anti platelet agents
DESCRIPTION
Physiology and Pathology of Platelet Aggregation, Anti Platelet Agents, Relevant Clincal Trial DataTRANSCRIPT
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Anti Platelet Agents
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Pathophysiology of the Thrombus
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Platelet-fibrin clot
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Wagner DD. Arterioscler Thromb Vasc Biol. 2005;25:1321-4.
Interaction between inflammation and hemostasis in vulnerable
plaque
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Platelet Activation Pathways
Arachidonicacid
TxA2
GP IIb/IIIa
Epinephrine
Collagen Thrombin
ADP
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Endothelial Cell/Monocyte
PLATELET RECRUITMENT
AA
PGH2
COX –1COX-2
ASA
COX-2 induced byshear stress and inflammation PGH2TXA2
PGG2
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Targets for anti-platelet therapy
AspirinNSAIDs
ADPreceptor
COX-1
TXA2
GPIIb - IIIa
Signalling
pathways
ADP receptor antagonistsClopidogrel THROMBIN
receptor
Thrombin inhibitorsII
Fibrinogen
Phosphodiesterase inhibitors
dipyridamole
Fibrinogen Receptor Antagonists
AAAA
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Curran MP, Keating GM. Drugs. 2005;65:2009-35.
Thrombolytics
AbciximabTirofiban
Eptifibatide
UFHLMWHsDirect thrombininhibitors
Aspirin
ThromboxaneA2
Collagen ADP Thrombin
Fibrinogen
Fibrin
GP IIb/IIIa activation
von Willebrand factor
Platelet aggregation
Thrombus formation
TiclopidineClopidogrel
Points of action for antithrombotics
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Resting platelet
GP IIb/IIIa receptors in unreceptive
state
Inhibition of platelet aggregation
GP IIb/IIIa receptors occupied by antagonists
AgonistADP,
thrombin, collagen
GP IIb/IIIa
antagonist
Fibrinogen
Aggregating platelets
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ASPIRIN 1832 Felix Hoffmann produced acetylsalicylic acid.1899 Bayer distributed aspirin to physicians.
1915 Aspirin available without prescription.
1953 Dr. Lawrence Craven observed aspirin prevented heart attacks in 400 patients prescribed aspirin.
1988 FDA approved aspirin for Secondary MI prevention.
2002 AHA and US Preventative Services Task Force recommends aspirin to prevent first MI in at-risk individuals.2004 Over 26 million Americans use aspirin routinely to reduce heart attack risk.
2005 100 Billion Aspirin consumed per year.
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Mechanism of Action of Aspirin
Platelet Recruitment
TXA2
AA
PGH2
COX-1
PGI2
ASA (low dose)
Endothelial Cell (temporary)
Platelet (permanent)
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Platelet cyclooxygense -1Catalytic site
Serine res 529
Arachidonic acid
PGG2
With Aspirin
Acetylserine
Aspirin
Platelet
TXA2
PGH2
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Aspirin and COX-2
• Aspirin also inactivates COX-2 (PGH-2-synthase) but is 50 to 100 times less potent at inhibiting COX-2 than COX –1.
• COX-2 is induced in monocytes in response to inflammatory stimuli and in endothelial cells in response to shear stress.
• COX-2 is present in megakaryocytes and young platelets, but not in mature platelets.
• COX-2 is not inhibited by low “antithrombotic” doses of aspirin.
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Definition of Aspirin Resistance
• Clinical event despite taking aspirin• Failure to show adequate level of platelet inhibition • Failure of low dose aspirin to inhibit a test of platelet
function that can be inhibited by higher doses of aspirin
• Generation of thromboxane A2 despite treatment with aspirin
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Definition of Aspirin Resistance
Clinical event despite aspirin
• ASA produces a 25% risk reduction, therefore 75% of patients with vascular disease ‘fail’
• Not surprising because ASA only inhibits one of a number of mechanisms of platelet activation
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Aspirin Resistance• 10% - 40% of patients appear to be resistant
• Variability due to several factors:– Method of measuring platelet function– Clinical status of patients– Conclusion
Aspirin resistance exists!Aspirin resistance is measurable!
-pharmcodynamically & clinicallyAspirin resistance has clinical consequence!
