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Anti Platelet Agents

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Physiology and Pathology of Platelet Aggregation, Anti Platelet Agents, Relevant Clincal Trial Data

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Anti Platelet Agents

  1. 1. Anti Platelet Agents
  2. 2. Pathophysiology of the Thrombus
  3. 3. Platelet-fibrin clot
  4. 4. Interaction between inflammation and hemostasis in vulnerable plaque Wagner DD. Arterioscler Thromb Vasc Biol. 2005;25:1321-4.
  5. 5. Platelet Activation Pathways Collagen Thrombin Epinephrine ADP Arachidonic acid TxA2 GP IIb/IIIa
  6. 6. Endothelial Cell/Monocyte COX –1 AA ASA COX-2 PGG2 COX-2 induced by shear stress and inflammation PGH2 TXA2 PGH2 PLATELET RECRUITMENT
  7. 7. Targets for anti-platelet therapy ADP receptor antagonists Clopidogrel Phosphodiesterase inhibitors dipyridamole ADP receptor II THROMBIN receptor COX-1 Signalling TXA2 Fi br Aspirin AA pathways GPIIb - IIIa Fibrinogen Receptor Antagonists Thrombin inhibitors in o ge n NSAIDs
  8. 8. Points of action for antithrombotics Aspirin Thromboxane A2 Collagen Thrombin ADP UFH LMWHs Direct thrombin inhibitors Ticlopidine Clopidogrel GP IIb/IIIa activation Abciximab Tirofiban Eptifibatide Fibrinogen von Willebrand factor Platelet aggregation Thrombus formation Fibrin Thrombolytics Curran MP, Keating GM. Drugs. 2005;65:2009-35.
  9. 9. GP IIb/IIIa antagoni st Inhibition of platelet aggregation Agoni st Resting platelet GP IIb/IIIa receptors in unreceptive state ADP, thrombin, collagen GP IIb/IIIa receptors occupied by antagonists Fibrinoge n Aggregating platelets
  10. 10. ASPIRIN 1832 Felix Hoffmann produced acetylsalicylic acid. 1899 Bayer distributed aspirin to physicians. 1915 1953 Aspirin available without prescription. Dr. Lawrence Craven observed aspirin prevented heart attacks in 400 patients prescribed aspirin. 1988 2002 2004 FDA approved aspirin for Secondary MI prevention. AHA and US Preventative Services Task Force recommends individuals. Over 26 million Americans use aspirin routinely to reduce heart attack risk. 2005 100 Billion Aspirin consumed per year. aspirin to prevent first MI in at-risk
  11. 11. Mechanism of Action of Aspirin AA COX-1 ASA (low dose) PGH2 TXA2 Platelet (permanent) PGI2 Endothelial Cell (temporary) Platelet Recruitment
  12. 12. Platelet cyclooxygense -1 With Aspirin Catalytic site Serine res 529 TXA2 PGH2 Acetyl serine PGG2 Arachidonic acid Aspirin Platelet
  13. 13. 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.
  14. 14. 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
  15. 15. 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
  16. 16. 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 & clinically Aspirin resistance has clinical consequence!
  17. 17. Mode of Action of Clopidogrel 1 CLOPIDOGREL C ADP ADP GPllb/llla Activation (Fibrinogen receptor) ASA COX TXA2 COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA2 (thromboxane A2) 1. Jarvis B, Simpson K. Drugs 2000; 60: 347–77. Collagen thrombin TXA 2
  18. 18. Effects of ADP-Receptor Activation ADP / ATP P2X1 P2Y1 P2T12 Gq coupled Cation influx Ca2+ No effect on fibrinogen receptor Calcium mobilization Ca2+ Platelet shape change Transient aggregation Gi2 coupled cAMP Fibrinogen receptor activation Thromboxane A2 generation Sustained aggregation response 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.
  19. 19. A Loading Dose of Clopidogrel Provides Rapid and Full Effect by 3 Hours 1 Healthy Volunteers Mean inhibition (%) 100 * 80 * 60 40 * * * * Clopidogrel 75 mg 20 Clopidogrel 300 mg 0 -20 1.5 3 6 24 27 48 (n = 20/group) Time (hours) *p < 0.002 vs clopidogrel 75 mg 1. Data on file, Sanofi-Synthélabo, 1999, internal report PDY 3494.
  20. 20. Effects of Clopidogrel on a Key Inflammatory Modulator (CD40L) 1 Effects ex vivo in healthy volunteers 0.5 CD40L (Mn X) 0.4 Control ADP, 30µM 0.3 0.2 * * 0.1 0 Control ASA Clopidogrel Clopidogrel plus ASA *p < 0.05 versus ADP-stimulated controls 1. Hermann A et al. Platelets 2001; 12: 74–82.
  21. 21. DNA synthesis (x fold increase) Effects of Clopidogrel on PlateletDependent Mitogenesis of Smooth Muscle Cells 1,2 40 30 20 * 10 * 0 Control ASA Clopidogrel Clopidogrel plus ASA *p < 0,05 versus control 1. Hermann A et al. Thromb Res 2002; 105: 173–5. 2. Hermann A et al. Arch Pharmacol 2001; 363(suppl 4): 442.
