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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

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

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 .Enrollment: >4.

Background .

N Engl J Med 2001. et al. JAMA 2002.CURE Efficacy CREDO Efficacy CURE Safety* CREDO Safety** Yusuf S. et al.288:2411-2420 .345:494-502 Steinhubl SR.

32:2999–3054 2010 ESC/EACTS guidelines on myocardial revascularization European Heart Journal 2010.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 .

  Dorler  et  al. JAMA 2012.261 OR=0·∙68  CI  95%  [0·∙42-­‐1·∙09]  P=0·∙11   Pre-treatment better 0 No Pre-treatment better 0.5 2 2.  Clopidogrel   Pretreatment   No  Pretreat   ARMYDA5  Preload   CIPAMI   CLARITY  PCI   CREDO   PCI  CURE   Davlouros  et  al.945 OR=1·∙04  CI  95%  [0·∙74-­‐1·∙46]  P=0·∙83   Observa2onal   Amin  et  al.5 1 1.   Feldman  et  al.5 3 3.   All   N=18.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.   Chan  et  al.   PRAGUE  8   All   N=8.   Szuk  et  al.   Fefer  et  al.308:2507-2516 .5 4 Bellemain-Appaix A 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.

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

Study Design .

ACCOAST design NSTEMI + Troponin ≥ 1. MI. Urg Revasc. Am Heart J 2011.5 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. at 7 days Montalescot G et al. GP IIb/IIIa bailout.161:650-656 . Stroke.

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.161:650-656 .Main Inclusion/Exclusion Criteria Inclusion ●  NSTEMI symptoms within 48 hours prior to study entry ●  Elevated troponin (≥1. Am Heart J 2011.

10) .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 (98.05) Lost  to  Follow-­‐up  2  (0.4%) Lost  to  Follow-­‐up  1  (0.

Baseline Characteristics Characteristics   Age (mean. yrs)   Female sex (%)   Weight (mean.0   82   28     20   45   61   33     42   58   . 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.

median à 1st LD to coronary angiogram.4 15.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 .6 4.2 57 43 57 43 Timing (hr) àSymptom onset to 1st LD.2 4.

Results .

No Pre-treatment=Placebo/Prasugrel 60 mg 4 24 .Pharmacodynamic Sub-Study 350 Placebo LD1 Pre-treatment (30/30) No Pre-treatment (0/60) 60 mg LD2 *P<0. LD = loading dose. Pretreatment=Prasugrel 30 mg/Prasugrel 30 mg.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. * p<0.5 1 2 3 Hours (post LD2) Data presented as median ± SEM.05 relative to the No pre-treatment group.

1° Efficacy End Point @ 7 + 30 days (All Patients) 15 CV Death.8 No Pre-treatment 9.84. Stroke. 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 . MI. UR.0 10 No Pre-treatment 10.02 (95% 0. 1. 0. GPIIb/IIIa Bailout Pre-treatment 10.8 Endpoint (%) Pre-treatment 10. 1.8 5 Hazard Ratio.98 0 0 No.83.81 Hazard Ratio.20) P=0.997 (95% 0. 1.25) P=0. at Risk.

1 10 Pre-treatment 14.8 No Pre-treatment 13. 1.01 (95% 0. Stroke. at Risk. MI. 1.1 CV Death.1 HR. GPIIb/IIIa Bailout PCI Cohort No Pre-treatment 13. 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 .84. 1.03 (95% 0.77 HR. UR.24) P=0.93 5 0 0 No.82.1° Efficacy Endpoint (PCI Patients) 20 Endpoint (%) 15 Pre-treatment 13.26) P=0. 1.

47) 0.93 1.09) 0.77) 1.68) 0.21) 0.21) 9 (7.14) 157 (9.60) 132 (11.75) 111 (9. 2.70) 0.07) 82 (8.03) 1.88 (0.08 (0.25) 1.97) 13 (10.72.25) PCI CABG Medical Management 2781 238 1014 185 (13.76 (0.80) 195 (10.73) 143 (9.45 2923 1110 152 (10.82 (0.82) 192 (9.67.20) 1.67) 37 (9.87. 1.02) 109 (10.05 (0.78.24) 0.65) 0.23) 1. 1.91 (0. 1.97 (0.86) 1.97) 195 (9. 1.03 (0.93) 0.54 205 3824 7 (6.79.82) 90 (8.92) 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 0.77) 83 (9. 1.94) 1.43) 1.67) 63 (7.02 (0.03 (0.96) 76 (8.26) 0.03.22.91) 105 (10.86) 86 (8.30 232 3801 11 (9.79. 1.83.24) 149 (10.20) 0.53) 162 (9.14 (0.37) 0.43) 0.02 (0.31) Overall (pre-treatment vs. 1. PCI includes 11 patients with PCI + CABG. 2.57.76.24) 47 (11.13 (0.23) 0.24) 1.2 0. 1.01) 1.86.79) 1.77) 1.76) 183 (9.75) 1.81. 4. 1.05) 44 (9. subgroup.83) 182 (9. 1.01 (0. 1.81.56 (0.11) 8 (6.20 820 3213 46 (11.99 (0.46) 0.44) 9 (1. 1.09 (0.76 1990 2008 84 (8. †Interaction p-value is from a Cox proportional hazards model with treatment.84.42.52.24) 51 (9.36 (1.88.30 3079 852 154 (10.62) 43 (11.55.76.79) 33 (9. and the treatment-by-subgroup interaction as fixed effects.87.24 2276 1711 125 (10.84) 6 (1.5 Pre-treatment better 1 2 5 No pre-treatment better *Hazard ratio not evaluated for <10 events. 1. 1.21 1692 2341 66 (7. 1.91 (0. 1.25 (0.24) 0.004 1998 2003 120 (12.84.14 (0. 1.99 (0.88) 0.74) 181 (13.24) 119 (11.45 (0. 1.1° 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. 1.1 0.09) 158 (9. 1.65) 137 (11.70) 0.36) 46 (8.64. Interaction P-value† 1.41.54 <75 years >75 years 3318 715 160 (9.20 (0.78) 0.09) 12 (11.31) . 1.28) 0.

