Clopidogrel:

Key Findings from

CAPRIE

Slide 1

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Rationale for CAPRIE

Patients with a wide spectrum of atherosclerotic disease

are at risk of all major atherothrombotic events

Atherothrombotic process is similar regardless of clinical

manifestation of underlying atherosclerosis

Clopidogrel was expected to benefit the entire spectrum

of atherosclerotic patients

Clopidogrel was hypothesized to provide approximately

10% additional relative risk reduction vs. aspirin

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

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Rationale for CAPRIE:

Antiplatelet Trialists Collaboration

Main finding:
From a meta-analysis of 142 trials, including more
than 73,000 high-risk patients, platelet aggregation inhibitors
reduced the risk of the composite outcome of ischemic stroke,
MI, or vascular death by 25%
The odds reduction was consistent:
Over a wide range of clinical manifestations (ischemic
cerebrovascular, coronary, and atherosclerotic peripheral
arterial disease)
Across subsets of patients at varying risks within
specific clinical disorders
Antiplatelet Trialists Collaboration. BMJ 1994;308:81-106.

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Clopidogrel: An ADP Receptor Antagonist

H

COOCH3

N
, H2SO4
S

Cl

Clopidogrel

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Clopidogrel Mechanism of Action

ADP
Clopidogrel

l
Clopidogre

ADP

Platelet

Fibrinogen Binding Site

Fibrinogen

Fibrinogen Binding Reduced

Acts by selective inhibition of ADP binding to its platelet

receptor and prevents subsequent platelet aggregation

Herbert. Exp Opin Invest Drugs 1994;3:449-455.

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CAPRIE Study: Methodology

Study design

Multicenter, prospective, randomized, blinded

Study population

19,185 patients with atherosclerotic

vascular disease
Ischemic stroke ( 1 week and 6 months)
Myocardial infarction (MI) ( 35 days)
Established peripheral arterial disease
Clopidogrel 75 mg once daily
Aspirin 325 mg once daily

Qualifying conditions

Study drugs
Primary end point

MI, ischemic stroke, or vascular death

Treatment duration

Up to 3 years (mean 1.6 years)

Investigational sites

384 in 16 countries

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

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CAPRIE Study: Patient Population

Qualifying conditions (one of the following):

Recent ischemic stroke (IS): 1 week to 6 months
Recent myocardial infarction (MI): within 35 days
Established peripheral arterial disease (PAD): current
intermittent claudication or prior arterial intervention

Patients with prior atherothrombotic events or atherosclerotic

disease in more than one arterial bed were included

Patients with known intolerance to aspirin or a history of

bleeding and peptic ulcers were excluded

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

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CAPRIE Study: Outcome Event Clusters

Primary analysis:
Ischemic stroke, myocardial infarction (MI), or vascular
death

Secondary analysis:
Ischemic stroke, MI, amputation, or
vascular death
Vascular death
Any stroke, MI, or death from any cause
Death from any cause

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

8

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Baseline Patient Characteristics in CAPRIE:

Risk Factors

Percent

60

Clopidogrel, n=9599
Aspirin, n=9586

40

20

Diabetes Mellitus

Hypertension

Hypercholesterolemia

Risk Factors

Cigarette Smoker
(Current)

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

9

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Baseline Patient Characteristics in CAPRIE:

30
History
of Ischemic Events
Clopidogrel, n=9599
Percent

Aspirin, n=9586
20

10

Ischemic
Stroke*

TIA/RIND

MI*

Angina
(Stable)

Angina
(Unstable)

Intermittent
Claudication*

History of Ischemic Events

*Excluding qualifying condition

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
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CAPRIE Study:
Specific Features of MI and PAD Subgroups
MI subgroup (n = 6,302)
Time to randomization, days*
MI location:
Anterior/lateral
Inferior/posterior
Other/indeterminate
PAD subgroup (n = 6,452)
Duration of disease, years*
Basis of eligibility:
Arterial intervention
Current claudication
Ankle/arm BP ratio*

Clopidogrel
17.5 + 10.1

Aspirin
17.7 + 10.3

34%
57%
8%

34%
57%
9%

4.1 + 4.7

4.2 + 4.9

62%
38%
0.56 + 0.15

64%
36%
0.57 + 0.16

*Mean + SD. Current claudicants only.

