Prasugrel provides faster, stronger, and more consistent platelet inhibition compared to clopidogrel. However, it also increases the risk of bleeding, especially in high-risk groups such as those over age 75, weighing less than 60kg, or with a history of stroke or transient ischemic attack. The TRITON-TIMI 38 trial found that prasugrel reduced cardiovascular events compared to clopidogrel in acute coronary syndrome patients undergoing percutaneous coronary intervention, but increased major bleeding risks. Subgroup analyses identified populations that may derive particular benefit or face specific bleeding risks with prasugrel.

1. Prasugrelau SMUR / Urgences ?Frédéric Munoz / Thierry CarrèresArgenteuil

2. Conflits d’intérêts Je ne suis pas un garçon intéressé… Ma femme ne travaille plus chez Lilly !

3. Cholesterol crystals rupture biological membranes and human plaques during acute cardiovascular events--a novel insight into plaque rupture by scanning electron microscopy. Abela GS et al. Scanning 2006;28:1-10.

6. Influence of Time Dynamic thrombus formation Fibrin r=0.38, p=0.01 Platelets r=-0.34, p=0.02 Silvain J et al. JACC In press

7. Avis de recherche: AAP idéal Effet rapide Effet puissant Effet constant Sans effet secondaire délétère

8. 600 500 400 300 200 100 0 0 6 12 18 24 Clopidogrel and Prasugrel: active metabolite plasma concentrations following oral loading dose Clopidogrel300 mg LD Prasugrel60 mg LD Plasma Concentration (ng/mL) Time From Dose (hours) AM=Active metabolite; LD=Loading dose Payne C et al. ThrombHaemost 2005;3(Supplement 1):P0952

10. Inhibition of Platelet Aggregation After Loading Dose in Patients With Elective PCI 100 *** *** *** 80 Prasugrel 60 mg *** 60 IPA % (20 µM ADP) Clopidogrel 600 mg 40 20 ***p<0.0001 Prasugrel vs. Clopidogrel 0 0.5 4 8 12 16 20 24 6 2 Hours IPA=inhibition of platelet aggregation; PCI=Percutaneous coronary intervention Wiviott SD et al. Circulation 2007;116(25):2923-2932

11. Background Variability Prasugrel60 mg LD Clopidogrel300 mg LD Crossover Study in Healthy Subjects Relationship between individual responses to prasugrel and clopidogrel, (administered in crossover fashion) as measured by IPA at 24 h postdose IPA % (20 mM ADP) Brandt JT et al. Am Heart J 2007;153(1):66.e9-16

12. TRITON TIMI 38: Timing of Benefit(Landmark Analysis) 8 6.9 Clopidogrel Clopidogrel 5.6 5.6 6 Primary Endpoint (%) 4.7 4 Prasugrel Prasugrel HR 0.82(0.71-0.96)P=0.01 HR 0.80(0.70-0.93)P=0.003 2 1 0 0 1 2 3 0 30 60 90 180 270 360 450 Days Loading Dose Maintenance Dose

13. Avis de recherche: AAP idéal Effet rapide Effet puissant Effet constant Sans effet secondaire délétère

14. 15 12.1 Clopidogrel 9.9 10 P<0.001 Prasugrel CV Death, MI, Stroke (%) 5 HR 0.81 (0.73-0.90) NNT= 46 0 0 30 60 90 180 270 360 450 Days Wiviott et al. New Engl J Med 2007;357:2001-2015 TRITON-TIMI 38: Efficacy / Safety P=0.002 5,0 P=0.03 P=0.01 1,8

15. Prasugrel Ticagrelor Clopidogrel 150 Clopidogrel 75 SAFETY: TIMI Major Non-CABG Bleeds (12-15 months) 9 8 7 6 p=0.03* p=0.025* p=0.001* 5 K-M estimated rate +27% +25% +22% 30 days ! 3.7 4 2.8 2.7 3 2.4 2.2 1.8 2 1.04 0.95 ASA only 1 0 CURRENT TRITON CURE PLATO 450 days 360 days 360 days

