Clopidogrel in ACS:Clopidogrel in ACS:OverviewOverview
Investigator, TIMI Study GroupAssociate Physician, Cardiovascular Division, BWH
Assistant Professor of Medicine, Harvard Medical School
Marc S. Sabatine, MD, MPHMarc S. Sabatine, MD, MPH
Clopidogrel: Mechanism
ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase.Adapted from Schafer AI. Am J Med. 1996;101:199-209.
CollagenThrombin
TXA2
ADP Receptor (P2YADP Receptor (P2Y1212))
TXATXA22
ADP
ADPADP
GP IIb/IIIaGP IIb/IIIareceptorreceptor
Activation
COX
Clopidogrel
Ticlopidine
Fibrinogen
Clopidogrel in NSTE ACS: CURE
CURE. NEJM 2001;345:494-502
12,563 Pts, GP IIb/IIIa & early invasive approach discouraged
RR 0.80, p<0.001
Clopidogrel(9.3%)
Placebo(11.4%)
CV
Dea
th,
MI,
Str
oke
Months of follow-up
0 3 6 9 120.0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Yusuf S et al. Circulation 2003;107:966-972
CURE: Very Early Efficacy of Clopidogrel in NSTE ACS
Hours After Randomization
0.0
0.005
0.010
0.015
0.020
0.025
0 2 4 6 8 10 12 14 16 18 20 22 24
P=.003
Placebo+ Aspirin(n=6303)
Clopidogrel+ Aspirin(n=6259)
34%Relative RiskReduction
CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours
Cu
mu
lati
ve H
aza
rd R
ate
Fox et al. Fox et al. Circulation.Circulation. 2004;110:1202-1208. 2004;110:1202-1208.
Medical Rx GroupMedical Rx Group
PlaceboPlacebo
ClopidogrelClopidogrelRR: 0.80 (0.69-0.92)RR: 0.80 (0.69-0.92)
0.200.20
44
0.150.15
0.100.10
0.050.05
0.00.0100100 200200 300300
ClopidogrelClopidogrel
0.200.20
44
0.150.15
0.100.10
0.050.05
0.00.0100100 200200 300300
PCI GroupPCI Group
PlaceboPlacebo
RR: 0.72 (0.57-0.90)RR: 0.72 (0.57-0.90)
0.200.20
44
0.150.15
0.100.10
0.050.05
0.00.0100100 200200 300300
CABG GroupCABG GroupPlaceboPlacebo
ClopidogrelClopidogrel
RR: 0.89 (0.71-1.11)RR: 0.89 (0.71-1.11)
CURE: Benefit by RevascularizationC
VD
/MI/S
tro
ke
CV
D/M
I/Str
oke
CV
D/M
I/Str
oke
CURE Safety Results
1.8 2.22.7 2.4
5.0
2.22.8
3.7
5.1
8.5
0
2
4
6
8
10
12
Life-Threatening
Trans 2U Major Minor Any
Eve
nt
Rat
e (%
)
Placebo
Clopidogrel
RR 1.38(95% CI 1.13-1.67)
P=0.001
NEJM 2001;345:494-502
Clopidogrel in STEMI
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 angio
randomize
Placebo
Double-blind, randomized, placebo-controlled trial in3491 patients, age 18-75 yrs with STEMI < 12 hours
StudyDrug
30-day clinical follow-up
Open-labelclopidogrelper MD in
both groups
ClopidogrelClopidogrel in STEMI in STEMI
15.0
21.7
0
5
10
15
20
25
Oc
clu
de
d A
rte
ry o
r D
ea
th/M
I (
%)
PlaceboPlaceboClopidogrelClopidogrel
36% P<0.0001
36% P<0.0001
Sabatine MS et al. NEJM 2005; 352: 1179
days
CV
Dea
th, M
I, o
r U
rg R
evas
c (%
)C
V D
eath
, MI,
or
Urg
Rev
asc
(%)
05
1015
0 5 10 15 20 25 30
PlaceboPlacebo
ClopidogrelClopidogrel
Odds Ratio 0.80Odds Ratio 0.80(95% CI 0.65-0.97)(95% CI 0.65-0.97)
P=0.026P=0.026
20%20%20%20%
BleedingBleeding
OutcomeOutcome Clopidogrel Clopidogrel (%)(%)
Placebo Placebo (%)(%)
P valueP value
Through angiographyThrough angiography
TIMI major TIMI major (Hgb (Hgb >5 g/dL or ICH) >5 g/dL or ICH) 1.31.3 1.11.1 NSNS
TIMI minor TIMI minor (Hgb (Hgb 3-5 g/dL) 3-5 g/dL) 1.01.0 0.50.5 NSNS
Intracranial hemorrhageIntracranial hemorrhage 0.50.5 0.70.7 NSNS
Through 30 daysThrough 30 days
TIMI majorTIMI major 1.91.9 1.71.7 NSNS
In those undergoing CABGIn those undergoing CABG 7.57.5 7.27.2 NSNS
CABG w/in 5 d of study medCABG w/in 5 d of study med 9.19.1 7.97.9 NSNS
TIMI minorTIMI minor 1.61.6 0.90.9 NSNSSabatine MS et al. NEJM 2005; 352: 1179
COMMIT: Clopidogrel (75 mg qd) in STEMI
9% relative risk reduction (P=.002)
Placebo (10.1%)
Clopidogrel (9.3%)
Days
Dea
th,
MI,
Str
oke
(%
)
9
8
7
6
5
4
3
2
1
00
Mo
rtal
ity
(%)
Days
Placebo (8.1%)
Clopidogrel (7.5%)
7% relative risk reduction (P=.03)
7
6
5
4
3
2
1
07 14 21 28 0 7 14 21 28
COMMIT Collaborative Group. Lancet. 2005;366:1607.
45,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)
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 Z et al. Lancet 2005;366:1607-21.
PCI – Rx following PCI
Following percutaneous coronary intervention (PCI), treatment with ADP receptor blockers such as ticlopidine or clopidogrel reduces thrombotic & ischemic complications.
Aspirin
Aspirin + warfarin
Aspirin + ticlopidine
P=0.001
CREDOSteinhubl et al. JAMA. 2002; 288: 2411.
12
10
8
6
4
2
0
STARSLeon et al. NEJM 1998; 339: 1665.
0 3 6 9 12Months after PCI
11.5%
8.5%
Placebo + ASA
Clopidogrel + ASA
27% RRRP = 0.02
Dea
th/M
I/s
tro
ke
PCI – PCI-CLARITY Design
30-day clinical follow-up
933 underwent PCI during index hosp.
930 underwent PCIduring index hosp.
3491 Patients Randomized into CLARITY-TIMI 28
1752 assigned clopidogrel300 mg 75 mg/d
1739 assigned placebo
Open-label clopidogrel w/ loading dose
recommended
(CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT)
A n g i o g r a p h y
PCI – CV Death, MI, or StrokeCV Death, MI, or Strokefollowingfollowing PCIPCI
02
46
8
0 10 20 30Days post PCI
Per
cen
tag
e w
ith
ou
tco
me
(%) No Pretreatment – 6.2%No Pretreatment – 6.2%
Clopidogrel – 3.6%Clopidogrel – 3.6%Pretreatment Pretreatment
46%46%46%46%
Odds Ratio 0.54Odds Ratio 0.54(95% CI 0.35-0.85)(95% CI 0.35-0.85)
P=0.008P=0.008
Odds Ratio 0.54Odds Ratio 0.54(95% CI 0.35-0.85)(95% CI 0.35-0.85)
P=0.008P=0.008
Sabatine MS et al. JAMA 2005;294:1224-32
Clopidogrel No
Trial Pretreatment Pretreatment
PCI-CURE 3.6 5.1
CREDO n/a n/a
PCI-CLARITY 4.0 6.1
Overall 3.7 5.5
Clopidogrel NoTrial Pretreatment Pretreatment
PCI-CURE 2.9 4.4
CREDO 6.0 7.1
PCI-CLARITY 3.3 5.4
Overall 3.9 5.5
Meta-Analysis of Clopidogrel PretreatmentMeta-Analysis of Clopidogrel Pretreatment
1.00.25 2.00.5
1.00.25 2.00.5OR (95% CI)
OR (95% CI)
CV Death or MI after PCI (%)CV Death or MI after PCI (%)CV Death or MI after PCI (%)CV Death or MI after PCI (%)
MI before PCI (%)MI before PCI (%)MI before PCI (%)MI before PCI (%)
OR 0.67OR 0.67P=0.005P=0.005OR 0.67OR 0.67P=0.005P=0.005
FavorsPretreatment
FavorsNo Pretreatment
OR 0.71OR 0.71P=0.004P=0.004OR 0.71OR 0.71P=0.004P=0.004
Sabatine MS et al. JAMA 2005;294:1224-32
Trial Clopi PreRx No PreRx
PCI-CURE 27/1039 (2.6) 39/988 (3.9)
CREDO 26/473 (5.5) 34/519 (6.6)
PCI-CLARITY 22/639 (3.4) 30/615 (4.9)
OVERALL 75/2151 (3.5) 103/2122 (4.9)
Trial Clopi PreRx No PreRx
PCI-CURE 14/274 (5.1) 23/357 (6.4)
CREDO 29/427 (6.8) 32/396 (8.1)
PCI-CLARITY 12/288 (4.2) 28/310 (9.0)
OVERALL 55/989 (5.6) 83/1063 (7.8)
Efficacy of Clopidogrel PreRx by GPI UseEfficacy of Clopidogrel PreRx by GPI Use
1.00.25 2.00.5
1.00.25 2.00.5OR (95% CI)
OR (95% CI)
OR 0.72OR 0.72(0.53-0.98)(0.53-0.98)
P=0.03P=0.03
OR 0.72OR 0.72(0.53-0.98)(0.53-0.98)
P=0.03P=0.03
FavorsPreRx
FavorsNo PreRx
OR 0.69OR 0.69(0.47-1.00)(0.47-1.00)
P=0.05P=0.05
OR 0.69OR 0.69(0.47-1.00)(0.47-1.00)
P=0.05P=0.05
Without GPIWithout GPIWithout GPIWithout GPI
P=0.85 for P=0.85 for heterogeneityheterogeneity
by GPI useby GPI use
With GPIWith GPIWith GPIWith GPI
Sabatine MS et al. AHJ in press.
Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA): Study Design
Double-blind treatment up to 1,040 primary efficacy events occur*
Aspirin 75–162 mg once daily
Clopidogrel75 mg once daily
(n=7600)
Placebo1 tab once
daily (n=7600)
Aspirin 75-162 mg once daily
Fina
l stu
dy v
isit
(fix
ed s
tudy
end
dat
e)
1-m
onth
vis
it3-
mon
th v
isit
Patients 45 years or older who are at high risk of atherothrombotic events
R = randomization.
N=15,603
R
Bhatt et al. Am Heart J. 2004;148:263
*Event-driven trial: primary efficacy outcome of vascular death, MI, stroke
Visits every 6 months(12 m, 18 m…),and intermediate phone callsin between(15 m, 21m…)
6-m
onth
vis
it
Overall Population: Primary Efficacy Outcome (CV Death, MI, or Stroke)
Bhatt DL et al. NEJM 2006;354:1706-17
Cu
mu
lati
ve e
ven
t ra
te (
%)
0
2
4
6
8
Months since randomization
0 6 12 18 24 30
Placebo + ASA 7.3%
Clopidogrel + ASA6.8%
RRR: 7.1% [95% CI: -4.5%, 17.5%]p=0.22
Overall Population: Safety Results
Clopidogrel Placebo + ASA + ASA
Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value
GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09
Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17
Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89
GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08) <0.001
*Adjudicated outcomes by intention to treat analysisICH= Intracranial Hemorrhage
Bhatt DL et al. NEJM 2006;354:1706-17
CHARISMA Study: Primary Efficacy Results (CV Death, MI, or Stroke) by Prespecified Entry Category
Population RR (95% CI) P value
Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.046(n=12,153)
Multiple Risk Factors 1.20 (0.91, 1.59)0.20 (n=3284)
Overall Population 0.93 (0.83, 1.05)0.22 (n=15,603)
0.6 0.8 1.41.2
Clopidogrel Better Placebo Better
1.60.4
(Pinteraction=0.045)
Bhatt DL et al. NEJM 2006;354:1706-17
Primary Endpoint (CV Death, MI, or Stroke) in Patients with Previous MI, IS, or PAD“CAPRIE-like Cohort”
RRR: 17.1 % [95% CI: 4.4%, 28.1%]p=0.01
Pri
mar
y o
utc
om
e ev
ent
rate
(%
)
0
2
4
6
8
10
Months since randomization
0 6 12 18 24 30
Clopidogrel + ASA7.3%
Placebo + ASA 8.8%
N=9,478
Bhatt DL et al. JACC 2007;49:1982
Conclusions
• Upstream clopidogrel given across the spectrum of ACS death and ischemic complications
• Treatment benefit emerges early and is comparable regardless of ultimate revasc.
• Treatment mandated in patients after stenting
• Clopidogrel pretreatment before PCI death or ischemic complications after PCI, regardless of GP IIb/IIIa use
• Long-term use not beneficial in 1° prevention; may be beneficial in 2° prevention
Clopidogrel in the Guidelines
Setting Society Recommendation Grade
UA/NSTEMI
ACC/AHA2007
300 mg upstream in INV strategy
300 mg upstream + GPI in INV
300 mg ASAP in CONS strategy
I
IIa
I
ESC 2007 300 mg immediately in all patients I
STEMI(non 1 PCI)
ACC/AHA2007
75 mg in all patients
300 mg load if age <75 yrs
I
IIa
PCI
ACC/AHA/SCAI 2005
300 mg 6 hrs before PCI I
ESC 2005 300 mg 6 hrs before PCI I