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

Coordinating Center: ACTION Study Group - Institute of Cardiology Piti-Salptrire University Hospital, Paris, FranceSponsors: Daiichi-Sankyo Company, Ltd. and Eli Lilly and CompanyGlobal Trial Operations: ICON Clinical Research and Quintiles (site management), Inventiv (data management and statistical services), Tata Consultancy Services (statistical programming)External Academic Statistical Center : ACTION Study Group Executive Committee: G Montalescot (Chairman), L Bolognese, D Dudek, P Goldstein, C Hamm, JF Tanguay, J ten Berg, P WidimskyEndpoint Adjudication Committee: M Flather (Chairman), A Bardaj, A Baumbach, M Dalby, A Kapur, F Philippe, P Sabouret, AF van den Heuvel, A ZamanData Safety Monitoring Board: M Bertrand (Chairman), C Di Mario, E Vicaut

Trial conduct

Enrollment: >4,000 patients in 19 Countries

Latvia: 5

Early Enrollment CompletionThe DSMB after the last scheduled meeting (Nov 2012) recommended to stop enrollment, pretreatment being associated with an increased risk of major bleeding with no reduction in CV events (but no between-group imbalance in mortality)

Investigators and Regulatory agencies were immediately notified the enrollment to the ACCOAST study was stopped.

Follow-up of patients continued. The PI and ACCOAST study team remained blinded until the datalock.

Sample size calculation: 400 patients with a 1 EP event (approximately 4100 patients needed) End of study: 398 patients had an event (4033 patients enrolled)

P2Y12 Pre-treatment ESC Recommendations

TitleCitationClassLOE2011 ESC guidelines for the management of acute coronary syndromes in patients presentingwithout persistent ST-segment elevationEuropean Heart Journal 2011;32:29993054A P2Y12 inhibitor as soon as possibleClopidogrel 600mgTicagrelorI

IIA

BB

2010 ESC/EACTS guidelines on myocardial revascularizationEuropean Heart Journal 2010;31:20:25012555 Clopidogrel 600mg as soon as possible

IC

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, to pre-treatment with clopidogrel, prasugrel or ticagrelor vs. no pre-treatment.

ACCOAST designPrasugrel 30 mgPrasugrel 60 mg Prasugrel 30 mg Prasugrel 10 mg or 5 mg (based on weight and age) for 30 daysPCI1 Endpoint: CV Death, MI, Stroke, Urg Revasc, GP IIb/IIIa bailout, at 7 days

Placebo

CoronaryAngiographyn~4100 (event driven)CoronaryAngiographyPCICABG orMedicalManagement(no prasugrel) CABG orMedicalManagement(no more prasugrel)Montalescot G et al. Am Heart J 2011;161:650-656Randomize 1:1Double-blindNSTEMI + Troponin 1.5 times ULN local lab valueClopidogrel naive or on long term clopidogrel 75 mg

Main Inclusion/Exclusion CriteriaInclusionNSTEMI 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

ExclusionSTEMI patientsMedical history contraindicating therapy with prasugrel History of stroke or transient ischemic attack (TIA)LD of any P2Y12 antagonist 7days of study entry

Montalescot G et al. Am Heart J 2011;161:650-656

Patient DispositionPre-treatmentN=2037 Lost to Follow-up 1 (0.05)ITT and All TreatedTotal RandomizedDay 30 Visit N=1958 (96.1%)Day 7N=2009 (98.6%)No Pre-treatmentN=1996Lost to Follow-up 2 (0.10)Day 30 VisitN=1924 (96.4%) Day 7N=1964 (98.4%)

Baseline Characteristics

CharacteristicsPre-treatment(N =2037)No Pre-treatment(N =1996)Age (mean, yrs)6464Female sex (%)2728.0Weight (mean, kg)8282BMI 30 (%)2928CV risk factors (%) Diabetes mellitus2020 Dyslipidemia4545 Hypertension6361 Current smoker3433Region of enrolment (%) Eastern Europe/Israel4242 Western Europe/Canada5858

Baseline Characteristics

CharacteristicsPre-treatment(N =2037)No Pre-treatment(N =1996)GRACE score (%)

Days From First Dose051015202530Endpoint (%)051015199620371788182117751809176918021762179717521791CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout 16211616No. at Risk, PrimaryEfficacy End Point:No pre-treatmentPre-treatment1 Efficacy End Point @ 7 + 30 days (All Patients)

1 Efficacy Endpoint Through 7 Days for Prespecified Subgroups (All Patients)*Hazard ratio not evaluated for

All TIMI (CABG or non-CABG) Major Bleeding (All Treated patients)Days From First Dose051015202530Endpoint (%)012345All TIMI Major Bleeding19962037194719721328133912971310128812991284129712631280No. at Risk, All TIMI Major Bleeding:No pre-treatmentPre-treatment

*Hazard ratio not evaluated for

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

Thank you to all investigators in 19 countries, at 171 Centers

***See page 2538 of 2010 ESC/EACTS guidelines on myocardial revascularizationSee page 2587 of 2011 ACCF/AHA/SCAI guideline forpercutaneous coronaryintervention[source: page 3018 Hamm et al Eur Heart J 2011;32(23):2999-3054. ][source: page 665-666 Jneid et al J Am Coll Cardiol 2012;60(7):645-81. ]

****tobacco, hypertension, hypercholesterolemia, brachial, prasugrel MD - removed

*tobacco, hypertension, hypercholesterolemia, prior clopi treatment, brachial, prasugrel MD *