Clopidogrel in the LongTerm Management of Patients at Risk of Atherothrombosis

1
Clopidogrel in the Long-Term Management of
Patients at Risk of Atherothrombosis
2
Pharmacology of Clopidogrel a Unique
Antiplatelet Agent
3
Molecular Structure

• Generic clopidogrel bisulfate
• Class ADP-receptor antagonist
• Molecular weight 419.9

1. Clopidogrel Prescribing Information, US,
February 2002.
4
Mode of Action of Clopidogrel1
COX (cyclo-oxygenase) ADP (adenosine
diphosphate) TXA2 (thromboxane A2)
1. Jarvis B, Simpson K. Drugs 2000 60 34777.
5
Effects of ADP-Receptor Activation
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.
6
Pharmacology of Clopidogrel (I)1

• Absorption (oral) rapid, not affected by food or
  antacids
• Metabolism rapid and extensive hepatic
  metabolism
• Half-life 8 hours (but has an irreversible
  effect on platelets, with a lifespan of
  approximately 710 days)
• Excretion 50 in urine and 46 in feces, after 5
  days
• Standard dosing 75 mg once daily
• Rapid onset of action with a loading dose of 300
  mg
• provides full antiplatelet effect within 3 hours

1. Jarvis B, Simpson K. Drugs 2000 60 34777.
7
Pharmacology of Clopidogrel (II)1

• No significant adverse drugdrug interaction with
  any frequently prescribed medication in
  cardiovascular patients benefit of clopidogrel
  over ASA maintained in patients taking
  concomitant medications
• Care should be exercised when used in combination
  with other antithrombotic medications (warfarin,
  heparin etc.)

