Clopidogrel in Patients with

Cerebrovascular Disease

Part 2: Clinical Evidence

Clopidogrel: a Unique Antiplatelet Agent

COX (cyclo-oxygenase)ADP (adenosine diphosphate)TxA2 (thromboxane A2)

CLOPIDOGREL

ASA COX

ADP

ADP

C

GPllb/llla(Fibrinogen receptor)

Collagen thrombinTXA2

Activation

TXA2

ASA

Mode of Action of Clopidogrel1

1. Schafer AI. Am J Med 1996; 101: 199–209.

Effects of ADP-Receptor Activation

Adapted from Savi P et al. Biochem Biophys Res Commun 2001; 283: 379–83, 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.15–35.

ADP / ATP

P2Y1P2X1 P2Y12

Gi2 coupled

Gq coupled

Ca2+ Ca2+ cAMP

Platelet shape change Transient aggregation

No effect on fibrinogen receptor

Cation influx Calcium mobilization

Fibrinogen receptor activation Thromboxane A2 generation

Sustained aggregation response

A Loading Dose of Clopidogrel Provides Rapid and Full Effect by 3 Hours1

1. Data on file, Sanofi-Synthélabo, 1999, internal report PDY 3494.

100

-20

0

20

40

60

80

1.5 3 6 24 27 48

Time (hours)

Mea

n in

hib

itio

n (

%)

Clopidogrel75 mg

Clopidogrel300 mg

*

*p < 0.002 vs clopidogrel 75 mg*p < 0.002 vs clopidogrel 75 mg

(n = 20/group)

** *

**

Healthy Volunteers

Effects of Clopidogrel on a Key Inflammatory Modulator (CD40L)1

1. Hermann A et al. Platelets 2001; 12: 74–82.

Effects ex vivo in healthy volunteers

**p < 0.05 versus ADP-stimulated controlsp < 0.05 versus ADP-stimulated controls

0

0.1

0.2

0.3

0.4

0.5

Control ASA Clopidogrel Clopidogrel plus ASA

CD

40L

(M

n X

)

* *

Control

ADP, 30µM

Effects of Clopidogrel on Platelet-Dependent Mitogenesis of Smooth Muscle Cells1,2

1. Hermann A et al. Thromb Res 2002; 105: 173–5. 2. Hermann A et al. Arch Pharmacol 2001; 363(suppl 4): 442.

*p < 0,05 versus control*p < 0,05 versus control

0

10

20

30

40

Control ASA Clopidogrel Clopidogrel plus ASA

DN

A s

ynth

esis

(x

fold

incr

ease

)

* *

Effects of Clopidogrel plus ASA vs Extended-Release Dipyridamole plus ASA on Total Platelet and Fibrin Deposition1

Cadroy Y , Circulation 2002, 106 (19) : II -181, 908

Clopidogrel plus ASA was significantly more effective in inhibiting total deposition of platelets (67% reduction) and of fibrin (58% reduction)

0

1

2

3

4

5

6

7

Dipyridamoleplus ASA

Day 10

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

0

1

2

3

4

5

6

7

Dipyridamoleplus ASA

Clopidogrelplus ASA

Day 10

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

Clopidogrel plus ASA

To

tal

pla

tele

t d

ep

os

itio

n (

Te

ra/m

²)

To

tal

fib

rin

de

po

sit

ion

(u

g/c

m²)

Total Platelet Deposition Total Fibrin Deposition

Current Clinical Evidencewith Clopidogrel

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

1. Bhatt D, Topol E. Nature Rev (Drug Dis) 2003; 3: 15–282. CAPRIE Steering Committee. Lancet 1996; 348: 1329–13393. Bertrand NE et al. Circulation 2000; 102: 624–6294. Steinhubl S et al. JAMA 2002; 288(19): 2411–2425. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–5026. Mehta SR et al. Lancet 2001; 358: 527–533

Current Clinical Evidence with clopidogrelMore than 35,000 patients in different studies1

Lancet, 1996

Circulation, 2000

JAMA, 2002

N Engl J Med, 2001

Lancet, 2001

19,185

1,020

2,116

12,562

2,658

36 months

6 weeks

12 months

12 months

12 months

Ischemic stroke, MI or PAD

Coronary stenting

PCI

Unstable angina or NQWMI

CURE patients undergoing PCI

CAPRIE2

CLASSICS3

CREDO4

CURE5

PCI-CURE*6

Published inNumber of patients

Maximum follow-up

PatientsStudy

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: 1329–39.

