TITAN Time to Integrilin Therapy in Acute myocardial infarctioN (TITAN)-TIMI 34

TITAN-TIMI 34: Goal To answer the following question: Among patients intended to undergo primary PCI, does a strategy of early initiation of eptifibatide in the ER prior to primary PCI yield superior pre-PCI angiographic outcomes compared to a strategy of initiating eptifibatide in the cardiac catheterization laboratory after diagnostic angiography? © TIMI Duplication prohibited by law

TITAN-TIMI 34: Trial Organization TIMI Study GroupEugene Braunwald, M.D. (Chairman) Brigham and Women’sC. Michael Gibson, M.S., M.D. (Principal Investigator) HospitalCarolyn McCabe, B.S. (Director) Ajay Kirtane, M.D. (Co-Investigator) Christopher P. Cannon, M.D. (Co-Investigator) Polly Fish, B.S. (Project Manager) Data Coordinating Center TIMI Data Coordinating Center Sabina A. Murphy, M.P.H. (Director Biostatistics) Jacqueline L. Buros, B.A. (Director Data Management) Angiographic Core LabTIMI Angiographic Core Lab Ajay Kirtane, M.D. (Principal Investigator) Lauren N. Ciaglo, B.A. EKG Core LabTIMI EKG Core Lab Benjamin Scirica, M.D. (Director) © TIMI Duplication prohibited by law

Primary PCI STEMI < 6 HRS Undergoing Primary PCI (n=343) TITAN TIMI 34: Study Design RANDOMIZE Open Label RANDOMIZE ASA mg po HEPARIN 60 U/kg bolus (Max 4000U) and 7U/kg infusion (Max 800 U/hr) “EARLY ER EPTIFIBATIDE” “CATH LAB EPTIFIBATIDE” EPTIFIBATIDE 180/2.0/180 TRANSFER TO CATH LAB DIAGNOSTIC ANGIO PRIMARY ENDPOINT: Pre PCI TIMI Frame Count EPTIFIBATIDE 180/2.0/180 TRANSFER TO CATH LAB DIAGNOSTIC ANGIO © TIMI Duplication prohibited by law

TITAN-TIMI 34: Enrollment Criteria Inclusion Criteria: > 18 years of age Clinical diagnosis of AMI ( ischemic pain > 20 min. ) Onset of symptoms < 6 hours ST elevation > 1 mm in 2 contiguous limb leads or >2 mm in 2 contiguous precordial leads Major Exclusion Criteria: Hemorrhagic risk factors Current episode previously treated by fibrinolytics Cardiogenic shock or hemodynamically significant arrhythmias Inclusion Criteria: > 18 years of age Clinical diagnosis of AMI ( ischemic pain > 20 min. ) Onset of symptoms < 6 hours ST elevation > 1 mm in 2 contiguous limb leads or >2 mm in 2 contiguous precordial leads Major Exclusion Criteria: Hemorrhagic risk factors Current episode previously treated by fibrinolytics Cardiogenic shock or hemodynamically significant arrhythmias © TIMI Duplication prohibited by law

LAD Frame 1: Dye Touches Both Borders & Moves Forward Frame 0: Dye Touches One or No Borders Last Frame Definition Frame 21: Dye first enters landmark First Frame Definition RCA LCX Distal Landmark Normal Flow in the Absence of MI : frames 1st branch off posterolateral 1st branch off posterolateral Last branch off most distal OM Last branch off most distal OM “Whale’s tail” or “pitchfork” or most distal branch LAD at apex “Whale’s tail” or “pitchfork” or most distal branch LAD at apex Gibson, Circulation 1996; 93: TITAN: Primary Endpoint Corrected TIMI Frame Count © TIMI Duplication prohibited by law

6.2% 4.4% 2.0% n = 203 n = 46 n = 434 TMP Grade 3 p = 0.05 Mortality (%) n = % Gibson et al, Circulation 2000 Normal ground glass appearance of blush Dye mildly persistent at end of washout Normal ground glass appearance of blush Dye mildly persistent at end of washout Dye strongly persistent at end of washout Gone by next injection Dye strongly persistent at end of washout Gone by next injection Stain present Blush persists on next injection Stain present Blush persists on next injection No or minimal blush TMP Grade 2 TMP Grade 1 TMP Grade 0 TITAN Other Angiographic Efficacy Endpoint: TIMI Myocardial Perfusion (TMP) Grades © TIMI Duplication prohibited by law