  22. 22. Clinical Efficacy of Clopidogrel Clinical Benefit of Clopidogrel in more than 30,000 Patients – from CAPRIE to CURE Trial Design CAPRIE1 Myocardial infarction, stroke, peripheral arterial disease CLASSICS2 CURE3 * Patients Maximum follow-up Number of patients Clopidogrel vs ASA 3 years 19,185 Coronary stenting Clopidogrel* vs ticlopidine* 4 weeks 1,020 Acute coronary syndrome† Clopidogrel* vs placebo* 1 year 12,562 On top of standard therapy (including ASA) Without ST segment elevation † 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.
  23. 23. Synergistic Mode of Action with Clopidogrel and ASA 1 CLOPIDOGREL C ADP ADP GPllb/llla Activation (Fibrinogen receptor) ASA ASA COX TXA2 COX (cyclo-oxygenase) ADP (adenosine diphosphate) TXA2 (thromboxane A2) 1. Schafer AI. Am J Med 1996; 101: 199–209. Collagen thrombin TXA2
  24. 24. Synergistic Action of Clopidogrel on top of ASA in Thrombus Formation 1 Experimental model Clopidogrel (10 mg/kg) Blood flow (% decrease) 0 Clopidogrel plus ASA (10 mg/kg plus 10 mg/kg) Placebo ASA (10 mg/kg) -20 -40 -60 -80 -100 0 5 10 15 20 25 30 Time (minutes) 1. Herbert JM et al. Thromb Haemost 1998; 80: 512–18. 35 40 45 50
  25. 25. Synergistic Action of Clopidogrel on top of ASA in Thrombosis 1 Stent model Control (unperfused) Thrombus weight 20 mg ASA 10 mg/kg IV Thrombus weight 18 mg Clopidogrel 5 mg/kg IV Thrombus weight 8 mg Clopidogrel 5 mg/kg IV plus ASA 10 mg/kg IV Thrombus weight 1 mg 1. Makkar RR et al. Eur Heart J 1998; 19: 1538–46.
  26. 26. GP IIb-IIIa Receptor Final common pathway to platelet aggregation White HD. Am J Cardiol. 1997; 80(4A):2B-10B.
  27. 27. Structure of the GP IIb/IIIa Site
  28. 28. Platelet GP IIb/IIIa Receptor in Vascular Injury: Adhesion and Activation Adhesion GP IIb/IIIa GP Ib-IX-V Endothelium Platelet GP Ia/IIa von Willebrand factor Collagen Activation Coller. Heart Disease, Update 4. 1995. GP IIb/IIIa Fibrinogen (or von Willebrand factor)
  29. 29. Platelet GP IIb/IIIa Receptor in Vascular Injury: Aggregation Fibrinogen (or von Willebrand factor) GP IIb/IIIa Aggregation ` Coller. Heart Disease, Update 4. 1995.
  30. 30. Inhibition of Platelet Aggregation GP IIb/IIIa Receptor Inhibitor Fibrinogen Resting Platelet Receptors in ligand-unreceptive state Activated Platelet Receptors in ligandreceptive state Aggregating Platelets GP IIb/IIIa receptors occupied by fibrinogen which forms bridges between adjacent platelets
  31. 31. GP IIb/IIIa antagonists block sCD40L release from platelets Unstimulated platelet Activated platelet André P et al. Circulation. 2002;106:896-9.
  32. 32. Proposed model for optimal use of GP IIb/IIIa inhibitors 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.
  33. 33. of thromboinflammation 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 Furman MI et al. J Thromb Haemost. 2005;3:312-20. Giugliano RP, Braunwald E. J Am Coll Cardiol. 2005;46:906-19.
  34. 34. 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
  35. 35. Abciximab • Human/murine chimeric monoclonal antibody Fab • KD 5 nmol/L • Indication: PCI
  36. 36. Eptifbatide • Cyclic peptide • KD 120 nmol/L • Acute coronary syndrome
  37. 37. Tirofiban • Nonpeptide • KD 15 nmol/L • Indication: acute coronary syndrome
  38. 38. Efficacy of GP IIb/IIIa inhibition on death or MI in PCI or ACS Death or MI at 30 days Trial Elective PCI N EPIC 4010 EPILOG 2792 CAPTURE 1265 RESTORE 2139 EPISTENT 2399 PRISM Favors placebo 2099 IMPACT II ACS Favors GP IIb/IIIa 3231 PRISM-PLUS PARAGON 1570* 2282 PURSUIT 10,948 Overall 30,366 0.79 (0.73–0.85) P < 10–9 0 *Does not include 345 patients In the tirofiban only group, which was stopped prematurely 1 Odds ratio (95% CI) 2 Antman EM et al. Am Heart J. 2003;146:S18-S22.
  39. 39. Special Mention
  40. 40. Altered platelet functions in diabetes ↓ Membrane fluidity ↓ Prostacyclin production Altered Ca+2 and Mg+2 homeostasis ↓ NO production ↑ Arachidonic acid metabolism ↑ Thromboxane A2 synthesis ↓ Antioxidants ↑ Activation-dependent adhesion molecules (eg, GP IIb/IIIa, P-selectin) These changes contribute to increased platelet aggregability and adhesiveness in diabetes Colwell JA, Nesto RW. Diabetes Care. 2003;26:2181-8.
  41. 41. PURSUIT: Outcomes in diabetic vs nondiabetic US patients 30-day death or MI Eptifibatide better Placebo better Diabetes No diabetes 0.33 1.0 3.0 Odds ratio (95% CI) Lincoff AM et al. Circulation. 2000;102:1093-100.
  42. 42. Will any drug ever prevent thrombosis without causing bleeding ? Thrombotic risk Bleeding risk

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