Clopidogrel in Patients with Cerebrovascular Disease Part 2: Clinical Evidence

1
Clopidogrel in Patients with Cerebrovascular
DiseasePart 2 Clinical Evidence
2
Clopidogrel a Unique Antiplatelet Agent
3
Mode of Action of Clopidogrel1
CLOPIDOGREL
C
ADP
ADP
GPllb/llla (Fibrinogen receptor)
Activation
ASA
COX
ASA
COX (cyclo-oxygenase) ADP (adenosine
diphosphate) TxA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996 101 199209.
4
Effects of ADP-Receptor Activation
ADP / ATP
P2Y1
P2X1
P2Y12
Gq coupled
Gi2 coupled
Cation influx
Calcium mobilization
Ca2
Ca2
cAMP
Platelet shape change Transient aggregation
No effect on fibrinogen receptor
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.
5
A Loading Dose of Clopidogrel Provides Rapid and
Full Effect by 3 Hours1
Healthy Volunteers
100


80



60

Mean inhibition ()
Clopidogrel
40
75 mg
20
Clopidogrel
300 mg
0
-20
(n 20/group)
1.5
3
6
24
27
48
Time (hours)
p lt 0.002 vs clopidogrel 75 mg
1. Data on file, Sanofi-Synthélabo, 1999,
internal report PDY 3494.
6
Effects of Clopidogrel on a Key Inflammatory
Modulator (CD40L)1
Effects ex vivo in healthy volunteers
0.5
0.4
Control
ADP, 30µM
0.3
CD40L (Mn X)
0.2


0.1
0
Control
ASA
Clopidogrel
Clopidogrel plus ASA
p lt 0.05 versus ADP-stimulated controls
1. Hermann A et al. Platelets 2001 12 7482.
7
Effects of Clopidogrel on Platelet-Dependent
Mitogenesis of Smooth Muscle Cells1,2
40
30
20
DNA synthesis (x fold increase)

10

0
Control
ASA
Clopidogrel
Clopidogrel plus ASA
p lt 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.
8
Effects of Clopidogrel plus ASA vs
Extended-Release Dipyridamole plus ASA on Total
Platelet and Fibrin Deposition1
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
9
Current Clinical Evidencewith Clopidogrel
10
Current Clinical Evidence with clopidogrel More
than 35,000 patients in different studies1

• 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
11
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.
12
CAPRIE Long-Term Efficacy of Clopidogrel versus
ASA1
Cumulative Event Rate (Myocardial Infarction,
Ischemic Stroke or Vascular Death)
8.7Overallrelativeriskreduction
ASA
Clopidogrel
Cumulative event rate ()
p 0.043, n 19,185
0
3
6
9
12
15
18
21
24
27
30
33
36
Months of follow-up

• ASA acetylsalicylic acid MI myocardial
  infarction Intention to treat analysis
• CAPRIE Steering Committee. Lancet 1996 348
  13291339.
• Antiplatelet Trialists' Collaboration. BMJ 2002
  324 7186.

13
CAPRIE Clopidogrel Reduces Hospitalizations
Compared with ASA
Cumulative event rate Re-hospitalization for
ischemia or bleeding1
9.1
20
Relativeriskreduction
ASA
Event rate per year
15
P0.018
ASA 8.85
Clopidogrel
10
Cumulative event rate ()
5
8.03 Clopidogrel
p 0.018
0
0
10
30
35
5
15
20
25
Months of follow-up
ASA acetylsalicylic acid 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
14
CAPRIE Amplified Benefit of Clopidogrel in
Patients with Higher Vascular Risk13
Events Prevented/1,000 Patients/Year over ASA
34
300
28
238
250
204
11
200
ASA
200
172
152
Clopidogrel
141
Event rate/1000 patients (average follow-up, 2
years)
150
100
50
0
All CAPRIE patients¹
Prior history of any
Prior history of major
(n19,825)
ischemic event²
acute event (MI or stroke)
3
(n8,854)
(n4,496)
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.
15
CAPRIE Amplified Benefit of Clopidogrel in
Patients with Diabetes1,2
Events Prevented/1,000 Patients/Year over ASA
38
250
215
21
200
177
177
11
156
137
150
ASA
126
Event rate/1000 patients/year
Clopidogrel
100
50
0
All CAPRIE patients¹
Diabetes²
Diabetes treated with
insulin²
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.
16
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.
17
CURE Early and Long-Term Efficacy of Clopidogrel