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COX (cyclo-oxygenase)ADP (adenosine diphosphate)TXA2 (thromboxane A2)
CLOPIDOGREL
ASA COX
ADP
ADP
C
GPllb/llla(Fibrinogen receptor)
Collagen thrombinTXA2
Activation
TXA2
Mode of Action of Clopidogrel1
1. Jarvis B, Simpson K. Drugs 2000; 60: 347–77.
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Effects of ADP-Receptor Activation
Adapted from Savi P et al. Biochem Biophys Res Commun 2001; 283: 379–83, 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.15–35.
ADP / ATP
P2Y1P2X1 P2T12
Gi2 coupled
Gq coupled
Ca2+ Ca2+ cAMP
Platelet shape change Transient aggregation
No effect on fibrinogen receptor
Cation influx Calcium mobilization
Fibrinogen receptor activation Thromboxane A2 generation
Sustained aggregation response
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A Loading Dose of Clopidogrel Provides Rapid and Full Effect by 3
Hours1
1. Data on file, Sanofi-Synthélabo, 1999, internal report PDY 3494.
100
-20
0
20
40
60
80
1.5 3 6 24 27 48
Time (hours)
Mea
n in
hibi
tion
(%)
Clopidogrel75 mg
Clopidogrel300 mg
*
*p < 0.002 vs clopidogrel 75 mg
(n = 20/group)
** *
**
Healthy Volunteers
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Effects of Clopidogrel on a Key Inflammatory Modulator (CD40L)1
1. Hermann A et al. Platelets 2001; 12: 74–82.
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 Clopidogrel plus ASA
CD
40L
(Mn
X)
* *
Control
ADP, 30µM
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Effects of Clopidogrel on Platelet-Dependent Mitogenesis of Smooth Muscle Cells1,2
1. Hermann A et al. Thromb Res 2002; 105: 173–5. 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 Clopidogrel plus ASA
DN
A s
ynth
esis
(x fo
ld in
crea
se)
* *
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Clinical Efficacy of Clopidogrel
Trial Patients Design Maximum follow-up
Number of patients
CAPRIE1 Myocardial infarction, stroke, peripheralarterial disease
Clopidogrelvs ASA
3 years 19,185
CURE3 Acute coronarysyndrome†
Clopidogrel*vs placebo*
1 year 12,562
CLASSICS2 Coronary stenting Clopidogrel* vs ticlopidine*
4 weeks 1,020
1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–39. 2. Bertrand NE et al. Circulation 2000; 102: 624–9 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502.
Clinical Benefit of Clopidogrel in more than 30,000 Patients – from CAPRIE to CURE
*On top of standard therapy (including ASA)†Without ST segment elevation
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COX (cyclo-oxygenase)ADP (adenosine diphosphate)TXA2 (thromboxane A2)
CLOPIDOGREL
ASA COX
ADP
ADP
C
GPllb/llla(Fibrinogen receptor)
Collagen thrombinTXA2
Activation
TXA2
ASA
Synergistic Mode of Action with Clopidogrel and ASA1
1. Schafer AI. Am J Med 1996; 101: 199–209.
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Synergistic Action of Clopidogrel on top
of ASA in Thrombus Formation1
1. Herbert JM et al. Thromb Haemost 1998; 80: 512–18.
-100
-80
-60
-40
-20
0
0 5 10 15 20 25 30 35 40 45 50
Time (minutes)
Blo
od fl
ow (%
dec
reas
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 on top of ASA in Thrombosis1
1. Makkar RR et al. Eur Heart J 1998; 19: 1538–46.
Control (unperfused)Thrombus weight 20 mg
ASA 10 mg/kg IVThrombus weight 18 mg
Clopidogrel 5 mg/kg IVThrombus weight 8 mg
Clopidogrel 5 mg/kg IV plus ASA 10 mg/kg IV Thrombus weight 1 mg
Stent model
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GP IIb-IIIa ReceptorGP IIb-IIIa Receptor
White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
Final common Final common pathway to pathway to
platelet platelet aggregationaggregation
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Structure of the GP IIb/IIIa Site
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Coller. Coller. Heart Disease, Update 4. Heart Disease, Update 4. 1995.1995.
Platelet GP IIb/IIIa Receptor in Vascular Injury: Adhesion and Activation
PlateletPlatelet
GP IIb/IIIaGP IIb/IIIaGP Ib-IX-VGP Ib-IX-V
EndotheliumEndothelium
von Willebrand factorvon Willebrand factorGP Ia/IIaGP Ia/IIa
CollagenCollagen
Fibrinogen Fibrinogen (or von (or von
Willebrand Willebrand factor)factor)GP IIb/IIIaGP IIb/IIIaActivationActivation
AdhesionAdhesion
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Coller. Coller. Heart Disease, Update 4Heart Disease, Update 4. 1995.. 1995.