CAPRIE: Long-Term Efficacy of Clopidogrel versus ASA1

Cumulative Event Rate(Myocardial Infarction, Ischemic Stroke or Vascular Death)

Months of follow-up

8.7%*

Overallrelative

riskreduction

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

Cu

mu

lati

ve

ev

en

t ra

te (

%)

ASA

p = 0.043, n = 19,185

Clopidogrel

ASA = acetylsalicylic acid MI = myocardial infarction *Intention to treat analysis1.CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.2. Antiplatelet Trialists' Collaboration. BMJ 2002; 324: 71–86.

1. Bhatt et al. Am Heart J 2000; 140: 67–73

Cumulative event rate: Re-hospitalization for ischemia* or bleeding**1

ASA = acetylsalicylic acid

* Transient ischemic attack, angina pectoris, peripheral arterial disease

** Gastrointestinal, central nervous system or other bleeding

CAPRIE: Clopidogrel Reduces Hospitalizations* Compared with ASA

0 5 10 15 20 25 30 35

Relativerisk

reduction

9.1%

P=0.018

Months of follow-up

Clopidogrel

Cu

mu

lati

ve

ev

en

t ra

te (

%)

0

5

10

15

20ASA

Event rate per year

p = 0.018

ASA8.85%

8.03%Clopidogrel

CAPRIE: Amplified Benefit of Clopidogrel in Patients with Higher Vascular Risk1–3

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77. 3. Ringleb PA et al. Eur Heart J 1999; 20: 666.

Events Prevented/1,000 Patients/Year over ASA

152

200

238

141

172

204

0

50

100

150

200

250

300

All CAPRIE patients¹(n=19,825)

Prior history of anyischemic event²

(n=8,854)

Prior history of majoracute event (MI or stroke)

(n=4,496)

Eve

nt

rate

* /100

0 p

atie

nts

(av

era

ge

foll

ow

-up

, 2

ye

ars)

ASAClopidogrel

11

28

34

3

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

CAPRIE: Amplified Benefit of Clopidogrel in Patients with Diabetes1,2

1. Bhatt DL et al. Am Heart J 2000; 140: 67–73. 2. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.

Events Prevented/1,000 Patients/Year over ASA

137

177

215

126

156

177

0

50

100

150

200

250

All CAPRIE patients¹ Diabetes² Diabetes treated withinsulin²

Eve

nt

rate

* /100

0 p

atie

nts

/ye

ar

ASA

Clopidogrel

11

21

38

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

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: 494–502.

CURE: Early and Long-Term Efficacy of Clopidogrel

*On top of standard therapy (including ASA)

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502 2. Data on file, 2002, p73 internal CSR-EFC 3307

p = 0.00009

Cumulative events (MI, stroke, or cardiovascular death)

Months of follow-up

20%*

Relativerisk

reduction

Placebo (+ASA)*

(n =6,303)

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

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

0 3 6 9 12

Cu

mu

lati

ve

ha

zard

ra

te

CURE : Early and Long-term Efficacy of Clopidogrel

5,4%

6,3%

4,3%

5,2%

0%

1%

2%

3%

4%

5%

6%

7%

8%

0 to 30 days >30 days to 1 year

Placebo (+ASA) Clopidogrel (+ASA)

*On top of standard therapy (including ASA)

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

p < 0.001

p < 0.001

Primary endpoint (stroke, MI or cardiovascular death)

CURE: Patients with a Previous Stroke

Event Rate(Myocardial Infarction, Stroke, or Cardiovascular Death)

*Number of events prevented/1,000 patients treated†On top of standard therapy (including ASA)

11.4%

9.3%

0%

5%

10%

15%

20%

25%

No previous stroken=12,056

Ev

en

ts (

%)

22.4%

17.9%

Previous stroken=506

45*

21*

Placebo (+ASA)†

Clopidogrel (+ASA)†

11.0%

8.9%

21*

All patientsn=12,562

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

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

1. Steinhubl S et al. JAMA 2002; 288(19): 2411–2420

2. Steinhubl S et al. Circulation 1999; 100 (18 Suppl): I–380. Abstract 1993

* On top of standard therapy including acetylsalicylic acid

CREDO: Long-term Efficacy of Clopidogrel *1

27% Relative Risk

Reduction

p = 0.02

Clopidogrel (+ ASA)*Placebo (+ ASA) † *

Com

bine

d en

dpoi

nt o

ccur

renc

e (%

)

Months from randomization

0 3 6 9 12

8.5%

11.5%

1-year results (Stroke, MI or death)

0

5

10

15

1. Steinhubl S et al. JAMA 2002; 288(19): 2411–2420

* On top of standard therapy including acetylsalicylic acid† All patients received clopidogrel post-PCI up to Day 28MI = myocardial infarctionPCI = percutaneous coronary intervention

n = 2,116

Endpoints % of patients with events RRR, 95% CI

(combined) Clopidogrel* Placebo*

(n=1053) (n=1063)