11

Data on file (CAPRIE Report No. 602-6-110, p. 86).

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CAPRIE Study:
Specific Features of Stroke Subgroup
Stroke Subgroup (n = 6,431)
Time to randomization, days*
Stroke type
Atherothrombotic
Lacunar
Retinal
Stroke severity
Mild
Moderate
Severe

Clopidogrel
Aspirin
53.3 + 47.6 52.7 + 47.3
60%
39%
1%

58%
41%
1%

22%
56%
22%

23%
55%
22%

*Mean + SD.
Data on file (CAPRIE Report No. 602-6-110, p. 86).
12

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CAPRIE Study Discipline

Clopidogrel
(n = 9,599)

Aspirin
(n = 9,586)

46 (0.5%)

40 (0.4%)

Early permanent study

drug discontinuation

2,041 (21.3%)

2,018 (21.1%)

Study drug compliance

90.6%

90.7%

Code breaks

11 (0.1%)

10 (0.1%)

Lost to follow-up

22 (0.2%)

20 (0.2%)

Measure
No study drug

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

13

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CAPRIE Study: Primary Analysis

Ischemic
Stroke

Total
First
Events

Event
Rate / Yr

Fatal

Nonfatal

Fatal

Other
Vascular
Death

405

33

226

49

226

939

5.32%

430

32

270

63

226

1021

5.83%

Nonfatal

Clopidogrel
Aspirin

Treatment
Group

MI

Relative Risk Reduction: 8.7% (p = 0.043)

(95% Confidence Interval: 0.3%, 16.5%)
CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
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CAPRIE Study: MI Paradox

Relative Risk Reduction* by
Qualifying Entry Criteria1
7.3
IS n=6431
-3.7

MI n=6302
23.8

n=6452

8.7
20

10

10

PAD

Total n=19185
20

30

clopidogrel better

Relative Risk Reduction of

Individual End Points
5.2
n=19,185

IS (fatal or
non-fatal)2

19.2

MI (fatal or
non-fatal)3

7.6

Vascular
death1
IS, MI,
vascular death1
20

10

8.7
0

10

20

30

clopidogrel better

*Cluster of IS, MI, or vascular death. 1CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
2
Easton. Neurology 1998;50(suppl 4):A157. 3Gent. Circulation. 1997;96(suppl):I-467.
15

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CAPRIE Study: Efficacy of Clopidogrel

Event Rate
at 3 Years
20.3
15.2
14.1

Cumulative Risk, %

16

12

Placebo1
Aspirin2

Event Rate
per Year

Clopidogrel2

7.7

5.8

p = 0.043,
clopidogrel
vs. aspirin

5.3

0
0

12

Placebo arm extrapolated from

APTC meta-analysis. Antiplatelet
Trialists Collaboration. BMJ 1994;
308:81-106, and CAPRIE
2
CAPRIE Steering Committee.
Lancet 1996;348:1329-1339.
p = 0.043.
1

15

18

21

24

27

30

33

36

Time from Randomization (Months)

16

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Different Measures of Efficacy

Treatment benefit can be expressed by different

measures, for example:
Relative risk reduction
Absolute risk reduction
Odds ratio

Number of events prevented (or number needed to

treat*) is a more meaningful expression for medical
decision makers

*Laupacis et al. N Engl J Med 1988;318:1728-1733.

17

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Number of Events Prevented

Correlated to:
Baseline risk
Relative risk reduction (RRR)
Examples:
Events prevented per
RRR
30%
30%
8%
18

Baseline risk
1%
8%
6%

1,000 patients treated

3
24
5
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Event Rate/1,000 Patients/Year

Efficacy of Clopidogrel: Events Prevented (Ischemic

Stroke, Myocardial Infarction, Vascular Death)
160

Event Rate per Year

80

77
58
53

40

24

19

12

15

18

21

24

27

30

33

Time from Randomization (Months)

Placebo arm extrapolated from APTC meta-analysis.
Antiplatelet Trialists Collaboration. BMJ 1994;308:81-106, and CAPRIE
19

7.7%

Aspirin2

5.8%

Clopidogrel2

5.3%

120

Placebo1

36

Based
on
the
APTC
findings,1 in a population
similar to CAPRIE, for each
1,000 patients treated per
year,
aspirin
can
be
expected to prevent 19
events and clopidogrel 24.2

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

p = 0.043.
2

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CAPRIE Study:
Clinical Evidence of Efficacy of Clopidogrel

*(MI, ischemic stroke,and vascular death)

**Based on the CAPRIE trial and Antiplatelet
Trialists Collaboration meta-analysis, aspirin
can be expected to prevent 19 ischemic
events* for every 1,000 patients treated per
year.1,2 In contrast, clopidogrel can be expected
to prevent 24 ischemic events* for every 1,000
patients treated per year, a 26% difference.
CAPRIE Steering Committee. Lancet
1996;348:1329-1339. 2Antiplatelet Trialists
Collaboration. BMJ 1994; 308:81-106.

Events Prevented/Year/1,000 Patients

Clopidogrel
prevents 26% more
ischemic events*
than aspirin**

25

26%

20
15

10

19

24

20

Aspirin1,2

Clopidogrel1,2
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Events Prevented by
Cardiovascular Pharmacotherapies
Treatment

Population

Clopidogrel1,2

Atherosclerotic IS, MI, vascular

death

24

Aspirin1,2

Atherosclerotic IS, MI, vascular

death

19

Antihypertensive
drugs3

Hypertension
(>60 yrs)

Fatal or non-fatal stroke,

MI, CHD death

ACE inhibitors4

Acute MI + LV
dysfunction

MI, vascular
death

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

Antiplatelet Trialists Collaboration. BMJ 1994;308:81-106.

21

Mean No. of Events

Prevented per 1,000
Patients per Year

End Point

8
18

SHEP Cooperative Research Group. JAMA 1991;265:3255-3264.

Pfeffer MA, et al. (SAVE Trial) N Engl J Med 1992;327:669-677.

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100,000 additional
events (IS, MI,
vascular death)
could be
prevented if all
atherothrombotic
patients in US and
EU (20 M) were
treated per year

22

Events Prevented/Year

Impact of Platelet Aggregation Inhibitors:

Extrapolation to US and EU Atherothrombotic Patients
500,000
400,000
300,000
200,000

100,000
380,000

480,000

Aspirin

Clopidogrel

100,000
0

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Adverse Events in the CAPRIE Study

% of Patients with Events
Aspirin
Clopidogrel
(325 mg/day) (75 mg/day)
Intracranial hemorrhage1
0.49
0.35
Gastrointestinal bleeding1
2.66*
1.99
1.15*
Gastrointestinal ulcers2
0.68
Indigestion/nausea/vomiting1
17.59*
15.01
Diarrhea1
3.36
4.46*
6.02*
Rash1
4.61
Neutropenia1
0.17
0.10
CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
2
Lok. Eur Heart J 1998;19(suppl):P487.
1

23

*p<0.05
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Number of Patients

CAPRIE Study: Hemorrhagic Events

300
Clopidogrel

250

Aspirin

200
150

191

100
50
0

255

71
104
(0.74%) (1.08%)
Hospitalization for GI
Bleeding Events1

GI Hemorrhages
(p<0.002)2

Trend to more cerebral hemorrhages, fatal or non-fatal, and more

hemorrhagic deaths in aspirin group: 37 versus 51 (0.39% vs. 0.53%)

Bogousslavsky. Cerebrovasc Dis 1998;8(suppl 4):43. Abstract CLI 76.