TITAN-TIMI 34: Angiographic Perfusion Score Integrates epicardial and myocardial perfusion Integrates epicardial and myocardial perfusion Integrates flow before and after PCI Integrates flow before and after PCI Sum of the following: Sum of the following: TIMI Flow Grade Before PCI (0-3) TIMI Myocardial Perfusion Grade Before PCI (0-3) TIMI Flow Grade After PCI (0-3) TIMI Myocardial Perfusion Grade After PCI (0-3) Integrates epicardial and myocardial perfusion Integrates epicardial and myocardial perfusion Integrates flow before and after PCI Integrates flow before and after PCI Sum of the following: Sum of the following: TIMI Flow Grade Before PCI (0-3) TIMI Myocardial Perfusion Grade Before PCI (0-3) TIMI Flow Grade After PCI (0-3) TIMI Myocardial Perfusion Grade After PCI (0-3) Total Angiographic Perfusion Score: Gibson CM. Am Heart J Aug;148(2): Failed 0-3; Partial 4-9; Full © TIMI Duplication prohibited by law

Relationship of Angiographic Perfusion Score to SPECT Infarct Size & Mortality © TIMI Duplication prohibited by law % SPECT Infarct Size Angiographic Perfusion Score 35.5% 16.2% 12.5% p= % 1.9% 0.0% p=0.01 % Death by 30 days Gibson CM. Am Heart J Aug;148(2):

Global Perfusion Score Methodology Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Total Potential Score: 54 points © TIMI Duplication prohibited by law

TITAN-TIMI 34: Top 10 Enrolling Sites Site Name Principal Investigator Research Coordinator Enrollment1 Mount Clemens General Hospital Samer Kazziha Rebecca Richmond 37 2 Carolina Cardiology Associates, PA Steve Rohrbeck Tammy Hedrick 32 3 University of North Carolina Mauricio Cohen Kim Wood 31 4 Northridge Hospital Ivan Rokos Kanchana Karunaratne 30 5 Tri-State Medical Group, Cardiology Jeffrey Lins Gretchen Kalenak 27 6 Genesis Medical Center Nicolas Shammas Caroline Sloane 20 7 St. Joseph's Regional Medical Center Mahesh Bikkina Karen Turnbull 16 8 University Of Cincinnati Saeb Khoury Cindy Werner 15 9 Brigham and Women's Hospital Daniel Simon Rachel Monbouquette Genesis Healthcare System Abdulhay Albirini Terri Campbell 14 © TIMI Duplication prohibited by law

TITAN-TIMI 34: Top Enrolling Sites Site Name Principal Investigator Research Coordinator Enrollment11 Trinity Medical Center Aswartha Pothula Cynthia Antonio Vanderbilt University Medical Center David Zhao Dawn Myers Cardiology Associates of Mississippi Barry Bertolet Kelly Glenn MedCentral Mansfield Greg Eaton Kathy Jurden 9 15 University Hospitals of Cleveland Tom Lassar Stacey Mazzurco 9 16 Decatur Memorial Hospital Peter Katsiyiannis Rebecka Songer 7 17 West Chester Cardiology Mian Jan Cindy Brockway 7 18 Seattle Cardiovascular Research Thomas Amidon Lynn Royal 6 19 Veterans Affairs Medical Center (111C2) Saeb Khoury Jackie Edwards 5 20 Northeast Cardiology Associates Peter Ver Lee Cindy Whited 5 © TIMI Duplication prohibited by law

TITAN-TIMI 34: Baseline Characteristics © TIMI Duplication prohibited by law Characteristic ER Eptifibatide n=174 Cath Lab Eptifibatide n=142 P value Age (yrs+SD) / yrs / yrs NS Male74.7%73.2%NS Hypertension42.2%40.9%NS Hyperlipidemia32.2%31.2%NS Current smoker 49.4%40.1%NS Diabetes15.5%18.3%NS Prior MI 14.9%10.6%NS Anterior MI 35.2%39.6%NS

TITAN-TIMI 34 Primary Endpoint: Pre-PCI TIMI Frame Count © TIMI Duplication prohibited by law p < 0.05 p=0.046 adjusting for infarct location Primary Analysis: Modified Intent-to-Treat Frame Count EREptifibatide Cath Lab Eptifibatide CTFC p < (n=137) (n=168) EREptifibatide Cath Lab Eptifibatide

© TIMI Duplication prohibited by law Pre - PCI TMPG 3 (%) EREptifibatide Cath Lab Eptifibatide 24.3% 14.2% p = (41/169)(20/141) p=0.025 adjusting for infarct location Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34: Secondary Angiographic Endpoint TIMI Flow Grades Pre - PCI TIMI 2 or 3 Flow (%) EREptifibatide Cath Lab Eptifibatide 46.2% 36.6% (79/171)(52/142) TIMI 2 or 3 p = % 19% p=NS TIMI 3