Cumulative events (MI, stroke, or cardiovascular
death)
20Relativeriskreduction
0.14
Placebo (ASA)(n 6,303)
0.12
p 0.00009
0.10
0.08
Clopidogrel ( ASA) (n 6,259)
Cumulative hazard rate
0.06
0.04
0.02
0.00
0
3
6
9
12
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
18
CURE Early and Long-term Efficacy of Clopidogrel
Primary endpoint (stroke, MI or cardiovascular
death)
p lt 0.001
p lt 0.001
On top of standard therapy (including ASA) 1. S.
Yusuf, Circulation 2003 107 966-72
19
CURE Patients with a Previous Stroke
Event Rate(Myocardial Infarction, Stroke, or
Cardiovascular Death)
25
45
22.4
20
17.9
21
21
15
Events ()
11.4
11.0
9.3
8.9
10
5
0
No previous stroke n12,056
Previous stroke n506
All patients n12,562
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.
20
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
21
CREDO Long-term Efficacy of Clopidogrel 1
1-year results (Stroke, MI or death)
15
11.5
27 Relative Risk Reduction p 0.02
n 2,116
10
8.5
Combined endpoint occurrence ()
5
Placebo ( ASA)
Clopidogrel ( ASA)
0
0
3
6
9
12
Months from randomization
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
1. Steinhubl S et al. JAMA 2002 288(19)
24112420
22
CREDO Consistent Efficacy Among Vascular
Endpoints including Stroke (at 1 Year)

• Endpoints of patients with events
  RRR, 95 CI
• (combined) Clopidogrel Placebo
• (n1053) (n1063)
• 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
23
Long-term Registry with ClopidogrelASA 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
24
Long-term Registry with ClopidogrelASA 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 CA
• No major or fatal bleeding events occurred in any
  patient on combination CA therapy
• Minor bleeding in 10 of 134 patients treated with
  CA (7.5) and 2 of 15 patients(13.3) treated
  with arterial procedure, followed by CA
• 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
25
Single Center Registry with Clopidogrel ASA
after Carotid Stenting (1)

• Population
• 162 patients with severe symptomatic (gt70) or
  asymptomatic (gt80) 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
26
Single Center Registry with Clopidogrel ASA
after Carotid Stenting (2)
Clopidogrel(n 139)
Ticlopidine(n 23)
Procedural and 30-day event rates
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)
Procedural events Stroke Intracranial
hemorrhage Myocardial Infarction Death Total 30
days (new events) Stroke Intracranial
hemorrhage Myocardial Infarction Death Total To
tal (all events)
p 0.03
Source D. Bhatt et al., J Invas Cardiol 2001
13, 767-71
PE pulmonary embolus MI Myocardial Infarction
27
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
28
CAPRIE Favorable Safety for Clopidogrel Compared
ASA
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.
29
CURE Bleeding Episodes
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.
30
CURE Life-Threatening Bleeding1
Placebo(n 6,303)
Clopidogrel(n 6,259)
P-value
Event
NS

• Life-threatening bleeding
• Fatal
• Causing drop inhemoglobin ? 5 g/dl
• Requiring transfusion? 4 units of blood
• Causing hemorrhagicstroke
• Requiring surgery
• Hypotension requiringintropic agents

