STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC ) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion EXTRACT – TIMI 25 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Antman EM, Am Heart J 2005;149:217-26

UFH ENOX Days % % RR = 0.83 p = RR = 0.81 p = Primary Results Primary Endpoint: Death or non-fatal re-MI by 30 days Main Secondary Endpoint: Death, non-fatal re-MI, urgent revascularization by 30 days Antman EM, N Engl J Med 2006;354: EXTRACT – TIMI 25

ENOX Better UFH Better Relative Risk RRR (%) 20 6 SEXMale Female All Interaction Tests P = NS P < ARD AGE (years)< 75 > 75 INFARCTAnterior LOCATIONOther DIABETESNo DM DM PRIOR MINo Prior MI Prior MI FIBRINOLYTICStreptokinase Fibrin-Specific TIME TO RX< Median > Median OVERALL20,479 EXTRACT – TIMI 25 Death or Nonfatal MI at 30 Days Antman EM, N Engl J Med 2006;354:

Bleeding Endpoints (TIMI) 30 Days UFH ENOX % Events Major Bleed (Total) ICH ARD 0.7% RR 1.53 P< ARD 0.1% RR 1.27 P = 0.14 Nonfatal Major Bleed ARD 0.4% RR 1.39 P = ARD 0.4% RR 1.84 P = Fatal Major Bleed Antman EM, N Engl J Med 2006;354: EXTRACT – TIMI 25 Bleeding Endpoints at 30 Days

Primary Endpoint: Death or Nonfatal MI by 30 days ENOX Days 13.8% Death or MI (%) UFH 10.7% RR 0.77 p=0.001 EXTRACT – TIMI 25 PCI Cohort Gibson CM, ESC Hotline Presentation 2006

EventENOXUFHRRP-Value n=2,236 n=2,375 TIMI Major Bleed1.4%1.6%0.87 ( )0.56 TIMI Minor Bleed3.3%2.4%1.34 ( )0.09 TIMI Major or 4.6%4.0%1.15 ( )0.31 Minor Bleed ICH 0.2%0.4%0.42 ( )0.18 Stroke0.3%0.9%0.30 ( )0.006 Safety Analysis EXTRACT – TIMI 25 PCI Cohort Gibson CM, ESC Hotline Presentation 2006

Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups CLARITY – TIMI 28 CLopidogrel as Adjunctive ReperfusIon TherapY Sabatine MS, Am Heart J 2005;149:227-33

Primary Endpoint Occluded Artery (or D/MI thru Angio/HD) PlaceboClopidogrel P= Odds Ratio 0.64 (95% CI ) Clopidogrel better Placebo better n=1752 n= % Odds Reduction 36% Odds Reduction Sabatine MS, N Engl J Med 2005;352: CLARITY – TIMI 28

ClopidogrelPlacebo OVERALL Age <65 yr  65 yr Gender Male Female Infarct location Anterior Non-anterior Fibrinolytic Fibrin-specific Non-fibrin specific Predominant heparin Low-molecular-weight Unfractionated None OddsEvent Rates (%) Reduction Clopidogrel better Placebo better CharacteristicOdds Ratio (95% CI) Primary Endpoint - Subgroups CLARITY – TIMI 28 Sabatine MS, N Engl J Med 2005;352:

CV Death, MI, RI  Urg Revasc days Percentage with endpoint (%) Placebo Clopidogrel Odds Ratio 0.80 (95% CI ) P= %20% Triple Endpoint Results CLARITY – TIMI 28 Sabatine MS, N Engl J Med 2005;352:

Outcome Clopidogrel (%) Placebo (%) P value Through angiography TIMI major (Hgb  >5 g/dL or ICH) NS TIMI minor (Hgb  3-5 g/dL) NS Intracranial hemorrhage0.50.7NS Through 30 days TIMI major1.91.7NS In those undergoing CABG7.57.2NS CABG w/in 5 d of study med9.17.9NS TIMI minor1.60.9NS Bleeding CLARITY – TIMI 28 Sabatine MS, N Engl J Med 2005;352:

CV Death, MI, or Stroke following PCI Days post PCI Percentage with outcome (%) No Pretreatment – 6.2% Clopidogrel – 3.6% Pretreatment 46%46% Adj Odds Ratio 0.54 (95% CI ) P=0.008 Adj Odds Ratio 0.54 (95% CI ) P=0.008 Sabatine MS, JAMA 2005;294: Adjusted for type of lytic, type of heparin, infarct location, and propensity to undergo PCI. Placebo N=1739 Clopidogrel N=1752 PCI Study CLARITY – TIMI 28

Clopidogrel No TrialPretreatmentPretreatment PCI-CURE CREDOn/an/a PCI-CLARITY Overall ClopidogrelNo TrialPretreatmentPretreatment PCI-CURE CREDO PCI-CLARITY Overall OR (95% CI) MI before PCI (%) OR 0.67 P=0.005 P=0.005 Favors Pretreatment Favors No Pretreatment OR 0.71 P=0.004 P=0.004 CV Death or MI after PCI (%) Meta-Analysis of Clopidogrel Pretreatment CLARITY – TIMI 28 Sabatine MS, JAMA 2005;294:

8.4% 2.0% 2.5% 8.4% 6.6% 5.1% 0% 2% 4% 6% 8% 10% No STResPartial STResComplete STRes ClopidogrelPlacebo 90 minute ST resolution AdjOR 0.98 (95%CI 0.58, 1.68) p=0.95 AdjOR 0.30 (95%CI 0.13, 0.67) p=0.003 AdjOR 0.49 (95%CI 0.24, 1.02) p=0.056 N= p for interaction=0.027 (<30%)(30-70%)(>70%) In - hospital Death/MI (%) 8.4% 2.0% 2.5% 8.4% 6.6% 5.1% 0% 2% 4% 6% 8% 10% No STResPartial STResComplete STRes ClopidogrelPlacebo 90 minute ST resolution AdjOR 0.98 (95%CI 0.58, 1.68) p=0.95 AdjOR 0.30 (95%CI 0.13, 0.67) p=0.003 AdjOR 0.49 (95%CI 0.24, 1.02) p=0.056 N= p for interaction=0.027 (<30%)(30-70%)(>70%) In - hospital Death/MI (%) Effect of Clopidogrel on Death/MI Stratified by STRes CLARITY – TIMI Scirica BM, J Am Coll Cardiol 2006;48:37-42

UA/NSTEMI for PCI of a native coronary artery with either 1) DM; 2) + Troponin; or 3) ST   0.5 mm Eptifibatide 180/180 mg/kg + 2 mg/kg/min Bivalirudin 0.75 mg/kg IVB mg/kg/h Eptifibatide 180/180 mg/kg + 2 mg/kg/min UFH 50 U/kg IVB - ACT 200s + Enoxaparin 0.5 mg/kg IV + PRIMARY EFFICACY: Coronary Flow Reserve post-PCI MAJOR SECONDARY: Duration of Ischemia p-PCI to 24h PRIMARY SAFETY: TIMI major bleeding at 48h (or hosp d/c) TRANSFER TO CATH LAB, DIAGNOSTIC ANGIOGRAM CONFIRM ELIGIBLE FOR PCI OF CULPRIT IN NATIVE ARTERY Design Features: Open-label, Randomized (1:1:1), Intention-to-treat N = 857 PROTECT – TIMI 30 A Randomized Trial To Evaluate The Angiographic Efficacy of Bivalirudin vs. Eptifibitide for Coronary Stenting

Gibson CM, J Am Coll Cardiol 2006;47:2364–73 Secondary Endpoint Primary Endpoint P=0.036 Coronary Flow Reserve Post-PCI Coronary Flow Reserve N=516 N=238 Median Duration (minutes) N=28 N=15 Duration of Ischemia P=0.013 Main Results PROTECT – TIMI 30

ASA, IV Heparin Randomize 30 Day Follow-up Death, recurrent MI, recurrent angina 2 mg/kg BB Patient with Acute ST Elevation MI < 6 hours 1 mg/kg BB Angio 60 Minutes A Phase II, Open-Label, Multi-Center, Dose Escalation Study to Determine the Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BB in ST Segment Elevation Myocardial Infarction 3 mg/kg BB mg/kg BB o Endpoint: TIMI Grade 3 Flow 2 o Endpoint: ST Resolution (1 & 3 hrs), Pharmacokinetics and Pharmacokinetics (n=21 to 84 depending upon dose finding) TIMI 31 A Dose Ranging Study of a Novel Fibrinolytic Agent in the Treatment of ST-Elevation Myocardial Infarction

TIMI 2 and 3 Flow at 60 Minutes by Dose: ITT Population n=7 n=6n= TFG 3 95% CI 0% % 0% % 0% % 9.5% % 0% % 6.2% % Main Results TIMI 31 Gibson CM, J Thromb Thrombolysis 2006;22:13-21

nSTE ACS -> Early Catheterization ASA, Glycoprotein IIb/IIIa, clopidogrel Open Label Heparin De-escalation Phase 2 consecutive panels of 10 mcg/kg rNAPc2 1) ½ dose UFH (n=26) 2) No UFH (n=26) Enoxaparin or UFH rNAPc2 (n=163) IV bolus q 48h 8 escalating dose groups (1.5, 2, 3, 4, 5, 7.5, 10 mcg/kg) Placebo IV q 48h n = 40 Continuous 3-lead ECG for 5-9 days PK and PD : pre-dose, 2-6h, 48h, d7, d42 Hemorrhage, Thrombosis to 7 days Clinical follow-up to 6 months Blinded Randomized 4:1 DOSE RANGING ANTHEM – TIMI 32 Anticoagulation with NAPc2 To Help Eliminate MACE Giugliano RP, Circulation;112:432

Incidence of Ischemia % pts P = 0.64 P = 0.13 P = way P = /34 25/93 9/96 Main Results ANTHEM – TIMI 32 Giugliano RP, Circulation;112:432

DISPERSE2 was a double-blind, double-dummy, parallel-group, randomized dose-confirmation and feasibility study of AZD6140 in addition to standard therapy with aspirin (75–100 mg qd) compared with clopidogrel combined with aspirin Treatment period was 4–12 weeks, with assessments at Weeks 4, 8, and 12, and a follow-up telephone call 7 days after the last visit 50% of patients in each AZD6140 arm received a loading dose of 270 mg In the clopidogrel arm, thienopyridine treatment-naive patients received a 300-mg loading dose Randomization Visit 1 Day 1 Visit 2Visit 3Visit 4Follow-up Week 4Week 8Week 12Final Visit +7 days AZD mg bid AZD mg bid Clopidogrel 75 mg qd Onset of chest pain and 48 h maximum to randomization DISPERSE2 DISPERSE 2 – TIMI 33 Dose Confirmation and Feasibility Study of AZD ASA Compared with Clopidogrel + ASA in Patients with Non-STE ACS

DISPERSE2 4 Weeks To Follow-up AZD mg AZD mg Clopidogrel AZD mg AZD mg Clopidogrel Minor bleeds Major bleeds % Bleeding Primary Endpoint: Total Bleeding DISPERSE 2 – TIMI 33 Main Results Cannon CP, Circulation 2005;112:615

TITAN – TIMI 34 TITAN – TIMI 34 Time to Integrillin Therapy in Acute Myocardial Infarction Primary PCI STEMI < 6 HRS Undergoing Primary PCI (n=343) 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

TITAN – TIMI 34 TITAN – TIMI 34 Main Results