with
symptomatic carotid stenosis.
Microemboli can be considered as a surrogate marker of clinical
efficacy for new antiplatelet agents

Objectives:
evaluate clopidogrel 300 mg loading dose, followed by 75mg OD +
ASA in reducing the incidence and frequency of microemboli
detected by TCD, in patients with recent symptomatic carotid
stenosis
to compare and evaluate also the effects on platelet aggregation and
activation as well as on safety
1. Reference : http://www.strokeconference.org/abstracts/ongoing28/CTP45.pdf. Last access : 05/2003

CARESS: Effects of Clopidogrel (+ ASA) on


Silent Cerebral Microemboli in Carotid Stenosis
Design
multicenter, randomized, double-blind trial
Treatment : Clopidogrel (300mg loading dose on Day 1
followed by 75mg once daily) or placebo
both groups receiving ASA 75mg once daily

Patients :
Symptomatic carotid stenosis 50%, with TIA or stroke within
last 3 months, and at least one characteristic MES detected
by TCD.
Planned sample size : 100 patients

1. Reference : http://www.strokeconference.org/abstracts/ongoing28/CTP15.pdf.. Last access : 05/2003

Clopidogrel
in Cerebrovascular Patients
- Conclusion

Conclusions

Clopidogrel is a potent platelet inhibitor with a mechanism of action different


from ASA (ADP-receptor antagonist)13

The landmark CAPRIE study confirms that clopidogrel offers improved


benefit over and above ASA in patients at risk of atherothrombotic events
(stroke, MI or vascular death) and has a favorable overall safety and
tolerability profile compared with ASA4

The landmark CURE trial provides proof of the benefits of dual antiplatelet
therapy with clopidogrel and ASA (in patients with acute coronary
syndrome)5

Clopidogrel is simple and easy to use 3

Clopidogrel is supported and investigated in one of the largest clinical trial


programs ever developed (with trials like MATCH, and CHARISMA,
ACTIVE)

1. Jarvis B, Simpson K. Drugs 3000; 60: 34777. 2. Schafer Al. Am J Med 1999; 101: 199209.
3. Clopidogrel Prescribing Information, February 2002. 4. CAPRIE Steering Committee. Lancet
1996; 348: 132939. 5. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.

Clopidogrel: Indications and Usage1


Clopidogrel is indicated for reduction of atherothrombotic events in:

recent myocardial infarction (MI), recent stroke or established peripheral


arterial disease (PAD)

For patients with a history of recent myocardial infarction (MI), recent stroke, or
established peripheral arterial disease, PLAVIX has been shown to reduce the rate of a
combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other
vascular death.

acute coronary syndrome (ACS)

For patients with acute coronary syndrome (unstable angina/non-Q-wave MI) including
patients who are to be managed medically and those who are to be managed with
percutaneous coronary intervention (with or without stent) or CABG, PLAVIX has been
shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or
stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or
refractory ischemia

1. Clopidogrel Prescribing Information, US, January, 2003.

Disclaimer
This slide kit presents data to support the rationale for the
use of ADP-receptor antagonists in registered and nonregistered indications.
The slide kit has been prepared for medical and scientific
purposes, and cannot be considered as an inducement to
use clopidogrel in non-registered indications.
Neither Sanofi-Synthlabo nor Bristol-Myers Squibb
recommends the use of clopidogrel in any manner
inconsistent with that described in the full prescribing
information.