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Low molecular weight heparin for venous thromboembolic disease

Authors
Gary E Raskob, MSc, PhD
Russell D Hull, MBBS, MSc
Section Editors
Lawrence LK Leung, MD
Jess Mandel, MD
Deputy Editor
Geraldine Finlay, MD

INTRODUCTION

Low molecular weight (LMW) heparin is prepared by depolymerization of unfractionated heparin using chemical methods or enzymes [1-4]. LMW heparin preparations for clinical use have been produced by several companies (table 1). They have an average molecular weight of 4000 to 6500 Daltons; by comparison, commercially available unfractionated heparin has an average molecular weight of 15,000 Daltons. Several LMW heparin preparations have been evaluated by clinical trials. The recommendations contained in this topic review are linked to the strength of the evidence from clinical trials [5]. A firm recommendation is made only when there is supporting evidence from definitive randomized clinical trials.

The current status of LMW heparin in the prevention and treatment of venous thromboembolic disease will be reviewed here. Issues relating to the general prevention of venous thromboembolic disease are discussed separately. (See "Prevention of venous thromboembolic disease in surgical patients" and "Overview of the treatment of lower extremity deep vein thrombosis (DVT)" and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

USAGE GUIDELINES

Formulations — The LMW heparin preparations have different biochemical and pharmacologic properties and are not interchangeable [2,4,6,7]. Thus, each preparation must be evaluated by clinical trials measuring the outcomes of thromboembolism, bleeding, and mortality. This variability has led to the following communication from the Food and Drug Administration (FDA) in the United States [7]:

"The FDA is alerting physicians and other health professionals to important considerations in the use of LMW heparins, most particularly to the fact that LMW heparins cannot be used interchangeably, unit for unit with heparin, nor can one individual LMW heparin be used interchangeably with another."

The decision to use a LMW heparin preparation for a specific clinical indication should be based upon the available clinical trial data for that particular preparation.

                           