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)
1. The CURE Trial Investigators. N Engl J Med
2001 345 494502.
31
CURE Relation Between Safety and ASA Dosage1
6.0
4.9
5.0
4.0
4.0
3.5
Bleeding rate ()
3.0
2.6
Placebo (ASA)
2.3
2.0
Clopidogrel (ASA)
2.0
1.0
0.0
100200 mg
gt 200 mg
lt 100 mg
ASA dose 75325 mg
On top of standard therapy (including ASA)
1. Clopidogrel Prescribing Information, US,
February 2002.
32
CREDO Safety End Points at 1 Year
On top of standard therapy including
acetylsalicylic acid
Source Steinhubl S et al. JAMA 2002 288(19)
24112420
33
Comparison of different antiplatelet drugs
34
Antithrombotic Trialists CollaborationEfficacy
of Single Antiplatelet Agents vs. ASA1
Antiplatelet agent odds reduction p
value Dipyridamole -2 NS Clopidogrel
10 0.03
1.0
0.5
0.0
1.5
2.0
ASA better
Newer antiplatelet agent better
1. Adapted from Antithrombotic Trialists
Collaboration. BMJ 2002 324 7186.
35
Antithrombotic Trialists CollaborationEfficacy
of Dual Antiplatelet Therapies vs. ASA alone1
Comparison odds reduction
Dipyridamole ASA 6 ADP-receptor
antagonist ASA 20
1.0
0.5
0.0
1.5
2.0
ASA alone better
Dual antiplatelet therapy
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.
36
Cochrane Review ADP-Receptor Antagonists vs ASA1
Cerebrovascular patients (n 9,840)
Odds ratio (and 95 CI)
Outcome
14
Stroke (fatal or not)
10
Myocardial infarction, stroke, or vascular death
1.0
0.6
0.8
1.2
1.4
ASA better
ADP-blocker better
1. Hankey GJ et al. Stroke 2000 31 177984.
37
Cochrane ReviewDipyridamole alone vs ASA alone
(n 3,436)
Odds ratio (and 95 CI)
Outcome
- 7
Vascular death
- 2
Vascular events
1.0
0.6
0.8
1.2
1.4
ASA alone better
Dipyridamole better
1. De Schrijver, Algra, van Gijn, The Cochrane
Library 2003, Issue 1
38
Cochrane ReviewDipyridamoleASA vs ASA alone
n 7,316
Odds ratio (and 95 CI)
Outcome
- 3
Vascular death
10
Vascular events
1.0
0.6
0.8
1.2
1.4
ASA alone better
DipyridamoleASA better
1. De Schrijver, Algra, van Gijn, The Cochrane
Library 2003, Issue 1
39
Indirect Comparison of Antiplatelet
DrugsReduction of vascular events

• Antithrombotic Trialists  Collaboration Review2
• Clopidogrel vs. ASA 10 RR
  (p0,03)
• Dipyridamole vs. ASA - 2 RR (NS)
• Cochrane Review1
• ADP-receptor antagonist vs. ASA 10 RR
  (plt0,05)
• 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.
40
Indirect Comparison of Dual Antiplatelet
Strategiesreduction of vascular events

• Antithrombotic Trialists  Collaboration Review2
• Dipyridamole ASA vs. ASA 6 RR (NS)
• Cochrane Review1
• Dipyridamole ASA vs. ASA 10 RR
  (p0.05)
• Recent Major Clinical trials
• CURE4 clopidogrel ASA vs. Placebo ASA
  20 RR (plt0.001)
• CREDO3 clopidogrel ASA vs. Placebo ASA
  27 RR (p0.02)

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
41
Clopidogrel Clinical Trials one of the largest
clinical trial programs ever developed
42
One of the Largest Clinical Trial Programs Ever
Developed More than 100,000 patients in studies
with clopidogrel1
Status of study (data expected)
Number of patients
Maximum follow-up
Patients
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
CAPRIE2 CLASSICS3 CREDO4 CURE5 PCI-CURE6
Ischemic stroke, MI or PAD Coronary
stenting PCI Unstable angina or NQWMICURE
patients undergoing PCI
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) Caroti
d 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
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
43
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
  patients4

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.
44
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/abs
tracts/ongoing28/CTP15.pdf. Last access 05/2003
45
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

Previous IS
Diabetes mellitus
Angina pectoris
Previous MI
Symptomatic PAD
Qualifying events transient ischemic attack
(22), ischemic stroke (78)
1. Reference http//www.strokeconference.org/abs
tracts/ongoing28/CTP15.pdf. Last access 05/2003
46
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/abs
tracts/ongoing28/CTP45.pdf. Last access 05/2003
47
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/abs
tracts/ongoing28/CTP15.pdf.. Last access 05/2003
48
Clopidogrel in Cerebrovascular Patients-
Conclusion
49
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 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 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.
50
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.
51
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.