Review of Anticoagulants: Unfractionated heparin Low molecular weight heparins Warfarin

1. Review of Anticoagulants:Unfractionated heparinLow molecular weight heparinsWarfarin Stephanie Inverso Polli, Pharm.D. September 22, 2010

2. Objectives Review the following related to unfractionated heparin (UFH), low molecular weight heparins (LMWH), and warfarin: • Pharmacology/ mechanism of action • Pharmacokinetics • Indications • Dosing • Contraindications • Adverse events • Monitoring

3. Review of the Clotting Cascade

4. Unfractionated and Low Molecular Weight Heparins

5. UFH Mechanism of Action • Anticoagulant actions due to pentasaccharide structure found on UFH that binds to antithrombin (AT) causing a conformational change • This facilitates inactivation of thrombin (factor IIa) and factors Xa, IXa, XIa, XIIa • 18 polysaccharide units needed to inhibit thrombin • Inhibition of thrombin and factor Xa ultimately prevents fibrin formation • UFH does not inactivate clot bound thrombin • It prevents the existing clot from propagating and new clots from forming Weitz et al. N Engl J Med.1997;337:688-98. Hirsh, et al. Chest.2008;133:141-159S

6. LMWH Mechanism of Action • Derived from unfractionated heparin • Final product is heterogeneous and about one-third of the size of original molecule • Contains the pentasaccharide sequence responsible for binding to antithrombin (AT) • Most LMWH molecules do not contain the required 18 polysaccharide units required to inhibit thrombin • LMWH primarily promote factor Xa inhibition, thus preventing fibrin formation Weitz et al. N Engl J Med.1997;337:688-98. Hirsh, et al. Chest.2008;133:141-159S

7. UFH and LMWH: Comparison of Mechanism of Action Weitz et al. N Engl J Med.1997;337:688-98.

8. Pharmacologic Differences Between UFH and LMWH *Subcutaneously

9. Pharmacologic Differences Between UFH and LMWH Con’t

10. Importance of Drug Characteristics- Case Review • Patient on enoxaparin 1mg/kg (100mg) q12 hours sub-Q for atrial fibrillation • Decision made to change to heparin drip • Enoxaparin administered at 0430 • Enoxaparin discontinued at 0817 and heparin bolus 60 units/kg (6000 units)/ drip 12 units/kg/hr (1200 units/hr) ordered 0825 and started 0900 • Heparin bolus and drip started 4.5 hours after enoxaparin dose

11. Importance of Drug Characteristics- Case Review, continued • Several hours later patient became hypotensive requiring fluids and pressors • Retroperitoneal hemorrhage suspected and CT scan ordered • Patient coded and died before CT scan obtained • Retroperitoneal hemorrhage noted on autopsy

12. Importance of Drug Characteristics- Case Review, continued • Heparin bolus and infusion started just after enoxaparin exerted its peak effect • Patient essentially received 2 full dose anticoagulants simultaneously • The heparin drip should have been started several hours after the enoxaparin without a bolus

13. UFH Indications • Treatment and prevention of various venous and arterial thrombotic and embolic diseases

14. UFH Prophylactic Dosing • Prophylaxis of venous thromboembolism (VTE) • 5000 units sub-q every 8 hours or every 12 hours Geerts WH, et al. Chest.2008;13:381-453S. Kearon C, et al. Chest.2008;133:454-545S. *Activated partial thromboplastin time

15. UFH for Prophylaxis of VTE in Medical Patients DVT % patients Greets WH, et al. Chest 2004;126:338-400S.

16. UFH Treatment Dosing, Con’t • IV Treatment doses • VTE • 80 units/kg bolus • 18 units/kg/hour infusion • Titrated to aPTT • Acute coronary syndromes (ACS) • 60 units/kg bolus (maximum recommended initial bolus 4000 units) • 12 units/kg/hour infusion (maximum recommended initial infusion 1000 units/hour) • Titrated to aPTT Kearon C, et al. Chest.2008;133:454-545S. Anderson JL, et al. JACC.2007;50:e1-e157. Antman E, et al. JACC.2008;51:210-47. Raschke R, et al. Ann Intern Med. 1993;874-81.