TITAN-TIMI 34: Pre-PCI Flow Throughout Heart © TIMI Duplication prohibited by law Primary Analysis: Modified Intent-to-Treat EREptifibatide Cath Lab Eptifibatide Global Perfusion Score n=125 n=99 p = p = 0.03 EREptifibatide Cath Lab Eptifibatide Global Frame Count (Ave. 3 Arteries)

© TIMI Duplication prohibited by law Pre - PCI MLD (mm) EREptifibatide Cath Lab Eptifibatide p = (n=169)(n=138) Pre - PCI % Stenosis EREptifibatide Cath Lab Eptifibatide 87.5% 91.0% p = (n=169)(n=139) Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34 Pre-PCI Quantitative Angiography

© TIMI Duplication prohibited by law Post - PCI CTFC EREptifibatide Cath Lab Eptifibatide p = 0.14 Post - PCI TIMI 3 Flow (%) EREptifibatide Cath Lab Eptifibatide 86.7% 89.1% p = NS Post - PCI TMPG 3 (%) EREptifibatide Cath Lab Eptifibatide 37.0% 36.7% p = NS (47/128)(57/154) (n=138) (n=116) (137/158) (122/137) Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34 Post-PCI Flow

TITAN-TIMI 34: Full Angiographic Perfusion © TIMI Duplication prohibited by law Full Angiographic Perfusion (APS 10-12) % EREptifibatide Cath Lab Eptifibatide 21.1% 12.5% p = (32/152)(16/128) Primary Analysis: Modified Intent-to-Treat Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J Aug;148(2):

TITAN-TIMI 34: Treated as Intended in Protocol Analysis © TIMI Duplication prohibited by law ER Group: Drug at least 15 minutes before 1 st injection on angio (n=127) (n=127) Cath Lab Group: Drug after 1 st injection on angio (n=114) First Injection on Angio = Time 0

© TIMI Duplication prohibited by law p = p=0.024 adjusting for infarct location Secondary Analysis: Treated per Protocol TITAN-TIMI 34 Primary Endpoint: Pre-PCI TIMI Frame Count EREptifibatide Cath Lab Eptifibatide Frame Count (n=124) (n=109) CTFC p = Cath Lab Eptifibatide EREptifibatide

FASTERFLOW TITAN-TIMI 34: Duration of Therapy and Pre-PCI TIMI Frame Count n=165 n=165 n=111 n=111 n=17 n=17 Mean TIMI Frame Count Duration of Therapy Before First Injection p = for linear trend In cath lab to 15 min prior 15 min to 60 min. prior > 60 min. prior Earlier Treatment © TIMI Duplication prohibited by law

TITAN-TIMI 34: Pre-PCI TIMI Grade 2 or 3 Flow and Full Perfusion © TIMI Duplication prohibited by law Pre - PCI TIMI 2 or 3 Flow (%) EREptifibatide Cath Lab Eptifibatide 46.8% 34.2% (59/126) (39/114) p = Secondary Analysis: Treated per Protocol Full Angiographic Perfusion (%) EREptifibatide Cath Lab Eptifibatide 23.9% 13.2% p = Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J Aug;148(2): (28/117) (14/106)

© TIMI Duplication prohibited by law Death (%) EREptifibatide Cath Lab Eptifibatide Death p = NS CHF (%) EREptifibatide Cath Lab Eptifibatide n=173 n=142 Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34 Clinical Endpoints at Discharge/Day 5 CHF p = n=173 n=142

© TIMI Duplication prohibited by law Outcome ER Eptifibatide (n=174) Cath Lab Eptifibatide (n=142) P-value TIMI Major (Hgb  >5 g/dL or ICH) 1.7%3.5%NS TIMI Minor (Hgb  3-5 g/dL) 5.2%4.2%NS TIMI Major or Minor 6.9%7.8%NS Transfusion PRBC 9.8%7.0%NS Stroke or ICH 0.0%0.0%NS Thrombocytopenia (Plt. < 100K) 2.3%1.4%NS TITAN-TIMI 34: Bleeding Events Non CABG Through Discharge; Site Assessment Primary Analysis: Modified Intent-to-Treat

TITAN-TIMI 34: Conclusions © TIMI Duplication prohibited by law A strategy of early initiation of eptifibatide in the emergency room prior to primary PCI for ST segment elevation MI yields superior pre-PCI TIMI frame counts (epicardial flow) and superior TIMI myocardial perfusion compared to a strategy of initiating eptifibatide in the cardiac catheterization laboratory

TITAN-TIMI 34: Clinical Implications © TIMI Duplication prohibited by law Among patients who are to undergo primary PCI for STEMI, GP IIbIIIa inhibition should be initiated as soon as possible prior to cardiac catheterization.