IV Heparin Baseline Angio Patient with Acute ST Elevation MI < 6 hours t-PA 80 mg / 3 hrs Streptokinase 1.5 MU / 60 mins Angio 10, 20, 30, 45, 60, 75, 90 Mins Double-blind TIMI 1 Protocol Design

Reperfusion of occluded arteries Patency at 90 minutes % of Patients t-PA SK *P<0.001 * * TIMI Study Group, N Engl J Med 1985;312: TIMI 1 Primary Outcome Comparison of t-PA and Streptokinase

TIMI 1 Impact of 90 Minute Patency on Mortality Weeks from Randomization Mortality (%) Patent (N=161) Occluded (N=128) Open Artery Theory Dalen JE, Am J Cardiol 1988;62:

IV t-PA Randomize 6 week ETT / RVG Immediate Invasive: Cath 2 hrs N=195 Acute MI < 4 hours onset Primary Endpoint: Pre-D/C EF Follow-up 1 year Delayed Invasive: Cath hrs N=194 Pre-D/C Angio and RVG TIMI IIA Protocol Design Conservative: Cath if +ETT or ischemia N=197

TIMI IIA Immediate PTCA vs. Delayed Invasive vs. Conservative Strategy post Thrombolysis Management Strategy TIMI IIA Investigators, JAMA 1988;260: Rogers WJ, Circulation 1990;81: Patency at Discharge (%)

TIMI IIA Immediate PTCA vs. Delayed Invasive vs. Conservative Strategy post Thrombolysis Management Strategy Death or MI by 6 weeks (%) TIMI IIA Investigators, JAMA 1988;260: Rogers WJ, Circulation 1990;81:

IV t-PA Heparin, ASA Randomize Pre-D/C ETT / RVG Acute MI < 4 hours onset : Conservative: Cath if +ETT or ischemia Primary Endpoint: Death or MI Follow-up 1 year Invasive: Cath hrs Revasc if feasible 6 week ETT / RVG TIMI IIB Protocol Design

TIMI Study Group, N Engl J Med 1989;320: Williams DO, Circulation 1992;85: PTCA or CABG to 1 Year Weeks % of Patients Invasive Conservative Weeks % of Patients P=NS 15.2% 14.7% Conservative Invasive *P<0.001 Death or MI to 1 Year 72.2% 35.5%* TIMI IIB Conservative vs. Delayed Invasive Management Strategy

1000 Pts 370Caths saved 400PTCAs saved $3,200,000 saved With no difference in outcome Williams DO, Circulation 1992;85: $3000 per Cath $4000 per PTCA TIMI IIB Cost Implications of Invasive Strategy Management Strategy

Roberts R, Circulation 1991;83: TIMI IIB IV Beta-Blockade Following Thrombolysis Adjunctive Therapy Reinfarction (%)Recurrent Ischemia (%) P = 0.02P = 0.005

IV Heparin, (ASA), Beta-blockers, Nitrates, Ca ++ blockers Randomize Angio hrs t-PA 0.8 mg/kg over 90 mins 391 Patients with Unstable Angina / NQWMI Placebo Primary Endpoint: Death, MI, Positive ETT 6 weeks Follow-up 6 weeks Baseline Angio Angio Exclusion: no CAD or LMain TIMI IIIA Protocol Design TIMI IIIA Investigators, Circulation 1993;87:38-52

Apparent thrombus 35% Possible thrombus 30% No thrombus 35% Improvement in Culprit Lesion: 25% t-PA vs. 19% placebo p=NS TIMI IIIA Effects of tPA on Coronary Lesions Primary Results B ASELINE A NGIORAPHY : A NGIORAPHY AFTER tPA: TIMI IIIA Investigators, Circulation 1993;87:38-52

TIMI IIIA Primary Results Measurable Improvement P = 0.25P = 0.003P = 0.16 Substantial ImprovementMeasurable Worsening % of Patients TIMI IIIA Investigators, Circulation 1993;87:38-52

ASA, IV Heparin, Beta-blockers, Nitrates, Ca ++ blockers Randomize ETT 6 weeks Early Invasive: Cath h PTCA/CABG prn 1473 Patients with Unstable Angina / NQWMI Early Conservative: ST Holter, ETT Thallium Cath/PTCA if +ischemia 1 o Endpoint Inv-Cons: Death, MI, Positive ETT - 6 weeks Follow-up 1 year Circulation 1994;89: x2 Factorial: t-PA vs. Placebo 1 o Endpoint t-PA: Death, MI, Rec Isch, + ETT, Thallium or ST Holter TIMI IIIB Protocol Design

TIMI IIIB Investigators, Circulation 1994;89: TIMI IIIB tPA vs. Placebo in Non-ST Elevation ACS Primary Results Composite EndpointDeath or MIICH % of Patients P = NSP = 0.05

Events at 42dInvasiveConservativepvalue Events at 42d Invasive Conservativep value No. Pts Death (%) NS MI (%) NS D/MI/+ETT (%) NS Rehosp Angina (%) <0.001 D/MI/Rehosp (%) LOS (days) <0.001 # Days rehosp <0.001 TIMI IIIB Investigators, Circulation 1994;89: TIMI IIIB Early Invasive vs. Conservative Strategy Primary Results

Risk Ratio to < to < to < to < to <9.0> 9.0 % Mortality at 42 days Cardiac Troponin I ng/ml Antman EM, N Engl J Med 1996;335: TIMI IIIB Results Troponin I Predicts Mortality in UA/NSTEMI

All consecutive patients admitted with unstable angina were screened. Inclusion Criteria: Ischemic pain >5 mins within 96 hrs with unstable pattern: At rest, accelerating, post MI Exclusion Criteria: Non-ischemic pain, ST elevation, admitted for revascularization procedure Patients in specific subgroups defined by gender, race and age were randomly selected for detailed evaluation and follow-up at 6 weeks and 1 year. TIMI III R EGISTRY Protocol Design

In-Hospital6 Weeks1 Year % of Patients ST deviation >0.1 mVLBBBTw changeNo ECG changes _ Stone PH, JAMA 1996;275: Cannon CP, J Am Coll Card 1997;30: TIMI III R EGISTRY Admission ECG as a prognostic indicator Risk Stratification Death or MI

Pt. with AMI < 6 hrs Heparin, ASA 90 min Angio hr Angio MIBI scan RVG, MIBI scan Follow-up 6 wks, 1 yr tPA Combination APSAC TIMI 4 Protocol Design

Unsatisfactory OutcomeOne Year Mortality Cannon CP, J Am Coll Card 1994;24: Days from Randomization Survival (% of Pts) t-PA Comb. APSAC *p=0.07 t-PA vs. APSAC p=0.13 t-PA vs. Comb. TIMI 4 Benefit of front-loaded tPA Primary Results *P = 0.06 *

Pt. with AMI < 6 hrs Day 5-6: RVG, MIBI scan 4 Ascending Hirudin Doses: 0.15 B, 0.05 IV 0.1 B, 0.1 IV 0.3 B, 0.1 IV 0.6 B, 0.2 IV 5000 U Bolus, 1000 U/h IV APTT secs TIMI 5 Protocol Design Heparin Hirudin ASA, tPA F/U 6 Weeks, 1 yr 90 min angio hr angio MIBI Scan

TIMI 5 Hirudin vs. Heparin: Angiographic Results Primary Results Heparin N = 84 Hirudin N = 162 Heparin N = 79 Hirudin N = 157 Heparin N = 60 Hirudin N = 123 TIMI 3 Flow at 90’ and h Reocclusion Cannon CP, J Am Coll Card 1994;23:

Pt. with AMI < 6 hrs Day 5-6: RVG, MIBI scan 3 Ascending Hirudin Doses: 0.15 B, 0.05 IV 0.3 B, 0.1 IV 0.6 B, 0.2 IV 5000 U Bolus, 1000 U/h IV APTT secs TIMI 6 Protocol Design Heparin Hirudin ASA, SK F/U 6 Weeks

TIMI 6 Heparin vs. Hirudin and stability of aPTT Adjunctive Therapy Hirudin Dose Lee VL, Am J Cardiol 1995;75:7-13 APTT range 30 seconds *p < *

ASA Randomize 30 Day Follow-up Hirulog 0.25 mg/kg/h Patient with Unstable Angina Hirulog 0.5 mg/kg/h Hirulog 1.0 mg/kg/h Hirulog 0.02 mg/kg/h TIMI 7 Protocol Design

TIMI 7 Hirulog in Unstable Angina Primary Results Fuchs J, Circulation 1995;92: P = P = 0.009

UA/NQMI < 24 hrs Primary Endpoint: Death or MI ASA Hirulog Follow-up: 30 days Heparin ( aPTT 50-70s) TIMI 8 Protocol Design

TIMI 8 Primary Results Antman E, Am Heart J 2002;143: OR (95 CI):0.30 (0.06,1.53)0.33 (0.08,1.30) P Fisher Exact :

Pt. with AMI < 12 hrs Thrombolytic Therapy (accel tPA or SK) Death, MI, CHF/Shock 30 days F/U 30 days F/U HEPARIN Bolus 5000 U Inf 1000 U/h 1300 u/h >80kg HIRUDIN Bolus 0.6 mg/kg Bolus 0.6 mg/kg Inf 0.2 mg/kg/h Inf 0.2 mg/kg/h Major Bleeding ASA 96 H Rx aPTT s TIMI 9A Protocol Design

TIMI 9A Results Antman E, Circulation 1994;90: p =.03 p = NS p =.06 N = 335 Major Bleeding by Treatment Group

Pt. with AMI < 12 hrs Sample Size =3000 pts (Power 90%, a.05, 25% Rx effect) Thrombolytic Therapy (accel tPA or SK) Death, MI, CHF/Shock 30 days 30 days HEPARIN Bolus 5000 U Inf 1000 U/h HIRUDIN Bolus 0.1 mg/kg Bolus 0.1 mg/kg Inf 0.1 mg/kg/h Inf 0.1 mg/kg/h Major Bleeding 96 H Rx aPTT s Protocol Design TIMI 9B

HIRUDIN HEPARIN UNSATISFACTORY OUTCOME DEATH + REINFARCTION %Pts Days post randomization p=NS Antman E, Circulation 1996;94: Primary Results Hirudin vs. Heparin with tPA for MI TIMI 9B

All Consecutive Patients with Acute STEMI/ LBBB enrolled at 20 Hospitals in US and Canada In 1994 N=840 Fibrinolysis n=505 (60%) Primary PCI n=76 (9%) No Reperfusion n=276 (31%) Cannon CP, Crit Path Cardiol 2002;1:44-52 Use of reperfusion Rx in Patients presenting < 12 hours: 65% 10% 25% TIMI 9 Registry Protocol Design

n=505n= 79 n=259 % % % % of Patients 3 way p<0.001 In-Hospital Mortality Cannon CP, Crit Path Cardiol 2002;1:44-52 Results TIMI 9 Registry

TIMI 10A Protocol Design TNK- tPA Bolus ASA + IV Heparin (APTT 55-85) Follow-up Hosp. Discharge to 30 days Pt. with Acute MI < 12h End Points: Pharmacokinetics Coagulation parameters TIMI grade 3 flow at 90' TIMI frame count Major hemorrhage Allergic Events 8 Ascending TNK- tPA Doses 5, 7.5, 10, 15, 20, 30, 40, 50 mg

TIMI 10A TIMI Flow Grade at 90 Minutes Primary Results Cannon CP, Circulation 1997;95:351-6 TNK-tPA Dose

ASA, IV Heparin Randomize 30 Day Follow-up TNK-tPA 30mg Patient with Acute ST Elevation MI < 12 hours TNK-tPA 40mg TNK-tPA 50mg* t-PA 100 mg Angio 60, 75, 90 Mins *Stopped early Replaced with 40 mg TIMI 10B Protocol Design

TIMI 10B TIMI Flow Grade at 90 Minutes Primary Results Cannon CP, Circulation 1998;98: % 79% 88% 82% N =

ASA, IV Heparin Randomize 30 Day Follow-up TNK-tPA 30mg Patient with Acute ST Elevation MI < 12 hours TNK-tPA 40mg TNK-tPA 50mg* *Stopped early Replaced with 40 mg ASSENT I (TIMI 10C) Protocol Design

Primary Results Incidence of Stroke at 30 Days Van de Werf F, Am Heart J 1999;137: ASSENT I (TIMI 10C)

p = p = 0.4 p = 0.01 Giugliano RP, Am Heart J 2001;141: ICH Pre/post Reduction in Heparin Adjunctive Therapy TIMI 10 B /ASSENT I (TIMI 10C)

> 65 kg TIMI 11A Protocol Design Dose 2 N=309 Dose 1 N=320 IV Bolus Wgt Adj Fixed Dose 30 mg 1.25 mg/kg Q 12 h (2-8d) 1.0 mg/kg Q 12 h (2-8d) < 65 kg> 65 kg 40 mg60 mg Q12 h 40 mg60 mg Q12 h Total Rx Period = 14 days < 65 kg Hospital PhaseHome Rx Dose-ranging trial of enoxaparin for patients with UA/NQMI

N= mg/kg Instrumented Spontaneous 6.5% 1.9% T3B Hep + Plac N= % N= mg/kg Dose Tier 1Dose Tier 2 % Primary Results Incidence of Major Hemorrhage thru 14 days TIMI 11A Investigators, J Am Coll Card 1997;29: TIMI 11A

Pt. with UA/NQMI < 24 h Death, MI, Severe Rec Isch Requiring Urgent Revasc Acute = Day 8 UFH iv > 72 h Major Bleeding Serious AEs ASA ENOX iv-b,sc Placebo sc ENOX sc Chronic = Day 43 Protocol Design TIMI 11B

P=0.029 RRR 15 % UFH ENOX 16.7 % 14.2 % % Days 14.5 % 12.4 % P=0.048 RRR 15 % Primary Results Death/MI/Urgent Revascularization at 14 Days Antman E, Circulation 1999;100: TIMI 11B

Primary Results Death/MI/Urgent Revascularization at 72 hours Antman E, Circulation 1999;100: TIMI 11B % Pts Hours from Randomization 7.3 % 5.5 % RRR 23.8% P=0.029 Log rank UFH ENOX

15 pts/dose 1 o End Point: % Inhibition of ADP- induced Plt aggregation Plt. Aggreg. / PK samples 0, 2, 4, 6, 9, 24, 36 h Follow-up visit Day 7 Phone Contact Day 14, 21 Sibrafiban 3 mg bid Sibrafiban 5 mg qd Sibrafiban 5 mg bid Sibrafiban 10 mg qd Additional Doses: 7 mg bid 15 mg qd 10 mg bid Plt. Aggreg. / PK samples 0, 2, 4, 6, 9, 24 h Cannon CP, Circulation 1998;97:340-9 Protocol Design TIMI 12 Patients 1-7 days post-ACS

3 mg bid 5 mg bid 7 mg bid 10 mg bid Mean % inhibition (ADP) D1 D28 Hours post-dose Cannon CP, Circulation 1998;97:340-9 Primary Results TIMI 12 Inhibition of Platelet Aggregation by Dose Grp

ST , lytic eligible, < 12 h Group I tPA < 100 mg Group II  dose tPA Group III  dose SK Group IV No lytic Angio (90 min), In Hospital Events, 30 day F/U No Abciximab Abx: bolus 0.25 mg/kg inf  g/kg/min x 12 h STD Heparin (70 U/kg ; 15 U/kg/h) Low Dose Heparin (60 U/kg ; 7 U/kg/h) vs Group V rPA 10+10U Group VI  dose rPA vs Protocol Design TIMI 14

Primary Results Speed and Extent of Thrombolysis: TIMI 3 Flow Antman E, Circulation 1999;99: tPA  tPA + Abciximab  2 Trend, p < TIMI 14

Normal Flow cTFC < 28 tPA 100 mg 36 tPA 50 (15b/35inf) + Abx 28 Abx 100 SK + Abx 45 cTFC Median P=0.005 % Patients Corrected TIMI Frame Count Efficacy Results TIMI Frame Count at 90 Min Antman E, Circulation 1999;99: TIMI 14

Protocol Design/Primary Results TIMI 15A Mean Inhibition of Platelet Aggregation Giugliano RP, Am Heart J 2000;140:81-93 various Doses ACS within 0-48h PK/PD at 0, 20m, 1-4h QD, pre-stop, 2-4h & 8-24h post stop Clinical f/u at 14d Safety and pharmacokinetics of various doses of the IV GP IIb/IIIa inhibitor RPR

Percent Platelet Inhibition TIMI 15B IV then oral RPR (3 doses) ACS within 0-72h Treatment for 4 wks IV then oral placebo Safety and pharmacokinetics of the GP IIb/IIIa inhibitor RPR given IV and orally Protocol Design/Primary Results Giugliano RP, Am Heart J 2000;140:81-93

ASA mg daily Patient with Unstable Coronary Syndrome <72 hours Orbofiban 50 mg BID Orbo 50 mg BID x 30 days then Orbo 30 mg BID PlaceboBID IV heparin, other med, Cath, PTCR, and CABG at the discretion of the treating physician Follow-up visits Day 14, Day 30 Follow-up visit every 3 months Randomize 1:1:1 Protocol Design Primary endpoint to 30 days + follow-up Death, MI Urgent Revasc, Ischemia -> Rehosp, or Stroke OPUS - TIMI 16

Composite Endpoint Cannon CP, Circulation 2000;102: placebo 50-30mg 50-50mg Mortality placebo 50-30mg 50-50mg Results OPUS - TIMI 16

ST Elev MI < 6 h Primary Endpoint: All Cause Mortality (30 days) ASA accel tPA < 100 mg/90 min Heparin ( aPTT 50-70s) 2 : 1 lanoteplase 120 KU/kg Follow-up: 30 days, 6 months, 12 months Protocol Design INTIME 2 - TIMI 17

Time (days) % Patients nPA tPA 24hr Mortality tPA: 2.49% nPA: 2.39% 30 Day Mortality tPA: 6.60% nPA: 6.77% Primary Results Lanoteplase vs tPA: 30 Day Mortality InTIME-II Investigators, Eur Heart J 2000; 21: N = 15, 078 INTIME 2 - TIMI 17

UA/ NQWMI Early Invasive Early Conservative PTCA/CABG Cath/PTCA/CABG Medical Rx Endpoint s 6 mos Randomize -24 hrs hrs 108 hrs Chest pain ASA, Hep, TIROFIBAN Angio Hour 0 ETT +ischemia Protocol Design Cannon CP, Am J Cardiol 1998;82:731-6 TACTICS - TIMI 18

Time (months) % Patients CONS INV O.R % CI (0.62, 0.97) p= % 15.9% Death, MI, Rehosp for ACS at 6 Months Cannon CP, N Engl J Med 2001;344: Primary Results TACTICS - TIMI 18

(%) CONS INV Troponin T Substudy TnT cut point = 0.01 ng/ml (54% of Pts TnT +) Death, MI, Rehosp ACS at 6 Months OR=0.55 *p<0.001 Interaction P=0.013 p=NS * N= Morrow DA, JAMA 2001;286: TACTICS - TIMI 18

Cost-Effectiveness Based on In-Trial Data 942$3, $61Troponin T < $24, $1,091 Troponin T  $40, $480No ST-changes 0.231$12, $864ST-changes $17, $586Overall sample % Dominated % Dominant CE ratio $ per Death/MI averted  Death/MI (C-I)  Costs (I-C) Results Mahoney EM, JAMA 2002;288: TACTICS - TIMI 18

if transport >30 min, 2nd bolus of Reteplase in ambulance Interventional Procedure + Abciximab prn Lysis 2nd bolus of Reteplase 10U Medical Therapy (no further lysis, no PTCA) Evaluation upon arrival in ED Reteplase 10 U in ambulance Acute MI Suspected 12 lead ECG Lytic Approved ( Medical Control) ER - TIMI 19 Protocol Design Pre-hospital Administration of rPA in ST Elevation MI

Ambulance Arrival ED ArrivalIn-hospital Lytic Results CONTROL GROUP N = 598 STUDY GROUP N = min ( ) Data = median times (Q1 - Q3) TIME SAVED 31 minp < * *Adjusted for any effect of site and interaction rPA Bolus 31 min ( ) Morrow DA, J Am Coll Cardiol 2002;40:71-7 ER - TIMI 19

Protocol Design STEMI within 6 hrs 60 minutes: TIMI flow ST-resolution, serum markers Control Experimental Full-dose TNK-tPA (0.5 mg/kg) TNK-tPA: % std dose Eptifibatide: Bolus #1: 180 mg/kg Bolus #2: 90 mg/kg Infusion: 2.0 mg/kg/m STD HeparinLow Dose Heparin No Eptifibatide ASA INTEGRITI – TIMI 20

Dose Confirmation Dose Finding + Confirmation TNKTNK 50% TNK + ept 180/180 50% TNK + ept 180/ % TNK + ept 180/180 50% TNK + ept 180/180 P=0.15P=0.17 Results 60 Minute Flow % Pts N= TIMI 2 Flow TIMI 3 Flow Giugliano RP, J Am Coll Cardiol 2003;41: INTEGRITI – TIMI 20

Angiographic & ECG Results at 60 Minutes % pts N: TFG 3 TrifectaComplete ST Res TMPG Giugliano RP, J Am Coll Cardiol 2003;41: INTEGRITI – TIMI 20

Protocol Design High Risk ACS (ST  /  or + Marker) Receiving Tirofiban High Risk ACS (ST  /  or + Marker) Receiving Tirofiban A Phase Z Phase If clinically stable and not low-risk Aggressive simvastatin Standard therapy Death, MI, refractory ischemia at 7 days EnoxaparinUF Heparin 40 mg/day x 30 d 80 mg day thereafter Placebo and diet x 4 months simvastatin 20 mg/day thereafter 1 year follow-up: CV death, MI, rehospitalization for ACS Blazing JA, Am Heart J 2001;142:211-7 A2Z – TIMI 21

Primary Endpoint - Death, MI and Refractory Ischemia Results A Phase Blazing JA, JAMA 2004;292:55-64 UFH Enoxaparin Days From Randomization Event Rates (%) 7 Day 8.4% (169 events) 9.4% (184 events) HR 0.89 (0.72,1.09) prespecified non-inferiority margin met A2Z – TIMI 21

Results Z Phase Month from Randomization KM Rate (%) Placebo/Simva 20 Rate = 16.7% Simvastatin 40/80 Rate = 14.4% HR 0.89, CI p = 0.14 Primary Endpoint Composite of Death, MI and Refractory Ischemia De Lemos J, JAMA 2004;292: A2Z – TIMI 21

PROVE IT - TIMI 22 Protocol Design Patients stabilized post ACS <10d Total cholesterol <240 mg/dL (N=4000) ASA & standard medical therapy Pravastatin 40 mg qd Gatifoxacin 400 mg qd x 10d/mo 2x2 factorial design Gatifoxacin 400 mg qd x 10d/mo Placebo Atorvastatin 80 mg qd Follow-up visit day 15 Follow-up visit day 30 then q4 months (average 2 years, minimum 18 months) 1 o Endpoint: death, MI, stroke, rehosp for UA, revasc* * Revascularization includes only procedures occurring > 30d post randomization Placebo Cannon CP, Am Heart J 2002;89:860-1

Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline ACS response lowers LDL-C from true baseline Rand.30 Days4 Mos.8 Mos.16 Mos.Final Pravastatin 40mg Atorvastatin 80mg 49%  21%  P<0.001 Median LDL-C (Q1, Q3) 95 mg/dl (79, 113) 95 mg/dl (79, 113) 62 mg/dl (50, 79) <24h Lipid Results LDL-C Cannon CP, N Engl J Med 2004;350: Changes in LDL PROVE IT - TIMI 22

Lipid Results Months of Follow-up DEATH, NON-FATAL MI, OR URGENT REVASCULARIZATION RRR 25% P= Pravastatin 40 mg 16.7% Atorvastatin 80 mg 12.9% Percent patients with events Cannon CP, N Engl J Med 2004;350: PROVE IT - TIMI 22

Lipid Results Days of Follow-up Percent patients with events DEATH, NON-FATAL MI, OR URGENT REVASCULARIZATION AT 30 DAYS PROVE IT - TIMI 22 Cannon CP, N Engl J Med 2004;350:

Lipid Results Ridker PM, J Am Coll Cardiol 2005;45: Median C-reactive protein (hsCRP) levels by treatment p=0.6 p<0.001 PROVE IT - TIMI 22

Lipid Results Risk of Death or MI after Day 30 P=0.005 for prava P=0.6 for atorva PROVE IT - TIMI 22 Ridker PM, J Am Coll Cardiol 2005;45:1644-8

Antibiotic Results Death from Any Cause or a Major CV Event % with Event Months of Follow-up Placebo(25.1%) Gatifloxacin(23.7%) 5% RR (P = 0.41) Cannon CP, N Engl J Med 2005;352: PROVE IT - TIMI 22

Low dose UFH ST MI < 6h Standard Reperfusion: Full Dose TNK Combination Reperfusion: Abx + dose TNK UFH ENOX Low dose ENOX Primary Endpoint: TIMI 3 Flow at 60 min Secondary Endpoints: ST Resolution, Clin. Events, a-Xa, IPA ASA Group : ABCD Protocol Design TIMI 23 ENTIRE – TIMI 23

Results N = % Pts Angio Evaluable Patients FULL Dose TNKHALF Dose TNK + Abx TIMI 3 Flow TIMI 2 Flow Antman EM, Circulation 2002;105: TIMI 2 and 3 Flow at 60 minutes ENTIRE – TIMI 23

% Pts All Treated Population Results P=0.01 FULL Dose TNK P= P=0.005 HALF Dose TNK + Abx Death MI N = P=0.002 Death and MI at 30 days ENTIRE – TIMI 23 Antman EM, Circulation 2002;105:1642-9

ST Elevation MI < 6 h STD Heparin Primary Endpoint Part A (Dose Finding): TIMI 3 Flow at 60 min Primary Endpoint Part B (Dose Confirmation): ST segment resolution at 60 min TNK-tPA 0.53 mg/kg Tirofiban bolus + infusion (10 to 15 µg/kg) 0.15 µg/kg/min Low Dose Heparin ASA  TNK-tPA dose Protocol Design FASTER - TIMI 24 Ohman EM. International Symposium on Thrombolysis and Interventional Therapy in AMI. 2002

% Pts N= Death MI Urgent Revasc 10.4%* 11.9%* 11.9%* *Corrected for multiple events Results 30 d Death, MI, Urgent Revasc % Pts TIMI Flow at 60 min FASTER - TIMI 24 Ohman EM, Am Hear J 2005;150:79-88