17. UFH Treatment Dosing, Con’t Within first 48 hours Within first 24 hours • Standard dose: 5000 units bolus; 1000 units/hr • Weight based dose: 80 units/kg bolus; 18 units/kg/hr • ¾ of patients in this study had VTE aPTT result aPTT result P value for all comparisons < 0.001 Raschke R, et al. Ann Intern Med. 1993;874-81.

18. UFH Treatment Dosing, Con’t • Sub-q treatment dosing • 5000 units IV bolus followed by 17,500 units sub-q every 12 hours or 250 units/kg sub-q every 12 hours • Titrate to aPTT* • 333 units/kg sub-q followed by 250 units/kg every 12 hours • Dose adjustments not done

19. Cooper UFH Protocols Several options available to allow for individualized patient care • Standard Dose No Bolus Target aPTT 67-101 seconds • 18 units/kg/hr • Standard Dose WITH BolusesTarget aPTT 67-101 seconds • Initial bolus: 80 units/kg • Initial infusion: 18 units/kg/hr • Low Dose No Bolus Target a PTT 67-84 seconds • Initial infusion: 12 units/kg/hr (may cap initial infusion dose for ACS) • Low Dose WITH BolusesTarget aPTT 67-84 seconds • Initial bolus: 60 units/kg (may cap initial bolus dose for ACS) • Initial infusion: 12 units/kg/hr (may cap initial infusion dose for ACS) • Vascular Surgery Post Op Target aPTT 40-52 seconds • 10 units/kg/hr Note: aPTT reference ranges may change with each new lot of reagent (typically annually)

20. FDA Approved Indications for LMWH

21. LMWH Prophylaxis Dosing • Indications: VTE prophylaxis in medically ill patients, orthopedic surgery, abdominal surgery, trauma • Subcutaneous administration Product information Lovenox 2007. Product information Fragmin 2007.

22. LMWH Dosing, Con’t • Prophylaxis in medical patients • Enoxaparin 40mg sub-q daily • Has been compared directly to UFH in medically ill patients • Lower rates of DVT in certain patient populations with enoxaparin compared to UFH • Heart failure • Stroke • Respiratory disease • Dalteparin 5000 units sub-q daily Product information Lovenox 2007. Product information Fragmin 2007. Shomaker, et al. Blood 1999. Leizorovicz, et al. Circulation 2004. Samama, et al. N EJM 1999.

23. LMWH for Prophylaxis of VTE in Medical Patients MEDENDOX Trial P<0.001 % patients Samama MM, et al. N Engl J Med 1999;341:793-800. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin

24. LMWH for Prophylaxis of VTE in Medical Patients PREVENT Study % patients Leizorovicz A, et al. Circulation 2004;110:874-79. SD= sudden death; VTE= venous thromboembolism; LMWH= low molecular weight heparin; Dalt= dalteparin

25. LMWH vs. UFH for Prophylaxis of VTE in Medical Patients TE Complications and death % patients P=0.04 Shomaker U, et al. Blood 1999;94 (supp1):399a. VTE= venous thromboembolism; Resp= respiratory LMWH= low molecular weight heparin; HF= heart failure; Enox= enoxaparin; UFH= unfractionated heparin

26. LMWH vs. UFH for Prophylaxis of VTE in Medical Patients The PRIME Study- VTE %patients Lechler E, et al. Haemostasis 1996;26 (suppl 2):49-56. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin; UFH= unfractionated heparin

27. LMWH vs. UFH for Prophylaxis of VTE in Medical Patients PRINCE Study- VTE %patients Kleber FX, et al. Am Heart J 2003;145:614-21. VTE= venous thromboembolism; Resp= respiratory LMWH= low molecular weight heparin; HF= heart failure; Enox= enoxaparin; UFH= unfractionated heparin

28. LMWH vs. UFH for Prophylaxis of VTE in Medical Patients PRINCE II Study- VTE %patients Kleber FX, et al. Circulation 1999;100 (suppl 18):I-619. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin; UFH= unfractionated heparin

29. LMWH vs. UFH for Prophylaxis of VTE in Medical Patients Bleeding %patients Shomaker U, et al. Blood 1999;94 (supp1):399a. Lechler E, et al. Haemostasis 1996;26 (suppl 2):49-56. Kleber FX, et al. Am Heart J 2003;145:614-21. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin; UFH= unfractionated heparin

30. LMWH Dosing, Con’t • Treatment of VTE • Enoxaparin • Outpatient DVT 1mg/kg sub-q twice daily • Inpatient DVT ± PE 1mg/kg sub-q twice daily or 1.5mg/kg sub-q daily • Dalteparin (off label use) • 100 units/kg sub-q twice daily • Tinzaparin • Inpatient DVT ± PE 175 units/kg sub-q daily • All in conjunction with warfarin until goal INR achieved Product information Lovenox 2007. Product information Fragmin 2007. Product information Innohep 2007. Kearon, et al. JAMA 2006.

31. LMWH Dosing, Con’t • Extended treatment of VTE in patients with cancer • Enoxaparin (off label use) • 1.5 mg/kg sub-q daily for 3 months • Dalteparin • 200 units/kg (up to 18,000 units) sub-q daily for 1st month • 150 units/kg ( up to 18,000 units) sub-q daily months 2-6 Product information Fragmin 2007. Meyer, et al. Arch Int Med.2002. Lee, et al. NEJM.2003.

32. LMWH versus UFH for Treatment of DVT • Compiled results from several studies • Mortality benefit with LMWH limited to those with cancer Kearon C, et al. Chest.2008;133:454-545.

33. LMWH Dosing, Con’t • Acute coronary syndromes/ myocardial infarction • Enoxaparin • NSTE ACS 1mg/kg sub-q twice daily • STEMI 30mg IV bolus followed by 1mg/kg sub-q twice daily (max 100mg for first 2 doses) • If 75 years or older, no IV bolus and 0.75 mg/kg sub-q twice daily (max 75 mg for first 2 doses) • Supplemental dosing in PCI • Enoxaparin 0.3mg/kg IV if last sub-q dose was greater than 8 hours prior to balloon inflation • Dalteparin • NSTE ACS 120 units/kg (up to 10,000 units) sub-q twice daily Product information Lovenox 2007. Product information Fragmin 2007.

34. LMWH Renal Dosing Adjustments • Clearance of LMWH decreased in patients with renal impairment resulting in increased risk of bleeding • No clear dosing adjustment recommendations for dalteparin or tinzaparin • Enoxaparin for patients with creatinine clearance less than 30 ml/min • Prophylactic doses 30 mg sub-q daily • Treatment doses 1 mg/kg sub-q daily • Consider LMWH (anti Xa) level monitoring if used in patients with severe renal impairment Product information Lovenox 2007. Sanderink, et al. Throm Res. 2002. Hirsh, et al. Chest. 2008;133;141-59S.

35. LMWH Renal Dosing Adjustments, con’t Participants received enoxaparin 40mg daily x 4 days Sanderink, et al. Throm Res. 2002

36. LMWH Dosing in Obese Patients • Significantly obese patients not well studied • Use actual weight for weight based dosing • May need higher prophylactic doses in significantly obese patients • Consider anti-Xa monitoring if used in patients with morbid obesity Hirsh, et al. Chest. 2008;133:141-59S. Geerts WH, et al. Chest.2008;133:381-453.

37. LMWH Dosing in Obese Patients, con’t Participants receives enoxaparin 1.5mg/kg daily x 4 days Sanderink, et al. Clin Pharm Ther. 2002

38. UFH and LMWH Contraindications • Active bleeding • Heparin induced thrombocytopenia • Hypersensitivity to pork products • Hypersensitivity to heparin (all LMWH) • Hypersensitivity to benzyl alcohol (LMWH multi-dose vials)

39. Warning: Neuraxial Anesthesia • Patients receiving neuraxial anesthesia are at high risk for developing epidural hematomas when given LMWH; no increased risk with low dose UFH sub-q • LMWH should be held at least 12 hours prior to removal of epidural catheters • LMWH may be restarted at least 2 hours after spinal needle/ epidural catheter is removed Product information Lovenox 2007. Product information Fragmin 2007. Product information Innohep 2007. Horlocker TT, et al. Reg Anesth Pain Mad.2003;28:172-97. Geerts WH, et al. Chest.2008;133:381-453S.

40. UFH and LMWH Adverse Events • Bleeding • Can occur at any site (GI, intracranial, retroperitoneal, urinary tract, etc) • Ecchymosis/ hematomas common at sub-q injection sites • Risk increases with concurrent antithrombotic drugs, recent surgery, trauma, invasive procedures, concomitant hemostatic defects Hirsh, et al. Chest.2008;133:141-159S.

41. UFH and LMWH Adverse Events, Con’t • Heparin Induced Thrombocytopenia (HIT) • Immune mediated platelet activation • Life and limb threatening hypercoagulable disorder • Platelets decrease to 50% of baseline or less than 100,000 • Must discontinue all forms of UFH or LMWH (including flushes and UFH coated catheters) • Less common with LMWH, but chance of cross-reactivity • Must treat with an alternate anticoagulant (argatroban or lepirudin followed by warfarin after platelet recovery) Hirsh, et al. Chest.2008;133:141-159S Warkentin TE, et al. Chest.2008;340-80S.

42. Thrombotic Complications of HIT

43. UFH and LMWH Adverse Events, Con’t • Osteoporosis • UFH binds to osteoblasts releasing substances that activate osteoclasts • Activation of osteoclasts results in osteopenia and osteoporosis with long term therapy • Most commonly seen in pregnant women as they are unable to use oral anticoagulants • Binding to osteoblasts less with LMWH than UFH Weitz et al. N Engl J Med.1997;337:688-98. Hirsh, et al. Chest.2008;133:141-159S.

44. UFH Monitoring • Complete blood count (hemoglobin/ hematocrit/ platelets) • Signs and symptoms of bleeding, thrombosis, HIT • UFH (therapeutic doses) • aPTT 6 hours after initiation and each rate change (mean half-life is 1.5 hours) • Therapeutic aPTT range is based on heparin levels (anti Xa levels) 0.3-0.7 units/ml • Heparin levels (anti Xa Levels) may be used in patients with elevated baseline aPTT Hirsh, et al. Chest.2008;133:141-159S.

45. Changes to Laboratory Monitoring of Unfractionated Heparin Therapy • UFH is a highly variable medication with substantial inter- and intra-patient variability • UFH has a narrow therapeutic range and a high risk of adverse events • Bleeding when above range • Thrombotic events when below range • aPTT has been the standard monitoring parameter for patients receiving UFH as a continuous IV infusion or high sub-Q doses (therapeutic, not prophylactic doses)

46. Limitations of aPTT • Indirect measure of heparin activity • Measures clotting time • No standard reference range for aPTT • Therapeutic ranges are institution specific • Wide variation in reference ranges • Changes with each new lot of reagent • Changes with different manufacturers of heparin

47. Limitations of aPTT, continued • Has poor correlation with UFH levels • Heparin response curve run with each new lot of reagent or new UFH manufacturer • All results plotted and a line of best fit determines the therapeutic aPTT range based on UFH levels of 0.3-0.7 units/ml • Can be affected by several diseases, acute phase reactants (ie fibrinogen, factor VIII), and medications rendering aPTT useless for UFH monitoring in certain situations

48. Cooper’s Heparin Response Curve September 2009

49. What Will Change Effective mid- fall (date to be determined) UFH levels will be used to monitor UFH continuous infusions and therapeutic dose sub-Q UFH

50. Advantages to Using UFH Levels UFH levels are a more direct way to measure the anticoagulant effect of UFH aPTT is not reliable in some situations Institutions using UFH levels have observed: Fewer UFH dose adjustments (decreased nursing time) Decreased frequency of blood draws (decreased nursing time; less patient discomfort) More time in therapeutic range (the ultimate goal)