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Heparin manufacturing

Heparin manufacturing. Combine 5,000 lbs. intestines, 200 gallons water, 10 gallons chloroform, and 5 gallons toluene. Hold at 90°F for 17 hours. Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide to adjust pH, and 235 gallons water. Bring to a boil; then filter.

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Heparin manufacturing

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  1. Heparin manufacturing • Combine 5,000 lbs. intestines, 200 gallons water, 10 gallons chloroform, and 5 gallons toluene. Hold at 90°F for 17 hours. • Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide to adjust pH, and 235 gallons water. Bring to a boil; then filter. • Add 200 gallons hot water to filtrate and allow to stand overnight, then skim off the fat. • Keep pancreatic extract at 100°F for three days, then bring to boil. • Filter solids and assay for heparin content.

  2. The Unfractionated Heparins - Limitations • variability of preparations • unpredictable neutralization by PF-4 • binds to endothelial cells, plasma proteins, macrophages • poor clot penetration • indirect anticoagulant - relies on AT III levels, structure • stimulates platelet aggregation • HIT(TS)!! • made of beef and pork intestine (and sausage, manure) • discovered by a medical student ! Adapted from Hirsh and Fuster, Circulation 1994;89:1449

  3. Characteristics of UFH and LMWH Chains 5,400 10,000 5,000 15,000 20,000 Molecular weight (daltons) Anti-Xa Anti-IIa and anti-Xa Resistant to PF4 Sensitivity to PF4 Little non-specific binding Non-specific binding Inhibition of thrombin generation Less inhibition thrombin generation Hirsh J, Levine MN. Blood. 1992; 79: 1-17

  4. Aspirin Ticlopidine Clopidogrel Enoxaparin DX-9065a UF Heparin Fondaparinux GPIIb/IIIa inhibitors Bivalirudin Hirudin Argatroban Ximelagatran Thrombo- lytics Sites of Anti-thrombotic Drug Action Intrinsic, Extrinsic Pathways Coagulation cascade Platelet cascade Platelet Agonists Plasma clotting cascade ADP Thromboxane A2 Prothrombin Factor Xa Conformational activation of GPIIb/IIIa AT III Thrombin Platelet aggregation Fibrinogen Fibrin Thrombus

  5. Unstable Angina Non-Q Wave MI Study Design: Acute Phase Enoxaparin 30 mg IV bolus + 1.0 mg/kg q 12 H subcutaneous Unfractionated heparin 70 U/kg IV bolus + 15U/kg/hr IV min 72 hours max 8 days

  6. Treatment—LMWH: Enoxaparin for Non ST  ACSTIMI 11B/ESSENCE Meta-Analysis of Death/MI UFH (%) Enox (%) p 5.3 4.1 0.02 6.5 5.2 0.02 8.6 7.1 0.02 TIMI 11B Day 8 ESSENCE Overall TIMI 11B Day 14 ESSENCE Overall TIMI 11B Day 43 ESSENCE Overall B B B B B B B B 0.5 0.6 0.7 0.8 0.9 1 2 LMWH Better UFH Better —Antman. 1998

  7. 14% 12% 11.97% 10% 8% Death/MI 6% 6.26% 4% p=0.003 2% 0% LOVENOX UFH (n=431) (n=493) Enoxaparin Outcomes ESSENCE and TIMI 11B patients undergoing PCI during index hospitalization (n=924) 51% RRR Fox KAA, et al. Am J Cardiol 2002;90:477-82.

  8. TESSMA: TIMI 11B + ESSENCEMeta-Analysis 1 Yr Follow-up D/MI/Urg Revasc HR 30 25.5% 0.90 (0.75,1.08) UFH Death 25 22.9% 20 0.91 (0.77,1.08) MI ENOX % Pts 15 P=0.008Log Rank 0.86 (0.76,0.98) Urg Revasc 10 5 0.88 (0.80,0.97) B D/MI/UR 0 UFH better 0.5 1 2 Enox better 0 2 4 6 8 10 12 Hazard Ratio Months

