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Enoxaparin – Future Prospects in Cardiovascular Diseases

Enoxaparin – Future Prospects in Cardiovascular Diseases. David Hasdai, MD Rabin Medical Center Tel Aviv University. EPILOG. EPIC. CAPTURE. PROTECT. Antithrombin agents in NSTE ACS and PCI Trials. ISAR-SWEET. GUSTO IIA. SYNERGY. ISAR-REACT. IMPACT 2. ACE. RESTORE. GUSTO IV.

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Enoxaparin – Future Prospects in Cardiovascular Diseases

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

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

  3. Anti-Xa:Anti-IIa Ratios for LMWHs Anti-Xa Anti-IIa Ratio (IU/mg dry substance) (IU/mg dry substance) Enoxaparin1 102.8 24.9 4.1 Nadroparin1 103.629.9 3.5 Reviparin2127 363.5 Dalteparin1 167.2 64.2 2.4 Tinzaparin199.6 53.7 1.9 Certoparin1 106.4 44.7 2.4 UFH3 193 193 1.0 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 time4

  4. 1.8–1.6–1.4–1.2–1.0–0.8–0.6–0.4–0.2–0– r2 = 0.97 Enoxaparin (mg/kg bid) Correlation Between Enoxaparin Dose – Anti-Xa Efficiency – Mortality Anti-Xa level (IU/mL) 30-d mortality (%) │ │ │ │ │ │0.5 0.6 0.7 0.8 0.9 1.0 Anti-Xa (IU/mL) Montalescot G, et al. Circulation. 2004; 27;110:392.

  5. 100 80 60 vWF (%) (vWF48 h – vWF0 h) 40 20 0 Release of von Willebrand Factor (vWF) P = 0.0006 NS Enoxaparin releases less vWF, resulting in reduced platelet aggregation compared with UFH or dalteparin at approvedtreatment doses for UA/NQMI Enoxaparin 1 mg/kg (100 IU anti-Xa/kg) bid Dalteparin 120 IU anti-Xa/kg bid UFH 5,000 IU anti-Xa IV bolus then aPTT-adjusted continuous infusion Montalescot G, et al. J Am Coll Cardiol. 2000;36:110.

  6. 50 40 30 20 10 0 0 2 4 6 8 10 12 ESSENCE: One-year follow-up Death, MI, recurrent angina p=0.022 UFH % Patients Enoxaparin Coronary revascularization 50 40 p=0.002 30 20 10 0 12 0 2 4 6 8 10 N=3,171 Time since enrollment (months) Goodman SG, et al. J Am Coll Cardiol 2000;36:693-8.

  7. TIMI 11BDeath/MI/Urgent Revasc: Early Tx Phase 9 7.3 % 8 UFH Enoxaparin 7 6 5 % Patients 5.5 % RRR 23.8% P=0.026 4 3 2 1 0 0 8 16 24 32 40 48 56 64 72 Hours from Randomization Antman EM, et al. Circulation 1999;100:1593-1601.

  8. 20 18 16 14 12 10 8 6 4 2 0 44 0 4 8 12 16 20 24 28 32 36 40 TIMI 11BDeath/MI/Urgent Revasc: Day 43 19.7 % UFH ENOXAPARIN 17.3 % % patients p=0.048RRR 12 % Days Antman EM, et al. Circulation 1999;100:1593-1601.

  9. p<0.001 2 for trend 60 50 UFH Enoxaparin 40 p=0.02 2 for trend % Triple endpoint (14d) 30 19.8 16.6 20 10 0 Total 0/1 2 3 4 5 6/7 Risk factors population Validation and Treatment Interaction for Enoxaparin (ESSENCE)

  10. Primary Efficacy Outcome 1.0 Hazard Ratio (95% CI) 0.95 30-Day Death/MI 30-Day Death/MI n n Freedom from Death / MI 0.9 0.85 0.8 1 1.2 1.1 0.8 1 1.2 Enoxaparin Enoxaparin UFH UFH Better Better 0.8 0 5 10 15 20 25 30 Days from Randomization 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. Pre-randomization UFH n = 2740 15.9% 30d Death/MI 7.9% TIMI Major 2.1% GUSTO Severe No prior therapy N= 2440 Enoxaparin n = 1212 * UFH n = 1512 UFH N= 2940 Enoxaparin n = 3398 13.3% 30d Death/MI 9.3% TIMI Major 2.9% GUSTO Severe Enoxaparin n = 1428 UFH n = 2108 * Enoxaparin N= 4294 30d Death/MI P = 0.0039 RRR = 16.4 Enoxaparin n = 2186 * No Statistical difference Pre-Specified Analysis N = 6138 Randomization UFH n = 1228

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

  13. 0.2 1.0 2.0 Intention-to-treat Population:Death or MI at 30 days Trial Enox (%) UFH (%) Odds ratio [95% CI] Odds ratio (95% CI) ESSENCE 5.8 7.5 0.76 [0.58, 1.01] TIMI 11B 7.4 8.3 0.88 [0.70, 1.11] ACUTE II 7.9 8.1 0.97 [0.51, 1.83] INTERACT 5.0 9.0 0.54 [0.30, 0.96] A to Z 7.4 7.9 0.94 [0.73, 1.20] SYNERGY 14.0 14.5 0.96 [0.86, 1.07] Overall 10.1 11.0 0.91 [0.83, 0.99] Enoxaparin better UFH better Petersen JL, et al. JAMA. 2004;292:89.

  14. 0.2 1.0 2.0 No Prerandomization Therapy Population:Death or MI at 30 Days Trial Enox (%) UFH (%) Odds ratio [95% CI] Odds ratio (95% CI) ESSENCE 5.8 7.5 0.76 [0.58, 1.01] TIMI 11B 6.4 7.8 0.81 [0.60, 1.10] INTERACT 4.6 8.1 0.55 [0.28, 1.08] A to Z 7.3 6.9 1.06 [0.68, 1.67] SYNERGY 12.6 14.8 0.84 [0.68, 1.05] Overall 8.0 9.4 0.81 [0.70, 0.94] Enoxaparin better UFH better Petersen JL, et al. JAMA. 2004;292:89.

  15. Anti-Xa Activity with LMW Heparin Administration Enoxaparin 1 mg/kg IV bolus Enoxaparin 0.75 mg/kg IV bolus Enoxaparin 1 mg/kg SQ 1.5 Sheath removal 1.0 Anti-Xa (U/ml) 0.5 5 10 15 25 20 Time (hours)

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

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