lopidogrel in nstable Angina
to Prevent ecurrent vents
Disclaimer
This slide kit presents new data to support the
rationale for the use of ADP receptor antagonists for
approved and unapproved indications.
The slide kit has been prepared for medical and
scientific purposes. It contains information on a use
that is not approved by the FDA and should not be
construed as an inducement to use clopidogrel for
unapproved indications. Neither Sanofi-Synthelabo
Inc., Bristol-Myers Squibb nor the partnership
recommends the use of clopidogrel in any manner
inconsistent with that described in the full prescribing
information.
CURE
Rationale

Despite treatment with aspirin and heparin, the incidence
of MI and CV death during hospitalization remains high,
6-8%

Long term, the incidence of these events remain high at
6-8% per year

The majority of patients (80%) who enter the hospital with
acute coronary syndrome (ACS) are already on aspirin
therapy

The negative findings of the oral GP IIb/IIIa’s underscores
the need for alternative strategies to treat ACS
CURE Study Investigators. Eur Heart J. 2000;21:2033-2041.
PURSUIT Investigators. Am J Cardiol. 1999;83:1147-1151.
CURE
Study Objectives
Primary

Evaluate the early and long-term efficacy of
clopidogrel vs placebo, both given in addition to
aspirin and other standard therapy in preventing
ischemic complications in patients with ACS
without ST-segment elevation (unstable angina or
non-ST-segment elevation MI)
Secondary

Evaluate the safety of clopidogrel in combination
with ASA therapy in patients with ACS
CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.
CURE
Study Design
Clopidogrel 300 mg
loading dose
Clopidogrel 75mg q.d.
+ ASA 75-325 mg q.d.*
(6259 patients)
Patients with
Acute Coronary
Syndrome
(unstable angina or
non-ST-segment
elevation MI)
R
3 months  double-blind treatment  12 months
R = Randomization
* In combination with other standard therapy
Placebo + ASA
75-325 mg q.d.*
(6303 patients)
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Key Inclusion Criteria
1

Age  21 years1

Suspected UA or NSTEMI (no ST   1.0 mm)2

Presentation  24 hours after onset of symptoms2

ECG changes compatible with ischemia or elevated
cardiac enzymes or troponin I or T  2 x ULN2
CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)
2 CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.
CURE
Key Exclusion Criteria
1 CURE

NYHA Class IV heart failure1

Uncontrolled hypertension2

Current use of anticoagulants1, clopidogrel, ticlopidine,
or NSAIDS2, or GP IIb/IIIa inhibitor within 3 days1

