CLARITY-TIMI 28 and COMMIT/CCS 2:
Trials of clopidogrel in STEMI
Christopher P Cannon MDSenior Investigator, TIMI Study GroupAssociate Professor of MedicineHarvard Medical SchoolCardiovascular DivisionBrigham and Women's HospitalBoston, MA
Background
Fibrinolytic treatment for STEMI limited by inadequate reperfusion and/or reocclusion in ~25% of patients.
An occluded infarct-related artery is associated with a doubling of long-term mortality.
0 8 16 24 32 40 480
5
10
15
20
Occluded
Patent
Weeks
Mo
rtal
ity
(%)
Dalen JE, Gore JM, Braunwald E, et al.Am J Cardiol. 1988; 62:179-185
Evidence for the open artery hypothesis:
TIMI 1
Study design
Fibrinolytic, ASA, heparin
Clopidogrel300 mg + 75 mg qd
Coronary angiogram(2-8 days)
Primary endpoint:Occludedartery (TIMI flow grade 0/1)or D/MI by timeof angiogram
Randomize
Placebo
Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 years with STEMI < 12 hours
Studydrug
30-day clinical follow-up
Open-labelclopidogrelper MD in
both groups
Sabatine MS. N Engl J Med 2005;352(12):1179
Primary endpoint:Occluded artery (or D/MI through angio/HD)
15.0
21.7
0
5
10
15
20
25
Occ
lud
ed a
rter
y o
r d
eath
/MI
(%
)
PlaceboClopidogrel
p=0.00000036p=0.00000036
Odds ratio 0.64(95% CI 0.53-0.76)
Odds ratio 0.64(95% CI 0.53-0.76)
1.00.4 0.6 0.8 1.2 1.6
Clopidogrelbetter
Placebobetter
n=1752 n=1739
36%Odds reduction
36%Odds reduction
Sabatine MS. N Engl J Med 2005;352(12):1179
CV death, MI, RI urgent revascularization
Days
Pe
rce
nta
ge
wit
h e
nd
po
int
(%)
0
5
10
15
0 5 10 15 20 25 30
Placebo
Clopidogrel
Odds ratio 0.80(95% CI 0.65-0.97)
p=0.026
20%
Sabatine MS. N Engl J Med 2005;352(12):1179
Bleeding
Outcome Clopidogrel (%)
Placebo (%)
p value
Through angiography
TIMI major (Hgb >5 g/dL or ICH) 1.3 1.1 NS
TIMI minor (Hgb 3-5 g/dL) 1.0 0.5 NS
Intracranial hemorrhage 0.5 0.7 NS
Through 30 days
TIMI major 1.9 1.7 NS
In those undergoing CABG 7.5 7.2 NS
CABG within 5 d of study med 9.1 7.9 NS
TIMI minor 1.6 0.9 NSSabatine MS. N Engl J Med 2005;352(12):1179
Summary
In patients with STEMI 75 years receiving a standard fibrinolytic regimen, a loading dose of 300 mg of clopidogrel followed by 75 mg daily resulted in:
• 36% reduction in the odds of an occluded infarct-related artery, or death/MI by time of angiogram (NNT = 16).
• Highly consistent benefit across all major subgroups.
• 20% reduction in CV death, MI, or recurrent ischemia leading to urgent revascularization through 30 days (NNT = 36).
• No excess in TIMI major or minor bleeding (including in those undergoing CABG) or in ICH.
Sabatine MS. N Engl J Med 2005;352(12):1179
57
30 32
25
18.4
11.7
0
10
20
30
40
50
60
Occ
lud
ed i
nfa
rct-
rela
ted
art
ery
(%)
TPASK
Evolution of pharmacologic reperfusion
TIMI 1
ASA +clopidogrel
ASA
NEJM 1985;312:932
APRICOT
Placebo ASA
Circ 1993;87:1524
36% p<0.00136% p<0.001
90 mins 3 mos 3.5 d
47% p<0.00147% p<0.001
22% p=0.2622% p=0.26
Sabatine MS. N Engl J Med 2005;352(12):1179
Conclusion
Clopidogrel offers an effective, simple, inexpensive, and safe means by which to
improve infarct-related artery patency and reduce ischemic complications.