1. Jarvis B, Simpson K. Drugs 2000 60 34777.
8
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.
9
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.
10
Effects of Clopidogrel on Platelet-Dependent
Mitogenesis of Smooth Muscle Cells1,2
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.
11
Clinical Efficacy of ClopidogrelFrom CAPRIE to
CURE
12
Clinical Efficacy of Clopidogrel
Clinical Benefit of Clopidogrel in more than
30,000 Patients from CAPRIE to CURE
Trial
Patients
Design
Maximum follow-up
Number of patients
CAPRIE1
Myocardial infarction, stroke,
peripheralarterial disease
Clopidogrelvs ASA
3 years
19,185
CLASSICS2
Coronary stenting
Clopidogrel vs ticlopidine
4 weeks
1,020
CURE3
Acute coronarysyndrome
Clopidogrelvs placebo
1 year
12,562
On top of standard therapy (including
ASA) Without ST segment elevation
1. CAPRIE Steering Committee. Lancet 1996 348
132939. 2. Bertrand NE et al. Circulation 2000
102 6249 3. The CURE Trial Investigators. N
Engl J Med 2001 345 494502.
13
CAPRIE 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.
14
CAPRIE Long-Term Benefit of Clopidogrel
Compared with 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
ITT analysis
1. CAPRIE Steering Committee. Lancet 1996 348
132939.
15
CAPRIE Benefit of Clopidogrel over ASA in the
Reduction of Myocardial Infarction1
Months of follow-up
ITT analysis
1. Gent M. Circulation 1997 96(suppl 8) I-467.
16
Synergistic Mode of Action with Clopidogrel and
ASA1
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.
17
Synergistic Action of Clopidogrel on top of ASA
in Thrombus Formation1
Experimental model
1. Herbert JM et al. Thromb Haemost 1998 80
51218.
18
Synergistic Action of Clopidogrel on top of ASA
in Thrombosis1
Stent model
1. Makkar RR et al. Eur Heart J 1998 19 153846.
19
Synergistic Action of Clopidogrel and ASA in
Healthy Volunteers1
Mean Reduction of Platelet Deposition vs ASA Alone
p NS
p 0.01
80
p lt 0.001vs ASA
p lt 0.001vs ASA
70
p lt 0.001vs ASA
60
Clopidogrel 300 mgplus ASA vs ASA alone
50
p 0.03vs ASA
p 0.03
40
Mean reduction ()
Clopidogrel 75 mg plus ASA vs ASA alone
30
p 0.04vs ASA
20
10
0
Day 1, 1.5 hrs
Day 1, 6 hrs
Day 6, 6 hrs
-10
n 18 for all comparisons
With or without loading dose
1. Cadroy Y et al. Circulation 2000 101 28238.
20
Acute Coronary Syndrome (ACS) is a Classic
Manifestation of Atherothrombosis
Unstable angina
Non-Q-W MI
Q-W MI
Stroke
PAD
Common underlying atherothrombosis
Plaque rupture
Platelet activationand aggregation
Thrombus formation
Atherothrombotic event (MI, stroke, vascular
death)
21
Atherothrombosis A Generalized and Progressive
Process
Unstable angina MI Ischemic stroke/TIA Critical
leg ischemia Cardiovasculardeath
ACS
Atherosclerosis
Atherothrombosis
Stable angina Intermittent
claudication
Adapted from Stary HC et al. Circulation. 1995
92 135574, and Fuster V et al. Vasc Med. 1998
3 2319.
22
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.
23
CURE Design1
Clopidogrel 300mg loadingdose
n 12,562 28 countries
Clopidogrel75mg o.d.(n 6,259)
ASA 75325 mg o.d.
Patients with acute coronarysyndrome
R
Double-blind treatment up to 12 months
(unstable angina or non-Q-wavemyocardial
infarction)
ASA 75325 mg o.d.
Placebo 1 tab o.d.(n 6,303)
Day 1
12 monthor final visit
3 month visit
1 month visit
6 month visit
9 month visit
Placebo loading dose
Discharge visit
R Randomization
1. The CURE Study Investigators. Eur Heart J
2000 21 203341.
24
CURE Early and Long-Term Benefits of
Clopidogrel1,2
Cumulative Events (Myocardial Infarction, Stroke,
or Cardiovascular Death)
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.
25
CURE Consistent Benefit Independent of Patient
History1
Baselinecharacteristics
Percent events
N
Clopidogrel
Placebo
Clopidogrel better
Placebo better
Overall Diagnosis Elev card enzy ST depr gt1.0
mm Diabetes Previous myocardial
infarction Previous stroke
Non-Q-W MI Unstable angina Other No Yes No Yes No
Yes No Yes No Yes
12,562 3,295 8,298 968 9,381 3,176 7,273 5,288 9,7
21 2,840 8,517 4,044 12,055 506
9.3 12.7 7.3 15.1 8.8 10.7 7.5 11.8 7.9 14.2 7.8 1
2.5 8.9 17.9
11.4 15.5 8.7 19.7 10.9 13.0 8.9 14.8 9.9 16.7 9.5
15.4 11.0 22.4
On top of standard therapy (including ASA)
1. Clopidogrel Prescribing Information, US,
February 2002.
26
CURE Consistent Benefit on Top of Various
Standard Therapies1
Concomitantmedication/therapy
Events ()
N
Clopidogrel
Placebo
Clopidogrel better
Placebo better
Heparin/LMWH ASA GPIIb/IIIa Antag Beta-blocker
ACEI Lipid-lowering PTCA/CABG
No Yes lt 100 mg 100200 mg gt 200
mg No Yes No Yes No Yes No Yes No Yes
951 11611 1927 7428 3201 11739 823 2032 10530 4813
7749 4461 8101 7977 4585
4.9 9.7 8.5 9.2 9.9 8.9 15.7 9.9 9.2 6.3 11.2 10.9
8.4 8.1 11.4
7.7 11.7 9.7 10.9 13.7 10.8 19.2 12.0 11.3 8.1 13.
5 13.1 10.5 10.0 13.8
On top of standard therapy (including ASA)
Hazard ratio (95 CI)
1. Clopidogrel Prescribing Information, US,
February 2002.
27
CURE Effects of Clopidogrel Stratified by TIMI
Risk Score at 12 Months1,2
ARR 1.6 1.6 4.8 RRR 29 15 27
Absolute risk reductionRelative risk reduction
1. The CURE Trial Investigators. N Engl J Med
2001 345 494502. 2. Budaj AJ et al J Am Coll
Cardiol 2002 39, (suppl B) 441B.
28
ACC/AHA 2002 Guidelines Update for UA and NSTEMI1
Class I Recommendations for Antithrombotic
Therapy
Definite ACS with continuing ischemia or other
high-risk features or planned PCI
Possible ACS
Likely/Definite ACS
Aspirin IV heparin/SC LMWHIV GP IIb/IIIa
antagonist
Aspirin SC LMWHor IV heparin
Clopidogrel
Clopidogrel
During hospital care Clopidogrel should be
administered to hospitalized patients who are
unable to take ASA because of hypersensitivity
or major GI intolerance Class IIa enoxaparin
preferred over unfractionated heparin, unless
CABG is planned within 24 hours
1. Braunwald E et al. American College of
Cardiology (ACC) and the American Heart
Association (AHA) Guidelines, USA ACC/AHA 2002.
29
ACC/AHA 2002 Guidelines Update for UA and NSTEMI1
Class I Recommendations for Long Term Therapy
ASA

Clopidogrel for 9 months

Beta-blockers

Lipid lowering therapy

ACE I
At hospital discharge and post-hospital
dischargeIn the absence of contraindications Cl
opidogrel should be administered to hospitalized
patients who are unable to take ASA because of
hypersensitivity or major GI intolerance
1. Braunwald E et al. American College of
Cardiology (ACC) and the American Heart
Association (AHA) Guidelines, USA ACC/AHA 2002.
30
From CAPRIE to CURE Conclusions

• In CAPRIE, clopidogrel was more effective than
  ASA in reducing the combined risk of myocardial
  infarction, ischemic stroke, or vascular death1
• Synergistic effects of clopidogrel and ASA have
  been demonstrated in ex vivo platelet studies and
  animal models25
• Clopidogrel on top of standard therapy (including
  ASA) demonstrates an early effect (within hours)
  and sustained long-term benefit throughout the
  entire 12 month study period in the CURE study6
• a 20 relative risk reduction in ischemic events
  with long-term use(up to 12 months) (p
  0.00009)7
• the Kaplan-Meier curves began to diverge within
  hours and continued to diverge over the 12-month
  period

1. CAPRIE Steering Committee. Lancet 1996 348
132939. 2. Cadroy Y et al. Circulation 2000
101 28238. 3. Herbert JM et al. Thromb Haemost
1998 80 5128. 4. Harker LA et al. Circulation
1998 98 24619. 5. Makkar RR et al. Eur Heart J
1998 19 153846. 6. The CURE Trial
Investigators. N Engl J Med 2001 345 494502.
7. Data on file, 2002, p73internal CSR-EFC 3307.
31
Clopidogrel in Interventional Cardiology From
Clinical Evidence to Standard Therapy
32
CLASSICS Superior Safety Profile of Clopidogrel
at 28 Days1
Major bleeding complications, neutropenia,
thrombocytopenia or early discontinuation of the
study drug for non-cardiac adverse events ()
Combined groups
1. Bertrand NE et al. Circulation 2000 102
6249.
33
Clopidogrel Reduces Major Adverse Cardiac Events
after Stenting1
The odds ratio plots with 95 confidence
intervals (CIs) for the rates of the individual
components of the composite end point. MI
(myocardial infarction) TVR (target vessel
revascularization) SAT (subacute stent
thrombosis) MACE (major adverse cardiac events).
1. Bhatt DL et al. J Am Coll Cardiol 2002 39
914.
34
PCI-CURE 31 Relative Risk Reduction at
Long-Term1
Endpoint Myocardial Infarction or Vascular Death
On top of standard therapy (including ASA)
1. Mehta SR et al. Lancet 2001 358 52733.
35
Clopidogrel in Interventional Cardiology
Conclusions

