On behalf of the TRILOGY ACS Investigators Prasugrel versus clopidogrel for patients with UA/NSTEMI medically managed after angiographic triage — Results from the TRILOGY ACS Trial   Stephen D. Wiviott, MD, Harvey D. White, MB, ChB, DSc, E. Magnus Ohman, MB, ChB, Keith A. A. Fox, MB, ChB, Paul W. Armstrong, MD, Dorairaj Prabhakaran, MD, DM, MSc, Gail Hafley, MS, William E. Boden, MD, Christian Hamm, MD, Peter Clemmensen, MD, DMSc, Jose C. Nicolau, MD, PhD, Alberto Menozzi, MD, PhD, Witold Ruzyllo, MD, Petr Widimsky, MD, DSc, Ali Oto, MD, Jose Leiva-Pons, MD, Gregory Pavlides, MD, Matthew T. Roe, MD, MHS, and Deepak L. Bhatt, MD, MPH On behalf of the TRILOGY ACS Investigators www.clinicaltrials.gov Identifier: NCT00699998

Authors and Disclosures* The TRILOGY ACS Trial was funded by Eli Lilly & Company and Daiichi Sankyo. Stephen D. Wiviott—grant/research support from Eli Lilly & Company, AstraZeneca,Merck, Eisai; Consulting fees/honoraria from Eli Lilly & Company, Daiichi Sankyo, AstraZeneca, BMS, Sanofi-Aventis, Eisai. Petr Widimsky—consulting fees/honoraria from Lilly, Ali Raif Ilac Sanayi, Bayer, Daiichi Sankyo, Medtronic, Boehringer Ingelheim, Abbott, AstraZeneca, Sanofi. Deepak L. Bhatt—honoraria and travel expenses from the Duke Clinical Research Institute; serving as a board member for Medscape Cardiology, Boston VA Research Institute, Society of Chest Pain Centers; grant funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, The Medicines Company; payment for developing educational presentations from WebMD; serving on clinical trial steering committees for the Duke Clinical Research Institute; serving as an editor for the American College of Cardiology and chief medical editor for Slack Publications. Gail Hafley and Witold Ruzyllo—nothing to report. *For all other authors, see MT Roe et al, NEJM 2012

Angiography Background The proportion of ACS (UA/NSTEMI) patients worldwide who are managed medically without revascularization (PCI or CABG) is 40–60%. This includes 2 distinct sets of patients: triaged to medical therapy after angiography for whom angiography is not performed Prasugrel, a thienopyridine P2Y12 inhibitor, improved ischemic outcomes in ACS patients undergoing PCI in the TRITON-TIMI 38 trial, with an increase in major bleeding. Wiviott SD et al NEJM 2007 3

Inclusion Criteria (Main Trial) Randomization within 10 days of a UA/NSTEMI event NSTEMI: CK-MB or troponin > ULN UA: ST depression > 1 mm in 2 or more leads Medical management strategy decision determined Angiography not required, but if performed, had to be done before randomization, and evidence of coronary disease in a major vessel (1 lesion > 30% or prior PCI/CABG) At least 1 of 4 enrichment criteria: Age > 60 years Diabetes mellitus Prior MI Prior revascularization (PCI or CABG)

Study Design 9326 patients in 8 regions, 52 countries (Primary: 7243 patients < 75 years old) Medically Managed UA/NSTEMI Patients Clopidogrel1 75 mg MD Prasugrel1 5 or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years) Clopidogrel1 300 mg LD + Prasugrel1 30 mg LD 5 or 10 mg MD Medical Management Decision ≤ 72 hrs (No prior clopidogrel given) — 4% of total Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR on chronic clopidogrel) — 96% of total Median Time to Enrollment = 4.5 Days Source: Q113, Q111, Q331 [Source: Figure 1 on page 19] Reference: Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM; TRILOGY ACS Steering Committee. Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J 2010;160(1):16-22.e1. All patients were on aspirin, and low-dose aspirin (< 100 mg) was strongly recommended. For patients < 60 kg or ≥ 75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1. Roe MT et al NEJM 2012 Pras00045111

Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months (Age < 75 years) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 Endpoint (%) HR (95% CI): 1.31 (0.81, 2.11) P = 0.27 Roe MT et al NEJM 2012

Overall TRILOGY ACS Results: Summary (Age < 75 years) No statistical differences in cardiovascular events or major bleeding Lower risk multiple recurrent ischemic events suggested with prasugrel using the pre-specified Andersen-Gill model (HR = 0.85, 95% CI: 0.72–1.00, P = 0.04) Significant interaction with treatment and time (HR for > 12 mos = 0.64, 95% CI: 0.48–0.86, Interaction P = 0.02) Roe MT et al NEJM 2012

Objectives of TRILOGY-ACS Angiography Sub-Study Within the TRILOGY ACS trial, to: Assess clinical characteristics and outcomes of subjects triaged to medical therapy with or without preceding angiography Assess effects of prasugrel vs. clopidogrel in these two groups and whether there is any differential effect based on how subjects entered the trial

Statistical Considerations: Angiographic Cohort Pre-specified analysis limited to the primary cohort of patients < 75 years of age (N = 7243) Stratified by pre-randomization variable Triaged after angiography: 3085 (43%) Triaged without angiography: 4158 (57%) For angiography vs no angiography comparisons — p-values unadjusted For prasugrel vs clopidogrel — p-value adjusted for clopidogrel stratum 9