Platelet GP IIb/IIIa Receptor in Vascular Injury: Aggregation
Fibrinogen Fibrinogen (or von Willebrand factor)(or von Willebrand factor)
`̀
GP IIb/IIIaGP IIb/IIIa
AggregationAggregation
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RestingRestingPlateletPlateletReceptors inReceptors inligand-unreceptiveligand-unreceptivestatestate
GP IIb/IIIaReceptor Inhibitor
Inhibition ofInhibition ofPlatelet Platelet AggregationAggregation
Activated PlateletActivated PlateletReceptors in ligand-Receptors in ligand-receptive statereceptive state
FibrinogenFibrinogen
AggregatingAggregatingPlateletsPlatelets
GP IIb/IIIa receptors occupied by fibrinogenGP IIb/IIIa receptors occupied by fibrinogenwhich forms bridges between adjacent plateletswhich forms bridges between adjacent platelets
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André P et al. Circulation. 2002;106:896-9.
Activated plateletUnstimulated platelet
GP IIb/IIIa antagonists block sCD40L release from platelets
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GP IIb/IIIa + PCI≥80% occupancy
GP IIb/IIIa + No PCI<80% occupancy>12 hours
Antman EM. Am Heart J. 2003;146(suppl):S18-22.
Proposed model for optimal use of GP IIb/IIIa inhibitors
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Furman MI et al. J Thromb Haemost. 2005;3:312-20.
Giugliano RP, Braunwald E. J Am Coll Cardiol. 2005;46:906-19.
Potential mechanisms for reduction of thrombo-
inflammation with GP IIb/IIIa inhibition
• Inhibit platelet activation
• Reduce sCD40L in ACS and PCI
• Blunt CRP increase in ACS and PCI
• Reverse endothelial dysfunction induced by PCI
• Reduce leukocyte-platelet aggregation in ACS
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Gp IIb/IIIa ANTAGONISTS• Platelet Gp IIb/IIIa receptors play a pivotal
role in platelet-mediated thrombus formation, binding to binds to fibrinogen and vWF
• IIb/IIIa antagonists differ in receptor affinity, reversibility, and specificity
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Abciximab
• Human/murine chimeric monoclonal antibody Fab
• KD 5 nmol/L
• Indication: PCI
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Eptifbatide
• Cyclic peptide
• KD 120 nmol/L
• Acute coronary syndrome
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Tirofiban
• Nonpeptide
• KD 15 nmol/L
• Indication: acute coronary syndrome
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Antman EM et al. Am Heart J. 2003;146:S18-S22.
Death or MI at 30 days
*Does not include 345 patients In the tirofiban only group, which was stopped prematurely
Efficacy of GP IIb/IIIa inhibition on death or MI in PCI or ACS
EPIC 2099IMPACT II 4010EPILOG 2792 CAPTURE 1265 RESTORE 2139 EPISTENT 2399
PRISM 3231 PRISM-PLUS 1570* PARAGON 2282 PURSUIT 10,948
Overall 30,366
Trial N
Odds ratio (95% CI)
FavorsGP IIb/IIIa
Favorsplacebo
1 2
0.79 (0.73–0.85)P < 10–9
Elective PCI
ACS
0
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Special Mention
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Colwell JA, Nesto RW. Diabetes Care. 2003;26:2181-8.
Altered platelet functions in diabetes
Membrane fluidity
Altered Ca+2 and Mg+2 homeostasis
Arachidonic acid metabolism
Thromboxane A2 synthesis
Prostacyclin production
NO production
Antioxidants
Activation-dependent adhesion molecules (eg, GP IIb/IIIa, P-selectin)
These changes contribute to increased platelet aggregability and adhesiveness in diabetes
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Lincoff AM et al. Circulation. 2000;102:1093-100.
30-day death or MI
No diabetes
Diabetes
0.33 1.0 3.0
Placebo betterEptifibatide better
PURSUIT: Outcomes in diabetic vs nondiabetic US patients
Odds ratio (95% CI)
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Bleedingrisk
Thromboticrisk
Will any drug ever prevent thrombosis without causing bleeding ?
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