PCI or CABG within 3 months1

History of severe thrombocytopenia or neutropenia2

At high risk for bleeding1

Contraindications to antithrombotic or antiplatelet therapy1
Study Investigators. Eur Heart J. 2000; 21:2033-2041.
2 CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)
CURE
Outcome Definitions
MI:
At least two of the following criteria: chest pain, ECG changes, elevation
of cardiac markers or enzymes (Troponin, CK, CK-MB)
Stroke:
Neurological deficit  24 hrs (CT/MRI encouraged)
CV Death:
Excludes any death for which there was no clearly documented non-CV cause
Refractory Ischemia:
In-hosp: recurrent ischemia on max med Rx + ECG changes + intervention
 1 day
After discharge: Rehosp for UA with ECG changes
Severe Ischemia:
Changes similar to in-hospital refractory ischemia, but no intervention
Recurrent Angina:
All other ischemic chest pain in hospital
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Efficacy Analyses
First Primary End Point
First occurrence of any component of the cluster of:
– Myocardial Infarction
– Stroke (ischemic, hemorrhagic, or of uncertain type)
– Cardiovascular death
Second Primary End Point
First occurrence of any component of the cluster of:
– Myocardial Infarction
– Stroke (ischemic, hemorrhagic, or of uncertain type)
– Cardiovascular death
– Refractory ischemia
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Baseline Characteristics
Placebo
N = 6303
Clopidogrel
N = 6259
Age (mean)
64.2
64.2
Mean time from pain onset to
randomization (hrs)
14.1
14.2
Mean heart rate (beats/min)
73.0
73.2
Mean systolic BP (mm Hg)
134.1
134.4
38.3
38.7
Unstable Angina (%)
74.9
74.9
Non–ST-segment elevation MI (%)
25.1
25.1
93.9
93.7
Female (%)
Diagnosis at Entry
ECG abnormalities (%)
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Patient History
Placebo
N = 6303
(%)
Clopidogrel
N = 6259
(%)
History of MI
32.0
32.4
CABG Surgery/PTCA
18.1
17.7
Stroke
3.7
4.4
Heart Failure
7.8
7.4
Hypertension
57.8
59.9
Diabetes
22.8
22.4
Current or former smoker
60.9
60.6
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
ECG Abnormality Type
Placebo
(%)
Clopidogrel
(%)
93.9
93.7
42.0
42.2
3.2
3.2
Major T-wave inversion
25.9
25.4
Other T-wave inversion
11.3
11.5
Other abnormalities
10.9
10.7
History Abnormal ECG
ST-segment Dep > 1 mm
ST-segment elevation < 1 mm
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Primary End Point - MI/Stroke/CV Death
Cumulative Hazard Rate
0.14
11.4%
Placebo
+ ASA*
0.12
9.3%
0.10
0.08
Clopidogrel
+ ASA*
0.06
0.04
20% RRR
P < 0.001
N = 12,562
0.02
0.00
0
3
6
9
Months of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
12
CURE
MI/Stroke/CV Death within 30 Days
Cumulative Hazard Rate
0.06
Placebo
+ ASA*
0.05
0.04
Clopidogrel
+ ASA*
0.03
0.02
21% RRR
P = 0.003
N = 12,562
0.01
0.00
0
10
20
Days of Follow-Up
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
30
CURE
Main Efficacy Results - Primary Endpoint
Placebo
+ ASA*
N = 6303
Clopidogrel
+ ASA*
N = 6259
11.4%
9.3%
20%
MI
6.7%
5.2%
23%
Stroke
1.4%
1.2%
14%
CV death
5.5%
5.1%
7%
Outcome
CV death, MI,
stroke (Primary
end point)
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Relative
Risk
Reduction
P value
< 0.001
CURE
Main Efficacy Results Second Primary End Point
Placebo
+ ASA*
Clopidogrel
+ ASA*
18.8%
16.5%
14%
Refractory Ischemia
– Refractory Ischemia
in hospital
– Refractory Ischemia
after discharge
9.3%
8.7%
7%
2.0%
1.4%
32%
7.6%
7.6%
1%
Severe Ischemia
3.8%
2.8%
26%
P = 0.003
22.9%
20.9%
9%
P = 0.01
4.4%
3.7%
18%
P = 0.03
End Point
Second Primary End Point
Recurrent Ischemia
Heart Failure†
* In combination with standard therapy
** Not significant
† Heart failure was a secondary end point
RRR
P value
< 0.001
NS**
P < 0.001
NS**
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Beneficial Outcomes with Clopidogrel in
Various Subgroups
Percentage of Patients with Event
Characteristic
Overall
Associated MI
No associated MI
Male sex
Female sex
65 yr old
> 65 yr old
ST-segment deviation
No ST-segment deviation
Enzymes elevated at entry
Enzymes not elevated at entry
Diabetes
No diabetes
Low risk
Intermediate risk
High risk
History of revascularization
No history of revascularization
Revascularization after randomization
No revascularization after randomization
No. of
Patients
Clopidogrel
+ ASA*
Placebo
+ ASA*
12562
3283
9279
7726
4836
9.3
11.3
8.6
9.1
9.5
11.4
13.7
10.6
11.9
10.7
6354
6208
6275
6287
3176
9386
2840
9722
5.4
13.3
11.5
7.0
10.7
8.8
14.2
7.9
7.6
15.3
14.3
8.6
13.0
10.9
16.7
9.9
4187
4185
4184
2246
10316
4577
7985
5.1
6.5
16.3
8.4
9.5
11.5
8.1
6.7
9.4
18.0
14.4
10.7
13.9
10.0
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
0.4
0.6
0.8
Clopidogrel Better
1.0
1.2
Placebo Better
Relative Risk (95% CI)
CURE
Thrombolytic and IV GP IIb/IIIa Inhibitor
Use After Randomization
Placebo
+ ASA*
N = 6303
Clopidogrel Relative
+ ASA*
Risk
N = 6259 Reduction
CI
P value
Thrombolytics
2.0%
1.1%
43%
0.43-0.76 < 0.001
IV GP IIb/IIIa Inhib
7.2%
5.9%
18%
0.72-0.93
* As part of standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
0.003
CURE
Definition of Bleeding
Bleeding was defined as “Major” and “Minor”
Major bleeding was defined as follows:

life threatening: fatal, symptomatic intracranial hemorrhage,
leading to a drop in hemoglobin of at least 5 g/dL, significant
hypotention requiring IV inotropes, requiring surgical
intervention, or requiring transfusion of 4 or more units of
blood
non-life-threatening: substantially disabling, intraocular
bleeding leading to vision loss, or requiring at least 2 units
of blood
Minor


