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Oral Antiplatelet Agents: A Cornerstone of Therapy for Atherothrombotic Disease

Oral Antiplatelet Agents: A Cornerstone of Therapy for Atherothrombotic Disease. Aspirin and clopidogrel: - Reduce the risks of myocardial infarction, ischemic stroke, and death in patients with atherosclerotic disease

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Oral Antiplatelet Agents: A Cornerstone of Therapy for Atherothrombotic Disease

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  1. Oral Antiplatelet Agents: A Cornerstone of Therapy for Atherothrombotic Disease • Aspirin and clopidogrel: - Reduce the risks of myocardial infarction, ischemic stroke, and death in patients with atherosclerotic disease - Yield greater antithrombotic effects and clinical efficacy in combination than with aspirin alone • Dual antiplatelet treatment with clopidogrel plus aspirin reduces CV events in patients with ST-elevation and non-ST-elevation ACS and in association with PCI procedures and coronary stenting ACS = acute coronary syndromes; CAD = coronary artery disease; CV = cardiovascular; PCI = percutaneous coronary intervention; PVD = peripheral vascular disease

  2. Limitations of Current Antiplatelet Therapy • Large variation in IPA response - 10%-30% of patients are “nonresponders” 1-3 • Modest inhibition of platelet response ex vivo • Irreversible P2Y12 receptor binding • Requirement for metabolic activation • Suboptimal onset of action for acute setting • Guidelines recommend stopping clopidogrel 5-7 days prior to invasive procedures ADP = adenosine diphosphate; IPA = inhibition of platelet aggregation Adapted from: Gurbel PA et al. Circulation 2003;107:2908-13; Muller l et al. Thromb Haemost. 2003;89:783-87.; Matetzky S et al, Circulation 2004;109:3171-75.

  3. Properties of AZD6140 for Improved PlateletADP P2Y12 Receptor Inhibition • Rapid onset of antiplatelet effect • No “low responders’ and less variability in platelet inhibitory effect • Greater and more consistent level of platelet inhibition • Direct action without need for metabolic activation • Reversible binding (can be stopped for CABG or other invasive procedures after 24 hours) CABG = coronary bypass graft AZD6140 is not currently approved for any indication

  4. AZD6140: A Reversible Antagonist • New chemical class of P2Y 12 inhibitors - Cyclo-pentyl-triazolo-pyrimidine (CPTP): not a thienopyridine or ATP analogue1 • Direct-acting - Not a prodrug; does not require metabolic activation2 - Onset (within 2 h)3; peak plasma levels within 2-3 h4 - Greater and more consistent inhibition of platelet aggregation vs. clopidogrel 3,5 • Reversibly bound - Degree of inhibition reflects plasma concentration - Offset of effect (within 48 h)6 - Functional recovery of all circulating platelets AZD6140 is not currently approved for any indication in Canada. Adapted from: 1Springthorpe B, et al. Bioorg Med. Chem lett 2007;17:6013-18, 2van Giezen JJJ, Humphries RG. Sem thromb Haemostas 2005; 31:195-204, 3Husted SE, et al; Eur Heart J 2006;27:1038-47; 4Peters G, Robbie G Haematologica. 2004;89(suppl 7): 14-15, 5Storey RF, et al. JACC 2007;19:1852-56, 6Data on File.

  5. DISPERSE: Greater and More Consistent IPAwith AZD6140 than with Clopidogrel (Final Extent) AZD6140 is not currently approved for any indication in Canada. Adapted from Husted S. at ESC 2005; data on file.

  6. DISPERSE2 Adjudicated Bleeding Rates (%) Week 4 and Overall (Week 12) AZD6140 is not currently approved for any indication in Canada. *Minor bleeding without major bleeding. Adapted from Cannon C et al. J Am Coll Cardiol 2007;50:1844-51.

  7. DISPERSE2 Cumulative Adjudicated Clinical End Point of MI Events AZD6140 is not currently approved for any indication in Canada. Adapted from Cannon C et al. J Am Coll Cardiol. 2007;50:1844-51.

  8. PLATO AZD6140 is not currently approved for any indication in Canada. ASA=acetylsalicyclic acid; bd=twice daily; CVD=cardiovascular death; ld=loading dose; MI=myocardial infarction; NSTEMI=non-ST-segment elevation MI; od=once daily; STEMI=ST-segment elevation MI; UA=unstable angina.

  9. Bleeding Definitions for PLATO • Major bleed (fatal / life-threatening) - Intracranial - Pericardial bleed with cardiac tamponade - Hypovolaemic shock or severe hypotension due to bleeding and requiring pressors or surgery - Clinically overt or apparent bleeding associated with a decrease in hemoglobin of more than 50 g/L - Transfusions of 4 or more units whole blood or PRBCs • Major bleed (other) - Significantly disabling (i.e., intraocular with permanent vision loss) - Clinically overt or apparent bleeding associated with a decrease in hemoglobin of 30 g/L to 50 g/L - Transfusions of 2 to 3 units (whole blood or PRBCs) PRBC = packed red blood cells

  10. Bleeding Definitions for PLATO • Minor Bleed • Requires medical intervention to stop bleeding • Transfusion of 1 unit (whole blood or PRBCs) • Minimal Bleed • All others (eg, bruising, bleeding gums, oozing from injection sites, etc) not requiring intervention or treatment

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