TIMI 11 B ESSENCE Enoxaparin for UANQMI TIMI

TIMI 11 B ESSENCE Enoxaparin for UA/NQMI: TIMI 11 B-ESSENCE Meta-Analysis Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8

TIMI 11 B ESSENCE Objectives of Meta-Analysis 1. Provide a more precise estimate of enoxaparin’s effects on: - death + cardiac ischemic events - major hemorrhage 2. Determine onset and duration of treatment effect with enoxaparin Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8

TIMI 11 B ESSENCE Comparison of Trials: Dose of Study Rx IV UFH Bolus Infusion a. PTT (x control) Med Dur. Rx (d) Enoxaparin (Acute) TIMI 11 B ESSENCE 70 U/kg 15 U/kg/h 1. 5 -2. 5 3. 0 5000 U 1000 U/h 1. 5 -2. 5 2. 6 Bolus 30 mg S. C. Q 12 h (mg/kg) 1. 0 Med Dur. Rx (d) 4. 6 Enoxaparin (Chronic-43 d) 40 mg (<65 kg) Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8 60 mg (>65 kg) None 1. 0 2. 6 None

TIMI 11 B ESSENCE Comparison of Trials: Patient Characteristics Age (y) Diabetes Mellitus Current Smoker HTN Prior MI ECG: ST dev Normal Presenting Ilness: Uns Ang NQMI Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8 TIMI 11 B (%) 66 20% 27% 50% 32% 37% 36% 59% 34% ESSENCE (%) 64 22% 24% 54% 46% 29% 44% 69% 21%

TIMI 11 B Methods ESSENCE • Prespecified Endpoints Death/MI/Urg Revasc Death/MI Major hemorrhage • Pooling Procedures : Odds Ratio (95%CI) Peto Method Mantel-Haenszel Method Der. Simonian + Laird Method • Heterogeneity Testing Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8

TIMI 11 B ESSENCE Enoxaparin for UA/NQMI: TIMI 11 B-ESSENCE Meta-Analysis Death/MI/Urgent Revasc N Day TIMI 11 B 8 43 3910 ESSENCE 3171 OVERALL 7081 TIMI 11 B 3910 ESSENCE 3171 OVERALL 7081 UFH Enox (%) OR % p B B 13. 5 11. 0 0. 79 (0. 69 -0. 91) 21 0. 001 0. 80 (0. 71 -0. 91) 20 0. 0005 B B 18. 8 0. 5 15. 6 0. 7 0. 8 0. 9 Enox Better Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8 1 Odds Ratio 2 UFH Better

TIMI 11 B ESSENCE TIMI 11 B-ESSENCE Meta-Analysis Death/MI/Urgent Revasc Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8

TIMI 11 B ESSENCE Enoxaparin for UA/NQMI: N Day TIMI 11 B 8 ESSENCE 3171 OVERALL 7081 TIMI 11 B 43 3910 TIMI 11 B-ESSENCE Meta-Analysis Death/MI UFH Enox (%) 5. 3 OR (%) B 4. 1 B 3910 ESSENCE 3171 OVERALL 7081 p % 0. 77 (0. 62 -0. 95) 23 0. 02 0. 82 (0. 69 -0. 97) 18 0. 02 B B 8. 6 7. 1 0. 5 B 0. 6 0. 7 0. 8 0. 9 1 Enox Better Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8 Odds Ratio 2 UFH Better

TIMI 11 B ESSENCE TIMI 11 B-ESSENCE Meta-Analysis Death/MI Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8

TIMI 11 B ESSENCE Early Rx Phase : TIMI 11 B vs ESSENCE Death/MI /Urgent Revasc. 9 8 7. 3 % % Pts RRR 24% P=0. 03 UFH ENOX 7 6 5. 5 % 5 5. 2 % 4 4. 2 % 3 TIMI 11 B ESSENCE RRR 18% P=0. 21 2 1 0 0 8 16 24 32 40 48 56 Hours from Randomization Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8 64 72

TIMI 11 B ESSENCE Major Hemorrhage (Wgt Adj Rx) OR (95 CI) UFH Enox (%) P TIMI 11 B 1. 0 1. 52 (0. 86 -2. 69) NS ESSENCE 1. 2 1. 1 0. 91 (0. 47 -1. 78) NS OVERALL 1. 1 1. 3 1. 23 (0. 80 -1. 89) NS Heterogeneity: All P=NS 0. 5 Favors ENOX Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8 1 O. R. Favors UFH 2

TIMI 11 B ESSENCE Conclusions Efficacy 20% in death and cardiac ischemic events Early onset of benefit (48 hours) Durable treatment effect (43 days) Safety No significant in major hemorrhage (wgt adj Rx) Clinical Implications--New Therapeutic Standard Enoxaparin is antithrombin for acute management of UA/NQMI Antman EM et al, Circulation 1999 Oct 12; 100(15): 1602 -8