6 2 All TIMI Major Bleeding 1 No Pre-treatment 1.26.19.08) P=0. 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 . 3.002 Endpoint (%) 4 Pre-treatment 2.4 0 No. 1.02) P=0.006 Hazard Ratio. 3.All TIMI (CABG or non-CABG) Major Bleeding (All Treated patients) 5 Hazard Ratio.90 (95% 1.5 0 No Pre-treatment 1.97 (95% 1.9 3 Pre-treatment 2. 1. at Risk.

5 0 N= 27 9 Non-CABG TIMI Major Bleeding 0.TIMI.2 20 4 GUSTO Severe or Life Threatening Non-CABG Bleeding 46 18 STEEPLE Non-CABG Major .3 P=0.3 2 P=0.001 1.9 0.001 2.0 0. GUSTO. STEEPLE Bleeding Endpoints Through 7 Days (All Treated Patients) Event Rate (%) 6 Pre-treatment (N=2037) No Pre-treatment (N=1996) 4 P<0.003 1.

23.4 Pre-treatment 1.All TIMI Major Bleeding (PCI Patients) 5 Endpoint (%) 4 3 HR. 2.7 0 0 No. 6.7 1 No Pre-treatment 0.70) P=0.5 No Pre-treatment 0.010 2 Pre-treatment 1. 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 .13.02 All TIMI Major Bleeding PCI Cohort HR.40) P=0. at Risk. 2. 5.65 (95% 1.69 (95% 1.

54) 18 (1.68) 5 (0.05) 2.71) 2.49) 3.89) 2.74 (1. PCI includes 11 patients with PCI + CABG.08) 1.20) 15 (1.09) 21 (3.54 (0.85) 47 (2.90 (1.19.91) 2.69 (0.31 2923 1110 31 (2.08. 3. 2.29. 4.94) 0.All TIMI Major Bleeding for Prespecified Subgroups Through 7 days (All Treated Patients) Total Patients Pre-tx (%) No Pre-tx (%) Overall (pre-treatment vs.09. 6.28) 0.71) 1.96.12) 0.75) 24 (2.83.87 2276 1711 29 (2.60) 22 (1.46.2 0.61 (1.00) 0.35) 1.86) 9 (0.98 (0.53) 18 (1.89) 1. 2.67 (1.76 (0.09.75. 2.22 1990 2008 28 (2.53) 2.19.87) 0.62 (0.16.16) 8 (2.23 1998 2003 27 (2. and the treatment-by-subgroup interaction as fixed effects. 3. ‡CRUSADE score is a post-hoc analysis. †Interaction p-value is from a Cox proportional hazards model with treatment.29 (1.09 205 3824 5 (4. 3.66) 16 (13.05) 0.95 (1.98 (0.09) 1.72) 24 (2.78 (1.41) 1. 3.02) PCI CABG Medical Management* 2781 238 1014 22 (1.78) 2.37) NE 1.43) 1 (0.00) 1.80) 21 (1.74 <75 years >75 years 3318 715 36 (2.59 (0.95) 1. 4.66 1692 2341 14 (1.47) 21 (1.82.46 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 0.50 (0.98) NE 0.45) 46 (2.5 Pre-treatment better 1 2 5 10 15 No pre-treatment better *Hazard ratio not evaluated for <10 events.32.81) 15 (1.97) 0 (0.29) 22 (1.95) 0.00) 1.75 (0. 4.46) 1.97) 10 (0.98) 26 (1. 2.24) 5 (0.22) 16 (3.96.55) 27 (1.35) 12 (1.16 (1. . 2.62) 0.51) 1.81. 8.80) 25 (20.10.80) 0.32) 0.62) 38 (3.43 (0.41 2051 1789 23 (2. no pre-treatment) Age Sex Hazard Ratio Interaction (95% CI) P-value† 4033 52 (2.16) 16 (4. 2.85.93.83) 6 (1. subgroup. 3.64 (0.03. 8. 7.35 820 3213 6 (1.28 (1.23) 27 (2. 2.46) 6 (1.98) 2.40) 18 (1.93) 0.90.47) 1.54) 22 (2. 5.57) 11 (0.59 3079 852 34 (2.33) 5 (1.25.70 (1. 4.58) 8 (0.97.92 (1. 2.

05 0 0.002 1.45 0.003 1.5 Pre-treatment (N=2037) Most Frequent Locations of Major Bleed No Pre-treatment (N=1996) 2.Non-CABG TIMI Major Bleeding Endpoints Through 7 Days (All Treated Patients) 3.5 1.83 P not evaluable 0.5 0.0 N= 27 9 Non-CABG TIMI Major Bleeding 1 0 Fatal Bleeding 17 3 Life Threatening Bleeding .0 Event Rate (%) 2.33 P=0.0 0.15 0.0 P=0.

Conclusions .

● No subgroup appears to have a favorable risk/benefit ratio of pre-treatment. . ● Reappraisal of routine pre-treatment strategies in NSTEACS is needed.Conclusions ● In NSTE-ACS patients managed invasively within 48 hours of admission. ● 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.

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

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