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)

CREDO: Consistent Efficacy Among Vascular Endpoints including Stroke (at 1 Year)

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

* On top of standard therapy including ASA

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 (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

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)

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

Procedural events

Stroke

Intracranial hemorrhage

Myocardial Infarction

Death

Total

30 days (new events)

Stroke

Intracranial hemorrhage

Myocardial Infarction

Death

Total

Total (all events)*

Clopidogrel(n = 139)

Ticlopidine(n = 23)

0

0

0

1 (PE)

3 (2.2%)

0

1

0

2

3 (2.2%)

6 (4.3%)

2

0

0

0

2 (8.7%)

0

0

0

unclear

1 (4%)

3 (13%)

PE = pulmonary embolus; MI = Myocardial Infarction

*p = 0.03

Procedural and 30-day event ratesProcedural and 30-day event rates

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

1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Harker LA et al. Drug Safety 1999; 21: 325–35.

*Patients with ASA intolerance were excluded†Clinically severe or resulting in early drug discontinuation

CAPRIE: Favorable Safety for Clopidogrel Compared ASA*

Adverse experiences†

Diarrhea (severe)1

Gastritis2

Gastro-intestinal ulcer2

Gastro-intestinal hemorrhage(severe)1

Intracranial hemorrhage1

Rash (severe)1

Neutropenia2

ASA(n = 9,586)

Clopidogrel(n = 9,599)

p value

NS< 0.001

0.001

< 0.05

NS

< 0.05

NS

0.11%1.32%1.15%

0.71%

0.49%

0.10%

0.17%

0.23%0.75%0.68%

0.49%

0.35%

0.26%

0.10%

CURE: Bleeding Episodes

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502. 2. Chesebro JH et al. Circulation 1987; 76: 142–54. 3. The GUSTO Investigators. N Engl J Med 1993; 329: 673–82.

Event

Major bleeding1

• Life-threatening

• Other major bleeding

Transfusions of 2 units of blood1

Minor bleeding1

Major bleeding byTIMI definition2

Major bleeding byGUSTO definition3

Placebo*

(n = 6,303)Clopidogrel*

(n = 6,259) p value

2.7%

1.8%

0.9%

2.2%

2.4%

1.2%

1.1%

3.7%

2.2%

1.5%

2.8%

5.1%

1.1%

1.2%

0.001

NS

0.002

0.02

< 0.001

0.70

0.48

*On top of standard therapy (including ASA)

CURE: Life-Threatening Bleeding1

1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.

Event

Life-threatening bleeding

• Fatal

• Causing drop inhemoglobin 5 g/dl

• Requiring transfusion 4 units of blood

• Causing hemorrhagicstroke

• Requiring surgery

• Hypotension requiringintropic agents

Placebo*

(n = 6,303)Clopidogrel*

(n = 6,259)

1.8%

0.2%

0.9%

1.0%

0.1%

0.7%

0.5%

2.2%

0.2%

0.9%

1.2%

0.1%

0.7%

0.5%

*On top of standard therapy (including ASA)

NS

P-value

CURE: Relation Between Safety and ASA Dosage1

1. Clopidogrel Prescribing Information, US, February 2002.

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%

Ble

edin

g r

ate

(%)

2.0%

2.6%2.3%

3.5%

4.0%

4.9%

ASA dose 75–325 mg

100–200 mg > 200 mg< 100 mg

Placebo (+ASA)*

Clopidogrel (+ASA)*

*On top of standard therapy (including ASA)

CREDO: Safety End Points at 1 Year

Adverse experiences†

Major bleeding1

AnyNonproceduralProcedural

Minor bleeding Any

NonproceduralProcedural

Clopidogrel* (n = 1,053)

Placebo*(n = 1,063)

p value

NSNSNS

NSNSNS

8.8%1.2%7.7%

5.3%0.7%4.7%

6.7%0.8%0.68%

5.6%0.8%4.9%

Source: Steinhubl S et al. JAMA 2002; 288(19): 2411–2420

* On top of standard therapy including acetylsalicylic acid

Comparison of different antiplatelet drugs

Antiplatelet agent % odds reductionp value

Dipyridamole -2%

NS

Clopidogrel 10%

0.03

1. Adapted from Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

Antithrombotic Trialists’ Collaboration:Efficacy of Single Antiplatelet Agents vs. ASA1

1.00.50.0 1.5 2.0ASA betterNewer antiplatelet agent better

1. Adapted from Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. 2. The CURE Trial Investigators. N Engl J Med 2001; 342: 494–502. 3. Data on file, 2002: p73 internal CSR-EFC 3307.

