1. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 PRasugrel IN Comparison to Clopidogrel for Inhibition of PLatelet Activation and AggrEgation (PRINCIPLE) – TIMI 44

2. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Study Design Loading Phase N=201 Maintenance Phase N=100 No PCI 6h* Labs, 15d Events Coronary Angiography Post-Angiography Labs Planned Elective PCI Baseline Laboratory Measures Prasugrel 60 mg Clopidogrel 600 mg 0.5 h Post-Loading Dose Labs PCI 6h* Labs, 18-24h Labs Clopidogrel 150 mg x 14d Prasugrel 10 mg x 14d Prasugrel 10 mg x 14d Clopidogrel 150 mg x 14d 15d Clinical Events, Labs, † CROSSOVER 29d Clinical Events, Labs † Clopidogrel naïve No planned GP IIb/IIIa use 1º EPs: *Loading = 6h IPA (20 µM ADP); † Maintenance = 15d or 29d IPA (20 µM ADP) Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007

3. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 PRIMARY EP Acute Phase: IPA 20 uM ADP Prasugrel 60 mg P<0.0001 for each IPA (%; 20  M ADP) Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Hours

4. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Maximal Platelet Aggregation (MPA) Prasugrel 60 mg P<0.0001 for each MPA (%; 20  M ADP) Hours

5. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 VASP Phosphorylation Ratio Prasugrel 60 mg P<0.0001 for each Hours VASP Phosphorylation Ratio

6. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Prasugrel 10 mg Difference Between Treatments: 14.9 [95% CI 10.6 – 19.3], P<0.0001 IPA (%; 20  M ADP) Days PRIMARY EP Chronic Phase: IPA 20 uM ADP

7. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Maximal Platelet Aggregation (MPA) Prasugrel 10 mg Difference Between Treatments: 11.3 [95% CI 8.1 – 14.5], P<0.0001 Clopidogrel 150 mg MPA (%; 20  M ADP) Days

8. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 VASP Phosphorylation Ratio Prasugrel 10 mg Difference Between Treatments: 20.1 [95% CI 14.5 – 25.7], P<0.0001 Clopidogrel 150 mg VASP Phosphorylation Ratio Days

9. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007 Thienopyridine Hyporesponsiveness: IPA 20 uM ADP < 20% P =0.06 P =0.18 P =0.0002 P =0.0005 P <0.0001 P =0.0008 Clopidogrel Prasugrel Hours Percent of Subjects

10. Copyright ©2007 American Heart Association Wiviott SD et al, Circulation 2007Implications PRINCIPLE – TIMI 44 extends the pharmacologic superiority of the TRITON – TIMI 38 dose of prasugrel (60 mg/10 mg) to higher doses of clopidogrel (600 mg/150mg) in PCI. TRITON – TIMI 38 1 tested hypothesis that an agent that with higher and more consistent IPA than standard approved clopidogrel (300 mg/ 75 mg) will improve clinical outcomes 1 Wiviott SD, Braunwald E, McCabe CH et al NEJM2007