Core CURE Slide Kit 9-06-011

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/IIIas underscores the

need for alternative strategies to treat ACS
CURE Study Investigators. Eur Heart J. 2000;21:2033-2041.
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
na 12
l V m.
isi
t
Placebo + ASA
75-325 mg q.d.*
(6303 patients)
Pl
ac
eb
o
or
Fi
isi
t
9m
.V
6m
.V
isi
t
isi
t
3m
.V
isi
t
3 months double-blind treatment 12 months
lo
Da
ad
y1
in
g
Di
d
sc
ha ose
rg
eV
isi
t
(unstable angina or
non-ST-segment
elevation MI)
1m
.V
Patients with
Acute Coronary
Syndrome
Clopidogrel 75mg q.d.

+ ASA 75-325 mg q.d.*
(6259 patients)
R = Randomization
The CURE Trial Investigators.

Investigators N Engl J Med. 2001;345:494-502.
CURE
Key Inclusion Criteria

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
1
2
CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)
CURE
Key Exclusion Criteria

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
At
of severe thrombocytopenia or neutropenia2
high risk for bleeding1
Contraindications
1
2
to antithrombotic or antiplatelet therapy1
CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

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

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

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
NonST-segment elevation MI (%)
25.1
25.1
93.9
93.7
Female (%)
Diagnosis at Entry
ECG abnormalities (%)

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

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

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
Months of Follow-Up
* In combination with standard therapy
12
CURE
MI/Stroke/CV Death within 30 Days

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
30
CURE
Main Efficacy Results - Primary Endpoint

Placebo
+ ASA*
N = 6303
Clopidogrel
+ ASA*
N = 6259
Relative
Risk
Reduction
P value
11.4%
9.3%
20%
< 0.001
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)
CURE
Main Efficacy Results Second Primary End Point

Clopidogrel
+ ASA*
RRR
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

** Not significant
Placebo
+ ASA*
P value
< 0.001
NS**
P < 0.001
NS**

CURE
Beneficial Outcomes with Clopidogrel in

Various Subgroups
Percentage of Patients with Event
Characteristic
Overall
No. of
Patients
Clopidogrel
+ ASA*
Placebo
+ ASA*
12562
9.3
11.4
Associated MI
No associated MI
3283
9279
11.3
8.6
13.7
10.6
Male sex
Female sex
7726
4836
9.1
9.5
11.9
10.7
65 yr old
65 yr old
6354
6208
5.4
13.3
7.6
15.3
ST-segment deviation
No ST-segment deviation
6275
6287
11.5
7.0
14.3
8.6
Enzymes elevated at entry

Enzymes not elevated at entry
3176
9386
10.7
8.8
13.0
10.9
Diabetes
No diabetes
2840
9722
14.2
7.9
16.7
9.9
Low risk
Intermediate risk
High risk
4187
4185
4184
5.1
6.5
16.3
6.7
9.4
18.0
2246
10316
8.4
9.5
14.4
10.7
4577
7985
11.5
8.1
13.9
10.0
History of revascularization
No history of revascularization
Revascularization after randomization
No revascularization after randomization
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
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

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
CURE
Life-Threatening Bleeding
Life-Threatening
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
CURE
Major Bleeding in IV GP IIb/IIIa Antagonists

ACS Trials vs CURE: within 30 Days
Trial
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
1265

Investigators N Engl J Med. 2001;345:494502.
* In addition to standard therapy including
PRISM-PLUS Investigators. N Engl J Med. 1998;338:1488-97.
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
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)
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 physicians 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
PCI-CURE
Study Design
CURE
PCI-CURE
Pretreatment
N = 2,658 patients undergoing PCI

Open-label thienopyridine
PLACEBO
+ ASA *
N = 1345
PCI
30 days post PCI
Open-label thienopyridine
CLOPIDOGREL
+ ASA *
Pretreatment
N = 1313

Mehta, SR. et al for the CURE Trial Investigators.
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
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 (%)

PCI-CURE
Interventional Characteristics
Placebo
+ ASA*
(N = 1345)
Clopidogrel
+ ASA*
(N = 1313)
10
10
PCI during initial hospitalization
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

PCI-CURE
Efficacy Outcomes
Placebo
+ ASA*
N = 1345
Clopidogrel
+ ASA*
N = 1313
RRR
P value
4.5%
30%
0.03
8.0%
6.0% 25%
From PCI to 30 days

MI, urgent revascularization
or CV death
6.4%
From PCI to follow-up
0.047
CV death or MI

PCI-CURE
Overall Long-Term Results

Composite of cardiovascular death or MI from randomization to end of follow-up
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

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
0.08
Placebo
+ ASA*
0.06
6.4%
4.5%
0.04
Clopidogrel
+ ASA*
0.02
0.0
0
10
15
20
Days of follow-up

25
30% RRR
P = 0.03
N = 2658
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

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

PCI-CURE
Bleeding Outcomes
Placebo
+ ASA*
Clopidogrel
+ ASA*
From PCI to 30 days

Major
1.4%
1.6%
Life threatening
0.7%
0.7%
Minor
0.7%
1.0%
Major
2.5%
2.7%
Life threatening
1.3%
1.2%
Minor
2.1%
3.5%
From PCI to end of follow-up
P = NS, P = 0.03
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
Up to 12 months
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


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lopidogrel in nstable Angina

to Prevent ecurrent vents

treatment with aspirin and heparin, the incidence of MI

term, the incidence of these events remain high at

majority of patients (80%) who enter the hospital with

negative findings of the oral GP IIb/IIIas underscores the

CURE Study Investigators. Eur Heart J. 2000;21:2033-2041.

CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

3 months double-blind treatment 12 months

Clopidogrel 75mg q.d.

The CURE Trial Investigators.

Key Inclusion Criteria

UA or NSTEMI (no ST 1.0 mm)2

24 hours after onset of symptoms2

changes compatible with ischemia or elevated

CURE Study Protocol (Data on file, Sanofi-Synthelabo, Inc.)

Key Exclusion Criteria

use of anticoagulants1, clopidogrel, ticlopidine,

or CABG within 3 months1

of severe thrombocytopenia or neutropenia2

high risk for bleeding1

to antithrombotic or antiplatelet therapy1

CURE Study Investigators. Eur Heart J. 2000; 21:2033-2041.

Neurological deficit 24 hrs (CT/MRI encouraged)

The CURE Trial Investigators.

First occurrence of any component of the cluster of:

Second Primary End Point

First occurrence of any component of the cluster of:

The CURE Trial Investigators.

Mean time from pain onset to

Mean heart rate (beats/min)

Mean systolic BP (mm Hg)

Unstable Angina (%)

NonST-segment elevation MI (%)

ECG abnormalities (%)

Current or former smoker

The CURE Trial Investigators.

ECG Abnormality Type

Major T-wave inversion

Other T-wave inversion

History Abnormal ECG

The CURE Trial Investigators.

Primary End Point - MI/Stroke/CV Death

MI/Stroke/CV Death within 30 Days

* In combination with standard therapy

Main Efficacy Results - Primary Endpoint

* In combination with standard therapy

Main Efficacy Results Second Primary End Point

* In combination with standard therapy

The CURE Trial Investigators.

Beneficial Outcomes with Clopidogrel in

Enzymes elevated at entry

* In combination with standard therapy

Relative Risk (95% CI)

Thrombolytic and IV GP IIb/IIIa Inhibitor

0.43-0.76 < 0.001

* As part of standard therapy

threatening: fatal, symptomatic intracranial hemorrhage,

other bleeds that led to interruption of study medication

The CURE Trial Investigators.

* In combination with standard therapy

5 g/dL drop hemoglobin

* In combination with standard therapy

Major Bleeding in IV GP IIb/IIIa Antagonists