  9. Unfractionated Heparin 70 U/kg (max. 5000 U) IV bolus 15 U/kg/hr infusion for >48 hrs Target aPTT 1.5-2x (50-70 sec) Enoxaparin 1 mg/kg (no max.) SC Q12H for min. 48 hrs (4 doses) Study Design and Protocol • ACS patients (n=746; 54 hospitals; 9/1/00-12/17/01) with significant ST deviation (0.1 mV ST ortransient ST in 2 contiguous leads)and/or positive serum marker (CK-MB >ULN or troponin I or T 3x ULN) ASA 160 mg initially  80-325 mg daily Eptifibatide 180 mg/kg IV bolus  2.0 mg/kg/min infusion for 48 hrs Other meds, cardiac catheterization, coronary revasc per MD • Baseline, 48 and 96 hr 12-lead ECGs • 96 hr Continuous ST Segment Monitoring • 30-Day Bleeding and Ischemic Events

  10. UF Heparin (n=366) Enoxaparin (n=380) 30-Day Composite Endpoints Death, (re)MI, or Recurrent Ischemia Death, (re)MI, or RI* with ECG changes Death or (re)MI % of Patients % of Patients % of Patients 20 p=0.30 16.2 15 p=0.064 13.5 12.6 p=0.031 10 9 8.4 5 5 0 * RI = Recurrent Ischemia

  11. 8.5 UF Heparin (n=366) Enoxaparin (n=380) 5.3 30-Day Major Bleeding TIMI Scale All Non-CABG-related % of Patients % of Patients 10 10 p=0.083 8 8 p=0.079 6 6 5.5 4 4 2.9 2 2 0 0

  12. Enoxaparin Meta-analysisTriple Composite Event Rates ENOX UFH Odds Ratio (95 % CI) 9.2 % 12.1 % ESSENCE (8 days) 12.4 % 14.5 % TIMI 11B (8 days) 6.3 % 9.6 % INTERACT (7 days) 8.4 % 9.4 % A to Z (7 days) Meta-analysis 0.3 1 2 3 favors ENOX favors UFH

  13. The SYNERGY Trial Superior Yield of the New strategy of Enoxaparin, Revascularization & GlYcoprotein IIb/IIIa Inhibitors

  14. High-RiskACS Patients • At least 2 of 3 required: • Age  60 • ST  (transient) or  • (+) CK-MB or Troponin Study Design Randomize(n = 10,000) Enoxaparin IV Heparin 60 U/kg  12 U/kg/hr (aPTT 50-70 sec) 1 mg/kg SC Q12H Early invasive strategy Other therapy per AHA/ACC Guidelines (ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa) Primary endpoint: Death or MI at 30 days

  15. Control group 15% death/MI • 17% reduction primary endpoint • Type I error of 5% (2-sided) • 90% power • Sample size ~10,000 patients zone of noninferiority 1.1 Sample size: 8000  10,000 pts For crossover and interim event rate Statistical Assumptions

  16. Primary Results (30 Days) Enoxaparin UFH Unadjusted(n = 4993) (n = 4985) P-value Death and MI (%) 14.0 14.5 0.396 Death (%) 3.2 3.1 0.705 MI (%) 11.7 12.7 0.135

  17. 1.0 0.95 Freedom from Death / MI 0.9 0.85 Enoxaparin UFH 0.8 0 5 10 15 20 25 30 Days from Randomization Death and MI at 30 Days 1.1 HR 0.96 (0.86-1.06)

  18. 3.1 1.8 No Pre-rando (n = 2440) 12.6 14.8 9.7 6.9 ConsistentTherapy* (n = 6138) 3.1 2.2 13.3 15.9 9.3 7.9 Prior Antithrombin Therapy: Efficacy and Safety BLEEDING GUSTO Severe TIMI Major 30-DAY DEATH / MI Enox UFH (%) (%) Enox UFH (%) (%) 2.9 2.4 Total(n = 9978) 14.0 14.5 9.1 7.6

  19. Enoxaparin UFH GUSTO Severe TIMI Major (n = 9180) (n =798) (n = 9978) (n = 9180) (n =798) (n = 9978) Crossovers: Relation to Bleeding Caution !!!

