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

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

Anti-Xa:Anti-IIa Ratios for LMWHs Anti-XaAnti-IIaRatio (IU/mg dry substance)(IU/mg dry substance) 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 Nadroparin Reviparin Dalteparin Tinzaparin Certoparin UFH

│ │ │ │ │ │ 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.

( vWF 48 h – vWF 0 h ) vWF (%) P = 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.

ESSENCE: One-year follow-up Death, MI, recurrent angina % Patients Coronary revascularization Time since enrollment (months) Goodman SG, et al. J Am Coll Cardiol 2000;36: UFH Enoxaparin p=0.022 p= N=3,171

% 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:

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

Validation and Treatment Interaction for Enoxaparin (ESSENCE) Risk factors % Triple endpoint (14d) UFH Enoxaparin Total0/123456/7 population p=0.02  2 for trend p<0.001  2 for trend

Primary Efficacy Outcome Freedom from Death / MI Days from Randomization UFH Enoxaparin 30-Day Death/MI 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.

UFH n = %30d Death/MI 7.9%TIMI Major 2.1%GUSTO Severe Enoxaparin n = %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 = d Death/MI P = RRR = 16.4 * * * No Statistical difference

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

TrialEnox (%)UFH (%)Odds ratio [95% CI]Odds ratio (95% CI) ESSENCE [0.58, 1.01] TIMI 11B [0.70, 1.11] ACUTE II [0.51, 1.83] INTERACT [0.30, 0.96] A to Z [0.73, 1.20] SYNERGY [0.86, 1.07] Overall [0.83, 0.99] Enoxaparin better UFH better Intention-to-treat Population: Death or MI at 30 days Petersen JL, et al. JAMA. 2004;292:89.

TrialEnox (%)UFH (%)Odds ratio [95% CI]Odds ratio (95% CI) ESSENCE [0.58, 1.01] TIMI 11B [0.60, 1.10] INTERACT [0.28, 1.08] A to Z [0.68, 1.67] SYNERGY [0.68, 1.05] Overall [0.70, 0.94] Enoxaparin better UFH better No Prerandomization Therapy Population: Death or MI at 30 Days Petersen JL, et al. JAMA. 2004;292:89.

Anti-Xa Activity with LMW Heparin Administration Anti-Xa (U/ml) Time (hours) Enoxaparin 1 mg/kg IV bolus Enoxaparin 0.75 mg/kg IV bolus Enoxaparin 1 mg/kg SQ SheathremovalSheathremoval

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