G Montalescot, L Bolognese, D Dudek, P Goldstein, C Hamm, JF Tanguay

,
JM ten Berg, DL Miller, TM Costigan, J Goedicke, J Silvain, P Angioli,
J Legutko, M Niethammer, Z Motovska, JA Jakubowski, G Cayla,
LO Visconti, E Vicaut, P Widimsky for the ACCOAST investigators

COI DISCLOSURE FOR DR. MONTALESCOT are availalble @ http://www.action-coeur.org

Trial Conduct

P Sabouret. J ten Berg. and Eli Lilly and Company -  Global Trial Operations: ICON Clinical Research and Quintiles (site management). JF Tanguay. France -  Sponsors: Daiichi-Sankyo Company. D Dudek. C Di Mario. Inventiv (data management and statistical services). F Philippe. Paris. M Dalby. Ltd. AF van den Heuvel.Trial conduct -  Coordinating Center: ACTION Study Group . Tata Consultancy Services (statistical programming) -  External Academic Statistical Center : ACTION Study Group •  Executive Committee: G Montalescot (Chairman). L Bolognese. P Goldstein. A Kapur.Institute of Cardiology – Pitié-Salpêtrière University Hospital. A Bardají. P Widimsky •  Endpoint Adjudication Committee: M Flather (Chairman). A Baumbach. C Hamm. E Vicaut . A Zaman •  Data Safety Monitoring Board: M Bertrand (Chairman).

Enrollment: >4.000 patients in 19 Countries Poland: 847 Sweden: 4 Canada: 146 Netherlands: 142 Belgium: 81 Portugal: 17 Germany: 529 France: 586 Czech Rep: 292 Austria: 172 Italy: 628 Finland: 42 Latvia: 5 Lithuania: 73 Slovakia: 47 Hungary: 134 Romania: 85 Turkey: 112 Israel: 131 .

Background .

N Engl J Med 2001.345:494-502 Steinhubl SR.CURE Efficacy CREDO Efficacy CURE Safety* CREDO Safety** Yusuf S. JAMA 2002. et al. et al.288:2411-2420 .

P2Y12 Pre-treatment ESC Recommendations Title Citation 2011 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation European Heart Journal 2011.31:20:2501–2555 “A P2Y12 inhibitor as soon as possible” Clopidogrel 600mg Ticagrelor “Clopidogrel 600mg as soon as possible” Class LOE I A I I B B I C .32:2999–3054 2010 ESC/EACTS guidelines on myocardial revascularization European Heart Journal 2010.

5 2 2.308:2507-2516 .5 3 3.  Clopidogrel   Pretreatment   No  Pretreat   ARMYDA5  Preload   CIPAMI   CLARITY  PCI   CREDO   PCI  CURE   Davlouros  et  al. JAMA 2012.   Feldman  et  al.Death Randomized  CT     1/204   1/164   13/933   18/1053   32/1313   0/103   1/513   66/4283   0/205   4/171   24/930   24/1063   31/1345   2/96   0/515   85/4325   Rela=ve     Weight  [%]   3·03 [0·12-74·80] 1·∙0%   0·26 [0·03-2·32] 2·∙2%   0·53 [0·27-1·05] 23·∙2%   0·75 [0·41-1·40] 28·∙3%   1·06 [0·64-1·75] 43·∙1%   0·18 [0·01-3·85] 1·∙2%   3·02 [0·12-74·25] 1·∙0%   0·80 [0·57-1·11] 100%   105/3511   114/5087   219/8598   49/1515   14/832   63/2347   0·92 [0·65-1·30] 1·34 [0·77-2·34] 1·04 [0·74-1·46] 68·∙2%   31·∙8%   100%   13/923   209/4879   12/217   18/467   6/1481   76/4477   334/12444   19/990   110/1076   6/166   18/574   18/2679   12/332   183/5817   0·73 [0·36-1·49] 0·39 [0·31-0·50] 1·56 [0·57-4·25] 1·24 [0·64-2·41] 0·60 [0·24-1·52] 0·46 [0·25-0·86] 0·68 [0·42-1·09] 16·∙2%   24·∙0%   11·∙9%   17·∙0%   12·∙9%   17·∙8%   100%   Events  /  Size.   PRAGUE  8   All   N=8.   Szuk  et  al.608 OR  [CI  95%]   OR=0·∙80  CI  95%  [0·∙57-­‐1·∙11]  P=0·∙17   Observa2onal  from  RCT   ACUITY  PCI   REPLACE  2   All   N=10.5 4 Bellemain-Appaix A et al.5 1 1.   Chan  et  al.   Dorler  et  al.   All   N=18.   Fefer  et  al.945 OR=1·∙04  CI  95%  [0·∙74-­‐1·∙46]  P=0·∙83   Observa2onal   Amin  et  al.261 OR=0·∙68  CI  95%  [0·∙42-­‐1·∙09]  P=0·∙11   Pre-treatment better 0 No Pre-treatment better 0.

