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Class I:Class I:• ASA should be administered as soon as possible after ASA should be administered as soon as possible after
presentation and continued indefinitely (IA)presentation and continued indefinitely (IA)• Clopidogrel 75 mg daily (in the absence of Clopidogrel 75 mg daily (in the absence of
contraindications) when ASA is not tolerated (IA)contraindications) when ASA is not tolerated (IA)• If early If early non-interventional approachnon-interventional approach is planned, is planned,
clopidogrel should be added to ASA as soon as possible clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (IA) on admission and administered for at least 1 month (IA) and for up to 9 months (IB)and for up to 9 months (IB)
• If If PCI plannedPCI planned, clopidogrel should be started and , clopidogrel should be started and continued for at least 1 month (IA) and up to 9 months continued for at least 1 month (IA) and up to 9 months in patients who are not at high risk for bleeding (IB)in patients who are not at high risk for bleeding (IB)
1. Braunwald E et al.FOR INTERNAL USE ONLY
ALBIONALBION Assessment of best Loading dose of clopidogrel to Blunt Assessment of best Loading dose of clopidogrel to Blunt platelet activation, Inflammation and Ongoing Necrosisplatelet activation, Inflammation and Ongoing Necrosis
103 patients aged 18 to 85 years103 patients aged 18 to 85 years UA NSTEMI within the 48 hours prior to randomisation. UA NSTEMI within the 48 hours prior to randomisation. 300mg, 600mg and 900mg300mg, 600mg and 900mg Blood monitored every hour during the first 6 hours then Blood monitored every hour during the first 6 hours then
at 24 hours to determine the kinetics of inhibition of at 24 hours to determine the kinetics of inhibition of platelet aggregation.platelet aggregation.
Within the first 24 hours, higher loading doses of Within the first 24 hours, higher loading doses of clopidogrel induced faster onset of action and higher clopidogrel induced faster onset of action and higher levels of inhibition of platelet aggregation than the levels of inhibition of platelet aggregation than the indicated loading dose of 300mg, in patients with ACSindicated loading dose of 300mg, in patients with ACS
Similar safety profile among different dosage groups.Similar safety profile among different dosage groups.
EuroPCR Congress in Paris on May 24EuroPCR Congress in Paris on May 24
Faster Onset of Action and Faster Onset of Action and Higher Level of Platelet InhibitionHigher Level of Platelet Inhibition
Maximum Inhibition of Platelet Aggregation (5 µM ADP)
0
5
10
15
20
25
30
35
40
45
1 2 3 4 5 6 24
Time (h)
(%) I
nhib
ition
300 mg LD600 mg LD900 mg LD
p< 0.05 vs. 300 mg LD
Shortened time to reach the highest level of inhibition of the 300 mg LD
Maximum Inhibition of Platelet Aggregation (20 µM ADP)
0
5
10
15
20
25
30
35
40
1 2 3 4 5 6 24
Time (h)
(%)
Inhi
bition
300 mg LD
600 mg LD
900 mg LD
Faster Onset of Action and Higher Level of Platelet Inhibition
p< 0.05 vs. 300 mg LD
Major Adverse Cardiac Events
300 300 mgmg
n = 35n = 35
600 mg600 mgn = 34n = 34
900 mg900 mgn = 34n = 34
Death (n)Death (n)
Non-fatal MI*(n)Non-fatal MI*(n)
Unplanned PCI (n)Unplanned PCI (n)
Hospitalization for recurrent Hospitalization for recurrent
angina (n)angina (n)
00
11
11
22
00
22
00
00
00
00
00
00
TOTAL – n (%)TOTAL – n (%) 4 4
(11.4)(11.4)
2 (5.9)2 (5.9) 00
* New Q wave or CK > 3 times the ULN
Safety
300 mg 300 mg n = 35n = 35
600 mg600 mgn = 34n = 34
900 mg900 mgn = 34n = 34
Bleeding* Day 1- Discharge Bleeding* Day 1- Discharge (n)(n)
SevereSevereModerateModerateMildMild
TOTALTOTAL
00
11
1010
1111
00
00
1010
1010
00
11
1313
1414
*GUSTO Classification
Study DesignStudy Design
*ASA=150–325 mg (if no ASA within prior 24 hours) as loading dose. Patients received heparin if they received a fibrin specific thrombolytic†All patients received ASA 75–162 mg/day plus other standard care
Study treatment until angiography (28 days) or
hospital discharge (maximum 8 days)
n=1752
n=1739
Thrombolysis, heparin and ASA*
Clopidogrel 300 mg loading dose / 75 mg QD†
Placebo†
R
Double-blind, randomized, placebo-controlled trial inpatients aged 1875 years with STEMI ≤12 hours
Clinical Follow-up at 30 days
Primary endpoint: occluded artery (TIMI flow grade [TFG] 0/1), death/MI by time of angiography
1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)
Angiographic Outcomes and Angiographic Outcomes and Long-term MortalityLong-term Mortality