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Literature review current through: Nov 2016. | This topic last updated: Fri Jul 15 00:00:00 GMT+00:00 2016.
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References
Top
  1. Salzman EW. Low-molecular-weight heparin: is small beautiful? N Engl J Med 1986; 315:957.
  2. Green D, Hirsh J, Heit J, et al. Low molecular weight heparin: a critical analysis of clinical trials. Pharmacol Rev 1994; 46:89.
  3. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:688.
  4. White RH, Ginsberg JS. Low-molecular-weight heparins: are they all the same? Br J Haematol 2003; 121:12.
  5. Cook DJ, Guyatt GH, Laupacis A, Sackett DL. Rules of evidence and clinical recommendations on the use of antithrombotic agents. Chest 1992; 102:305S.
  6. Young E, Wells P, Holloway S, et al. Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thromb Haemost 1994; 71:300.
  7. Nightingale SL. From the Food and Drug Administration. JAMA 1993; 270:1672.
  8. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:141S.
  9. AHFS Drug InformationAmerican. Society of Health-System Pharmacists., McEvoy GK (Ed), American Hospital Formulary Service, Bethesda 2005.
  10. Murray L. Physicians' Desk Reference. Thompson PDR, Montvale, NJ.
  11. Compendium of Pharmaceuticals and Specialties. The Canadian Drug Reference for Health Professionals. Canadian Pharmacists Association, Ottawa, ON, Canada 2005.
  12. Anderson DR, O'Brien BJ, Levine MN, et al. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med 1993; 119:1105.
  13. O'Brien BJ, Anderson DR, Goeree R. Cost-effectiveness of enoxaparin versus warfarin prophylaxis against deep-vein thrombosis after total hip replacement. CMAJ 1994; 150:1083.
  14. Menzin J, Colditz GA, Regan MM, et al. Cost-effectiveness of enoxaparin vs low-dose warfarin in the prevention of deep-vein thrombosis after total hip replacement surgery. Arch Intern Med 1995; 155:757.
  15. Rodger M, Bredeson C, Wells PS, et al. Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis. CMAJ 1998; 159:931.
  16. Hull R, Raskob G, Pineo G, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med 1993; 329:1370.
  17. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin vs warfarin for prophylaxis of deep vein thrombosis after hip or knee implantation. An economic perspective. Arch Intern Med 1997; 157:298.
  18. Gould MK, Dembitzer AD, Sanders GD, Garber AM. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A cost-effectiveness analysis. Ann Intern Med 1999; 130:789.
  19. Merli G, Ferrufino C, Lin J, et al. Hospital-based costs associated with venous thromboembolism treatment regimens. J Thromb Haemost 2008; 6:1077.
  20. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:381S.
  21. Low-molecular-weight heparin (enoxaparin) vs dextran 70. The prevention of postoperative deep vein thrombosis after total hip replacement. The Danish Enoxaparin Study Group. Arch Intern Med 1991; 151:1621.
  22. Hamulyák K, Lensing AW, van der Meer J, et al. Subcutaneous low-molecular weight heparin or oral anticoagulants for the prevention of deep-vein thrombosis in elective hip and knee replacement? Fraxiparine Oral Anticoagulant Study Group. Thromb Haemost 1995; 74:1428.
  23. Gent M, Hirsh J, Ginsberg JS, et al. Low-molecular-weight heparinoid orgaran is more effective than aspirin in the prevention of venous thromboembolism after surgery for hip fracture. Circulation 1996; 93:80.
  24. RD heparin compared with warfarin for prevention of venous thromboembolic disease following total hip or knee arthroplasty. RD Heparin Arthroplasty Group. J Bone Joint Surg Am 1994; 76:1174.
  25. Levine MN, Hirsh J, Gent M, et al. Prevention of deep vein thrombosis after elective hip surgery. A randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med 1991; 114:545.
  26. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med 1996; 124:619.
  27. Prandoni P. Heparins and venous thromboembolism: current practice and future directions. Thromb Haemost 2001; 86:488.
  28. Testroote M, Stigter W, de Visser DC, Janzing H. Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization. Cochrane Database Syst Rev 2008; :CD006681.
  29. Agnelli G, Piovella F, Buoncristiani P, et al. Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 1998; 339:80.
  30. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996; 335:701.
  31. PROTECT Investigators for the Canadian Critical Care Trials Group and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Cook D, Meade M, et al. Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med 2011; 364:1305.
  32. Fitzgerald RH Jr, Spiro TE, Trowbridge AA, et al. Prevention of venous thromboembolic disease following primary total knee arthroplasty. A randomized, multicenter, open-label, parallel-group comparison of enoxaparin and warfarin. J Bone Joint Surg Am 2001; 83-A:900.
  33. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000; 160:2199.
  34. Francis CW, Pellegrini VD Jr, Totterman S, et al. Prevention of deep-vein thrombosis after total hip arthroplasty. Comparison of warfarin and dalteparin. J Bone Joint Surg Am 1997; 79:1365.
  35. Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med 2001; 161:1952.
  36. Dahl OE, Andreassen G, Aspelin T, et al. Prolonged thromboprophylaxis following hip replacement surgery--results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin). Thromb Haemost 1997; 77:26.
  37. Lassen MR, Borris LC, Anderson BS, et al. Efficacy and safety of prolonged thromboprophylaxis with a low molecular weight heparin (dalteparin) after total hip arthroplasty--the Danish Prolonged Prophylaxis (DaPP) Study. Thromb Res 1998; 89:281.
  38. Comp PC, Spiro TE, Friedman RJ, et al. Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. Enoxaparin Clinical Trial Group. J Bone Joint Surg Am 2001; 83-A:336.
  39. Planes A, Vochelle N, Darmon JY, et al. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo. Lancet 1996; 348:224.
  40. Bergqvist D, Benoni G, Björgell O, et al. Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 1996; 335:696.
  41. Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators. Arch Intern Med 2000; 160:2208.
  42. Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med 2001; 135:858.
  43. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001; 358:9.
  44. Samama CM, Vray M, Barré J, et al. Extended venous thromboembolism prophylaxis after total hip replacement: a comparison of low-molecular-weight heparin with oral anticoagulant. Arch Intern Med 2002; 162:2191.
  45. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:454S.
  46. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000; 160:181.
  47. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334:677.
  48. Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996; 334:682.
  49. Hull R, Pineo G, Brant F. Effect of low molecular weight heparin versus warfarin sodium on mortality in long-term treatment of proximal-vein thrombosis. Clin Appl Thromb Hemost 1996; 2(Suppl):S4.
  50. Hull RD, Pineo GF, Brant RF, et al. Self-managed long-term low-molecular-weight heparin therapy: the balance of benefits and harms. Am J Med 2007; 120:72.
  51. Veiga F, Escribá A, Maluenda MP, et al. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial. Thromb Haemost 2000; 84:559.
  52. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349:146.
  53. Hull RD, Pineo GF. Low molecular weight heparin treatment of venous thromboembolism. Prog Cardiovasc Dis 1994; 37:71.
  54. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995; 155:601.
  55. Prandoni P, Lensing AW, Büller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339:441.
  56. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326:975.
  57. Simonneau G, Charbonnier B, Decousus H, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med 1993; 153:1541.
  58. Lindmarker P, Holmström M, Granqvist S, et al. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 72:186.
  59. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130:800.
  60. Charbonnier BA, Fiessinger JN, Banga JD, et al. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODI group. Thromb Haemost 1998; 79:897.
  61. Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998; 158:2001.
  62. Schraibman IG, Milne AA, Royle EM. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev 2001; :CD003076.
  63. Hull RD, Pineo GF, Brant R, et al. Home therapy of venous thrombosis with long-term LMWH versus usual care: patient satisfaction and post-thrombotic syndrome. Am J Med 2009; 122:762.
  64. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. The Columbus Investigators. N Engl J Med 1997; 337:657.
  65. Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med 1997; 337:663.
  66. Hull RD, Raskob GE, Brant RF, et al. Low-molecular-weight heparin vs heparin in the treatment of patients with pulmonary embolism. American-Canadian Thrombosis Study Group. Arch Intern Med 2000; 160:229.