Prespecified Analysis of Angiographic Cohort ITT Population N = 9326 Primary Population Age < 75 N = 7243 Triaged after Angiography* N = 3085 (43%) Randomized to Prasugrel N = 1524 Randomized to Clopidogrel N = 1561 Trigaged without Angiography* N = 4158 (57%) N = 2096 N = 2062 Age ≥ 75 N = 2083 *For angiography vs no angiography comparisons — p-values unadjusted, for prasugrel vs clopidogrel — p-value adjusted for clopidogrel stratum

Baseline Characteristics   Age < 75 Years (N = 7243) Angiography (N = 3085) No Angio (N = 4158) P-Value Age—yr 62 (56–68)  63 (57–68) 0.0007 Female sex—% 33.3 37.8 < 0.0001 Body weight < 60 kg—% 8.9 16.0 Disease classification—% NSTEMI 78.7 59.2 Unstable angina 21.3 40.8 Medical history—% Diabetes mellitus 39.3 38.6 0.56 Current/recent smoking 29.3 19.2 Prior myocardial infarction 42.6 45.2 0.03 Prior PCI 33.9 23.7 Prior CABG 21 11.3 Baseline risk assessment GRACE risk score 112 (99–124) 117 (102–131) Creatinine clearance—mL/min 86 (68–109) 77 (59–98)

Regional Differences in Angiography Pre-randomization 995 630 106 527 968 571 1021 2429

Baseline Characteristics: Angiographic Results Notes: 1. Non-obstructive = 30 – <50% stenosis 2. LM disease — 6.2% of subjects

Incidence of Outcomes by Angiography Status (Age < 75 years)

Primary Efficacy Endpoint to 30 Months (Age < 75 years) Angio N=3085 No Angio N=4158 10.7% vs 14.9% P = 0.031 HR (95% CI): 0.77 (0.61, 0.98) 16.3% vs 16.7% P = 0.954 HR (95% CI): 1.01 (0.84, 1.20) P interaction = 0.08

Evaluation of All Ischemic Events over Time* (Age < 75 years) Lower risk of multiple recurrent ischemic events suggested with prasugrel in the angiography group using the pre-specified Andersen-Gill model Angiography No Angiography   Pras Clop ≥ 1 event 137 168 262 261 ≥ 2 events 23 45 59 69 3–7 events 6 10 13 15 HR (CI) 0.75 (0.58–0.98) 0.91 (0.74–1.11) * Pre-specified evaluation of all CV death, MI, or stroke events by treatment P interaction = 0.26

Myocardial Infarction Angio No Angio 7.2% vs 10.3% P = 0.042 HR (95% CI): 0.74 (0.55, 1.00) 9.2% vs 10.6% P = 0.989 HR (95% CI): 1.00 (0.79, 1.26) P interaction = 0.12

Stroke Angio No Angio P interaction = 0.02 0.6% vs 2.4% P = 0.004 HR (95% CI): 0.30 (0.13,0.71) 2.2% vs 2.0% P = 0.933 HR (95% CI): 1.03 (0.58,1.83) P interaction = 0.02

CV Death Angio No Angio P interaction = 0.90 4.2% vs 5.2% P = 0.626 HR (95% CI): 0.91 (0.61,1.34) 8.4% vs 7.9% P = 0.569 HR (95% CI): 0.93 (0.73,1.20) P interaction = 0.90

CV Death Angio No Angio All-Cause Death P interaction = 0.85 Angio: HR (95% CI): 0.98 (0.69,1.38) No Angio: HR (95% CI): 0.94 (0.75,1.18) All-Cause Death 4.2% vs 5.2% P = 0.626 HR (95% CI): 0.91 (0.61,1.34) 8.4% vs 7.9% P = 0.569 HR (95% CI): 0.93 (0.73,1.20) P interaction = 0.90

TIMI Major Bleeding Angio No Angio P interaction = 0.16 2.7% vs 1.4% P = 0.074 HR (95% CI): 1.84 (0.93, 3.63) 1.6% vs 1.5% P = 0.851 HR (95% CI): 0.92 (0.47, 1.83) P interaction = 0.16

TIMI Major or Minor Bleeding TIMI Major Bleeding Angio No Angio P interaction = 0.65 Angio: HR (95% CI): 1.68 (1.00, 2.83) No Angio: HR (95% CI): 1.42 (0.83, 2.41) TIMI Major or Minor Bleeding 2.7% vs 1.4% P = 0.074 HR (95% CI): 1.84 (0.93, 3.63) 1.6% vs 1.5% P = 0.851 HR (95% CI): 0.92 (0.47, 1.83) P interaction = 0.16

Limitations Reason for pursuing strategy not fully known: Angiography Medical therapy Cannot make direct comparisons between angiography and no angiography and infer causality Subgroup analysis of a neutral trial Prespecified Pre-randomization variable Large sample size Interaction testing is underpowered

Conclusions Substantial differences in baseline characteristics exist among patients triaged for medical therapy with or without angiography from TRILOGY-ACS. Geographically, subjects from North America, Western Europe, Australasia, South Africa, and the Mediterranean region had higher rates of angiography pre-randomization Patients with angiography more often were enrolled with NSTEMI, and had prior history or PCI or CABG Patients with angiography had lower composite endpoint event (CV death, MI, or stroke), particularly CV death. 24

Conclusions Overall, in the TRILOGY ACS Trial prasugrel did not reduce cardiovascular events among patients managed medically for ACS. When treated with prasugrel compared to clopidogrel, patients triaged to medical therapy following angiography tended to have: Lower rates of the combined endpoint of CVD/MI/CVA Lower rates of MI, CVA alone, and recurrent ischemic events A trend to higher rates of TIMI major bleeding. Though hypothesis generating, these results are consistent with previous trials and suggest that when angiography is performed and coronary disease is confirmed, the benefits and risks of intensive antiplatelet therapy exist whether medical therapy or PCI is elected. 25