plavix ua-nstemi slidekit 2010(2)
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Clopidogrel(PLAVIX)
In the Management of Unstable Angina /NSTEMI in the light of Clinical Trials
Presented By:
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Pharmacology of Clopidogrel(PLAVIX) a Unique Antiplatelet Agent
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Molecular Structure
Generic: clopidogrel bisulfate
Class: ADP-receptor antagonist
Molecular weight = 419.9
1. Clopidogrel Prescribing Information, US, February 2002.
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COX (cyclo-oxygenase)ADP (adenosine diphosphate)TXA2 (thromboxane A 2)
CLOPIDOGREL
ASA COX
ADP
ADP
C
GPllb/llla(Fibrinogen receptor)
Collagen thrombinTXA 2Activation
TXA2
Mode of Action of Clopidogrel(PLAVIX) 1
1. Jarvis B, Simpson K. Drugs 2000; 60: 34777.
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Effects of ADP-Receptor Activation
Adapted from Savi P et al. Biochem Biophys Res Commun 2001; 283: 37983, and Ferguson JJ.
The Physiology of Normal Platelet Function . In: Ferguson JJ, Chronos N, Harrington RA (Eds).Antiplatelet Therapy in Clinical Practice . London: Martin Dunitz; 2000: pp.1535.
ADP / ATP
P2Y 1P2X 1 P2T 12
Gi2 coupledGq coupled
Ca 2+ Ca 2+ cAMP
Platelet shape changeTransient aggregation
No effect onfibrinogen
receptor
Cation influx Calcium mobilization
Fibrinogen receptor activationThromboxane A 2 generation
Sustained aggregation response
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Pharmacology of Clopidogrel(PLAVIX) (I) 1
Absorption (oral): rapid, not affected by food or antacids Metabolism: rapid and extensive hepatic metabolism
Half-life: 8 hours (but has an irreversible effect onplatelets, with a lifespan of approximately 710 days)
Excretion: 50% in urine and 46% in feces, after 5 days
Standard dosing: 75 mg once daily
Rapid onset of action with a loading dose of 300 mg provides full antiplatelet effect within 3 hours
1. Jarvis B, Simpson K. Drugs 2000; 60: 34777.
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Pharmacology of Clopidogrel(PLAVIX) (II) 1
No significant adverse drugdrug interaction with anyfrequently prescribed medication in cardiovascular patients; benefit of clopidogrel over ASA maintained inpatients taking concomitant medications
Care should be exercised when used in combinationwith other antithrombotic medications (warfarin,heparin etc.)
1. Jarvis B, Simpson K. Drugs 2000; 60: 34777.
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A Loading Dose of Clopidogrel (PLAVIX)Provides Rapid and Full Effect by 3 Hours 1
1. Data on file, Sanofi-Synthlabo, 1999, internal report PDY 3494.
100
-20
0
20
40
60
80
1.5 3 6 24 27 48
Time (hours)
Me a n in hib it io n ( % )
Clopidogrel75 mg
Clopidogrel300 mg
*
*p < 0.002 vs clopidogrel 75 mg
(n = 20/group)
** *
**
Healthy Volunteers
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Effects of Clopidogrel (PLAVIX) on aKey Inflammatory Modulator (CD40L) 1
1. Hermann A et al . Platelets 2001; 12: 7482.
Effects ex vivo in healthy volunteers
*p < 0.05 versus ADP-stimulated controls
0
0.1
0.2
0.3
0.4
0.5
Control ASA Clopidogrel Clopidogrelplus ASA
C D40 L ( Mn X)
* *
Control
ADP, 30M
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Effects of Clopidogrel (PLAVIX) on Platelet-Dependent Mitogenesis of Smooth Muscle Cells 1,2
1. Hermann A et al . Thromb Res 2002; 105: 1735. 2. Hermann A et al . Arch Pharmacol 2001;363(suppl 4): 442.
*p < 0,05 versus control
0
10
20
30
40
Control ASA Clopidogrel Clopidogrelplus ASA
DN
A s y n t he s is ( x fo ld i nc re a s e )
**
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Clinical Efficacy of Clopidogrel (PLAVIX)
From CAPRIE to CURE
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Clinical Efficacy of Clopidogrel(PLAVIX)
Trial Patients Design Maximumfollow-up
Number of patients
CAPRIE 1 Myocardial infarction,stroke, peripheralarterial disease
Clopidogrelvs ASA
3 years 19,185
CURE 3 Acute coronarysyndrome
Clopidogrel *vs placebo *
1 year 12,562
CLASSICS 2 Coronary stenting Clopidogrel * vs ticlopidine *
4 weeks 1,020
1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Bertrand NE et al. Circulation 2000; 102: 6249 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.