• Clopidogrel has a superior safety/tolerability
  profile to that of ticlopidine in patients
  undergoing coronary stenting1
• Clopidogrel is at least as efficacious as
  ticlopidine in reducing major adverse cardiac
  events after stent deployment2
• Clopidogrel provides early beneficial effects
  and sustained long-term (up to 12 months) benefit
  in ACS patients requiring PCI3

On top of standard therapy (including ASA)
1. Bertrand ME et al. Circulation 2000 102
6249. 2. Bhatt DL et al. J Am Coll Cardiol 2002
39 914. 3. Mehta SR et al. Lancet 2001 358
52733.
36
Clopidogrel in Patients with a Cerebrovascular
Ischemic Accident
37
ADP-Receptor Antagonists vs ASA1
High-risk patients (n 22,656)
Odds ratio (and 95 CI)
Outcome
12
Stroke (fatal or not)
9
Myocardial infarction, stroke, or vascular death
1.0
0.6
0.8
1.2
1.4
ASA better
ADP-blocker better
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.
38
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)
1. Data on file, Sanofi-Synthélabo, 2001, study
PDY 4418.
39
CURE Clopidogrel in Patients with a Previous
Stroke1
Event Rate(Myocardial Infarction, Stroke, or
Cardiovascular Death)
Number of events prevented/1,000 patients
treated On top of standard therapy (including
ASA)
1. Data on file, 2002, p87 internal CSR-EFC 3307.
40
MATCH RationaleManagement of ATherothrombosis
with Clopidogrel in High-risk patients with
recent transient ischemic attack (TIA) or
ischemic stroke (IS)

• Patients with a recent TIA or IS 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.
41
MATCH Objectives and Endpoint

• Objectives
• Evaluate whether long-term treatment with
  clopidogrel plus ASA is superior to clopidogrel
  alone in reducing ischemic events in patients
  with a recent transient ischemic attack (TIA) or
  ischemic stroke (IS) and at high risk of
  recurrent ischemic events
• Evaluate safety of long-term administration of
  combined clopidogrel and ASA treatment in
  patients with a history of cerebrovascular
  disease
• Primary endpoint
• First occurrence of myocardial infarction, IS,
  vascular death, or rehospitalization for an acute
  ischemic event (rehospitalization for TIA, angina
  or worsening of peripheral arterial disease)
  during the 18 months of follow-up

42
MATCH Design
R Randomization Transient ischemic
attack Ischemic stroke Previous IS, previous
myocardial infarction, angina, symptomatic
peripheral arterial disease, or diabetes
43
MATCH Status

• Recruitment completed April 2002
• n 7,601
• Mean age 66 years (range, 4092 years)
• Men 63/Women 37

100
80
68
60
Percentage of patients ()
33
40
16
14
20
12
0
Previous IS
Diabetes mellitus
Angina pectoris
Symptomatic PAD
Previous MI
Qualifying events transient ischemic attack
(22), ischemic stroke (78)
1. Data on file, 2002.
44
Clopidogrel in Cerebrovascular Disease
Conclusions

• A Cochrane review demonstrated that ADP-receptor
  antagonists are significantly more effective than
  ASA in reducing the risk of stroke (fatal or not)
  and other serious vascular events1
• In an experimental model, clopidogrel was shown
  to be more effective than dipyridamole on total
  platelet deposition and fibrin deposition (both
  in combination with ASA)2
• In the CURE trial, consistent long-term benefits
  were seen in patients, with or without a history
  of ischemic stroke, notably a significant 20
  relative risk reduction with clopidogrel on top
  of standard therapy (including ASA)3
• The MATCH trial is evaluating the long-term
  efficacy and safety of clopidogrel in
  combination with ASA in high-risk transient
  ischemic attack and stroke patients. Recruitment
  has been completed (with a total of 7,601
  patients included in the trial)