1. Gibson CM et al. Circulation 2002; 105: 19091913.
0
2
4
6
8
10
12
14
16
0
2
4
6
8
10
12
14
16
TFG 0/1
2-ye
ar m
ort
alit
y (%
)
14.5%
TFG 2/3 TMPG 0/1 TMPG 2/3
6.4%
4.8%
9.1%
HR: 0.41 (p=0.001) HR: 0.51 (p=0.038)
TIMI flow grade TIMI myocardial perfusion grade*
*90 minute angiogram in TIMI 10b trial; HR=hazard ratio
• % of occluded infarct related artery (TFG 0/1) on pre-% of occluded infarct related artery (TFG 0/1) on pre-discharge angiogramdischarge angiogram
• Death or MI before CAGDeath or MI before CAG• Death or MI by hospital discharge (maximum 8 days) if no Death or MI by hospital discharge (maximum 8 days) if no
angiography performedangiography performed
Study EndpointsStudy Endpoints
*CV death, MI, stroke or recurrent ischemia leading to urgent target vessel revascularization
FOR INTERNAL USE ONLY1. Sabatine MS et al. New Engl J Med 2005; 352
*Based on odds of an occluded infarct-related artery (TFG 0/1), death or MI by angiography for clopidogrel versus placebo (OR: 0.64 [0.53 to 0.76]; p <0.001)
Placebo(n=1739)
Clopidogrel(n=1752)
21.7
15.0
5
10
15
20
25P
rim
ary
end
po
int*
(%
)36% reduction*
p <0.001
1. Sabatine MS et al. New Engl J Med 2005; 352 (available at www.nejm.org)
CLARITY: CLARITY: Reduction of Primary Endpoint by 36%Reduction of Primary Endpoint by 36%
ClopidogrelClopidogrel PlaceboPlacebo Odds ratioOdds ratio
(n=1752) (n=1752) (n=1739)(n=1739) (95% CI)(95% CI) p value p value
CLARITY :CLARITY : Clinical Events at 30 Days Clinical Events at 30 Days
CV death, MI or recurrent ischemia leading to urgent revascularization
Time (days)
Inci
den
ce o
f cl
inic
al e
nd
po
ints
(%
)
0
5
10
15
0 5 10 15 20 25 30
PlaceboClopidogrel 20%*
p=0.03
1. Sabatine MS et al. New Engl J Med 2005
SafetySafetyClopidogrelClopidogrel PlaceboPlacebo(n=1733) (n=1733) (n=1719)(n=1719) p valuep value
Primary bleeding endpointPrimary bleeding endpoint (%) (%) TIMI major TIMI major 23 (1.3)23 (1.3) 19 (1.1)19 (1.1) 0.640.64
Secondary bleeding endpointsSecondary bleeding endpoints (%) (%) TIMI minor TIMI minor 17 (1.0)17 (1.0) 9 (0.5)9 (0.5) 0.170.17 TIMI major or minor TIMI major or minor 40 (2.3)40 (2.3) 28 (1.6)28 (1.6) 0.180.18 Intracranial hemorrhageIntracranial hemorrhage 8 (0.5)8 (0.5) 12 (0.7)12 (0.7) 0.380.38
Bleeding through 30 daysBleeding through 30 days (%) (%) TIMI major TIMI major 33 (1.9)33 (1.9) 30 (1.7)30 (1.7) 0.800.80 TIMI minor TIMI minor 27 (1.6)27 (1.6) 16 (0.9)16 (0.9) 0.120.12 TIMI major or minor TIMI major or minor 59 (3.4)59 (3.4) 46 (2.7)46 (2.7) 0.240.24