Clinical Benefit of Clopidogrel in more than30,000 Patients from CAPRIE to CURE
*On top of standard therapy (including ASA)Without ST segment elevation
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CAPRIE: Design 1
Objective: to compare the efficacy and safety of clopidogrel 75 mg with active control ASA 325 mg
Double-blind, randomized, prospective trial
Multicenter (384 centers in 16 countries)
Follow-up of 19,185 patients from 1 to 3 years with: Ischemic atherothrombotic stroke
Myocardial infarction (MI)
Peripheral arterial disease Combined primary endpoint: cluster of ischemic
stroke, MI, and vascular death
1. CAPRIE Steering Committee. Lancet 1996; 348: 132939.
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CAPRIE: Long-Term Benefit of Clopidogrel (PLAVIX) Compared with ASA 1
Cumulative Event Rate(Myocardial Infarction, Ischemic Stroke or Vascular Death)
*ITT analysis
1. CAPRIE Steering Committee. Lancet 1996; 348: 132939.
Months of follow-up
8.7% *Overallrelative
riskreduction
0
4
8
12
16
0 3 6 9 12 15 18 21 24 27 30 33 36
C u mu la t ive e ve nt ra t e ( % )
ASA
p = 0.043, n = 19,185
Clopidogrel
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CAPRIE: Benefit of Clopidogrel (PLAVIX) over ASA in the Reduction of Myocardial Infarction 1
1. Gent M. Circulation 1997; 96(suppl 8): I-467.
Months of follow-up
0
1
2
3
4
5
0 3 6 9 12 15 18 21 24 27 30 33 36
C u mu la t ive e ve nt ra t e ( % )
p = 0.008, n = 19,185
ASA 3.6%
Clopidogrel 2.9%
Clopidogrel
ASA 19.2% *Relative
riskreduction
*ITT analysis
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COX (cyclo-oxygenase)ADP (adenosine diphosphate)TXA2 (thromboxane A 2)
CLOPIDOGREL
ASA COX
ADP
ADP
C
GPllb/llla(Fibrinogen receptor)
Collagen thrombinTXA2
Activation
TXA2
ASA
Synergistic Mode of Action withClopidogrel (PLAVIX) and ASA 1
1. Schafer AI. Am J Med 1996; 101: 199209.
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Synergistic Action of Clopidogrel (PLAVIX) ontop of ASA in Thrombus Formation 1
1. Herbert JM et al. Thromb Haemost 1998; 80: 51218.
-100
-80
-60
-40
-20
0
0 5 10 15 20 25 30 35 40 45 50
Time (minutes)
Blo o d flo w ( % d e c re a s e )
Clopidogrel plus ASA(10 mg/kg plus 10 mg/kg)
Clopidogrel (10 mg/kg)
ASA (10 mg/kg) Placebo
Experimental model
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Synergistic Action of Clopidogrel (PLAVIX)on top of ASA in Thrombosis 1
1. Makkar RR et al. Eur Heart J 1998; 19: 153846.
Control (unperfused)Thrombus weight 20 mg
ASA 10 mg/kg IVThrombus weight 18 mg
Clopidogrel 5 mg/kg IV
Thrombus weight 8 mg
Clopidogrel 5 mg/kg IV plus ASA10 mg/kg IV Thrombus weight 1 mg
Stent model
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Synergistic Action of Clopidogrel (PLAVIX)* and ASA in Healthy Volunteers 1Mean Reduction of Platelet Deposition vs ASA Alone
1. Cadroy Y et al. Circulation 2000; 101: 28238.
n = 18 for all comparisons
-10
0
1020
30
40
5060
70
80
Day 1, 1.5 hrs Day 1, 6 hrs Day 6, 6 hrs
Me a n re d u c t io n ( % ) Clopidogrel 300 mg
plus ASAvs ASA alone
Clopidogrel 75 mgplus ASAvs ASA alone
p = 0.03vs ASA
p < 0.001vs ASA
p = 0.04vs ASA
p < 0.001vs ASA
p < 0.001vs ASA
p = 0.03
p = 0.01
p = NS
*With or without loading dose
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Acute Coronary Syndrome (ACS) is aClassic Manifestation of Atherothrombosis
Unstableangina Non-Q-W MI Q-W MI Stroke PAD
Common underlying
atherothrombosis
Atherothrombotic event(MI, stroke, vascular death)
Plaque rupture Platelet activationand aggregation
Thrombus formation
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Atherothrombosis: A Generalizedand Progressive Process
UnstableanginaMIIschemicstroke/TIACritical legischemiaCardiovasculardeath
ACS
Atherosclerosis
Adapted from Stary HC et al. Circulation . 1995; 92: 135574, and Fuster V et al . Vasc Med .1998; 3: 2319.
