2. STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC ) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage Extract: Protocol Design UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion Antman EA et al. NEJM 2006;354

3. ExTRACT-TIMI 25: Primary End Point (ITT) Death or Nonfatal MI Primary End Point (%) Enoxaparin UFH Relative Risk 0.83 (95% CI, 0.77 to 0.90) P<.001 Days after Randomization 9.9% 12.0% Lost to follow-up = 3 17% RRR Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488.

4. Bleeding Endpoints (TIMI) 30 Days UFH ENOX % Events Major Bleed (fatal + nonfatal) ICH ARD 0.7% RR 1.53 P<0.0001 ARD 0.1% RR 1.27 P = 0.14 Nonfatal Major Bleed ARD 0.4% RR 1.39 P = 0.014 Antman EA et al. NEJM 2006;354

14. Major Hemorrhagic Events (Acute Phase) No significant increase in rate of major hemorrhage 0 20 40 60 ESSENCE n = 3171 TIMI 11B n = 3910 TESSMA n = 7081 UFH Enoxaparin Antman EM et al. Circulation 1999;100:1602-8 UFH, unfractionated heparin; NS, not significant NS Number of patients

15. GUSTO V Benefit vs. risk Death or re-MI Severe / moderate hemorrhageReteplase Abciximab + reteplase 8.8% 7.4% 2.3% 4.6% D = 2.3% P < 0.001 D = 1.4% P = 0.001 0246810246 Percentage of patients GUSTO V Investigators. Lancet. 2001;357:1905.

19. Low-Molecular-Weight Heparin  Indirect thrombin inhibitor  Less reversible  Difficult to monitor (no aPTT or ACT)  Renally cleared  Long half-life  Risk of HIT Disadvantages  Increased anti-Xa to anti-IIa activity  inhibits thrombin generation more effectively  Induces ↑ release of TFPI vs UFH  Not neutralized by platelet factor 4  Less binding to plasma proteins (eg, acute-phase reactant proteins)  more consistent anticoagulation  Lower rate of HIT vs UFH  Lower fibrinogen levels  Easy to administer (SC administration)  Long history of clinical studies and experience, FDA-approved indications  Monitoring typically unnecessary Advantages Hirsh J, et al. Circulation. 2001;103:2994-3018. TFPI = tissue factor pathway inhibitor; UFH = unfractionated heparin; SC = subcutaneous; aPTT = activated partial thromboplastin time; ACT = activated coagulation time.

20. AT IIa Hep UFH IIa S C Direct antithrombin LMWH AT Xa

21. Clot Burden in ACS patient

22. Heparin fails to effectively inhibit Clot-bound Thrombin

23. Bivalirudin inhibits Clot-Bound and Circulating Thrombin

24. Bivalirudin Does not activate Platelets

25. Bivalirudin: Unique mechanism of action overcomes the limitation of Heparin