Antithrombotic Trialists’ Collaboration:Efficacy of Dual Antiplatelet Therapies vs. ASA alone1

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

ASA alone betterDual antiplatelet therapy

Dipyridamole + ASA 6%

ADP-receptor antagonist* + ASA 20%

Comparison % odds reduction

1.00.50.0 1.5 2.0

1. Hankey GJ et al. Stroke 2000; 31: 1779–84.

Cochrane Review: ADP-Receptor Antagonists vs ASA1

ASA betterADP-blocker better

10%

14%

Odds ratio (and 95% CI)Outcome

Stroke (fatal or not)

Myocardial infarction, stroke, or vascular death

1.00.6 0.8 1.2 1.4

Cerebrovascular patients (n = 9,840)

Cochrane Review:Dipyridamole alone vs ASA alone

ASA alone betterDipyridamole better

- 2%

- 7%

Odds ratio (and 95% CI)Outcome

Vascular death

Vascular events

1.00.6 0.8 1.2 1.4

(n= 3,436)

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

Cochrane Review:Dipyridamole+ASA vs ASA alone

ASA alone betterDipyridamole+ASA better

10%

- 3%

Odds ratio (and 95% CI)Outcome

Vascular death

Vascular events

1.00.6 0.8 1.2 1.4

n = 7,316

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

Indirect Comparison of Antiplatelet Drugs:Reduction of vascular events

• Antithrombotic Trialists ’ Collaboration Review2

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

– Dipyridamole vs. ASA : - 2% RR (NS)

• Cochrane Review1

– 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: 1779–84.; Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

Indirect Comparison of Dual Antiplatelet Strategies:reduction of vascular events

• Antithrombotic Trialists ’ Collaboration Review2

– Dipyridamole +ASA vs. ASA : 6 % RR (NS)

• Cochrane Review1

– Dipyridamole +ASA 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: 1779–84.; Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86. 3) Steinhubl S et al. JAMA 2002; 288(19): 2411–2420 ; 4) The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502

Clopidogrel Clinical Trials :one of the largest clinical trial

programs ever developed

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

Published (Lancet, 1996)

Published (Circulation, 2000)

Published (JAMA, 2002)

Published (N Engl J Med, 2001)

Published (Lancet, 2001)

19,185

1,020

2,116

12,562

2,658

36 months

4 weeks

12 months

12 months

12 months

Ischemic stroke, MI or PAD

Coronary stenting

PCI

Unstable angina or NQWMI

CURE patients undergoing PCI

CAPRIE2

CLASSICS3

CREDO4

CURE5

PCI-CURE*6

Ongoing (2007)

Ongoing (2006)

Ongoing (2004)

Ongoing (2005)

Ongoing (2005)

Ongoing (2004)

Ongoing (2004)

~14,000

~2,000

~100

~15,200

~45,000

3,000

7,601

48 months

30 months

10 days

42 months

4 weeks

4 weeks

18 months

Atrial fibrillation

PAD (post-angioplasty)

Carotid stenosis

Coronary, cerebrovascular,

PAD, or major risk factors

Acute MI

Acute MI

TIA or ischemic stroke

ACTIVE

CAMPER

CARESS

CHARISMA

COMMIT (CCS-2)

CLARITY

MATCH

Status of study (data expected)

Number of patients

Maximum follow-up

PatientsStudy

1) Bhatt D, Topol E. Nature Rev (Drug Dis) 2003; 3: 15–282) CAPRIE Steering Committee. Lancet 1996; 348: 1329–13393) Bertrand NE et al. Circulation 2000; 102: 624–6294) Steinhubl S et al. JAMA 2002; 288(19): 2411–2425) The CURE Trial Investigators. N Engl J Med 2001; 345: 494–5026) Mehta SR et al. Lancet 2001; 358: 527–533

One of the Largest Clinical Trial Programs Ever DevelopedMore than 100,000 patients in studies with clopidogrel1

1. Makkar RR et al. Eur Heart J 1998; 19: 1538–46. 2. Herbert JM et al. Thromb Haemost 1998; 80: 512–8. 3. Cadroy Y et al. Circulation 2000; 101: 2823–8. 4. Ringleb PA. Eur Heart J 1999; 20: 666.

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 data1–3

• Benefit of clopidogrel is amplified in high-risk patients4

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

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

68%

33%

14% 16%12%

0

20

40

60

80

100

Per

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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%

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

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)1–3

• 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 use3

• 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: 347–77. 2. Schafer Al. Am J Med 1999; 101: 199–209. 3. Clopidogrel Prescribing Information, February 2002. 4. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 5. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.

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 non-registered 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-Synthélabo nor Bristol-Myers Squibb recommends the use of clopidogrel in any manner inconsistent with that described in the full prescribing information.