Anti Platelet Agents

Pathophysiology of the Thrombus

Platelet-fibrin clot

Wagner DD. Arterioscler Thromb Vasc Biol. 2005;25:1321-4.

Interaction between inflammation and hemostasis in vulnerable

plaque

Platelet Activation Pathways

Arachidonicacid

TxA2

GP IIb/IIIa

Epinephrine

Collagen Thrombin

ADP

Endothelial Cell/Monocyte

PLATELET RECRUITMENT

AA

PGH2

COX –1COX-2

ASA

COX-2 induced byshear stress and inflammation PGH2TXA2

PGG2

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

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

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

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.

Mechanism of Action of Aspirin

Platelet Recruitment

TXA2

AA

PGH2

COX-1

PGI2

ASA (low dose)

Endothelial Cell (temporary)

Platelet (permanent)

Platelet cyclooxygense -1Catalytic site

Serine res 529

Arachidonic acid

PGG2

With Aspirin

Acetylserine

Aspirin

Platelet

TXA2

PGH2

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.

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

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

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!

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.

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

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

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

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)

* *

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

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.

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

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

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

Structure of the GP IIb/IIIa Site

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

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

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

André P et al. Circulation. 2002;106:896-9.

Activated plateletUnstimulated platelet

GP IIb/IIIa antagonists block sCD40L release from platelets

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

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

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

Abciximab

• Human/murine chimeric monoclonal antibody Fab

• KD 5 nmol/L

• Indication: PCI

Eptifbatide

• Cyclic peptide

• KD 120 nmol/L

• Acute coronary syndrome

Tirofiban

• Nonpeptide

• KD 15 nmol/L

• Indication: acute coronary syndrome

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

Special Mention

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

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)

Bleedingrisk

Thromboticrisk

Will any drug ever prevent thrombosis without causing bleeding ?