Stable anginaIntermittent claudication
Atherothrombosis
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CURE: Design 1
Objective: to evaluate the early and long-term efficacy and safetyof clopidogrel (300/75 mg) on top of standard therapy (includingASA)
Double-blind, randomized, prospective trial
Multicenter (482 centers in 28 countries)
Follow-up of 12,562 patients from 3 months to 1 year with acutecoronary syndromes (without ST segment elevation)
Primary endpoint: first occurrence of any component of thecluster of:
cardiovascular death myocardial infarction
stroke (ischemic, hemorrhagic, or of uncertain type)
1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.
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1. The CURE Study Investigators. Eur Heart J 2000; 21: 203341.
CURE: Design 1
Double-blind treatment up to 12 months
ASA 75325 mg o.d.
Clopidogrel75mg o.d.(n = 6,259)
Placebo1 tab o.d.
(n = 6,303)
ASA 75325 mg o.d.
Day 1
6 mon
th visit
9 mon
th visit
12 m
onth
or fina
l visit
Clop
idog re
l
300m
g loadin
g
dose
3 mon
th visit
Disc
harg
e visit
1 mon
th visit
Patients withacute coronary
syndrome
(unstable anginaor non-Q-wave
myocardialinfarction)
Plac
ebo
load
ing dos
e
R = Randomization
n = 12,562
28 countries
R
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CURE: Early and Long-Term Benefitsof Clopidogrel 1,2
1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Data on file, 2002,p73 internal CSR-EFC 3307.
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0 3 6 9 12
Months of follow-up
C u mmu la t ive ha za rd ra t e Placebo *
(n = 6,303)
Clopidogrel * (n = 6,259)
20% Relativerisk reduction
p = 0.00009
Cumulative Events(Myocardial Infarction, Stroke, or Cardiovascular Death)
*On top of standard therapy (including ASA)
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CURE: Consistent Benefit Independentof Patient History 1
1. Clopidogrel Prescribing Information, US, February 2002.
Baseline
characteristics
Overall
Diagnosis
Elev card enzy
ST depr >1.0 mm
Diabetes
Previous myocardialinfarction
Previous stroke
Non-Q-W MI
Unstable angina
Other
No
Yes
No
Yes
No
Yes
No
Yes
No
Yes
12,562
3,295
8,298
968
9,381
3,176
7,273
5,288
9,721
2,840
8,517
4,044
12,055
506
9.3
12.7
7.3
15.1
8.8
10.7
7.5
11.8
7.9
14.2
7.8
12.5
8.9
17.9
11.4
15.5
8.7
19.7
10.9
13.0
8.9
14.8
9.9
16.7
9.5
15.4
11.0
22.4
N Clopidogrel * Placebo *
Percent events
Clopidogrel better Placebo better
0.4 0.6 0.8 1.0 1.2
*On top of standard therapy (including ASA)
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CURE: Consistent Benefit on Top of Various Standard Therapies 1
*On top of standard therapy (including ASA)
1. Clopidogrel Prescribing Information, US, February 2002.
0.4 0.6 0.8 1.0 1.2Hazard ratio (95% CI)
Concomitantmedication/therapy
Heparin/LMWH
ASA
GPIIb/IIIa Antag
Beta-blocker
ACEI
Lipid-lowering
PTCA/CABG
No
Yes
< 100 mg
100200mg
> 200 mgNo
Yes
No
Yes
No
Yes
No
Yes
No
Yes
951
11611
1927
7428
3201
11739
823
2032
10530
4813
7749
4461
8101
7977
4585
4.9
9.7
8.5
9.2
9.9
8.9
15.7
9.9
9.2
6.3
11.2
10.9
8.4
8.1
11.4
7.7
11.7
9.7
10.9
13.7
10.8
19.2
12.0
11.3
8.1
13.5
13.1
10.5
10.0
13.8
N Clopidogrel*
Placebo*
Events (%)
Clopidogrel better Placebo better
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5.7
11.4
20.7
4.1
9.8
15.9
0
5
10
15
20
25
Low risk Moderate risk High risk
MI, s t ro k e o r va s c u la r d e a t h ( % )
Placebo
Clopidogrel
p = 0.03
p = 0.02
p = 0.003
n = 3,276
n = 7,297
n = 1,989
CURE: Effects of Clopidogrel (PLAVIX)Stratified by TIMI Risk Score at 12 Months
1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Budaj AJ et al J Am Coll Cardiol 2002; 39, (suppl B): 441B.