●  Pre-treatment with aspirin and a P2Y12 antagonist has been a class I recommendation and common practice for the treatment of NSTE-ACS ●  However. prasugrel or ticagrelor vs. no pre-treatment. . no trial has ever randomized patients presenting with NSTE-ACS. invasively managed. to pre-treatment with clopidogrel.

Study Design .

5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg n~4100 (event driven) Randomize 1:1 Double-blind CABG or Medical Management (no more prasugrel) Prasugrel 30 mg Placebo Coronary Angiography Coronary Angiography Prasugrel 30 mg Prasugrel 60 mg PCI PCI CABG or Medical Management (no prasugrel) Prasugrel 10 mg or 5 mg (based on weight and age) for 30 days 1° Endpoint: CV Death. MI.161:650-656 . Stroke. Urg Revasc. Am Heart J 2011. GP IIb/IIIa bailout. at 7 days Montalescot G et al.ACCOAST design NSTEMI + Troponin ≥ 1.

161:650-656 . Am Heart J 2011.Main Inclusion/Exclusion Criteria Inclusion ●  NSTEMI symptoms within 48 hours prior to study entry ●  Elevated troponin (≥1.5 times ULN) per local lab(s) ●  Patient to be scheduled for coronary angiography and PCI within 2 hours to 24 hours of randomization and no later than 48 hours after randomization Exclusion ●  STEMI patients ●  Medical history contraindicating therapy with prasugrel ●  History of stroke or transient ischemic attack (TIA) ●  LD of any P2Y12 antagonist ≤7 days of study entry Montalescot G et al.

10) .05) Lost  to  Follow-­‐up  2  (0.4%) Lost  to  Follow-­‐up  1  (0.4%) Day 30 Visit N=1958 (96.Patient Disposition Total Randomized N=4038 5 Subjects Revoked Consent ITT and All Treated N= 4033 Pre-treatment N=2037 No Pre-treatment N=1996 Day 7 N=2009 (98.1%) Day 30 Visit N=1924 (96.6%) Day 7 N=1964 (98.

0   82   28     20   45   61   33     42   58   .Baseline Characteristics Characteristics   Age (mean. kg)   BMI ≥ 30 (%)   CV risk factors (%)   Diabetes mellitus   Dyslipidemia   Hypertension   Current smoker   Region of enrolment (%)   Eastern Europe/Israel   Western Europe/Canada   Pre-treatment (N =2037)   64   27   82   29     20   45   63   34     42   58   No Pre-treatment (N =1996)   64   28. yrs)   Female sex (%)   Weight (mean.

2 4.Baseline Characteristics Characteristics GRACE score (%) <140 ≥140 CRUSADE score (median) Pre-treatment (N =2037) No Pre-treatment (N =1996) 76 24 34 78 22 34 14. median Access (%)ǁ‖ Femoral Radial .4 15.2 57 43 57 43 Timing (hr) àSymptom onset to 1st LD. median à 1st LD to coronary angiogram.6 4.

Results .

LD = loading dose. No Pre-treatment=Placebo/Prasugrel 60 mg 4 24 . * p<0.05 P2Y12 Reaction Units 300 250 Approximate time of PCI 200 150 100 30 mg LD1 * * 50 0 30 mg LD2 Pre LD1 Pre LD2 (baseline) 0.05 relative to the No pre-treatment group.5 1 2 3 Hours (post LD2) Data presented as median ± SEM.Pharmacodynamic Sub-Study 350 Placebo LD1 Pre-treatment (30/30) No Pre-treatment (0/60) 60 mg LD2 *P<0. Pretreatment=Prasugrel 30 mg/Prasugrel 30 mg.

84.83.0 10 No Pre-treatment 10. 0.8 5 Hazard Ratio.997 (95% 0. at Risk.8 Endpoint (%) Pre-treatment 10. 1.1° Efficacy End Point @ 7 + 30 days (All Patients) 15 CV Death. GPIIb/IIIa Bailout Pre-treatment 10.25) P=0. Stroke. MI. UR.02 (95% 0.8 No Pre-treatment 9.20) P=0. 1. Primary Efficacy End Point: No pre-treatment Pre-treatment 5 10 15 20 25 30 1752 1791 1621 1616 Days From First Dose 1996 2037 1788 1821 1775 1809 1769 1802 1762 1797 .98 0 0 No.81 Hazard Ratio. 1.

03 (95% 0.1 HR. Stroke. UR.93 5 0 0 No.24) P=0.01 (95% 0. 1. 1.8 No Pre-treatment 13.26) P=0.82.77 HR.84. 1. 1. GPIIb/IIIa Bailout PCI Cohort No Pre-treatment 13.1° Efficacy Endpoint (PCI Patients) 20 Endpoint (%) 15 Pre-treatment 13.1 10 Pre-treatment 14. MI. Efficacy End Point: No pre-treatment Pre-treatment 5 10 15 20 25 30 1177 1186 1177 1172 Days From First Dose 1372 1389 1191 1206 1187 1202 1183 1194 1179 1189 .1 CV Death. at Risk.

24) 0.64.99 (0. PCI includes 11 patients with PCI + CABG.62) 43 (11.86. 1.08 (0.78.24 2276 1711 125 (10.83) 182 (9.14) 157 (9.88 (0.82) 90 (8.22.93 1.91) 105 (10.84.09) 158 (9.25) PCI CABG Medical Management 2781 238 1014 185 (13.02) 109 (10.21) 0.68) 0. 1. 1. and the treatment-by-subgroup interaction as fixed effects.07) 82 (8.65) 137 (11.02 (0. no pre-treatment) Age Sex Male Female Weight <60 kg >60 kg Diabetes Yes No Prior clopidogrel treatment Yes No Time from Sx to LD <median >median Time from first LD to angio/PCI <median >median GRACE score <140 >140 Access Femoral Radial Region Eastern Europe/Israel Western Europe/Canada 0.03 (0.82 (0.67) 37 (9.02 (0.44) 9 (1.57.82) 192 (9.77) 1.80) 195 (10.88. 1.13 (0.91 (0.77) 1.14 (0.24) 51 (9.09 (0.56 (0.20 820 3213 46 (11.20) 1. 1.5 Pre-treatment better 1 2 5 No pre-treatment better *Hazard ratio not evaluated for <10 events.43) 1.03.20 (0.36) 46 (8.30 3079 852 154 (10. 1.21) 9 (7.84) 6 (1.77) 83 (9.24) 119 (11.79) 1.72. 1.37) 0.97) 195 (9.99 (0.43) 0.25 (0.03 (0.45 2923 1110 152 (10.73) 143 (9.88) 0.54 205 3824 7 (6.96) 76 (8.92) 0.87.25) 1.54 <75 years >75 years 3318 715 160 (9.91 (0.75) 111 (9. 1.28) 0. 1.31) Overall (pre-treatment vs. 1. 1.47) 0.46) 0.11) 8 (6. Interaction P-value† 1. 1.24) 1.76 1990 2008 84 (8. †Interaction p-value is from a Cox proportional hazards model with treatment.31) .2 0.86) 86 (8. 1.79.97 (0.30 232 3801 11 (9.45 (0. 1.74) 181 (13.97) 13 (10.03) 1. subgroup.60) 132 (11.81.1 0.23) 1.24) 0.42.70) 0.84. 1.83. 4.21 1692 2341 66 (7.76) 183 (9.004 1998 2003 120 (12.78) 0.67.76. 1. 1.55. 1. 1.24) 47 (11. 1. 2.01) 1.76.76 (0.81.09) 0.20) 0.65) 0.67) 63 (7.26) 0.75) 1.23) 0.24) 149 (10.05) 44 (9. 2.70) 0.94) 1.79) 33 (9.36 (1.14 (0.79. 1.86) 1.05 (0.93) 0.41.87.09) 12 (11.52.1° Efficacy Endpoint Through 7 Days for Prespecified Subgroups (All Patients) Total Patients Pre-tx n (%) No Pre-tx n (%) Hazard Ratio (95% CI) 4033 203 (9.53) 162 (9.01 (0.

006 Hazard Ratio. All TIMI Major Bleeding: No pre-treatment Pre-treatment 5 10 15 20 25 30 1284 1297 1263 1280 Days From First Dose 1996 2037 1947 1972 1328 1339 1297 1310 1288 1299 .08) P=0.All TIMI (CABG or non-CABG) Major Bleeding (All Treated patients) 5 Hazard Ratio.9 3 Pre-treatment 2.97 (95% 1. 1.90 (95% 1. 1.02) P=0.002 Endpoint (%) 4 Pre-treatment 2.6 2 All TIMI Major Bleeding 1 No Pre-treatment 1.4 0 No. 3.19.5 0 No Pre-treatment 1. 3.26. at Risk.

001 2. STEEPLE Bleeding Endpoints Through 7 Days (All Treated Patients) Event Rate (%) 6 Pre-treatment (N=2037) No Pre-treatment (N=1996) 4 P<0.TIMI.3 P=0.0 0. GUSTO.001 1.2 20 4 GUSTO Severe or Life Threatening Non-CABG Bleeding 46 18 STEEPLE Non-CABG Major .5 0 N= 27 9 Non-CABG TIMI Major Bleeding 0.9 0.003 1.3 2 P=0.

2. 2. 6. at Risk. All TIMI Major Bleeding: No pre-treatment Pre-treatment 5 10 15 20 25 30 1268 1280 1249 1269 Days From First Dose 1372 1389 1356 1364 1302 1314 1280 1293 1272 1282 .02 All TIMI Major Bleeding PCI Cohort HR.13.010 2 Pre-treatment 1.65 (95% 1. 5.69 (95% 1.5 No Pre-treatment 0.7 1 No Pre-treatment 0.40) P=0.70) P=0.4 Pre-treatment 1.23.7 0 0 No.All TIMI Major Bleeding (PCI Patients) 5 Endpoint (%) 4 3 HR.

87 2276 1711 29 (2.35 820 3213 6 (1.60) 22 (1.02) PCI CABG Medical Management* 2781 238 1014 22 (1. 3.97) 10 (0. 8.81) 15 (1.76 (0.70 (1.19.86) 9 (0.31 2923 1110 31 (2. and the treatment-by-subgroup interaction as fixed effects.16) 8 (2. 4.98) 26 (1.29 (1.71) 1.61 (1.78 (1.All TIMI Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients) Total Patients Pre-tx (%) No Pre-tx (%) Overall (pre-treatment vs.85. 2.94) 0.05) 0.66 1692 2341 14 (1.90 (1.41) 1.98 (0.69 (0.43) 1 (0. 4.20) 15 (1.55) 27 (1.75) 24 (2.25.80) 0.87) 0.09.80) 25 (20.72) 24 (2.35) 12 (1. no pre-treatment) Age Sex Hazard Ratio Interaction (95% CI) P-value† 4033 52 (2.91) 2.49) 3.74 (1.16) 16 (4. 2.67 (1.51) 1.66) 16 (13.93) 0. 4.19.08) 1.62) 38 (3.24) 5 (0. 2.12) 0.47) 21 (1.23 1998 2003 27 (2.64 (0.53) 2.89) 2.58) 8 (0.75.46) 1.71) 2.46) 6 (1.10.29) 22 (1.09 205 3824 5 (4. PCI includes 11 patients with PCI + CABG.08.41 2051 1789 23 (2.93.33) 5 (1.59 3079 852 34 (2.23) 27 (2. 2. 3.09) 1.2 0.45) 46 (2. 3.46.00) 1. †Interaction p-value is from a Cox proportional hazards model with treatment.40) 18 (1.09. 2. 5.81.16 (1.89) 1.00) 0.98) NE 0. 8.96.05) 2.80) 21 (1.29.54 (0.54) 22 (2.50 (0.82.09) 21 (3.5 Pre-treatment better 1 2 5 10 15 No pre-treatment better *Hazard ratio not evaluated for <10 events.85) 47 (2. 2.62 (0.32.90.98) 2.53) 18 (1.43 (0.22) 16 (3.16.74 <75 years >75 years 3318 715 36 (2. 2.83. 7.78) 2.32) 0.28) 0.00) 1.35) 1.37) NE 1.57) 11 (0. 2.59 (0. 3. ‡CRUSADE score is a post-hoc analysis.97) 0 (0.28 (1.95) 0.83) 6 (1.03.95 (1.75 (0. 6.96. 3. subgroup.46 Male Female Weight <60 kg* >60 kg Diabetes Yes No Time from Sx to LD <median >median Time from first LD to angio/PCI <median >median CRUSADE score‡ <median >median GRACE score <140 >140 Access Femoral Radial Region Eastern Europe/Israel Western Europe/Canada 0.62) 0.92 (1.22 1990 2008 28 (2.68) 5 (0.95) 1. 4.98 (0.47) 1.97.54) 18 (1. .

5 1.Non-CABG TIMI Major Bleeding Endpoints Through 7 Days (All Treated Patients) 3.05 0 0.83 P not evaluable 0.0 P=0.15 0.5 Pre-treatment (N=2037) Most Frequent Locations of Major Bleed No Pre-treatment (N=1996) 2.0 0.0 Event Rate (%) 2.33 P=0.002 1.5 0.45 0.0 N= 27 9 Non-CABG TIMI Major Bleeding 1 0 Fatal Bleeding 17 3 Life Threatening Bleeding .003 1.

Conclusions .

● The results are consistent among patients undergoing PCI supporting treatment with prasugrel once the coronary anatomy has been defined. pre-treatment with prasugrel does not reduce major ischemic events through 30 days but increases major bleeding complications. . ● Reappraisal of routine pre-treatment strategies in NSTEACS is needed. ● No subgroup appears to have a favorable risk/benefit ratio of pre-treatment.Conclusions ● In NSTE-ACS patients managed invasively within 48 hours of admission.

Thank  you  to  all  inves=gators  in  19   countries.  at  171  Centers   .

Slides available at www.action-coeur.org .