any other bleeds that led to interruption of study medication
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Bleeding Results
End Point
Major bleeding
Placebo
+ ASA*
N = 6303
Clopidogrel
+ ASA*
N = 6259
2.7%
3.7%**
Life-threatening bleeding
1.8%
2.2% †
Non-life-threatening bleeding
0.9%
1.5% ‡
2.4%
5.1% §
Minor bleeding
* In combination with standard therapy
** P = 0.001; † P = NS; ‡ P = 0.002; § P < 0.001.
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Life-Threatening Bleeding
Placebo
+ ASA*
N = 6303
Clopidogrel
+ ASA*
N = 6259
(%)
(%)
1.8
2.2
Fatal
0.2
0.2
5 g/dL drop hemoglobin
0.9
0.9
Hypotension-inotropic therapy
0.5
0.5
Surgery required
0.7
0.7
Hemorrhagic stroke
0.1
0.1
 4 Blood units
1.0
1.2
Life-Threatening
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Major Bleeding in IV GP IIb/IIIa Antagonists
ACS Trials vs CURE: within 30 Days
Trial
N
Placebo*
Active*
Diff
12562
1.5%
2.0%
+0.5%
PRISM-PLUS
1915
0.8%
1.4%
+0.6%
PURSUIT
9375
9.1%
10.6%
+1.5%
1.3%
3.0%
+1.7%
1.9%
3.8%
+1.9%
CURE:
IV GP IIb/ IIIa Trials:
excluding CABG
CAPTURE
* In addition to standard therapy including
aspirin and heparin
1265
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-97.
PURSUIT Investigators. N Engl J Med. 1998;339:436-43.
CAPTURE Investigators. Lancet. 1997;349 (9063):1429-1435.
CURE
Conclusions
In the CURE study of 12,562 patients with ACS without STsegment elevation:

clopidogrel demonstrated a 20% relative risk reduction in MI,
stroke or cardiovascular death with long-term use† (P <0.001)

the Kaplan-Meier curves began to diverge within hours and
continued to diverge over the course of 12 months

clopidogrel also demonstrated a 14% relative risk reduction in MI,
stroke, cardiovascular death or refractory ischemia (P <0.001)
Clopidogrel in addition to aspirin and other standard therapy
demonstrated an early effect (within hours) and sustained longterm benefit throughout the entire study period of 12 months
†
Up to 12 months
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
CURE
Conclusions
Minor bleeding was increased, but there was no increase
in life-threatening bleeds (including intracranial bleeds)
18% Relative Risk Reduction in heart failure
(P = 0.03)
Significant reductions in the reported use of:
– IV GP IIb/IIIa inhibitor: 18% (P = 0.003)
– thrombolytics: 43% (P < 0.001)
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
PCI-CURE
Design
Prospectively designed study of patients undergoing PCI
who were randomized to double-blind therapy with
clopidogrel or placebo, both in addition to aspirin and other
standard therapy in the CURE trial
Objectives

to test the hypothesis that pre-treatment with clopidogrel in
addition to aspirin and other standard therapy would be more
effective than aspirin and standard therapy alone in
preventing major ischemic events within the first 30 days
after PCI

to determine if long-term treatment (up to 1 year) with
clopidogrel in addition to aspirin and other standard therapy
after PCI would provide additional clinical benefit
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Study Design

Patients randomized to clopidogrel or placebo at CURE trial
entry, both in addition to aspirin and standard therapy

All patients undergoing PCI during the course of the CURE
trial were included in PCI-CURE

Timing of PCI was at the physician’s discretion

At time of PCI, study drug was interrupted and open-label
therapy was initiated for 2-4 weeks

During open-label therapy, thienopyridines in combination with
ASA was permitted

Follow-up ranged from 3-12 months
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Study Design
CURE
PCI-CURE
Pretreatment
N = 2,658 patients undergoing PCI
Open-label thienopyridine
PLACEBO
+ ASA *
R
N = 1345
PCI
30 days post PCI
Open-label thienopyridine
CLOPIDOGREL
+ ASA *
N = 1313
Pretreatment
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
End of follow-up
Up to 12 months
after randomization
PCI-CURE
End Points
Composite of the following within 30 days of PCI:

myocardial infarction

urgent target-vessel revascularization

cardiovascular death
Composite of the following from PCI to end
of follow-up:

myocardial infarction

cardiovascular death
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Baseline Characteristics
Placebo
+ ASA*
(N = 1345)
Clopidogrel
+ ASA*
(N = 1313)
Age (mean, years)
61.4
61.6
Male (%)
69.9
69.7
Diabetes (%)
19.0
19.0
Previous MI (%)
26.0
27.3
Prior PCI (%)
13.8
13.4
Prior CABG (%)
13.0
12.0
ST-segment depression (%)
42.4
43.2
4.4
5.1
ST-segment elevation (%)
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Interventional Characteristics
Placebo
+ ASA*
(N = 1345)
Clopidogrel
+ ASA*
(N = 1313)
10
10
PCI during initial hospitalization
6
6
PCI after initial hospitalization
49
49
81.3
82.4
Before PCI (%)
24.7
26.4
Overall (%)
84.1
82.9
Overall median days after
randomization on which
PCI was done
Stent use (%)
Use of open-label thienopyridine
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Efficacy Outcomes
Placebo
+ ASA*
N = 1345
Clopidogrel
+ ASA*
N = 1313
RRR
P value
4.5%
30%
0.03
6.0%
25%
0.047
From PCI to 30 days
MI, urgent revascularization
or CV death
6.4%
From PCI to follow-up
CV death or MI
8.0%
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Overall Long-Term Results
Composite of cardiovascular death or MI from randomization to end of follow-up
Cumulative Hazard Rate
0.15
12.6%
Placebo
+ ASA*
8.8%
0.10
Clopidogrel
+ ASA*
0.05
31% RRR
P = 0.002
N = 2658
0.0
0
100
200
Days of follow-up
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.
300
400
PCI-CURE
30 Day Results
Composite of cardiovascular death, MI, or urgent revascularization
Cumulative Hazard Rate
0.08
Placebo
+ ASA*
0.06
6.4%
4.5%
0.04
Clopidogrel
+ ASA*
0.02
30% RRR
P = 0.03
N = 2658
0.0
0
5
10
15
20
Days of follow-up
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
25
30
PCI-CURE
Subgroup Analysis
Placebo
+ ASA*
Clopidogrel
+ ASA*
RR
95% CI
Overall
12.6%
8.8%
0.69
0.54-0.87
Stent
No stent
11.7%
16.2%
8.7%
9.4%
0.73
0.56
0.56-0.95
0.34-0.95
Age  65
Age > 65
9.8%
16.9%
5.9%
13.4%
0.59
0.79
0.41-0.84
0.57-1.08
Male
Female
11.9%
14.1%
7.9%
11.0%
0.65
0.77
0.48-0.87
0.52-1.15
Diabetes
No diabetes
16.5%
11.7%
12.9%
7.9%
0.77
0.66
0.48-1.22
0.50-0.87
During initial hosp
After initial hosp
12.0%
13.8%
8.3%
9.8%
0.68
0.70
0.50-0.92
0.48-1.02
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
0.1
1.0
10.0
Clopidogrel Better
Placebo Better
Relative Risk (95% CI)
PCI-CURE
Other Outcomes
Placebo
+ ASA*
N = 1345
Clopidogrel
+ ASA*
N = 1313
RRR
P value
IV GP IIb/ IIIa use
26.6%
20.9%
21%
0.001
Second
revascularization
17.1%
14.2%
18%
0.049
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Bleeding Outcomes
Placebo
+ ASA*
Clopidogrel
+ ASA*
1.4%
1.6% †
0.7%
0.7% †
0.7%
1.0% †
2.5%
2.7% †
1.3%
1.2% †
2.1%
3.5% ‡
From PCI to 30 days
Major
Life threatening
Minor
From PCI to end of follow-up
Major
Life threatening
Minor
* In combination with standard therapy
†
P = NS, ‡ P = 0.03
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Conclusions
For the composite of MI or cardiovascular death in the 2658
patients who underwent PCI in the CURE trial:

clopidogrel plus aspirin* demonstrated a 31% relative risk
reduction from randomization to the end of follow-up
(P = 0.002)

clopidogrel plus aspirin* demonstrated a 25% relative risk
reduction in the composite of MI or cardiovascular death with
long-term use† from PCI to end of follow-up (P = 0.04)

clopidogrel in addition to aspirin and other standard therapy
provides early beneficial effects and sustained long-term†
benefit in ACS patients requiring PCI
* In combination with standard therapy
† Up to 12 months
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.
PCI-CURE
Conclusions
†

Long-term† administration of clopidogrel plus aspirin*
resulted in an overall 25% relative risk reduction in MI and
CV death from PCI to end of follow-up
– Pretreatment with clopidogrel plus aspirin* resulted in a
30% relative risk reduction in CV death, MI and target
vessel revascularization in 30 days post PCI

There was an increase in minor bleeding, but was
no significant difference in major or life-threatening
bleeding between the two treatment groups
Up to 12 months
* In combination with standard therapy
Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.