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

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 P2Y 12 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: ; Muller l et al. Thromb Haemost. 2003;89: ; Matetzky S et al, Circulation 2004;109:

Properties of AZD6140 for Improved Platelet ADP P2Y 12 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

AZD6140: A Reversible Antagonist New chemical class of P2Y 12 inhibitors - Cyclo-pentyl-triazolo-pyrimidine (CPTP): not a thienopyridine or ATP analogue 1 Direct-acting - Not a prodrug; does not require metabolic activation 2 - Onset (within 2 h) 3 ; peak plasma levels within 2-3 h 4 - 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: 1 Springthorpe B, et al. Bioorg Med. Chem lett 2007;17: , 2 van Giezen JJJ, Humphries RG. Sem thromb Haemostas 2005; 31: , 3 Husted SE, et al; Eur Heart J 2006;27: ; 4 Peters G, Robbie G Haematologica. 2004;89(suppl 7): 14-15, 5 Storey RF, et al. JACC 2007;19: , 6 Data on File.

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

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:

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

PLATO 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. AZD6140 is not currently approved for any indication in Canada.

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

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