Prasugrel Compared to Clopidogrel in Patients with Acute Coronary Syndromes Undergoing PCI with Stenting: the TRITON - TIMI 38 Stent Analysis Stephen D. Wiviott, Elliott M. Antman, Ivan Horvath, Matyas Keltai, Jean- Paul R. Herrman, Frans van de Werf, William Downey, Benjamin M. Scirica, Sabina A. Murphy, Carolyn H. McCabe, Eugene Braunwald SCAI – ACCi Chicago, Illinois Disclosure Statement: The TRITON-TIMI 38 trial was supported by a research grant to the Brigham and Women’s Hospital from Daiichi Sankyo Co. Ltd and Eli Lilly & Co. STENT ANALYSIS

Main Trial Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoint: Stent Thrombosis Safety endpoints: TIMI major bleeds, Life-threatening bleeds Duration of therapy: 6-15 months N= 13,608 Wiviott SD, Antman EM et al AHJ 2006 STENT ANALYSIS

Trial Organization Trial Leadership: TIMI Study Group Eugene Braunwald,Chairman, Elliott M. Antman, PI, Carolyn H. McCabe, Director, Stephen D. Wiviott, Gilles Montalescot, Sabina A. Murphy, Susan McHale Sponsors: Daiichi Sankyo and Eli Lilly J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra J. Anthony Ware, Jeffrey Riesmeyer, William Macias, James Croaning, Govinda Weerakkody, Francis Plat, Tomas Bocanegra Data Center and Site Management: Quintiles Inc Data Safety Monitoring Board David Williams (Chair), Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets David Williams (Chair), Christophe Bode, Spencer King, Ulrich Sigwart, David DeMets STENT ANALYSIS

HR 0.81 ( ) P= Prasugrel Clopidogrel Days Endpoint (%) HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel Main Trial: Primary Results CV Death / MI / Stroke TIMI Major NonCABG Bleeds Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

Goals of Stent Analysis To compare the efficacy and safety of PRASUGREL and CLOPIDOGREL in 12,844 patients with at least one stent as part of the index procedure with respect to: Stent Thrombosis (ARC definitions) Ischemic Events, Bleeding Overall and stratified by stent type received STENT ANALYSIS

Patient Population Randomized 13,608 Stent Placed 12,844 (94%) STENT ANALYSIS BMS Only 6461 (47%) DES Only 5743 (42%) Both BMS/DES 640 (5%) PES Only 2766 (20%) SES Only 2454 (18%) Other/Mixed 523 (4%)

Any Stent (N=12844) 94 % UA/NSTEMI75 STEMI25 Age, median (IQR) > 75 y 60 (53,69) y 13 Female26 Diabetes23 Smoker38 North America32 Prior MI17 CrCl (ml/min) >60 < Baseline Characteristics STENT ANALYSIS

Key Efficacy, Safety EP: Stratified by Stent Type CVD/MI/CVANon-CABG TIMI Major Bleeding STENT ANALYSIS HR 0.80 ( ) p=0.003 HR 0.82 ( ) p=0.02 HR 1.37 ( ) p=0.09 HR 1.19 ( ) p=0.34 N=6461 N=5743 CLOPIDOGREL PRASUGREL % of Subjects

ARC ST Definitions Blinded CEC review of using source documents incl imaging reports: Definite: total occlusion w/in or < 5 mm of the stent or thrombus w/in or< 5 mm of the stent AND a clinical syndrome <48 h. Probable: unexplained death < 30 days or MI in stented territory w/o angiographic confirmation ST AND w/o alternative cause Possible: unexplained death > 30 days following stenting Early: 0 – 30 days after randomization Late > 30 days after randomization (landmark analysis) Based on ARC Definitions Mauri L et al NEJM 2007 STENT ANALYSIS

Death Following ST Mortality During Follow up (%) Post-Stent Thrombosis STENT ANALYSIS N=210N=12634 HR 13.1 (9.8 – 17.5) P< % of Subjects

Definite/Probable ST: Any Stent (N=12844) % of Subjects HR 0.48 [ ] P< year: 1.06 vs 2.15% HR 0.48 [ ], P< % 1.13% 52% STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL

Definite/Probable ST: Any Stent (N=12844) % of Subjects HR 0.41 [ ] P< HR 0.60 [ ] P=0.03 DAYS EARLY STLATE ST STENT ANALYSIS 1.56% 0.64% 59% 0.82% 0.49% 40% CLOPIDOGREL PRASUGREL

Stent Thrombosis By ARC Category (N=12844) STENT ANALYSIS DEF/PROB HR 0.48 ( ) P< DEFINITE HR 0.42 ( ) P< DEF/PROB/POSS HR 0.56 ( ) P< CLOPIDOGREL PRASUGREL % of Subjects

Stent Thrombosis Subgroups STENT ANALYSIS PRASUGREL BETTER CLOPIDOGREL BETTER PRASCLOPRISK (%) % % % % % % % % % % % % % % % % % %

Definite/Probable ST: DES Only (N=5743) % of Subjects HR 0.36 [ ] P< year: 0.74% vs 2.05% HR 0.35 [ ], P< % 0.84% 64% STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL

Definite/Probable ST: DES Only (N=5743) % of Subjects HR 0.29 [ ] P= HR 0.46 [ ] P=0.04 DAYS STENT ANALYSIS EARLY STLATE ST 1.44% 0.42% 71% 0.91% 0.42% 54% CLOPIDOGREL PRASUGREL

Stent Thrombosis DES Subtypes Trial Duration STENT ANALYSIS N=2454 N=2766 Sirolimus Only HR 0.33 ( ) p=0.004 Paclitaxel Only HR 0.33 ( ) p=0.002 CLOPIDOGREL PRASUGREL 67% % of Subjects

2.41% 1.27% Definite/Probable ST: BMS Only (N=6461) % of Subjects HR 0.52 [ ] P= year: 1.22 vs 2.27% HR 0.53 [ ], P= % STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL

Definite/Probable ST: BMS Only (N=6461) % of Subjects HR 0.45 [ ] P= HR 0.68 [ ] P=0.24 DAYS STENT ANALYSIS EARLY STLATE ST 1.66% 0.75% 55% 0.78% 0.53% 32% CLOPIDOGREL PRASUGREL

Summary Intensive antiplatelet therapy with PRASUGREL in stented patients compared to CLOPIDOGREL: Substantial reduction in ST: Regardless of stent type or ST definition Early and Late A broad range of clinical/procedural characteristics Fewer ischemic events, more major bleeding STENT ANALYSIS

Balance of Efficacy and Safety (Stented Population) STENT ANALYSIS Stent Thrombosis CVD/MI/CVA w/o ST Events per 1000 patients treated

Conclusions/Implications Stent Thrombosis is a rare, but devastating complication of PCI associated with a high mortality. Efforts to reduce ST have focused on compliance w/ and duration of ASA/clopidogrel Our data indicate that an agent w/ more rapid, consistent, and greater inhibition of platelet aggregation (prasugrel) results in major reductions (~50%) in ST across a broad array of clinical procedural characteristics STENT ANALYSIS

STENT ANALYSIS

Clinical Endpoints Net Clinical Benefit STENT ANALYSIS HR 0.88 ( ) p=0.07 HR 0.86 ( ) p=0.002 HR 0.84 ( ) p=0.025 N=12844 N=6461 N=5743 % of Subjects

Primary EP (D/MI/CVA) Not Related to ST % of Subjects 10.3% 8.7% 15% HR 0.85, P=0.005 STENT ANALYSIS DAYS CLOPIDOGREL PRASUGREL

Key Efficacy, Safety EP: Stratified by Stent Type CVD/MI/CVAMajor Bleeding STENT ANALYSIS HR 0.80 ( ) p=0.003 HR 0.81 ( ) p= HR 0.82 ( ) p=0.02 HR 1.37 ( ) p=0.09 HR 1.27 ( ) p=0.06 HR 1.19 ( ) p=0.34 N=12844 N=6461 N=5743 CLOPIDOGREL PRASUGREL