ARR * 1.6 1.6 4.8RRR 29% 15% 27%
*Absolute risk reductionRelative risk reduction
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ACC/AHA 2007Guidelines for the
Management of Patients With UnstableAngina/NonST-Elevation
Myocardial Infarction
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3.2.1. Antiplatelet TherapyRecommendations
CLASS I1. Aspirin should be administered to UA/NSTEMI patients as soon aspossible after hospital presentation and continued indefinitely inpatients not known to be intolerant of that medication. (Level of
Evidence: A)2. Clopidogrel (loading dose followed by daily maintenance dose)should be administered to UA/NSTEMI patients who are unable totake ASA because of hypersensitivity or major gastrointestinalintolerance. (Level of Evidence: A)
3. In UA/NSTEMI patients with a history of gastrointestinal bleeding,when ASA and clopidogrel are administered alone or in combination,drugs to minimize the risk of recurrent gastrointestinal bleeding(e.g., proton-pump inhibitors) should be prescribed concomitantly.(Level of Evidence: B)
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4. For UA/NSTEMI patients in whom an initial invasive strategy isselected, antiplatelet therapy in addition to aspirin should beinitiated before diagnostic angiography (upstream) with either Clopidogrel (loading dose followed by daily maintenance dose)* or An intravenous GP IIb/IIIa inhibitor. (Level of Evidence: A)Abciximab as the choice for upstream GP IIb/IIIa therapy isindicated only if there is no appreciable delay to angiography andPCI is likely to be performed; otherwise, IV eptifibatide or tirofiban is
the preferred choice of GP IIb/IIIa inhibitor. (Level of Evidence: B)
5. For UA/NSTEMI patients in whom an initial conservative (i.e.,noninvasive) strategy is selected (see Section 3.3), clopidogrel(loading dose followed by daily maintenance dose)* should be
added to ASA and anticoagulant therapy as soon as possible after admission and administered for at least 1 month (Level of Evidence:A) and ideally up to 1 year. (Level of Evidence: B)
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6. For UA/NSTEMI patients in whom an initial conservative strategy
is selected, if recurrent symptoms/ischemia, HF, or serious
Arrhythmias subsequently appear, then diagnostic angiographyshould be performed. (Level of Evidence: A) Either
an intravenous GP IIb/IIIa inhibitor (eptifibatide or tirofiban; Level of
Evidence: A ) or clopidogrel (loading dose followed by daily
Maintenance dose; Level of Evidence: A) * should be added to ASAAnd anticoagulant therapy before diagnostic angiography
(upstream). (Level of Evidence: C)
CLASS IIa
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1. For UA/NSTEMI patients in whom an initial conservative strategy isselected and who have recurrent ischemic discomfort with clopidogrel,ASA, and anticoagulant therapy, it is reasonable to add a GPIIb/IIIa antagonist before diagnostic angiography. (Level of Evidence: C)
2. For UA/NSTEMI patients in whom an initial invasive strategy isselected, it is reasonable to initiate antiplatelet therapy with bothclopidogrel (loading dose followed by daily maintenance dose)* andan intravenous GP IIb/IIIa inhibitor. (Level of Evidence: B) Abciximabas the choice for upstream GP IIb/IIIa therapy is indicated only if there is no appreciable delay to angiography and PCI is likely to beperformed; otherwise, IV eptifibatide or tirofiban is the preferredchoice of GP IIb/IIIa inhibitor. (Level of Evidence: B)
3. For UA/NSTEMI patients in whom an initial invasive strategy is
selected, it is reasonable to omit upstream administration of anintravenous GP IIb/IIIa antagonist before diagnostic angiography if bivalirudin is selected as the anticoagulant and at least 300 mg of clopidogrel was administered at least 6 h earlier than plannedcatheterization or PCI. (Level of Evidence: B)
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CLASS IIb
For UA/NSTEMI patients in whom an initial conservative (i.e.,noninvasive) strategy is selected, it may be reasonable to add eptifibatide
Or tirofiban to anticoagulant and oral antiplatelet therapy. (Level of
Evidence: B)
CLASS III
Abciximab should not be administered to patients in whom PCI is not
planned. (Level of Evidence: A)
L T A ti l t Th t
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Long-Term Anticoagulant Therapy atHospital Discharge After UA/NSTEMI
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