TRITON TIMI-38 STEMI cohort 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.

TRITON TIMI-38 STEMI cohort Clopidogrel limitations Slow onset Low level of inhibition Too much variability

TRITON TIMI-38 STEMI cohort TrialClopi PreRxNo PreRx PCI-CURE27/1039 (2.6)39/988 (3.9) CREDO26/473 (5.5)34/519 (6.6) PCI-CLARITY22/639 (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) Clopidogrel PreRx OR (95% CI) OR 0.72 ( )P=0.03 ( )P=0.03 Favors PreRx Favors No PreRx OR 0.69 ( )P=0.05 ( )P=0.05 Without GPI P=0.85 for heterogeneity by GPI use With GPI Sabatine MS et al. ESC 2006

TRITON TIMI-38 STEMI cohort High clopidogrel doses

TRITON TIMI-38 STEMI cohort TRITON-TIMI 38 TRITON allowed recruitment of STEMI patients undergoing primary PCI when they presented < 12 hours of symptom onset or secondary PCI when they presented late P=0.03 P=0.01 P=0.002 Wiviott et al. New Engl J Med 2007;357: HR 0.81 ( ) Days CV Death, MI, Stroke (%) NNT= 46 Prasugrel Clopidogrel P<0.001

TRITON TIMI-38 STEMI cohort 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%)* ClopidogrelN=1235PrasugrelN=1203 ClopidogrelN=530PrasugrelN=564 Montalescot et al. ESC 2008 TRITON-TIMI 38 STEMI * 2 patients were missing data for primary or secondary

TRITON TIMI-38 STEMI cohort 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% Baseline demographics and disposition Montalescot et al. ESC 2008

TRITON TIMI-38 STEMI cohort Baseline characteristics of patients with primary or secondary PCI Montalescot et al. ESC 2008 Variable Primary PCI (%) Secondary PCI (%) p Age (years) History of diabetes Prior CABG Multivessel PCI GPIIb/IIIa inhibitor Creatinine clear. < 60mL/min

TRITON TIMI-38 STEMI cohort Primary EP (CV death, MI and stroke at 15 months) Montalescot et al. ESC 2008 Time (Days) Proportion of patients (%) HR=0.79 (0.65–0.97) NNT=42 p=0.02 RRR=21% p=0.002 RRR=32% Clopidogrel Prasugrel Age-adjusted HR=0.81 ( )

TRITON TIMI-38 STEMI cohort Montalescot et al. ESC 2008 Key secondary EP (CV death, MI, and UTVR at 30 days) HR=0.75 (0.59–0.96) NNT= Time (Days) Proportion of patients (%) p=0.02 RRR=25% Clopidogrel Prasugrel Age-adjusted HR=0.77 ( )

TRITON TIMI-38 STEMI cohort Efficacy endpoints at 30 days Montalescot et al. ESC 2008 * ARC def/probable All DeathMIUTVRStent Thrombosis* CV Death/ MI CV Death/ MI/UTVR CV Death/ MI/Stroke Proportion of population (%) p= 0.04 p= 0.01 p= 0.13 p= p= p= 0.02 p= Clopidogrel Prasugrel

TRITON TIMI-38 STEMI cohort Montalescot et al. ESC 2008 Efficacy endpoints at 15 months Clopidogrel Prasugrel p= 0.11 p= 0.02 p= 0.09 p= 0.02 p= p= 0.03 p= 0.02 Proportion of population (%) All DeathMIUTVRStent Thrombosis* CV Death/ MI CV Death/ MI/UTVR CV Death/ MI/Stroke * ARC def/probable

TRITON TIMI-38 STEMI cohort Montalescot et al. ESC 2008 Stent thrombosis ARC Definite/probable HR=0.58 (0.36–0.93) NNT=83 p=0.02 RRR=42% Proportion of patients (%) Time (Days) p=0.008 RRR=51% Clopidogrel Prasugrel Age-adjusted HR=0.59 ( )

TRITON TIMI-38 STEMI cohort TIMI major non-CABG bleeding Montalescot et al. ESC HR=1.11 (0.70–1.77) NNH=333 Proportion of patients (%) Time (Days) p= Clopidogrel Prasugrel Age-adjusted HR=1.19 ( )

TRITON TIMI-38 STEMI cohort TIMI life-threatening non-CABG bleeding Montalescot et al. ESC 2008 HR=1.11 (0.59–2.10) NNH=500 Life threatening bleeding (%) Time (Days) p=0.75 Clopidogrel Prasugrel Age-adjusted HR=1.20 ( )

TRITON TIMI-38 STEMI cohort Bleeding events over 15 months Montalescot et al. ESC 2008 Major non-CABG Life threatening Intra-cranial haemorrhage Minor non-CABG Major or minor non-CABG Major or minor CABG/non-CABG Proportion of population (%) Clopidogrel Prasugrel p=NS

TRITON TIMI-38 STEMI cohort Net clinical benefit at 15 months Montalescot et al. ESC 2008 p=0.02 NNT=42 Death / non-fatal MI / non-fatal stroke or major non-CABG bleeding Death / MI /stroke/ major bleeding (CABG and non-CABG) p=0.04 NNT=45 Clopidogrel Prasugrel Proportion of population (%)

TRITON TIMI-38 STEMI cohort Conclusions In STEMI patients undergoing PCI Montalescot et al ESC 2008 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