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The TRITON-TIMI 38 Trial is supported by Daiichi Sankyo Co. Ltd. and Eli Lilly and Co.

Clopidogrel Under Fire: Is Prasugrel in Primary PCI or Recent MI Superior? Insights From TRITON-TIMI-38. Gilles Montalescot, Stephen D. Wiviott, Eugene Braunwald, Sabina A. Murphy, C. Michael Gibson, Carolyn H. McCabe and Elliott M. Antman, for the TRITON–TIMI 38 Investigators.

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The TRITON-TIMI 38 Trial is supported by Daiichi Sankyo Co. Ltd. and Eli Lilly and Co.

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  1. Clopidogrel Under Fire: Is Prasugrel in Primary PCI or Recent MI Superior? Insights From TRITON-TIMI-38 Gilles Montalescot, Stephen D. Wiviott, Eugene Braunwald, Sabina A. Murphy, C. Michael Gibson, Carolyn H. McCabe and Elliott M. Antman, for the TRITON–TIMI 38 Investigators The TRITON-TIMI 38 Trial is supported by Daiichi Sankyo Co. Ltd. and Eli Lilly and Co. G. Montalescot, disclosure: Institutional research grant, consulting and speaker fees from Daiichi Sankyo, Eli Lilly, Sanofi Aventis, BMS.

  2. Clopidogrel limitations • Slow onset • Low level of inhibition • Too much variability

  3. Clopidogrel PreRx Without GPI TrialClopi PreRxNo PreRx PCI-CURE 27/1039 (2.6)39/988 (3.9) CREDO 26/473(5.5)34/519 (6.6) PCI-CLARITY 22/639 (3.4)30/615 (4.9) OVERALL75/2151 (3.5)103/2122 (4.9) TrialClopi PreRxNo PreRx PCI-CURE14/274 (5.1)23/357 (6.4) CREDO29/427 (6.8)32/396 (8.1) PCI-CLARITY12/288 (4.2)28/310 (9.0) OVERALL55/989 (5.6)83/1063 (7.8) Favors PreRx Favors No PreRx OR 0.72 (0.53-0.98) P=0.03 0.25 0.5 1.0 2.0 OR (95% CI) With GPI P=0.85 for heterogeneityby GPI use OR 0.69 (0.47-1.00) P=0.05 0.25 0.5 1.0 2.0 Sabatine MS et al. ESC 2006 OR (95% CI)

  4. High clopidogrel doses

  5. 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 P=0.002 P=0.03 P=0.01 • TRITON allowed recruitment of STEMI patients undergoing primary PCI when they presented < 12 hours of symptom onset or secondary PCI when they presented late

  6. TRITON-TIMI 38 STEMI 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 * 2 patients were missing data for primary or secondary Montalescot et al. ESC 2008

  7. Baseline demographics and disposition • Baseline characteristics were well matched between the treatment groups, with the exception of: • Age (59 [IQR 52, 69] for clopidogrel and 58 [IQR 51, 67] for prasugrel, p=0.04) • Tobacco (43.7% clopidogrel and 47.2% prasugrel, p=0.04) and • Killip class >1 (6.4% clopidogrel and 8.8% prasugrel, p= 0.007) • The median treatment duration was 15.2 months • PCI was performed on 97% of patients: 92% received 1 intracoronary stent, 59% received bare metal stent only and 33% received drug eluting stent • The follow-up rate was > 99% Montalescot et al. ESC 2008

  8. Baseline characteristics of patients with primary or secondary PCI Montalescot et al. ESC 2008

  9. Primary EP (CV death, MI and stroke at 15 months) 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) Montalescot et al. ESC 2008

  10. Key secondary EP (CV death, MI, and UTVR at 30 days) Clopidogrel Prasugrel 10 8.8 p=0.02 RRR=25% 6.7 5 Proportion of patients (%) HR=0.75 (0.59–0.96) NNT=48 Age-adjusted HR=0.77 (0.60-0.97) 0 0 5 10 15 25 25 30 Time (Days) Montalescot et al. ESC 2008

  11. Efficacy endpoints at 30 days Clopidogrel Prasugrel p= 0.002 10 p= 0.004 p= 0.02 8 p= 0.01 6 Proportion of population (%) 4 p= 0.008 p= 0.04 p= 0.13 2 0 All Death MI UTVR Stent Thrombosis* CV Death/MI CV Death/ MI/UTVR CV Death/ MI/Stroke * ARC def/probable Montalescot et al. ESC 2008

  12. Efficacy endpoints at 15 months Clopidogrel Prasugrel 14 p= 0.02 p= 0.03 p= 0.007 12 p= 0.02 10 8 Proportion of population (%) p= 0.11 6 p= 0.09 4 p= 0.02 2 0 All Death MI UTVR Stent Thrombosis* CV Death/MI CV Death/ MI/UTVR CV Death/ MI/Stroke * ARC def/probable Montalescot et al. ESC 2008

  13. Clopidogrel Prasugrel 3 2.8 2.4 p=0.02 RRR=42% 2 p=0.008 RRR=51% 1.6 Proportion of patients (%) 1.2 1 HR=0.58 (0.36–0.93) NNT=83 0 Age-adjusted HR=0.59 (0.37-0.96) 0 100 200 300 400 Time (Days) Stent thrombosisARC Definite/probable Montalescot et al. ESC 2008

  14. TIMI major non-CABG bleeding 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

  15. TIMI life-threatening non-CABG bleeding 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) Montalescot et al. ESC 2008

  16. Bleeding events over 15 months p=NS 7 p=NS Clopidogrel 5.9 6 Prasugrel 5.1 4.8 5 4.7 p=NS 4 p=NS Proportion of population (%) 2.8 2.7 3 p=NS 2.4 2.1 2 p=NS 1.3 1.1 1 0.3 0.2 0 Major non-CABG Life threatening Intra-cranial haemorrhage Minor non-CABG Major or minor non-CABG Major or minor CABG/non-CABG Montalescot et al. ESC 2008

  17. Net clinical benefit at 15 months p=0.02 NNT=42 p=0.04 NNT=45 Clopidogrel Prasugrel Proportion of population (%) Death / non-fatal MI / non-fatal stroke or major non-CABG bleeding Death / MI /stroke/ major bleeding (CABG and non-CABG) Montalescot et al. ESC 2008

  18. Conclusions In STEMI patients undergoing PCI • Prasugrel was superior to standard dose clopidogrel to prevent ischaemic events • Prasugrel did not have more bleeding events compared to those who were treated with clopidogrel, and this was equally true for: • Primary PCI • Secondary PCI • Major bleeding • Minor bleeding • These data make prasugrel an especially attractive alternative to clopidogrel in PCI for STEMI Montalescot et al ESC 2008

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