16. Events per 1000 pts + Major Bleed(non CABG) MI Net Clinical Benefit: Death, MI, Stroke, Major Bleed (non CABG) 15 Clopidogrel 13.9 ITT= 13,608 12.2 Prasugrel HR 0.87(0.79-0.95)P=0.004 10 Endpoint (%) 5 0 0 30 60 90 180 270 360 450 Days

17. Net Clinical Benefit: Bleeding Risk Subgroups Post-hoc analysis Risk (%) + 54 Yes Prior Stroke / TIA -16 No Pint = 0.006 -1 >=75 Age -16 Pint = 0.18 < 75 +3 < 60 kg Wgt Pint = 0.36 -14 >=60 kg -13 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR Wiviott SD, Braunwald E, McCabe CH et al NEJM 2007

18. All ACS/PCI patients N=13608 UA/NSTEMI patients N=10074 STEMI patients N=3534 Primary PCI N=2438 (69%) Secondary PCI N=1094 (31%)* Clopidogrel N=1235 Prasugrel N=1203 Clopidogrel N=530 Prasugrel N=564 TRITON-TIMI 38 STEMI Beforeknowledge of coronaryanatomy * 2 patients were missing data for primary or secondary Montalescot et al. ESC 2008

19. Clopidogrel Prasugrel 15 12.4 p=0.02 RRR=21% 10.0 10 9.5 p=0.002 RRR=32% Proportion of patients (%) 6.5 5 HR=0.79 (0.65–0.97) NNT=42 0 Age-adjusted HR=0.81 (0.66-0.99) 0 50 100 150 200 250 300 350 400 450 Time (Days) TRITON STEMI :PrimaryEP (CV death, MI andstrokeat 15 months) Montalescot et al. ESC 2008

20. Clopidogrel Prasugrel 6 5.1 p=0.65 4.7 4 Proportion of patients (%) 2 HR=1.07 (0.79–1.47) NNH=250 Age-adjusted HR=1.14 (0.83-1.55) 0 50 0 100 200 300 400 150 250 350 450 Time (Days) TIMI majororminor non-CABG bleeding Montalescot et al. ESC 2008

21. TRITON: Efficacy for IIb/IIIa use. Prasugrel triple AP therapy more effective and as safe as Clopidogrel triple AP Therapy Percentage of subjects reaching the Primary Endpoint The trial was not randomized against GP IIb/IIIa inhibitors. As its use was left to the discretion of the physicians, patients receiving GPI were likely to be at higher risk for ischemic events.

22. En résumé… Effet rapide >> clopidogrel Effet puissant >> clopidogrel Effet constant >> clopidogrel Risque hémorragique > clopidogrel Population à risque identifiée GP IIbIIIa possibles dans le STEMI / souhaitables ?

23. 23 ESC Guidelines 2010 European Heart Journal 2010

26. 27 Bassand JP, et al. The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. European Heart Journal 2007, 28:1598-1660

27. 28

28. STEMI PatientsSubgroupanalysis by time of LD relative to PCI

29. Clopidogrel Prasugrel 2.5 2.4 p=0.65 2.0 2.1 1.5 1.0 Proportion of patients (%) 0.5 HR=1.11 (0.70–1.77) NNH=333 Age-adjusted HR=1.19 (0.75-1.89) 0 0 100 200 300 400 Time (Days) Montalescot et al. ESC 2008 TRITON STEMI: TIMI major non-CABG bleeding

30. Clopidogrel Prasugrel p=0.75 Life threatening bleeding (%) HR=1.11 (0.59–2.10) NNH=500 Age-adjusted HR=1.20 (0.63-2.26) Time (Days) TIMI life-threatening non-CABG bleeding Montalescot et al. ESC 2008

31. TRITON: Safety for IIb/IIIa use: No differences between Prasugrel and Clopidogrel at 3 days. The Co-Administration of a GP IIb/IIIa inhibitor with the loading dose increased the risk of instrumentation related TIMI major bleeding in both prasugrel- and clopidogrel-treated subjects, particularly in the STEMI population.

32. Prasugrel dans le camion ?