CLARITY-TIMI 28 and COMMIT/CCS 2:

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


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%


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.


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


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%)


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)


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


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.


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….


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


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

Documents

CLARITY-TIMI 28 and COMMIT/CCS 2: