1. The TIMI Trials 1984 - 1999 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

2. 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

3. 62 70 31 43 Reperfusion of occluded arteries Patency at 90 minutes 0 20 40 60 80 % of Patients t-PA SK *P<0.001 * * TIMI Study Group N Engl J Med 1985;312:397- 401 TIMI 1 Primary Outcome Comparison of t-PA and Streptokinase

4. TIMI 1 Impact of 90 Minute Patency on Mortality 081624324048 Weeks from Randomization 0 5 10 15 20 Mortality (%) Patent (N=161) Occluded (N=128) Open Artery Theory Dalen, et. al. Am J Cardiol 1988; 62:179-85

5. 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

6. 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 18-48 hrs N=194 Pre-D/C Angio and RVG TIMI IIA Protocol Design Conservative: Cath if +ETT or ischemia N=197

7. 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;81:1457-76 Patency at Discharge (%)Death or MI by 6 weeks (%)

8. 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 18-48 hrs Revasc if feasible 6 week ETT / RVG TIMI IIB Protocol Design

9. TIMI Study Group. NEJM 1989;320:618. Williams DO, Circulation 1992;85:533-42. PTCA or CABG to 1 Year 07142128354252 Weeks 0 20 40 60 80 % of Patients Invasive Conservative 07142128354252 Weeks 0 5 10 15 20 % 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

10. 1000 Pts 370Caths saved 400PTCAs saved $3,200,000 saved With no difference in outcome Williams DO, et al. Circulation 1992;85:533-42. $3000 per Cath $4000 per PTCA TIMI IIB Cost Implications of Invasive Strategy Management Strategy

11. Roberts et al. Circulation 1991;83:422-37. TIMI IIB IV Beta-Blockade Following Thrombolysis Adjunctive Therapy Reinfarction (%)Recurrent Ischemia (%) P = 0.02P = 0.005

12. IV Heparin, (ASA), Beta-blockers, Nitrates, Ca ++ blockers Randomize Angio 18-36 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

13. 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;87:38-52. TIMI IIIA Effects of tPA on Coronary Lesions Primary Results B ASELINE A NGIORAPHY : A NGIORAPHY AFTER tPA:

14. ASA, IV Heparin, Beta-blockers, Nitrates, Ca ++ blockers Randomize ETT 6 weeks Early Invasive: Cath 18-48 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;89:1545-56 2x2 Factorial: t-PA vs. Placebo 1 o Endpoint t-PA: Death, MI, Rec Isch, + ETT, Thallium or ST Holter TIMI IIIB Protocol Design

15. TIMI IIIB Investigators. Circulation 1994;89:1545-56 TIMI IIIB tPA vs. Placebo in Non-ST Elevation ACS Primary Results Composite EndpointDeath or MIICH % of Patients P = NSP = 0.05

16. Events at 42dInvasiveConservativepvalue Events at 42d Invasive Conservativep value No. Pts 740 733 Death (%) 2.4 2.5 NS MI (%) 5.1 5.7 NS D/MI/+ETT (%) 16.2 18.1 NS Rehosp Angina (%) 7.8 14.1<0.001 D/MI/Rehosp (%) 15 22 0.007 LOS (days) 10.2 10.9<0.001 # Days rehosp 365 930<0.001 TIMI IIIB Investigators. Circulation 1994;89:1545-56 TIMI IIIB Early Invasive vs. Conservative Strategy Primary Results

17. 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

18. 2.6 3.6 11 0.8 6.6 22.9 1.6 3.7 6.8 1.6 3.7 8.2 In-Hospital6 Weeks1 Year 0 5 10 15 20 25 % of Patients ST deviation >0.1 mVLBBBTw changeNo ECG changes _ Stone PH, TIMI III Registry Study Group. JAMA 1996;275:1104-1112. Cannon CP et al for ECG Substudy Investigators. JACC 1997;30:133-40. TIMI III R EGISTRY Admission ECG as a prognostic indicator Risk Stratification Death or MI

19. Antman et al. NEJM 1996; 335:1342-9 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

20. Pt. with AMI < 6 hrs Heparin, ASA 90 min Angio 18-36 hr Angio MIBI scan RVG, MIBI scan Follow-up 6 wks, 1 yr tPA Combination APSAC TIMI 4 Protocol Design