1. Hankey GJ et al. Stroke 2000 31 177984. 2.
Data on file, Sanofi-Synthélabo, 2001, study PDY
4418. 3. Data on file, 2002, p87 internal CSR-EFC
3307.
45
Evidence for the efficacy of ADP-Receptor
Antagonists, including Clopidogrel, in
Peripheral Arterial Disease
46
Effect of Antiplatelet Therapy on Vascular
Events in Peripheral Arterial Disease (PAD)1
Vascular events myocardial infarction, stroke
or vascular death
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
47
Evidence with ASA and ADP-Receptor Antagonists
in Peripheral Arterial Disease1,2
Only six trials studied the use of ASA only in
peripheral arterial diseaseCAPRIE trial
included 19,185 patients of which 6,432 had
established peripheral arterial
diseasePicotamide, suloctidil, indobufen,
sulphinpyrazone
1. Robless P. Br J Surg 2001 88 787800. 2.
Girolami B et al. Thromb Haemost 1999 81
71522.
48
Long-Term Effects of an ADP-Receptor Antagonist
on Peripheral Patency1
Improvement of graft patency
Months
Of femoropopliteal or femorotibial saphenus-vein
bypass grafts of the legs
1. Becquemin JP. N Engl J Med 1997 337 172631.
49
Long-Term Effects of an ADP-Receptor Antagonist
on Peripheral Patency1
Of femoropopliteal or femorotibial saphenus-vein
bypass grafts of the legsOutcomes at 24 months
after randomization, according to the
intention-to-treat analysis
1. Becquemin JP. N Engl J Med 1997 337 172631.
50
Effects of Antiplatelet agents on the Carotid
Artery Intima-Media Thickness (IMT) Progression1
IMT Progression of the Carotid Artery in Patients
With Type 2 Diabetes, with Asymptomatic Carotid
Stenosis
p lt 0.01
Reduction of the progression of carotid IMT was
0,041 mm/year with an ADP-receptor antagonist
(ticlopidine) and 0,032 mm/year with ASA
1. Kodama M et al. Thromb Res 2000 97 23945.
51
Effects of Different Antiplatelet Agents
Therapies on Long-Term Patency after Peripheral
Revascularization1
Improvement of loss of patency compared with
non-active control Odds ratio 0.69 with 95
confidence interval, 0.53 to 0.90 Odds ratio
0.53 with 95 confidence interval, 0.33 to 0.85
1. Girolami B et al. Eur J Vasc Endovasc Surg
2000 19 37080.
52
CAPRIE Benefit with Clopidogrel Compared with
ASA in Peripheral Ischemia
Relative risk reduction with clopidogrel
compared with ASA ()
Angina, transient ischemic attack, or severe
limb ischemia
1. Bhatt DL et al. Am Heart J 2000 140 6773.
53
Planned Additional Clinical Trials with
Clopidogrel in PAD
Patients
Design
Maximumfollow-up
Number ofpatients
Trial
CAP
Peripheral angioplasty
Clopidogrelvs placebo
1 year
2,000
CASPAR
Peripheralbypass surgery
1,600
1 year
Clopidogrelvs placebo
On top of standard therapy (including ASA)
54
Clopidogrel in Peripheral Arterial Disease
Conclusions

• Antiplatelet therapy significantly reduces the
  risk of myocardial infarction, stroke and
  vascular death in patients with peripheral
  arterial disease (PAD), including patients with a
  history of angioplasty or bypass surgery1,2
• Most of the evidence with antiplatelet therapy in
  PAD is from ADP-receptor antagonists including
  clopidogrel1,3
• An ADP-receptor antagonist significantly improves
  the long-term peripheral patency after
  revascularization procedures2
• Clopidogrel is significantly more effective than
  ASA in reducing serious vascular ischemic events,
  including rehospitalization for limb ischemia, in
  PAD patients4
• Additional clinical trials will further evaluate
  the benefit of clopidogrel on top of standard
  therapy (including ASA) in PAD patients

1. Robless P et al. Br J Surg 2001 88 787800.
2 Becquemin JP. N Engl J Med 1997 337
172631. 3. Girolami B et al. Eur J Vasc Endovasc
Surg 2000 19 37080. 4. Bhatt DL et al. Am
Heart J 2000 140 6773.
55
Clopidogrel in Patients at Risk
56
Risk Assessment of Further Atherothrombotic
Events in Actual Practice1
Atherothrombotic Events/100 Patients Per Year
1. Caro J et al. Eur Heart J 2001 22(abstr
suppl) 522.
57
CAPRIE Amplified Benefit of Clopidogrel in
Patients with Higher Vascular Risk
Event Rate(Myocardial Infarction, Ischemic
Stroke, or Vascular Death)
Number of events prevented/1,000 patients/year
over ASA Cumulative proportion of patients
experiencing event over 3 years (mean follow-up,
2 years) 3-year event rate
1. CAPRIE Steering Committee. Lancet 1996 348
132939. 2. Jarvis B, Simpson K. Drugs 2000 60
34777.
58
CAPRIE Consistent Benefit of Clopidogrel over
ASA in Both Low- and High-Risk Patients
Event Rate (Fatal or Non-Fatal Myocardial
Infarction)
Relative risk reduction
1. Cannon C. J Am Coll Cardiol 2002 39 (abstr
suppl) 290A.
59
CAPRIE Amplified Benefit of Clopidogrel in
Patients with Diabetes
Event Rate(Myocardial Infarction, Stroke,
Vascular Death, or Hospitalization)
25
For ischemic events or bleedingNumber of
events prevented/1,000 patients/year over ASA
1. Bhatt DL et al. Am Heart J 2000 140 6773.
2. Jarvis B, Simpson K. Drugs 2000 60 34777.
60
CAPRIE Amplified Benefit of Clopidogrelin
Patients with Prior CABG1
Event Rate(Myocardial Infarction, Stroke,
Vascular Death, or Hospitalization)
For ischemic events or bleedingNumber of
events prevented/1,000 patients/year over ASA
1. Bhatt DL et al. J Am Coll Cardiol 2000
35(suppl A) 383.
61
CAPRIE Amplified Benefit of Clopidogrel in
Patients with Hypercholesterolemia1
Event rate(Myocardial Infaction, Stroke,
Vascular Death, or Hospitalization)
Overall benefit p 0.026 multivariate analysis
For ischemic events or bleedingNumber of
events prevented/1,000 patients/year over ASA
1. Bhatt DL et al. J Am Coll Cardiol 2000
35(suppl A) 326.
62
CURE Clopidogrel on Top of Standard Therapy in
Patients with Diabetes
Event Rate (Myocardial Infarction, Stroke, or
Vascular Death)
No previous diabetesn 9,721
Diabetesn 2,840
Number of events prevented/1,000 patients
treated/9 months On top of standard therapy
(including ASA)
1. Clopidogrel Prescribing Information, US,
February 2002.
63
Favorable Safety and Tolerability Profile with
Clopidogrel
64
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.
65
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.
66
CURE Life-Threatening Bleeding1
On top of standard therapy (including ASA)
1. The CURE Trial Investigators. N Engl J Med
2001 345 494502.
67
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
2.3
2.0
Clopidogrel
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.
68
PCI-CURE Bleeding Outcomes1
1. Mehta SR et al. Lancet 2001 358 52733.
69
Clopidogrel Indications and Usage1

• Clopidogrel is indicated for reduction of
  atherosclerotic events in
• recent myocardial infarction (MI), recent stroke
  or established peripheral arterial disease (PAD)
• in patients with a history of recent MI, stroke
  or established PAD, clopidogrel 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)
• in patients with ACS (unstable angina/non-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, clopidogrel has been
  shown to decrease the rate of combined endpoint
  of cardiovascular death, MI, or stroke, as well
  as the rate of the combined endpoint of
  cardiovascular death, MI, stroke, or refractory
  ischemia

Note labelling may differ from country to
country and information provided for medical
purposes only
1. Clopidogrel Prescribing Information, US,
February 2002.
70
Estimated Clinical Benefit of Clopidogrel
Relative to Other Long-Term CV Drug Treatments
Calculation incidence in control group
incidence in active group at end of follow
up/average treatment duration expressed in
years Primary endpoint Secondary endpoint
death due to CHD or MI plus secondary endpoint
any stroke Without ST segment elevation
1. CAPRIE Steering Committee. Lancet 1996 348
132939. 2. HOPE Study Investigators. N Engl J
Med 2000 342 14553. 3. LIPID Study Group. N
Engl J Med 1998 339 134957. 4. The CURE Trial
Investigators. N Engl J Med 2001 345 494502.
71
Ongoing Major Clinical Trials with Clopidogrel
Ongoing Trials are Recruiting up to 50,000
Patients
Patients
Design
Maximumfollow-up
Number ofpatients
Trial
CREDO
Coronary stenting
Clopidogrel 1 monthvs clopidogrel 1 year
12 months
2,000
COMMIT
Acute myocardial infarction
Clopidogrelvs placebo
1 month
40,000
MATCH
Transient ischemic attack/stroke
Clopidogrel plus ASAvs clopidogrel
18 months
7,600
On top of standard therapy (including ASA)
72
Planned Major Clinical Trials with Clopidogrel
More than 30,000 Patients to be Recruited
Patients
Design
Maximumfollow-up
Number ofpatients
Trial
CHARISMA
Vascular disease and additional risk factors
Clopidogrelvs placebo
3 years
15,000
3 years
ACTIVE
Atrial fibrillation
Clopidogrel plus ASA vs OAC (elective
OAC) Clopidogrel plus ASA vs ASA (non-elective
OAC)
14,000
CLARITY
Acute myocardial infarction
2,200
1 month
Clopidogrelvs placebo
On top of standard therapy (including low-dose
ASA) OAC oral anticoagulants
73
Conclusions

• Clopidogrel is a potent platelet inhibitor with a
  mechanism of action different from ASA
  (ADP-receptor antagonist), and is simple and easy
  to use13
• The landmark CAPRIE study demonstrates that
  clopidogrel offers improved benefit over and
  above ASA in patients at risk of atherothrombosis
  and has a favorable overall safety and
  tolerability profile compared with ASA4
• The landmark CURE trial demonstrates that
  clopidogrel offers a highly significant 20
  relative risk reduction on top of standard
  therapy (including ASA), in the early and
  long-term (up to 1 year) reduction of myocardial
  infarction, stroke and cardiovascular death in
  patients with acute coronary syndrome5
• Clopidogrel is easier, safer and probably also
  more effective than ticlopidine as shown in
  studies developed in interventional cardiology
  (stenting)6
• Clopidogrel is supported by an extensive clinical
  trial program to evaluate benefits when used in
  addition to standard therapy (including ASA)

1. Jarvis B, Simpson K. Drugs 3000 60 34777.
2. Schafer Al. Am J Med 1999 101 199209. 3.
Clopidogrel Prescribing Information, US, February
2002. 4. CAPRIE Steering Committee. Lancet 1996
348 132939. 5. The CURE Trial Investigators. N
Engl J Med 2001 345 494502. 6. Taniuchi M et
al. Circulation 1999 100 (suppl I) I-379.
74
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75
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.