FOR INTERNAL USE ONLY1. Sabatine MS et al. New Engl J Med 2005; 352
1. Chen ZM et al. ACC 2005.
COMMIT/CCS-2: COMMIT/CCS-2: CCllOOpidogrel pidogrel and and MMetoprolol in etoprolol in MMyocardial yocardial
IInfarction nfarction TTrialrial
Double-blind treatment until hospital discharge or for a maximum of 4 weeks
(n ~ 23,000)
n=~46,000R
Patients with acute STEMI 24 hours
* All patients received a background of ASA 162mg/day during the study
(2 2 Factorial with metoprolol)
Study DesignStudy DesignClopidogrel 75 mg QD*
Placebo*
(n ~ 23,000)
1. Chen ZM et al. ACC 2005.
0 7 14 21 280
1
2
3
4
5
6
7
8
9
10
Days since randomization(up to 28 days)
Clopidogrel(9.3%)
Placebo (10.1%)
Eve
nts
(%
)RRR=9%
P=0.002
COMMIT: Composite EndpointCOMMIT: Composite Endpoint(Death, MI, or Stroke)(Death, MI, or Stroke)
FOR INTERNAL USE ONLY1. Chen ZM et al. ACC 2005.
0 7 14 21 280
1
2
3
4
5
6
7
8
9
Days since randomization (up to 28 days)
Clopidogrel(7.5%)
Placebo(8.1%)
RRR=7%p=0.03
Mo
rtal
ity
(%)
COMMIT: MortalityCOMMIT: Mortality
1. Chen ZM et al. ACC 2005.
COMMIT: SummaryCOMMIT: Summary
• For STEMI, ASA + clopidogrel 75mg OD + Lytic:For STEMI, ASA + clopidogrel 75mg OD + Lytic:• 7% reduction mortality7% reduction mortality• No significant excess in TIMI major bleeding or No significant excess in TIMI major bleeding or
ICHICH
FOR INTERNAL USE ONLY
GP IIb/IIIa Receptor AntagonistsGP IIb/IIIa Receptor Antagonists
A murine monoclonalantibody that completely blocks
the binding of fibrinogen to platelets produces
a thrombasthenic-like state in normal platelets and binds to
glycoproteinsIIb and/or IIIa. J Clin Invest 1983
Coller BS, Peerschke EI, Scudder LE, Sullivan CA. Fc fragment of murine monoclonal antibody against Gp2b3a, 7E3,
was removed to prevent immunogenicity and Fab fragments joined with the constant regions of human immunoglobulin, forming a chimeric compound (abciximab, or c7E3).
RGD sequence
Gp IIb/IIIa in ACSGp IIb/IIIa in ACS
Gp IIb/IIIa blockers are recommended Gp IIb/IIIa blockers are recommended (Class I) for UA/NSTEMI treated with (Class I) for UA/NSTEMI treated with
interventional approach.interventional approach.
For non-interventional patients with For non-interventional patients with ongoing ischemia (Class II)ongoing ischemia (Class II)
ISAR-REACT:ISAR-REACT:30-d adverse reactions in low-to-moderate risk undergoing 30-d adverse reactions in low-to-moderate risk undergoing
PCI after 600mg Clopidogrel loading dosePCI after 600mg Clopidogrel loading dose
Antiplatelet therapy is essential in the management of Antiplatelet therapy is essential in the management of patients with ACSpatients with ACS
Medically treatedMedically treated Percutaneous interventionPercutaneous intervention New studies support expanding role of ADP New studies support expanding role of ADP
antagonists in the management of STEMIantagonists in the management of STEMI
ConclusionsConclusions
FOR INTERNAL USE ONLY1. Chen ZM et al. ACC 2005.
Thank you for your Thank you for your attention.attention.