The TIMI Trials Brigham and Women’s Hospital Harvard Medical School Boston, MA P ART I.R ESULTS OF TIMI 1 - TIMI 17 P ART II.T RIAL D ESIGNS FOR TIMI 18-24

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, et. al. Am J Cardiol 1988; 62:179-85

TIMI Grade Flow Scoring System Monitoring Reperfusion TIMI 1 TIMI 0 Complete occlusion TIMI 1 Penetration of obstruction by contrast but no distal perfusion TIMI 2 Perfusion of entire artery but delayed flow TIMI 3 Full perfusion, normal flow Flygenring BP et al. JACC 1991;17:275 Mortality at 42 Days P < 0.005

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 Invest. JAMA 1988;260:2849. Rogers, et al. Circulation 1990;81: Patency at Discharge (%)Death or MI by 6 weeks (%)

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. NEJM 1989;320:618. 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, et al. Circulation 1992;85: $3000 per Cath $4000 per PTCA TIMI IIB Cost Implications of Invasive Strategy Management Strategy

Roberts et al. 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 Circulation 1993;87:38-52 Baseline Angio Angio Exclusion: no CAD or LMain TIMI IIIA Protocol Design

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

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

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, TIMI III Registry Study Group. JAMA 1996;275: Cannon CP et al for ECG Substudy Investigators. JACC 1997;30: TIMI III R EGISTRY Admission ECG as a prognostic indicator Risk Stratification Death or MI

Antman et al. NEJM 1996; 335: Enrolled 0-6 hrs Enrolled 6-24 hrs Enrolled 0-24 hrs P<0.001 P <0.05 P<0.001 TIMI IIIB cTnI to Predict Risk of Mortality in ACS Risk Stratification

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, et al., TIMI 4 Investigators J Am Coll Cardiol 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, et al. J Am Coll Cardiol 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 et al. for the TIMI 6 Investigators. 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, Cannon for the TIMI 7 Investigators Circulation 92 : 727, 1995 P = P = 0.009

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

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

Pt. with AMI < 12 hrs Sample Size =3000 pts (Power 90%, .05, 25% Rx effect) Sample Size =3000 pts (Power 90%, .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 ASA 96 H Rx aPTT s Protocol Design TIMI9B TIMI 9B

HIRUDIN HEPARIN UNSATISFACTORY OUTCOME DEATH + REINFARCTION %Pts Days post randomization p=NS TIMI9B TIMI 9B E. Antman for The TIMI 9B Investigators Circulation 1996;94: 911. Primary Results Hirudin vs. Heparin with tPA for MI

TIMI 9 Influence of Heparin/Hirudin Dosing Safety Observations Antman et al. Circulation 1994 and 1996 Major Hemorrhage: TIMI 9A (N=713)TIMI 9B (N = 2929)

TIMI 9 R EGISTRY Initial Management Strategy in AMI Critical Pathways All Patients Pts presenting  12 hrs Cannon CP et al. J Am Coll Cardiol 1995; A.

TIMI9B TIMI 9B Risk Stratification Prediction of Mortality at 30 Days Age > 70, Prior MI Anterior MI, Atrial fibrillation Rales Hypotension and  HR Female gender Diabetes P<0.001 % Pts: 26% 37% 24% 10% 3% Cannon CP et al. JACC 1999;33(Suppl. A):396A. Hillis et al. TIMI 2

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 Cannon CP et al. Circulation 1995;92:I-415.

TIMI 10A TIMI Flow Grade at 90 Minutes Primary Results Cannon CP, TIMI 10A Investigators. 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 for the TIMI 10B Investigators. Circulation 1998;98: * 77% 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 Protocol Design

ASSENT I Primary Results Incidence of Stroke at 30 Days Van de Werf F, Cannon CP for the ASSENT 1 Investigators Am Heart J 1999;137:786-91

p = p = 0.4 p = 0.01 Giugliano RP, Circ 1997;96:I-535 (abstract) TIMI 10B/ASSENT I ICH Pre/post Reduction in Heparin Adjunctive Therapy

Dose 2 N=309 Dose 1 N=320 IV Bolus IV Bolus Wgt Adj Fixed Dose 30 mg 30 mg 1.25 mg/kg 1.25 mg/kg Q 12 h (2-8d) 1.0 mg/kg 1.0 mg/kg Q 12 h (2-8d) < 65 kg > 65 kg 40 mg 60 mg Q12 h 40 mg 60 mg Q12 h Total Rx Period = 14 days < 65 kg > 65 kg Hospital PhaseHome Rx TIMI 11A Protocol Design

N= mg/kg Instrumented Spontaneous 6.5% 1.9% T3B Hep + Plac N= % N= mg/kg Dose Tier 1Dose Tier 2 % TIMI 11 A Investigators. JACC 29: 1474,1997 TIMI 11A Primary Results Incidence of Major Hemorrhage thru 14 days

CRP Concentration N = 437N = 346 TIMI 11A Risk Stratification Baseline C-reactive Protein and Mortality Morrow et al. JACC 1998;31:1460-5

ENOX Bolus 30 mg IV Bolus 30 mg IV 1.0 mg / kg Q12h Pt. with UA/NQMI < 24 h Primary Endpoint: UFH > 3 days Bolus 70 U / kg INF 15 U / kg / h Major Bleeding Serious AEs ASA aPTT x control Hosp DC (or 8 days) TIMI 11B Protocol Design Death, MI, Urgent Revascularization Acute Phase Protocol

P=0.029 RRR 15 % UFH ENOX 16.7 % 14.2 % % Days 14.5 % 12.4 % P=0.048 RRR 15 % TIMI 11B Primary Results Death/MI/Urgent Revascularization at 14 Days E. Antman for The TIMI 11B Investigators Circulation 1999.

% Pts UFH ENOX 5.2 % 4.2 % RRR 18% P= % 5.5 % RRR 24% P=0.02 ESSENCE TIMI 11 B Hours from Randomization Efficacy Results Death/MI/Urgent Revasc. Early Rx Phase TIMI 11B E. Antman for The TIMI 11B Investigators Circulation 1999.

Efficacy Results TIMI 11B - ESSENCE Meta-Analysis OVERALL ESSENCE TIMI 11B OVERALL ESSENCE TIMI 11B OVERALL ESSENCE TIMI 11B Day Odds Ratio Enox Better UFH Better OR%p 0.77 ( ) ( ) ( ) N         UFH (%) Enox (%) Death/MI Antman E, Cohen M for The TIMI 11B & ESSENCE Investigators Circulation 1999.

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 TIMI 11B Protocol Design

Days P=0.048 RRR 12 % UFH ENOX 19.7 % 17.3 % % TIMI 11B Primary Results: Chronic Phase Death/MI/Urgent Revascularization at 43 Days E. Antman for The TIMI 11B Investigators Circulation 1999.

TIMI 11B Efficacy Results Efficacy of Enoxaparin Stratified by Baseline Risk High (N=593) Inter (N=1645) Low (N=1672) UFH (%) ENOX (%) OR (95 CI) Favors ENOX Favors UFH O.R (0.55,1.13) (0.66,1.08) 0.94 (0.72,1.23) B B % P=0.079 trend Day 43 Death/MI/UR at 43 Days Holper E. AHA 1998

TIMI 11B Efficacy Results Efficacy of Enoxaparin Stratified by Rx Strategy Med Rx Guzman ESC 1999 PCICABG OR (95 CI) 0.85 (0.62,1.16) 0.77 (0.45,1.31) 1.04 (0.55,1.95) D/MI/UR

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 et al. Circulation 1998;97:340 Protocol Design TIMI 12 Patients 1-7 days post-ACS

3 mg bid 5 mg bid 10 mg bid 7 mg bid Minor or Major Bleeding (% of Pts) R 2 =0.95 Cannon CP et al Circulation 1998;97:340-9 Primary Results TIMI 12 Platelet Inhibition and Bleeding Risk

3 mg bid 5 mg bid 7 mg bid 10 mg bid Mean % inhibition (ADP) D1 D28 Hours post-dose Cannon et al. Circulation 1998;97:340 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) ASA TIMI 14 vs Group V rPA 10+10U Group VI  dose rPA vs

TIMI 14 Primary Results Speed and Extent of Thrombolysis: TIMI 3 Flow Antman et al. Circulation 1999;99:2720 tPA  tPA + Abciximab  2 Trend, p < 0.002

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 TIMI 14 Efficacy Results TIMI Frame Count at 90 Min Antman et al. Circulation 1999;99:2720

Control Full Dose Lytic: rPA U Reduced Dose Lytic rPA 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 Low Dose Heparin (60 U/kg ; 7 U/kg/h) Very Low Dose Heparin (30 U/kg ; 4 U/kg/h) ST Elevation, Lytic Eligible, < 12 h ASA No Abciximab STD Heparin (70 U/kg ; 15 U/kg/h) TIMI 14 Protocol Design - rPA Phase

TIMI 14 Risk Stratification ST Resolution and Mortality in Patients with Patent IRA STRES  70% STRES < 70% P = 0.01 de Lemos et al for the TIMI 14 Investigators. Am J Cardiol, 1999

TIMI 14 Risk Stratification ST Resolution and TIMI Flow Grade TIMI 3 Flow: p < for trend STRES  30% STRES 30-70% STRES  70% de Lemos et al for the TIMI 14 Investigators. Am J Cardiol, 1999

TIMI 14 Treatment Effects Effect of Abciximab on ST Resolution All Patients Patent IRA TIMI 3 Flow P < N de Lemos et al for the TIMI 14 Investigators. Circulation, 1999

45/0.660/0.8 ACS within 0-48h 30/0.4 Aspirin Aspirin Heparin (opt) OtherDoses 60/0.5 60/0.5 75/0.2 75/0.2 75/0.4 75/0.4 90/0.2 90/0.2100/0.5120/0.4 Bolus/Infusion (  g/kg) (  g/kg/m) for h PK/PD at 0, 20m, 1-4h QD, pre-stop, 2-4h & 8-24h post stop Clinical f/u at 14d Protocol Design TIMI 15A

  Only 1 specimen for each pt 8-24h post drug Primary Results TIMI 15A Mean Inhibition of Platelet Aggregation Giugliano ACC 1998

TIMI 15B Protocol Design IV  Oral IIb/IIIa Inibitor in ACS Unstable Angina or non-STE-MI ( hrs) Klerval 175 BID po x 4wks Klerval 200 BID po x 4 wks Klerval 150 TID po x 4 wks IV Klerval 100 ug/kg bolus 0.50 ug/kg/min infusion for hrs Placebo BID po x 4 wks Placebo TID po x 4 wks IV Placebo Bolus + infusion for h RANDOMIZE Aspirin Panel 1: Heparin (opt) Panel 2: Enoxaparin STE-MI (no lytic) ( hrs) STE-MI (with lytic) (6-72 hrs)

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 Primary endpoint through follow-up (Avg. 1 yr, min. 6 mos) Randomize 1:1:1 Protocol Design

No. Pts Composite (%) Death MI Urg revasc Rehosp StrokePlacebo Orbo50/30* Orbo50/ P values P values Each Dose vs. Placebo Data as of Jun NS / 0.03 NS / NS *Orbofiban 50mg bid x 30 days, then 30mg bid Primary Results Clinical Events Through 300 Days

Time (days) % Patients with primary endpoint placebo mg mg F/U pl v : p=0.14 pl v : p= d pl v : p=0.73 pl v : p=0.08 Data as of Jun Primary Results Patients  PCI on Study Drug Cannon et al. AHA 1999

h12h24h % inhibition (ADP) 36h IV infusion: (Eptifibatide 180 ug/kg ug/kg/min) (mean +/- Std. Dev) N=48 IntravenousOral Data on File, COR/Key Ferguson et al JACC 1998;31:185A (abstract) h6h 0h 6h 80 Oral : (Orbofiban 50 mg BID) = Mean = Mean Pharmacodynamics IV vs. Oral GP IIb/IIIa Inhibition

l Orbofiban: minimal benefit with small excess in mortality l Major bleeding (3.5%) and thrombocytopenia (0.6%) rates higher than placebo (2%, 0%) but acceptable l Need to optimize dosing strategy of oral IIb/IIIa inhibitors è Peaks/troughs in % inhibition seen è Low blood levels at trough -> ? Proaggregatory effects è High blood levels in some Pts -> ? increased events l 30% benefit in PCI patients on study drug l Other trials ongoing with other agents + trial designs Clinical Implications

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 Followup: 30 days, 6 months, 12 months Protocol Design

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 Neuhaus KL. ACC 1999 N = 15, 078

nPA BettertPA Better Relative Risk & 95% CI for 30 day event rates Severe CHF Recurrent MI Urgent Revasc (in-hosp) Death + MI Death + MI + Severe CHF Death + MI + Severe HF + non-fatal stroke Efficacy Results Lanoteplase vs tPA: Secondary Endpoints Neuhaus KL. ACC 1999

N Giugliano R. EHJ 1999;20:519 (abstract) Practice Patterns Mortality by Geographic Region 24 Hours30 Days

P < Llevadot J. EHJ 1999;20:356 (abstract) Practice Patterns Revascularization Rates & Cath Lab Availability In-Hospital 30 Day

P = NS Llevadot J. EHJ 1999;20:356 (abstract) Practice Patterns Death/MI at 30 Days and Cath Lab Availability All Cause Mortality Death or MI