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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.

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Presentation on theme: "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."— Presentation transcript:

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) n discovered by a medical student ! Adapted from Hirsh and Fuster, Circulation 1994;89:1449

3 Characteristics of UFH and LMWH Chains Molecular weight (daltons) 10,000 15,00020,0005,000 5,400 Anti-XaAnti-IIa and anti-Xa Resistant to PF4Sensitivity to PF4 Little non-specific bindingNon-specific binding Inhibition of thrombin generationLess inhibition thrombin generation Hirsh J, Levine MN. Blood. 1992; 79: 1-17

4 Sites of Anti-thrombotic Drug Action Intrinsic, Extrinsic Pathways Plasma clotting cascade Prothrombin Thrombin FibrinogenFibrin Thrombus Platelet aggregation Conformational activation of GPIIb/IIIa Platelet Agonists Thromboxane A 2 ADP AT III Factor Xa Coagulation cascade Coagulation cascade Platelet cascade Platelet cascade Bivalirudin Hirudin Argatroban Ximelagatran UF Heparin Fondaparinux Thrombo- lytics Enoxaparin DX-9065a Aspirin Ticlopidine Clopidogrel GPIIb/IIIa inhibitors

5 TIMI 11B Study Design: Acute Phase Enoxaparin 30 mg IV bolus mg/kg q 12 H subcutaneous Unfractionated heparin 70 U/kg IV bolus + 15U/kg/hr IV Unstable Angina Non-Q Wave MI min 72 hours max 8 days

6 Treatment—LMWH: Enoxaparin for Non ST  ACS TIMI 11B/ESSENCE Meta-Analysis of Death/MI LMWH Better UFH Better UFH (%)Enox (%)p UFH (%)Enox (%)p TIMI 11B Day 8ESSENCE Overall TIMI 11B Day 14ESSENCE Overall TIMI 11B Day 43ESSENCE Overall TIMI 11B Day 8ESSENCE Overall TIMI 11B Day 14ESSENCE Overall TIMI 11B Day 43ESSENCE Overall B B B B B B B B B B B B B B B B —Antman. 1998

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

8 TESSMA: TIMI 11B + ESSENCE Meta-Analysis 1 Yr Follow-up B D/MI/UR Urg Revasc MI Death Months % Pts Hazard Ratio HR 0.90 (0.75,1.08) 0.91 (0.77,1.08) 0.86 (0.76,0.98) 0.88 (0.80,0.97) 25.5% 22.9% P=0.008 Log Rank D/MI/Urg Revasc ENOX UFH Enox better UFH better

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

10 30-Day Composite Endpoints % of Patients Death or (re)MI p= % of Patients Death, (re)MI, or Recurrent Ischemia p= % of Patients Death, (re)MI, or RI* with ECG changes p=0.064 * RI = Recurrent Ischemia Enoxaparin (n=380) UF Heparin (n=366)

11 30-Day Major Bleeding % of Patients All p= Non-CABG-related p=0.079 Enoxaparin (n=380) UF Heparin (n=366) TIMI Scale

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

13 S uperior Y ield of the N ew strategy of E noxaparin, R evascularization & G l Y coprotein IIb/IIIa Inhibitors The SYNERGY Trial

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

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

16 Primary Results (30 Days) EnoxaparinUFH Unadjusted (n = 4993)(n = 4985) P-value Death and MI (%) Death (%) Death (%) MI (%) MI (%)

17 Death and MI at 30 Days Freedom from Death / MI Days from Randomization UFH Enoxaparin HR 0.96 ( ) 1.1

18 Prior Antithrombin Therapy: Efficacy and Safety Enox UFH (%) (%) 30-DAY DEATH / MI BLEEDING GUSTO Severe TIMI Major BLEEDING GUSTO Severe TIMI Major Enox UFH (%) (%) Total (n = 9978) No Pre-rando (n = 2440) Consistent Therapy* (n = 6138)

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

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

21 LMWH in ACS/AMI and PCI Pre-Treatment +/- GP IIb/IIIa 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 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 Post-Thrombolysis for AMI  ASSENT – 3 (n = 590)  ENTIRE / TIMI – 23 (n = 121 ) Total n = 3,808

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

23 PEPCI0.3 mg/kg(none) NICE-30.3 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 Enoxaparin in PCI PCI -12 hr -8 hr Last dose of subq enox before PCI IV enox at PCI GP 2b/3a Trial selective 12 hr+

24 NICE 1 and NICE 4 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 Safety (bleeding, MACE) Compare to EPILOG, EPISTENT

25 NICE-1 and 4: Enoxaparin in PCI NICE-1NICE-4 Patients Enoxaparin1.0 mg/kg IV0.75 mg/kg IV GP IIb/IIIaNoneAbcix. B+I 30 day Death1.3%0.4% MI2.6%1.7% U. Revasc.1.9%0.6% CK >3x3.3%2.7% Maj. Bleed0.6%1.1% Plt <20 K00 J Invas Cardiol 2000;12:1A-5A

26 NICE 1 (n = 828) NICE 4 (n = 818) Major Major Non-Any TransfusionMajor Non-CABG CABGTransfusion NICE 1 and NICE 4 Incidence of Major Bleeding EPILOGEPISTENT ———%——— Major Bleeding Non-CABG Bleeding Any Transfusion Percentage of Patients

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

28 NICE 3 Safety Major (TIMI)2.1 % Non-CABG 1.4 % Minor (TIMI)4.5 % Major (TIMI)2.1 % Non-CABG 1.4 % Minor (TIMI)4.5 % Bleeding Death 0.7 %1.0 % MI 4.5 %4.9 % Death / MI 5.2 %5.9 % Urg revasc 2.1 %6.6 % Death 0.7 %1.0 % MI 4.5 %4.9 % Death / MI 5.2 %5.9 % Urg revasc 2.1 %6.6 % Efficacy Inhosp 30 day TACTICSTACTICS (inv)(cons) Protocol5.5%3.3% TIMI major1.9%1.3% TACTICSTACTICS (inv)(cons) Death2.2%1.6% MI3.1%5.8% Death/MI4.7%7.0% PCI Patients (n = 628)

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

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34 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

35 Enoxaparin pK Modeling 1 mg/kg sc renal function

36 Enoxaparin in PCI in Patients with ACS 451 pts with UA/NQWMI rx’d with enoxaparin for 48 hrs. 451 pts with UA/NQWMI rx’d with enoxaparin for 48 hrs. 293 underwent cath within 8 hrs of AM enox. dose 293 underwent cath within 8 hrs of AM enox. dose 132 ad hoc PCI, no additional UFH/LMWH 132 ad hoc PCI, no additional UFH/LMWH 30d: Death=1.5%, MI=3.0%, Maj. Bleeding = 0.8% 30d: Death=1.5%, MI=3.0%, Maj. Bleeding = 0.8% Mean anti-Xa at PCI= IU/ml, Mean anti-Xa at PCI= IU/ml, Collet JP Circ 2001;103: Anti-Xa Activity (IU/mL) % of Patients N = 293 Collet et al. Circulation 2001;103:658

37 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.

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

39 Moliterno RapidPoint Baseline After 1 mg/kg Enoxaparin ENOX Clotting Time (sec) % of Samples

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

41 Moliterno ELECT SC SC IV IV All SC SC IV IV All + IIb/IIIa- IIb/IIIa+ IIb/IIIa- IIb/IIIaGroups N TIMI Major % 0.2% TIMI Minor % 0.9% 0.7% Any Bleed 19.4% 0 8.5% 2.8% 7.9% Transfusion 6.5% 0 1.0% 0 1.3% Enoxaparin Treatment Groups Bleeding

42 Moliterno MACE ELECT SC SC IV IV All SC SC IV IV All + IIb/IIIa- IIb/IIIa+ IIb/IIIa- IIb/IIIaGroups N Death1 (3.2%) - 1 (0.3%) - 0.4% MI2 (6.5%) - 14 (4.7%) 5 (4.7%) 4.9% Urgent TVR (1.6%) - 1.1% Composite2 (6.5%) - 17 (5.6%) 5 (4.7%) 5.4% Enoxaparin Treatment Groups

43 Moliterno ELECT Citrated ENOX Clotting Time (sec) Probability of MACE Enoxaparin + IIb/IIIa Rx

44 Enoxaparin Key Principles n Subcutaneous dosing l delay between dose and effect (peak 3-4h) l not therapeutic from dose 1 l steady-state only after 3-4 doses l ~5% of patients still <0.6 anti-Xa IU/ml n Cath lab considerations l no monitoring available l t ½ of subq enox ~8h (sheath pull) l adverse interactions between enox + UFH, enox + GP IIb/IIIa (↑ anticoagulation → bleeding, adverse events) l pharmacodynamics of IV enox = IV UFH n Subcutaneous dosing l delay between dose and effect (peak 3-4h) l not therapeutic from dose 1 l steady-state only after 3-4 doses l ~5% of patients still <0.6 anti-Xa IU/ml n Cath lab considerations l no monitoring available l t ½ of subq enox ~8h (sheath pull) l adverse interactions between enox + UFH, enox + GP IIb/IIIa (↑ anticoagulation → bleeding, adverse events) l pharmacodynamics of IV enox = IV UFH

45 Enoxaparin ED to Diagnostic Cardiac Catheterization n ED (AMI, ACS): l 1.0 mg/kg subq (0.75 mg/kg if age >75) l (optional 30 mg IV bolus if age <75) n inpatient: 1.0 mg/kg subq q12° n dx cath: l <12h since subq dose: no additional anticoagulation l >12h since subq dose: manage anticoag as de novo n sheath pull timing: l ~4 hrs after 1 subq dose l ~6 hrs after 2 subq doses l ~8 hrs after >2 subq doses n ED (AMI, ACS): l 1.0 mg/kg subq (0.75 mg/kg if age >75) l (optional 30 mg IV bolus if age <75) n inpatient: 1.0 mg/kg subq q12° n dx cath: l <12h since subq dose: no additional anticoagulation l >12h since subq dose: manage anticoag as de novo n sheath pull timing: l ~4 hrs after 1 subq dose l ~6 hrs after 2 subq doses l ~8 hrs after >2 subq doses

46 n PCI: l 1 dose subq enoxaparin <8h: 0.3 mg/kg IV l >2 doses subq, last dose <8h: 0.1 mg/kg IV l last subq enoxaparin 8-12h: 0.3 mg/kg IV l >12h, or de novo: with GP IIb/IIIa: mg/kg IV without GP IIb/IIIa: mg/kg IV n sheath pull timing (whichever is greater) : l IV enoxaparin only: ~4h after dose l 1-2 doses of subq enoxaparin: ~6h after dose l >3 doses of subq enoxaparin: ~8h after dose n PCI: l 1 dose subq enoxaparin <8h: 0.3 mg/kg IV l >2 doses subq, last dose <8h: 0.1 mg/kg IV l last subq enoxaparin 8-12h: 0.3 mg/kg IV l >12h, or de novo: with GP IIb/IIIa: mg/kg IV without GP IIb/IIIa: mg/kg IV n sheath pull timing (whichever is greater) : l IV enoxaparin only: ~4h after dose l 1-2 doses of subq enoxaparin: ~6h after dose l >3 doses of subq enoxaparin: ~8h after dose Enoxaparin Percutaneous Coronary Intervention


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