  20. Total Population Death / MI Consistent Rx Death / MI (n = 9180) (n =798) (n = 6130) (n = 5637) (n =493) (n = 9978) Crossovers: Relation to Outcome Caution !!! Caution !!! Enoxaparin UFH

  21. LMWH in ACS/AMI and PCI • Pre-Treatment +/- GP IIb/IIIa • ESSENCE/TIMI-11b (n = 239) • PEPCI (n = 48) • NICE – 3 (n = 661) • Collet Trial (n = 132) • No Pre-Treatment +/- GP IIb/IIIa • NICE – 1 (n = 828) • NICE – 4 (n = 818) • CRUISE (n = 129) • Choussat Trial (n = 242) • Post-Thrombolysis for AMI • ASSENT – 3 (n = 590) • ENTIRE / TIMI – 23 (n = 121 ) Total n = 3,808

  22. hours and hours of boredom punctuated by brief moments of sheer terror. -- J. Tcheng (1988) Performing angioplasty is like flying a jet airplane –

  23. Enoxaparin in PCI Last dose of subq enox before PCI IV enox at PCI GP 2b/3a Trial PEPCI 0.3 mg/kg (none) NICE-3 0.3 mg/kg NICE-3 (none) Collet (none)(none) NICE-1 (none)1.0 mg/kg(none) NICE-4 (none)0.75 mg/kg CRUISE (none)0.75 mg/kg Choussat (none)0.5 mg/kg selective -12 hr -8 hr PCI 12 hr+

  24. NICE 1 (n = 828) Enoxaparin 1 mg/kg IV without GP IIb/IIIa NICE 4 (n = 818) Enoxaparin 0.75 mg/kg IV with GP IIb/IIIa NICE 1 and NICE 4 Safety (bleeding, MACE) Compare to EPILOG, EPISTENT

  25. NICE-1 and 4: Enoxaparin in PCI NICE-1 NICE-4 Patients 828 818 Enoxaparin 1.0 mg/kg IV 0.75 mg/kg IV GP IIb/IIIa None Abcix. B+I 30 day Death 1.3% 0.4% MI 2.6% 1.7% U. Revasc. 1.9% 0.6% CK >3x 3.3% 2.7% Maj. Bleed 0.6% 1.1% Plt <20 K 0 0 J Invas Cardiol 2000;12:1A-5A

  26. NICE 1 and NICE 4 EPILOG EPISTENT ———%——— Major Bleeding 2.0 1.5 Non-CABG Bleeding 1.1 0.8 Any Transfusion 2.8 2.8 10 NICE 1 (n = 828) 9 NICE 4 (n = 818) 8 7 6 Percentage of Patients 5 Incidence of Major Bleeding 4 2.7 3 1.8 1.3 1.2 2 1.1 0.5 0.4 1 0.2 0 Major Major Non- Any Transfusion Major Non-CABG CABG Transfusion

  27. NICE 3Protocol 671 patients enrolled All treated with enoxaparin 46 clinical sites in USA/Canada [Enoxaparin alone] (n = 43) Tirofiban (n = 229) Eptifibatide (n = 272) Abciximab (n = 127) Sheath removal: If last enoxaparin given IV: 4 – 6 h after last dose If last enoxaparin given SC: 8 h after last dose If patients went to the cath lab, combination Rx continued; no UFH used If within 8 h of last enoxaparin, no additional Rx If > 8 h from last dose, 0.3 mg/kg enoxaparin IV Patients receiving GP IIb/IIIa (n = 628) Inhospital, 14-day, and 30-day follow-up

  28. Safety Efficacy Inhosp 30 day Bleeding Death 0.7 % 1.0 % MI 4.5 % 4.9 % Death / MI 5.2 % 5.9 % Urg revasc 2.1 % 6.6 % Major (TIMI) 2.1 % Non-CABG 1.4 % Minor (TIMI) 4.5 % NICE 3 PCI Patients (n = 628) TACTICS TACTICS (inv) (cons) Death 2.2% 1.6% MI 3.1% 5.8% Death/MI 4.7% 7.0% TACTICS TACTICS (inv) (cons) Protocol 5.5% 3.3% TIMI major 1.9% 1.3%

  29. CRUISE: Enoxaparin vs UFH in PCI with Eptifibatide Eptifibatide: 180, 180 ug/kg bolus + 2 ug/kg/min, 18-24 hr Enoxaparin: 0.75 ug/kg IV, no monitoring UFH: 60 U/kg IV, ACT >200sec. P=NS P=NS % patients P=NS Bhatt D, JACC 2003;41:20

  30. 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 1.0 Anti-Xa (U/ml) 0.5 5 10 15 25 20 Time (hours)

