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12
3
17
13
3
20
8
1.5
20
0
10
20
30
Death Stroke Urgentreadmission for
cardiac event
Pat
ien
ts (
%)
STEMI (4074)NSTEMI (3526)UA (5065)
Total outcomes: Total outcomes: admission to 6 monthsadmission to 6 months
Largest multinational registry covering the full spectrum of ACS
ESC 2001ESC 2001
• Randomized, double-blind trial: clopidogrel vs placebo in patients with ACS
• All patients receive ASA (75-325 mg)
• International trial (28 countries), 12,562 patients
• Central randomization
• Primary outcome: -CV death, MI, strokes
Study DesignCURECURE
CURE Study
3 months > double-blind treatment < 12 months
Aspirin 75-325mg
Clopidogrel75mg o.d.
(~6,250 patients)
Placebo1 tab o.d.
(~6,250 patients)
Aspirin 75-325mgD
ay 1
6 m
. Vis
it
9 m
. Vis
it
12 m
.
or F
inal
Vis
it
300m
g load
ing
dose
3 m
. Vis
it
1 m
. Vis
it
Patients withAcute Coronary
Syndrome
(UA or MI Without STelevation)
R
load
ing
dose
CURECURE
CV Death: Excludes clear non-CV deaths
MI: Two of three standard criteria: (Chest Pain, ECG, enzyme changes)
Stroke: Neurological deficit 24 hrs (CT/MRI)
Outcome Definitions CURECURE
Refractory Ischemia: Inhosp*: recurrent ischemia on max med Rx + ECG changes + intervention 1 day
After discharge: Rehosp for UA with ECG changes
Severe Ischemia*: Changes similar to RFA, but no intervention
Recurrent Angina*: All other ischemic CP in hospital
Months of Follow-up
Cu
mu
lative
Ha
za
rd R
ate
s
0.0
0.0
20
.04
0.0
60
.08
0.1
00
.12
0.1
4
0 3 6 9 12
Cumulative Hazard Rates for CV Death/MI/Stroke
Clopidogrel
Placebo
Cum
ulat
ive
Haz
ard
Rat
es
Months of Follow-up0 3 6 9 12
6203
6259
5778
5864
4660
4780
3599
3640
2378
2414
Plac
Clop
No of Pts
6303
6259
P = 0.00005
CURECURE
Days of Follow-up
Cu
mu
lative
Ha
za
rd R
ate
s
0.0
0.0
10
.02
0.0
30
.04
0.0
50
.06
0 10 20 30
Cumulative Hazard Rates for CV Death/MI/Stroke up to 30 Days
P=0.003
Clopidogrel
Placebo
Cum
ulat
ive
Haz
ard
Rat
es
Days of Follow-up0 10 20 30
6303
6259
6097
6093
5994
6027
5954
5981
No. Plac
No. Clop
CURECURE
Very Early Events
Placebo vs Clopidogrel
Day 1 Day 2 Day 3
CVD, MI, Stroke
(RR)
48 v 38
(0.80)
80 v 65
(0.82)
102 v 86
(0.85)Above + RFA
(RR)
86 v 65
(0.76)
140 v 104
(0.75)*
178 v 142
(0.80)*Severe
(RR)
103 v 65
(0.63)**
174 v 114
(0.66)***
211 v 153**
(0.73)Primary + Severe
(RR)
149 v 100 (0.67)***
247 v 173 (0.70)***
302 v 228
(0.75)****p<0.05 **<0.01 *** <0.002
CURECURE
Events During Initial HospitalizationEvents During Initial Hospitalization
Plac Clop RR (95% CI) P
% %
Refract Ang 2.1 1.4 0.69 (0.53-0.91) 0.008
Other Severe Ischemia
3.7 2.8 0.74 (0.61-0.90) 0.0028
Other Recurrent Angina
22.9 21.0 0.92 (0.86-0.98) 0.01
Heart Failure 4.4 3.7 0.83 (0.70-0.98) 0.029
CURECURE
CURE: Who Benefits and When?
• Similar benefits across all major treatment groups• On or off lipid lowering treatment, beta-blockers, heparin,
ACE inhibitors• Irrespective of revascularization or not • RR 0.81 with and RR 0.78 without, both significant
• Higher and lower risk groups show similar risk reduction
• Curves separate early and remain separated• Primary outcome at 24hrs: • 143 vs 93 clopidogrel (RR 0.65 CI 0.50 – 0.85)
Life Threatening Bleed
Plac Clop
# Patients 6303 6259
Percent Percent
Life Threatening 1.8 2.2
• Fatal 0.2 0.2
• 5 g/L Drop Hemoglobin 0.9 0.9
• Hypotension-inotropes 0.5 0.5
• Surgery Required 0.7 0.7
• Hemorrhagic Stroke 0.1 0.1
• 4+ Blood Units 1.0 1.2
CURECURE
Bleeds With CABG
Placebo Clopidogrel
% % RR CI
# Patients 1061 1011
All Major 6.6 8.3 1.26 0.93-1.71
Life Threatening 5.0 6.4 1.29 0.90-0.83
Other Major 1.6 1.9 1.17 0.61-2.24
TIMI Major 3.1 2.6 0.83 0.50-1.37
GUSTO Severe/LT 3.6 4.5 1.24 0.81-1.90
CURECURE
CURE: Magnitude of Benefit
• Primary Outcome:• MI, stroke or CV death: 11.4% placebo, • 9.2%** clopidogrel (22 per 1000 absolute difference)• (Non-CV death 0.7 vs 0.7%)
Treating 1000 patients for 9 months: prevents 28 vascular events with 6 individuals requiring transfusion
TIMI bleeding criteria: 68 clopidogrel,73 placebo RR 0.94 (CI 0.68-1.30)TIMI bleeding criteria: 68 clopidogrel,73 placebo RR 0.94 (CI 0.68-1.30)GUSTO criteria: 78 clopidogrel, 70 placebo RR 1.11 (CI 0.81-1.55)GUSTO criteria: 78 clopidogrel, 70 placebo RR 1.11 (CI 0.81-1.55)
Study Design
RandomizePCIPCIPCIPCI
PLACEBOPLACEBO + ASA+ ASAPLACEBOPLACEBO + ASA+ ASA
CLOPIDOGRELCLOPIDOGREL+ ASA+ ASACLOPIDOGRELCLOPIDOGREL+ ASA+ ASA
30 d. post PCI30 d. post PCI30 d. post PCI30 d. post PCIEnd of follow-up:End of follow-up:
12 months12 monthsEnd of follow-up:End of follow-up:
12 months12 months
Open-label thienopyridineOpen-label thienopyridine
Pretreatment
PretreatmentN=2,658 patients undergoing PCI
N = 1345
N = 1313
CURE PCI-CURE
PCI-
Open-label thienopyridineOpen-label thienopyridine
Baseline CharacteristicsBaseline Characteristics
43.2%42.4%ST depression
12.0%13.0%Prior CABG
13.4%13.8%Prior PCI
27.3%26.0%Previous MI
19.0%19.0%Diabetes
30.3%30.1%Sex (%F)
61.661.4Age (yrs)
Clopidogrel
n=1254
Placebo
n=1272
PCI-
0.0
0.0
50
.10
0.1
5
0 40 100 200 300 40010 100 200 300 400
A B Days following PCI
Cu
mu
lati
ve H
aza
rd R
ate
P=0.002P=0.002
ClopidogrelClopidogrel
PlaceboPlacebo
A=median time to PCIB=30 days after PCI
Overall Results: CV Death or MI
Lancet 2001: 358:527-33
PCI-
Events Before PCI
Placebo
N=1345
Clop.
N=1313
RR 95% CI P
MI or Refract. Ischemia
15.3% 12.1% 0.76 0.62-0.93 0.008
MI 5.1% 3.6% 0.68 0.47-0.99 0.04
PCI-
Lancet 2001: 358:527-33
Events Placebo
N=1345
Clopid.
N=1313
RR 95% CI P
CV death, MI, urg. revasc.*
6.4% 4.5% 0.70 0.50-0.97 0.03
CV death, MI 4.4% 2.9% 0.66 0.44-0.99 0.04
CV death 1.0% 1.1% 1.10 0.52-2.35
MI 3.8% 2.1% 0.56 0.35-0.89
Q wave MI 2.4% 0.8% 0.35 0.18-0.70
Urg Rev. 2.8% 1.9% 0.67 0.41-1.11
Major Outcomes:Major Outcomes: From PCI to 30 days From PCI to 30 daysPCI-
Lancet 2001: 358:527-33 *Primary endpoint
Other OutcomesPCI-
Placebo+ ASA*
N = 1345
Clopidogrel +ASA*
N=1313
RRR PValue
GP IIb/IIIa Inhibitior 26.6% 20.9% 81% 0.001
Need for secondrevascularization
17.1% 14.2% 18% 0.049
Mehta SR et. al. Lancet 2001: 358:527-33
Events Placebo N = 1345
Clopid N = 1313
RRR 95% CI P
From PCI to End of Followup
CV death, MI, any revasc
21.7% 18.3% 17% 0.56-0.99 0.03
CV Death or MI 8.1% 6.0% 26% 0.56-1.00 0.047
From >30 after PCI to end of follow-up
CV death, MI, any rehosp
28.9% 25.3% 14% 0.74-1.00 0.05
CV Death or MI 3.9% 3.1% 21% 0.53-1.20
Before and After PCI
CV death or MI 12.6% 8.8% 32% 0.54-0.87 0.002
Major Outcomes: Long Term Treatment
PCI-
Lancet 2001: 358:527-33
Clinical Suspicion of ACS:Physical examination, ECG
Blood samples
No persistent STelevation
Aspirin-blocker“heparin”
clopidogrel
Persistent STelevation
Thrombolysisor
Primary PCI
Stress TestPre- or post-
discharge
GP IIb/IIIacoronary
angio
High Riskrecurrent ischaemia
elevated troponinhaemodynamic instabilityarrhythmia with ischaemia
early post-MI unstable angina
Low Riskstable
normal troponin
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