2
CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
1

24

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CAPRIE Study: Gastrointestinal Tolerability

Events

Clopidogrel, %

Aspirin, %

Ulcers1

0.68

1.15

Indigestion,
nausea,
vomiting2

15.01

17.59

Higher incidence of ulcers in aspirin group: 110 (1.15%) vs. 65 (0.68%) in

clopidogrel group (p<0.05)1

More GI disorders in aspirin group (p<0.001)2

Overall incidence of GI events (abdominal pain, dyspepsia, gastritis,
constipation): 27.1% for clopidogrel, 29.8% for aspirin 1

Lok. Eur Heart J 1998;19(suppl):P487.

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

1
2

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CAPRIE Study: Skin Disorders

Events

All, %
Clopidogrel

Severe, %
Aspirin

Clopidogrel

Aspirin

Any rash*

6.02

4.61**

0.26

0.10**

Any allergic reaction*

0.92

1.01

0.08

0.11

Incidence of any rash is statistically different (p<0.001)

Few severe rashes in either group
Small number of rashes led to early premature discontinuation:
(0.90% for clopidogrel and 0.41% for aspirin)

*The two groups of events are mutually exclusive.

**p<0.05

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

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CAPRIE Study: Diarrhea

Events

All, %
Clopidogrel

Diarrhea

4.46

Severe, %
Aspirin

3.36*

Clopidogrel

0.23

Aspirin

0.11

Incidence of diarrhea is statistically different (p<0.001)

Few cases of severe diarrhea in either group
Diarrhea rarely led to early permanent discontinuation
(0.42% for clopidogrel and 0.27% for aspirin)

*p<0.05
CAPRIE Steering Committee. Lancet 1996;348:1329-1339.
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CAPRIE Study:
Validated Cases of Low Neutrophil Counts
Clopidogrel
(n=9,599)

Aspirin
(n=9,586)

Neutropenia
(<1200/mm3)

10 (0.10%)

16 (0.17%)

Severe neutropenia
(<450/mm3)

5 (0.05%)

4 (0.04%)

Category

CAPRIE Steering Committee. Lancet 1996;348:1329-1339.

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Clopidogrel: Summary 1

Mechanism of action: ADP receptor antagonist providing effective

inhibition of platelet aggregation

Clopidogrel is more effective than aspirin1:

Clopidogrel prevents 26% more ischemic events* than
aspirin**
19.2% more effective than aspirin in reducing the risk of
myocardial infarction (relative risk reduction 19.2%, p=0.008)3
Favorable effect on each component of the outcome cluster

*(MI, ischemic stroke and vascular death) **Based on the CAPRIE trial and Antiplatelet Trialists Collaboration meta-analysis, aspirin can
be expected to prevent 19 ischemic events* for every 1,000 patients treated per year. 1,2 In contrast, clopidogrel can be expected to prevent
24 ischemic events* for every 1,000 patients treated per year, a 26% difference.
1
CAPRIE Steering Committee. Lancet 1996;348:1329-1339. 2Antiplatelet Trialists Collaboration. BMJ 1994;308:81-106.
3
Gent M. Circulation 1997;96(suppl):I-467.
29

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Clopidogrel: Summary 2

Favorable safety profile1

Less GI bleeding and fewer related hospitalizations vs.
aspirin2
Better GI safety and improved gastric tolerability vs.
aspirin (325 mg)

Difference in favor of clopidogrel for GI bleeding is likely to

be underestimated in CAPRIE due to study exclusion criteria

Convenient dosing: 75 mg once daily with no dose

adjustments necessary

CAPRIE Steering Committee. LANCET 1996;348:1329-1339.

Bogousslavsky. Cerebrovasc Dis 1998;8(suppl 4):43. Abstract CLI 76.

1
2

30

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