  31. Enoxaparin pK Modeling1 mg/kg sc renal function

  32. Enoxaparin in PCI in Patients with ACS % of Patients • 451 pts with UA/NQWMI rx’d with enoxaparin for 48 hrs. • 293 underwent cath within 8 hrs of AM enox. dose • 132 ad hoc PCI, no additional UFH/LMWH • 30d: Death=1.5%, MI=3.0%, Maj. Bleeding = 0.8% • Mean anti-Xa at PCI=0.98+0.03 IU/ml, 25 N = 293 20 15 10 5 0 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Anti-Xa Activity (IU/mL) Collet et al. Circulation 2001;103:658 Collet JP Circ 2001;103:658

  33. Enoxaparin in PCI 0.3 mg/kg IV at 8 hours or more after last sc injection allows optimal therapeutic levels Martin JL, et al. Presented at ESC 2001.

  34. Rapidpoint ENOX Test Monitoring of the anticoagulant effect (anti-Xa effect) of enoxaparin on clotting

  35. Baseline After 1 mg/kg Enoxaparin RapidPoint % of Samples 0 200 400 600 ENOX Clotting Time (sec)

  36. ELECT Elective PCI N = 673 Non-citrated N = 228 Citrated ENOX N = 445 SC Enoxaparin N = 33 IV Enoxaparin N = 412 With GP IIb/IIIa Rx N = 31 Without GP IIb/IIIa Rx N = 2 With GP IIb/IIIa Rx N = 305 Without GP IIb/IIIa Rx N = 107

  37. Enoxaparin Treatment Groups SC SC IV IV All + IIb/IIIa - IIb/IIIa + IIb/IIIa - IIb/IIIa Groups N 31 2 305 107 445 TIMI Major 0 0 0 0.9% 0.2% TIMI Minor 0 0 0.7% 0.9% 0.7% Any Bleed 19.4% 0 8.5% 2.8% 7.9% Transfusion 6.5% 0 1.0% 0 1.3% ELECT Bleeding

  38. Enoxaparin Treatment Groups SC SC IV IV All + IIb/IIIa - IIb/IIIa + IIb/IIIa - IIb/IIIa Groups N 31 2 305 107 445 Death 1 (3.2%) - 1 (0.3%) - 0.4% MI 2 (6.5%) - 14 (4.7%) 5 (4.7%) 4.9% Urgent TVR - - 5 (1.6%) - 1.1% Composite 2 (6.5%) - 17 (5.6%) 5 (4.7%) 5.4% ELECT MACE

  39. Probability of MACE 0.40 0.30 0.20 0.10 0.00 200 250 300 350 400 450 500 550 600 Citrated ENOX Clotting Time (sec) ELECT Enoxaparin + IIb/IIIa Rx

  40. EnoxaparinKey Principles • Subcutaneous dosing • delay between dose and effect (peak 3-4h) • not therapeutic from dose 1 • steady-state only after 3-4 doses • ~5% of patients still <0.6 anti-Xa IU/ml • Cath lab considerations • no monitoring available • t½ of subq enox ~8h (sheath pull) • adverse interactions between enox + UFH, enox + GP IIb/IIIa (↑ anticoagulation → bleeding, adverse events) • pharmacodynamics of IV enox = IV UFH

  41. EnoxaparinED to Diagnostic Cardiac Catheterization • ED (AMI, ACS): • 1.0 mg/kg subq (0.75 mg/kg if age >75) • (optional 30 mg IV bolus if age <75) • inpatient: 1.0 mg/kg subq q12° • dx cath: • <12h since subq dose: no additional anticoagulation • >12h since subq dose: manage anticoag as de novo • sheath pull timing: • ~4 hrs after 1 subq dose • ~6 hrs after 2 subq doses • ~8 hrs after >2 subq doses www.discc.duke.edu/heart_it/enox.htm

  42. EnoxaparinPercutaneous Coronary Intervention • PCI: • 1 dose subq enoxaparin <8h: 0.3 mg/kg IV • >2 doses subq, last dose <8h: 0.1 mg/kg IV • last subq enoxaparin 8-12h: 0.3 mg/kg IV • >12h, or de novo: • with GP IIb/IIIa: 0.5-0.6 mg/kg IV • without GP IIb/IIIa: 0.75-1.0 mg/kg IV • sheath pull timing (whichever is greater): • IV enoxaparin only: ~4h after dose • 1-2 doses of subq enoxaparin: ~6h after dose • >3 doses of subq enoxaparin: ~8h after dose www.discc.duke.edu/heart_it/enox.htm

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