M A R C H 9, 2 0 0 5
Sabatine MS, Cannon CP, Gibson CM,Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ,Cools F, Hill KA, Skene AM, McCabe CH and Braunwald E
for the CLARITY-TIMI 28 Investigators.
N Engl J Med. 2005;352:1179-1189 www.nejm.org.
ACC 2005 LBCT Slide Set available at www.timi.org.
TREATMENT: Clopidogrel 75 mg daily vs placebo(aspirin 162 mg daily in both groups)
INCLUSION: Suspected acute MI (ST change or LBBB) within 24 hours of symptom onset
EXCLUSION: Primary PCI or high-risk of bleeding
1 OUTCOMES: Death, and death, re-MI, or stroke up to 4 weeks in hospital (or prior discharge)
Mean treatment and follow-up: 16 days
COMMIT: Study design
Chen ZM. Presented ACC 2005
COMMIT: Effects of clopidogrel on death, re-MI or stroke
Days since randomization (up to 28 days)
Event (%)
9% (SE3) relative riskreduction (2P=0.002)
Placebo: 2311 events (10.1%)Clopidogrel:2125 events (9.3%)
Chen ZM. Presented ACC 2005
COMMIT: Effect of clopidogrel on death in hospital
Dead(%)
Days since randomization (up to 28 days)
Placebo: 1846 deaths (8.1%)
Clopidogrel:1728 deaths (7.5%)
7% (SE3) relative riskreduction (2P=0.03)
Chen ZM. Presented ACC 2005
Type Clopidogrel Placebo (n=22 958) (n=22 891)
CerebralFatal 39 40
Non-fatal 16 15
Non-cerebralFatal 36 37Non-fatal 46 36
Any major bleed 134 124 (0.58%) (0.54%)
COMMIT: Major bleed in hospital
Chen ZM. Presented ACC 2005
COMMIT/CCS-2: Conclusions
• Adding 75 mg daily clopidogrel to aspirin in acute MI prevents ~10 major vascular events per 1000 treated.
• No excess of cerebral, fatal, or transfused bleeds (even with fibrinolytic therapy and in older people).
• Each million MI patients treated for ~2 weeks would avoid 5000 deaths and 5000 non-fatal events.
Chen ZM. Presented ACC 2005
Milestones in the evolution of thrombolysis in myocardial infarction
Mortality
1988 ISIS-2 SK 25% ↓
ASA 23% ↓
1993 GUSTO-1 tPA 14%↓
2005 COMMIT/ Clopidogrel 7% ↓
CCS-2Chen ZM. Presented ACC 2005
Drugs that failed to show mortality reduction in STEMI in the past decade
Double-bolus t-PA
TNK
rPA
nPA
GP IIb/IIIa inhibitor + lytic
Oral GP IIb/IIIa
Bivalirudin
Hirudin
Pexelizumab
Magnesium
Adenosine
PSGL
GIK
etc….
Chen ZM. Presented ACC 2005
Clopidogrel in STEMI
• Evidence from two large trials in ~50 000 patients
• Benefit in opening infarct-related artery and in reducing mortality and morbidity
• No excess in major bleeding• Low cost
A new addition to treatment of STEMI
Chen ZM. Presented ACC 2005
Clopidogrel trials – ACS/CAD
COMMITCOMMIT(CCS-2)(CCS-2)
CAPRIECAPRIELancet 1996Lancet 1996
MI / stroke PAD
Vasc dis/risk
Up to 3.5 years
STEMI
Acute STEMI Long-term 2o (1o) preventionUA/NSTEMI PCI
PCIUA/ NSTEMI
+ Benefit + Benefit
1 year 1 year
+ Benefit
1-3 years30 days
+ Benefit
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