21. Unsatisfactory OutcomeOne Year Mortality Cannon CP, et al., TIMI 4 Investigators J Am Coll Cardiol 1994;24:1602-10 0306090120150180210240270300330365 Days from Randomization 0.7 0.8 0.9 1 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 *

22. 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 65-90 secs TIMI 5 Protocol Design Heparin Hirudin ASA, tPA F/U 6 Weeks, 1 yr 90 min angio 18-36 hr angio MIBI Scan

23. 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 18-36 h Reocclusion Cannon CP, et al. J Am Coll Cardiol 1994;23:993-1003.

24. 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 65-90 secs TIMI 6 Protocol Design Heparin Hirudin ASA, SK F/U 6 Weeks

25. 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 < 0.001 *

26. 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

27. TIMI 7 Hirulog in Unstable Angina Primary Results Fuchs, Cannon for the TIMI 7 Investigators Circulation 92 : 727, 1995 P = 0.008 P = 0.009

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

29. 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 60-90 s TIMI 9A Protocol Design

30. 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 55-85 s Protocol Design TIMI9B TIMI 9B

31. 051015202530 0 2 4 6 8 10 12 14 HIRUDIN HEPARIN UNSATISFACTORY OUTCOME DEATH + REINFARCTION %Pts Days post randomization p=NS 12.9 11.9 9.7 9.5 TIMI9B TIMI 9B E. Antman for The TIMI 9B Investigators Circulation 1996;94: 911. Primary Results Hirudin vs. Heparin with tPA for MI

32. 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)

33. 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;231-232A.

34. 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

35. 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.

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

37. 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

38. TIMI 10B TIMI Flow Grade at 90 Minutes Primary Results Cannon CP for the TIMI 10B Investigators. Circulation 1998;98:2805-14 * 77% 79% 88% 82% N = 311 304 146 76

39. 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

40. 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

41. p = 0.046 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

42. 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

43. N=321 1.25 mg/kg Instrumented Spontaneous 6.5% 1.9% T3B Hep + Plac N=735 3.2% N=309 1.0 mg/kg 0 2 4 6 8 10 Dose Tier 1Dose Tier 2 % TIMI 11 A Investigators. JACC 29: 1474,1997 TIMI 11A Primary Results Incidence of Major Hemorrhage thru 14 days

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

45. 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 1.5-2.5 x control Hosp DC (or 8 days) TIMI 11B Protocol Design Death, MI, Urgent Revascularization Acute Phase Protocol

46. 2 4 6 8 10 12 14 16 18 20 0 2468101214 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.

47. 0 1 2 3 4 5 6 7 8 9 081624324048566472 % Pts UFH ENOX 5.2 % 4.2 % RRR 18% P=0.20 7.3 % 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.

48. Efficacy Results TIMI 11B - ESSENCE Meta-Analysis OVERALL ESSENCE TIMI 11B OVERALL ESSENCE TIMI 11B OVERALL ESSENCE TIMI 11B 0.512 Day 8 14 43 0.60.70.80.9 Odds Ratio Enox Better UFH Better OR%p 0.77 (0.62-0.95) 230.02 0.79 (0.65-0.96) 210.02 0.82 (0.69-0.97) 180.02 N 7081 3910 3171         UFH (%) Enox (%) 5.34.1 6.55.2 8.67.1 Death/MI Antman E, Cohen M for The TIMI 11B & ESSENCE Investigators Circulation 1999.

49. 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

50. Days 0 2 4 6 8 10 12 14 16 18 20 0481216202428323640 44 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.

51. TIMI 11B Efficacy Results Efficacy of Enoxaparin Stratified by Baseline Risk 0.512 High (N=593) Inter (N=1645) Low (N=1672) UFH (%) ENOX (%) OR (95 CI) Favors ENOX Favors UFH O.R. 29.60.78 (0.55,1.13)24.8 20.517.9 15.014.1 0.85 (0.66,1.08) 0.94 (0.72,1.23) B B 22 15 6 % P=0.079 trend Day 43 Death/MI/UR at 43 Days Holper E. AHA 1998

52. 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) 1286 265 275 396 3741314 D/MI/UR

53. 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

54. 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

55. 3 mg bid 5 mg bid 7 mg bid 10 mg bid 0 25 50 75 100 061224 Mean % inhibition (ADP) 06 122436 D1 D28 Hours post-dose Cannon et al. Circulation 1998;97:340 Primary Results TIMI 12 Inhibition of Platelet Aggregation by Dose Grp

56. 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 0.125  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

57. 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

58. 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 0 10 20 30 40 50 60 70 80 90100 0 Corrected TIMI Frame Count 20406080100 TIMI 14 Efficacy Results TIMI Frame Count at 90 Min Antman et al. Circulation 1999;99:2720

59. Control Full Dose Lytic: rPA 10 + 10 U Reduced Dose Lytic rPA Angio (90 min), In Hospital Events, 30 day F/U No Abciximab Abx: bolus 0.25 mg/kg inf 0.125  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

60. 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

61. TIMI 14 Risk Stratification ST Resolution and TIMI Flow Grade TIMI 3 Flow: p < 0.001 for trend STRES  30% STRES 30-70% STRES  70% de Lemos et al for the TIMI 14 Investigators. Am J Cardiol, 1999

62. TIMI 14 Treatment Effects Effect of Abciximab on ST Resolution All Patients Patent IRA TIMI 3 Flow P < 0.001 N 12522110219180151 de Lemos et al for the TIMI 14 Investigators. Circulation, 1999

63. 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 24-96 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

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

65. TIMI 15B Protocol Design IV  Oral IIb/IIIa Inibitor in ACS Unstable Angina or non-STE-MI (0 - 72 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 24-96 hrs Placebo BID po x 4 wks Placebo TID po x 4 wks IV Placebo Bolus + infusion for 24-96 h RANDOMIZE Aspirin Panel 1: Heparin (opt) Panel 2: Enoxaparin STE-MI (no lytic) (0 - 72 hrs) STE-MI (with lytic) (6-72 hrs)

66. ASA 150-162 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

67. No. Pts Composite (%) Death MI Urg revasc Rehosp StrokePlacebo 20.3 3.1 5.5 8.0 11.3 0.9 Orbo50/30* 20.2 4.4 5.1 6.1 12.1 1.1Orbo50/50 20.1 4.1 5.4 6.1 11.2 1.1 P values P values Each Dose vs. Placebo Data as of Jun 10 1999 NS 0.002 / 0.03 NS 0.001 / 0.003 NS *Orbofiban 50mg bid x 30 days, then 30mg bid Primary Results Clinical Events Through 300 Days

68. Time (days) 050100150200250300 0 5 10 15 20 25 30 % Patients with primary endpoint placebo 50-30 mg 50-50 mg F/U pl v. 50-30: p=0.14 pl v. 50-50: p=0.02 30d pl v. 50-30: p=0.73 pl v. 50-50: p=0.08 Data as of Jun 10 1999 Primary Results Patients  PCI on Study Drug Cannon et al. AHA 1999

69. 0 25 50 75 100 06h12h24h % inhibition (ADP) 36h IV infusion: (Eptifibatide 180 ug/kg + 2.0 ug/kg/min) (mean +/- Std. Dev) N=48 IntravenousOral Data on File, COR/Key Ferguson et al JACC 1998;31:185A (abstract) 0 50100 0h6h 0h 6h 80 Oral : (Orbofiban 50 mg BID) = Mean = Mean Pharmacodynamics IV vs. Oral GP IIb/IIIa Inhibition

70. 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

71. 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

72. Time (days) % Patients 0 2 4 6 051015202530 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

73. 0.50.7511.251.5 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

74. 888228944072873888228944072873N Giugliano R. EHJ 1999;20:519 (abstract) Practice Patterns Mortality by Geographic Region 24 Hours30 Days

75. P < 0.0001 Llevadot J. EHJ 1999;20:356 (abstract) Practice Patterns Revascularization Rates & Cath Lab Availability In-Hospital 30 Day

76. 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