Escolar Documentos
Profissional Documentos
Cultura Documentos
in Patients with
Cerebrovascular
Disease
Part 2: Clinical Evidence
Clopidogrel:
a Unique Antiplatelet Agent
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
P2X1
P2Y1
P2Y12
Gq coupled
Cation influx
Ca2+
No effect on
fibrinogen
receptor
Calcium mobilization
Ca2+
Gi2 coupled
cAMP
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.
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.
0.4
Control
ADP, 30M
0.3
0.2
0.1
0
Control
ASA
Clopidogrel
Clopidogrel
plus ASA
10
0
Control
ASA
Clopidogrel
Clopidogrel
plus ASA
p < 0.0001
ratio [CI 95%]
0.325 [0.21; 0.51]
6
5
4
3
2
1
0
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
Study
Patients
Maximum
follow-up
Number of
patients
Published in
CAPRIE2
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
12 months
2,658
Lancet, 2001
CURE5
PCI-CURE*6
1.
2.
3.
4.
5.
6.
Overall
relative
risk
Clopidogrel reduction
16
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
20
9.1%
Relative
risk
reduction
ASA
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
30
35
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)
ASA
Clopidogrel
250
200
150
137
1
1
177
2
1
215
3
8
177
156
ASA
Clopidogrel
126
100
50
0
All CAPRIE patients
Diabetes
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)
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
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)
Clopidogrel (+ASA)
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
Previous stroke
n=506
15
11.5%
n = 2,116
10
8.5%
27%
Relative Risk
Reduction
p = 0.02
5
Placebo (+ ASA) *
Clopidogrel (+ ASA)*
0
0
12
(combined)
Clopidogrel*
(n=1053)
(n=1063)
RRR, 95% CI
Placebo*
11.5
MI, Death
7.9
10.4
Death
1.7
2.3
MI
6.6
8.5
Stroke
0.9
1.1
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
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
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%)
*p = 0.03
Source: D. Bhatt et al., J Invas Cardiol 2001: 13, 767-71
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
p value
Placebo*
(n = 6,303)
Clopidogrel*
(n = 6,259)
p value
2.7%
3.7%
0.001
Life-threatening
1.8%
2.2%
NS
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
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
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
> 200 mg
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
Comparison of different
antiplatelet drugs
% odds reduction
p value
Dipyridamole
-2%
NS
Clopidogrel
10%
0.03
0.0
0.5
1.0
1.5
2.0
ASA better
% odds reduction
Dipyridamole + ASA
6%
20%
0.0
0.5
1.0
1.5
2.0
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
14%
10%
0.6
0.8 1.0
ADP-blocker better
1.2
1.4
ASA better
Cochrane Review:
Dipyridamole alone vs ASA alone
(n= 3,436)
Outcome
Vascular death
- 7%
Vascular events
- 2%
0.6 0.8 1.0
Dipyridamole better
1.2
1.4
Cochrane Review:
Dipyridamole+ASA vs ASA alone
n = 7,316
Outcome
Vascular death
- 3%
Vascular events
10%
0.6 0.8 1.0
Dipyridamole+ASA better
1.2
1.4
Dipyridamole
Cochrane Review 1
ADP-receptor antagonist
Dipyridamole
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.
Cochrane Review 1
Dipyridamole +ASA
Study
Patients
Maximum
follow-up
Number of
patients
Status of study
(data expected)
CAPRIE2
36 months
19,185
CLASSICS3
Coronary stenting
4 weeks
1,020
CREDO4
PCI
12 months
2,116
12 months
12,562
CURE5
PCI-CURE*6
12 months
2,658
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)
Acute MI
4 weeks
~45,000
Ongoing (2005)
CLARITY
Acute MI
4 weeks
3,000
Ongoing (2004)
MATCH
18 months
7,601
Ongoing (2004)
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 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
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
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
Clopidogrel
in Cerebrovascular Patients
- Conclusion
Conclusions
The landmark CURE trial provides proof of the benefits of dual antiplatelet
therapy with clopidogrel and ASA (in patients with acute coronary
syndrome)5
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.
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.
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
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.