TIMI IIIA Protocol Design 391 Patients with Unstable

TIMI IIIA Protocol Design 391 Patients with Unstable Angina / NQWMI IV Heparin, (ASA), Beta-blockers, Nitrates, Ca++ blockers Baseline Angio Randomize t-PA 0. 8 mg/kg over 90 mins Primary Endpoint: Death, MI, Positive ETT 6 weeks Angio Exclusion: no CAD or LMain Placebo Angio 18 -36 hrs Follow-up 6 weeks Circulation 1993; 87: 38 -52

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

TIMI IIIB Protocol Design 1473 Patients with Unstable Angina / NQWMI ASA, IV Heparin, Beta-blockers, Nitrates, Ca++ blockers Early Invasive: Cath 18 -48 h PTCA/CABG prn 1 o Endpoint Inv-Cons: Death, MI, Positive ETT - 6 weeks Randomize 2 x 2 Factorial: t-PA vs. Placebo ETT 6 weeks Circulation 1994; 89: 1545 -56 Follow-up 1 year Early Conservative: ST Holter, ETT Thallium Cath/PTCA if +ischemia 1 o Endpoint t-PA: Death, MI, Rec Isch, + ETT, Thallium or ST Holter

TIMI IIIB Primary Results t. PA vs. Placebo in Non-ST Elevation ACS Death or MI ICH % of Patients Composite Endpoint P = NS P = 0. 05 TIMI IIIB Investigators. Circulation 1994; 89: 1545 -56

TIMI IIIB Primary Results Early Invasive vs. Conservative Strategy Events at 42 d No. Pts Death (%) MI (%) D/MI/+ETT (%) Invasive Conservative p value 740 733 2. 4 2. 5 NS 5. 1 5. 7 NS 16. 2 18. 1 NS Rehosp Angina (%) 7. 8 D/MI/Rehosp (%) 15 LOS (days) 10. 2 # Days rehosp 365 14. 1 22 10. 9 930 <0. 001 0. 007 <0. 001 TIMI IIIB Investigators. Circulation 1994; 89: 1545 -56

TIMI III REGISTRY Protocol Design • 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.

Risk Stratification TIMI III REGISTRY Admission ECG as a prognostic indicator ST deviation_>0. 1 m. V LBBB Tw change 25 % of Patients 20 No ECG changes 22. 9 Death or MI 15 11 10 5 0 6. 8 6. 6 2. 6 0. 8 1. 6 In-Hospital 3. 6 8. 2 3. 7 6 Weeks 1 Year 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 IIIB Risk Stratification c. Tn. I to Predict Risk of Mortality in ACS Enrolled 0 -6 hrs P<0. 001 Enrolled 6 -24 hrs P <0. 05 P<0. 001 P <0. 05 Enrolled 0 -24 hrs Antman et al. NEJM 1996; 335: 1342 -9