1. Enoxaparin – Future Prospects in Cardiovascular Diseases David Hasdai, MD Rabin Medical Center Tel Aviv University

2. TIMI 8 BAT GUSTO IIA OASIS Pilot TIMI 7 CURE CAPRIE CREDO ISAR-REACT EPICEPILOGCAPTURE TARGET GUSTO IV RESTORE IMPACT 2 ESPRIT ACE ISAR-SWEET EPISTENT PURSUIT PRISMPRISM-PLUS REPLACE 2 OASIS 2 GUSTO IIB HELVETICA FRISC FRIC RITA 3 A to Z INTERACT SYNERGY CADILLAC TACTICS ESSENCE FRAXIS FRISC 2 ACUTE 2 TIMI 11B PROTECT Antithrombin agents in NSTE ACS and PCI Trials

3. Anti-Xa:Anti-IIa Ratios for LMWHs Anti-XaAnti-IIaRatio (IU/mg dry substance)(IU/mg dry substance) 1. 1. European Pharmacopeia Commission (March 1994). 2. Knoll Pharma. 3. Hirsh J, et al. Chest. 1998;114:489S. 4. Bergqvist D, et al. Br J Surg. 1995;82:496. Anti-Xa activity was measured using an amidolytic assay (chromogenic substrate S-2222). Anti-IIa activity was measured using activated partial thromboplastin time 4 Enoxaparin 1 102.824.94.1 Nadroparin 1 103.629.93.5 Reviparin 2 127363.5 Dalteparin 1 167.264.22.4 Tinzaparin 1 99.653.71.9 Certoparin 1 106.444.72.4 UFH 3 193 1931.0

4. │ │ │ │ │ │ 0.50.60.70.80.91.0 Correlation Between Enoxaparin Dose – Anti-Xa Efficiency – Mortality Anti-Xa level (IU/mL) Enoxaparin (mg/kg bid) 1.8 – 1.6 – 1.4 – 1.2 – 1.0 – 0.8 – 0.6 – 0.4 – 0.2 – 0 – r 2 = 0.97 Anti-Xa (IU/mL) 30-d mortality (%) Montalescot G, et al. Circulation. 2004; 27;110:392.

5. ( vWF 48 h – vWF 0 h ) vWF (%) 10080 60 40 20 0 P = 0.0006 Dalteparin 120 IU anti-Xa/kg bid Enoxaparin 1 mg/kg (100 IU anti-Xa/kg) bid UFH 5,000 IU anti-Xa IV bolus then aPTT-adjusted continuous infusion NS Release of von Willebrand Factor (vWF) Enoxaparin releases less vWF, resulting in reduced platelet aggregation platelet aggregation compared with UFH or dalteparin at approved treatment doses for UA/NQMI Montalescot G, et al. J Am Coll Cardiol. 2000;36:110.

6. ESSENCE: One-year follow-up Death, MI, recurrent angina % Patients Coronary revascularization Time since enrollment (months) 024681012 0 10 20 30 40 50 Goodman SG, et al. J Am Coll Cardiol 2000;36:693-8. UFH Enoxaparin p=0.022 p=0.002 0 10 20 30 40 50 0246810 12 N=3,171

7. 0 1 2 3 4 5 6 7 8 9 081624324048566472 % Patients Hours from Randomization 7.3 % 5.5 % RRR 23.8% P=0.026 UFH Enoxaparin TIMI 11B Death/MI/Urgent Revasc: Early Tx Phase Antman EM, et al. Circulation 1999;100:1593-1601.

8. p=0.048 RRR 12 % UFH ENOXAPARIN 19.7 % 17.3 %201816141210864200481216202428323640 44 % patients Days Antman EM, et al. Circulation 1999;100:1593-1601. TIMI 11B Death/MI/Urgent Revasc: Day 43

9. Validation and Treatment Interaction for Enoxaparin (ESSENCE) 19.8 16.6 Risk factors % Triple endpoint (14d) UFH Enoxaparin 0 10 20 30 40 50 60 Total0/123456/7 population p=0.02  2 for trend p<0.001  2 for trend

10. Primary Efficacy Outcome 051015202530 0.8 0.85 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization UFH Enoxaparin 30-Day Death/MI 0.8 1 1 1.2 Hazard Ratio (95% CI) Enoxaparin Better UFH Better 1.1 Enoxaparin is as effective as UFH in the treatment of high-risk patients with ACS undergoing a rapid invasive strategy SYNERGY Trial Investigators. JAMA 2004;292:45-54.

11. UFH n = 2740 15.9%30d Death/MI 7.9%TIMI Major 2.1%GUSTO Severe Enoxaparin n = 3398 13.3%30d Death/MI 9.3%TIMI Major 2.9%GUSTO Severe Pre-Specified Analysis N = 6138 RandomizationPre-randomization Enoxaparin N= 4294 No prior therapy N= 2440 UFH N= 2940 UFH n = 1228 UFH n = 1512 UFH n = 2108 Enoxaparin n = 1212 Enoxaparin n = 1428 Enoxaparin n = 2186 30d Death/MI P = 0.0039 RRR = 16.4 * * * No Statistical difference

12. SYNERGY Population, 6-Month Freedom from Death/MI Consistent Therapy, NO Crossover HR (95% CI) = 0.831 (0.733, 0.942) Kleiman NS. TCT 2004 Late-Breaking Trials.

13. TrialEnox (%)UFH (%)Odds ratio [95% CI]Odds ratio (95% CI) ESSENCE5.87.50.76 [0.58, 1.01] TIMI 11B7.48.30.88 [0.70, 1.11] ACUTE II7.98.10.97 [0.51, 1.83] INTERACT5.09.00.54 [0.30, 0.96] A to Z7.47.90.94 [0.73, 1.20] SYNERGY14.014.50.96 [0.86, 1.07] Overall10.111.0 0.91 [0.83, 0.99] Enoxaparin better UFH better 0.21.02.0 Intention-to-treat Population: Death or MI at 30 days Petersen JL, et al. JAMA. 2004;292:89.

14. TrialEnox (%)UFH (%)Odds ratio [95% CI]Odds ratio (95% CI) ESSENCE 5.87.50.76 [0.58, 1.01] TIMI 11B6.47.80.81 [0.60, 1.10] INTERACT4.68.10.55 [0.28, 1.08] A to Z7.36.91.06 [0.68, 1.67] SYNERGY12.614.80.84 [0.68, 1.05] Overall8.09.40.81 [0.70, 0.94] Enoxaparin better UFH better 0.21.02.0 No Prerandomization Therapy Population: Death or MI at 30 Days Petersen JL, et al. JAMA. 2004;292:89.

18. Anti-Xa Activity with LMW Heparin Administration Anti-Xa (U/ml) Time (hours) 51015 20 25 Enoxaparin 1 mg/kg IV bolus Enoxaparin 0.75 mg/kg IV bolus Enoxaparin 1 mg/kg SQ 0.5 1.0 1.5 SheathremovalSheathremoval

42. ENOXAPARIN – THE ANTICOAGULANT FROM ADMISSION THROUGH PERCUTANEOUS CORONARY INTERVENTION WITHOUT CROSSOVER!!!