CLARITYTIMI 28 and COMMITCCS 2: Trials of clopidogrel in STEMI

1
CLARITY-TIMI 28 and COMMIT/CCS 2Trials of
clopidogrel in STEMI

• Christopher P Cannon MD
• Senior Investigator, TIMI Study Group
• Associate Professor of Medicine
• Harvard Medical School
• Cardiovascular Division
• Brigham and Women's Hospital
• Boston, MA

2
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.

20
Evidence for the open artery hypothesis TIMI 1
Occluded
15
10
Mortality ()
5
Patent
Dalen JE, Gore JM, Braunwald E, et al.Am J
Cardiol. 1988 62179-185
0
48
0
8
16
24
32
40
Weeks
3
Study design
Double-blind, randomized, placebo-controlled
trial in3491 patients, age 18-75 years with
STEMI lt 12 hours
Fibrinolytic, ASA, heparin
Randomize
Clopidogrel 300 mg 75 mg qd
Placebo
Study drug
Primary endpoint Occludedartery (TIMI flow
grade 0/1) or D/MI by timeof angiogram
Coronary angiogram (2-8 days)
Open-label clopidogrel per MD inboth groups
30-day clinical follow-up
Sabatine MS. N Engl J Med 2005352(12)1179
4
Primary endpointOccluded artery (or D/MI
through angio/HD)
Odds ratio 0.64(95 CI 0.53-0.76)
36 Odds reduction
p0.00000036
1.0
0.4
0.6
0.8
1.2
1.6
n1752
n1739
Clopidogrel better
Placebo better
Placebo
Clopidogrel
Sabatine MS. N Engl J Med 2005352(12)1179
5
CV death, MI, RI ? urgent revascularization
15
Placebo
20
10
Clopidogrel
Percentage with endpoint ()
Odds ratio 0.80 (95 CI 0.65-0.97) p0.026
5
0
0
5
10
15
20
25
30
Days
Sabatine MS. N Engl J Med 2005352(12)1179
6
Bleeding
Sabatine MS. N Engl J Med 2005352(12)1179
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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 2005352(12)1179
8
Evolution of pharmacologic reperfusion
TIMI 1
APRICOT
90 mins
3 mos
3.5 d
47 ? plt0.001
22 ? p0.26
36 ? plt0.001
TPA
SK
ASA clopidogrel
ASA
Placebo
ASA
NEJM 1985312932
Circ 1993871524
Sabatine MS. N Engl J Med 2005352(12)1179
9
M A R C H 9, 2 0 0 5

• Conclusion
• Clopidogrel offers an effective, simple,
  inexpensive, and safe means by which to improve
  infarct-related artery patency and reduce
  ischemic complications.

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.
20053521179-1189 www.nejm.org.
ACC 2005 LBCT Slide Set available at www.timi.org.
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COMMIT Study design

• 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

Chen ZM. Presented ACC 2005
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COMMIT Effects of clopidogrel on death, re-MI
or stroke
Placebo 2311 events (10.1)
Clopidogrel 2125 events (9.3)
9 (SE3) relative risk reduction (2P0.002)
Event ()
Days since randomization (up to 28 days)
Chen ZM. Presented ACC 2005
12
COMMIT Effect of clopidogrel on death in
hospital
Placebo 1846 deaths (8.1)
Clopidogrel 1728 deaths (7.5)
7 (SE3) relative risk reduction (2P0.03)
Dead ()
Days since randomization (up to 28 days)
Chen ZM. Presented ACC 2005
13
COMMIT Major bleed in hospital

• Type
  Clopidogrel Placebo
  
  
  (n22 958)
  (n22 891)
• Cerebral
• Fatal 39 40
• Non-fatal 16 15
• Non-cerebral
• Fatal 36 37
• Non-fatal 46 36
• Any major bleed 134 124
• 
  (0.58) (0.54)

Chen ZM. Presented ACC 2005
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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
15
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-2

Chen ZM. Presented ACC 2005
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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
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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
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Clopidogrel trials ACS/CAD
UA/NSTEMI PCI
Long-term 2o (1o) prevention
Acute STEMI
CAPRIE Lancet 1996
COMMIT (CCS-2)
MI / stroke PAD
STEMI
PCI
UA/ NSTEMI
Vasc dis/risk Up to 3.5 years
1 year
1 year
1-3 years
30 days
Benefit
Benefit
Benefit
Benefit