Study Drug in Lab Prior to PCI; Stratify Based on IV GP IIb/IIIa Use Maintenance Rx for 30 days 1 o endpoint: Significant Bleeding (non CABG) bleeding through 30 days 2 o endpoints: Major bleeding (non CABG) through 30 days CV MACE through 30 days Significant bleeding + CV MACE through 30 days Major exclusions: Prim PCI for STEMI, L Main > 50%, Target in SVG or Art Conduit, EF < 30% or NYHA CHF II Bleeding Risks, Oral A/C, thienopyridine < 5 d, Rx with PPI Protocol Design Elective or Urgent PCI with intent to stent Double-blind ASA 325 mg Parallel Randomization CS – 747 Low dose (Load/ Maintenance) CS – 747 Low dose (Load/ Maintenance) Clopidigrel Loading Dose 300 mg Maint. Dose 75 mg CS – 747 Intermed dose (Load/ Maintenance) JUMBO – TIMI 26

R/N Results P= NS 3/254 11/650 3/199 4/200 4/251 R/N P = 0.77 Prasugrel LD/MD Treatment Group Dose Ranging Clop. vs Prasugrel 1 0 EP: Significant Non-CABG Bleeding 30 D Time to MACE Death, MI, CTVT, Stroke, and Recurrent Ischemia Wiviott SD, Circulation 2005;111: JUMBO – TIMI 26

PROXIMATE -TIMI 27 Protocol Design cH36 Bolus Dose # 1 n = 7 Stable CAD Receiving ASA (n = 28) Measured at multiple time points: cH36 levels Factor Xa activity Hgb/Hct PT/PTT/fibrinogen Platelet count Serum chemistries Human anti-chimeric ab If no safety concerns, proceed to higher dose cH36 Bolus Dose # 2 n = 7 cH36 Bolus Dose # 3 n = 7 Membrane Factor VIIa Factor X anti-TF Tissue Factor cH36 Bolus Dose # 4 n = 7 PROXimal Inhibition of coagulation using a Monclonal Antibody to Tissue factor (Sunol cH36) - TIMI 27

Results Enrolled, N Major bleeding (pts) Minor bleeding (pts) SpontaneousProvoked Any minor* (Exact CI %) (13) 2 (25) (3, 65%) (50) 1 (25) 3 (75) (19, 99%) (50) 0 2 (50) (7, 93%) (86) 1 (14) 6 (86) (44,100%) (100) 1 (33) 3 (100) (29,100%) Dose Sunol cH36 *Provoked bleeds were those that occurred at the site of IV insertion or as the result of minor trauma; all others were classified as spontaneous. Morrow DA, J Am Coll Cardiol 2005;26:682-8 PROXIMATE -TIMI 27

ADVANCE MI - TIMI day Composite Death or CHF Combination Rx + Facilitated PCI Eptifibitide + ½ dose TNK Immediate PCI GP 2b/3a monotherapy + Direct PCI Eptifibitide + TNK-placebo Immediate PCI Acute STEMI Enoxaparin UFH Enoxaparin UFH Protocol Design

p=.09 p=.02 p=.0001 ADVANCE MI Investigators, Am Heart J 2005;150: ADVANCE MI - TIMI 29 Results

PROtein Markers of Ischemia Using Proteomic Testing PROtein Markers of Ischemia Using Proteomic Testing Protocol Design 155 patients referred for ETT to evaluate for CAD STRESS TEST STRESS IMAGING REST IMAGING END OF STUDY PARTICIPATION Blood draws Baseline 24 hrs 30 mins 2 hrs4 hrs post test Development of Novel Protein Markers of Myocardial Ischemia Version 1.0: August 28, 2000 Protocol Schema Page 1 of 1 Evaluate: cardiac biomarkers novel protein, peptide, and metabolite markers of ischemia PROMPT – TIMI 35

None Mild / Moderate Severe P=0.31 P= P=0.017 P= None, but sx/ECG  s   cath P=0.019 for trend Myocardial Ischemia (IQR – 24.4) (IQR – 24.5) (IQR -3.2 – 43.5) (IQR -5.8 – 32.4) Results Acute Changes in BNP levels in response to ETT PROMPT – TIMI 35 Sabatine MS, J Am Coll Cardiol 2004;44: