Evolution of heparin anticoagulants to ultra-low-molecular-weight heparins: A review of pharmacologic and clinical differences and applications in patients with cancer

Critical Reviews in Oncology/Hematology

Volumn 88, Issue 1, 2013, Pages 1-18

  Walenga, Jeanine M ^a   Lyman, Gary H ^b  

^a LOYOLA UNIVERSITY MEDICAL CENTER   (United States)

^b DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Anticoagulants; Heparin; Low molecular weight heparin; Neoplasms; Venous thromboembolism

Indexed keywords

ACETYLSALICYLIC ACID; APIXABAN; BEMIPARIN; CERTOPARIN; DALTEPARIN; ENOXAPARIN; FONDAPARINUX; HEPARIN; LENALIDOMIDE; LOW MOLECULAR WEIGHT HEPARIN; NADROPARIN; PLACEBO; RO 14; SEMULOPARIN; THALIDOMIDE; TINZAPARIN; UNCLASSIFIED DRUG; VITRONECTIN; WARFARIN;

ABDOMINAL CANCER; BLEEDING; BRAIN CANCER; BRAIN TUMOR; CANCER CHEMOTHERAPY; CANCER PATIENT; CANCER SURGERY; CLINICAL TRIAL (TOPIC); COLORECTAL CANCER; COMPRESSION STOCKING; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; GLIOMA; GYNECOLOGIC CANCER; HUMAN; MALIGNANT NEOPLASTIC DISEASE; MULTIPLE MYELOMA; NONHUMAN; PANCREAS CANCER; PELVIS CANCER; REVIEW; THROMBOSIS PREVENTION; TREATMENT DURATION; TREATMENT OUTCOME; VENOUS THROMBOEMBOLISM;

ANTICOAGULANTS; HEPARIN; LOW-MOLECULAR-WEIGHT HEPARIN; NEOPLASMS; VENOUS THROMBOEMBOLISM;

ANTICOAGULANTS; CHEMOPREVENTION; HEPARIN; HEPARIN, LOW-MOLECULAR-WEIGHT; HUMANS; NEOPLASMS; VENOUS THROMBOEMBOLISM;

EID: 84884158528     PISSN: 10408428     EISSN: 18790461     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2013.06.007     Document Type: Review

References (87)

1. Heit J.A., Silverstein M.D., Mohr D.N., Petterson T.M., O'Fallon W.M., Melton L.J. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Archives of Internal Medicine 2000, 160:809-815.
2. Khorana A.A., Francis C.W., Culakova E., Kuderer N.M., Lyman G.H. Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients. Cancer 2007, 110:2339-2346.
3. Blom J.W., Vanderschoot J.P., Oostindier M.J., Osanto S., van der Meer F.J., Rosendaal F.R. Incidence of venous thrombosis in a large cohort of 66,329 cancer patients: results of a record linkage study. Journal of Thrombosis and Haemostasis 2006, 4:529-535.
4. Stein P.D., Beemath A., Meyers F.A., Skaf E., Sanchez J., Olson R.E. Incidence of venous thromboembolism in patients hospitalized with cancer. American Journal of Medicine 2006, 119:60-68.
5. Chew H.K., Wun T., Harvey D., Zhou H., White R.H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Archives of Internal Medicine 2006, 166:458-464.
6. Khorana A.A., Streiff M.B., Farge D., et al. Venous thromboembolism prophylaxis and treatment in cancer: a consensus statement of major guidelines panels and call to action. Journal of Clinical Oncology 2009, 27:4919-4926.
7. Lee A.Y., Rickles F.R., Julian J.A., et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. Journal of Clinical Oncology 2005, 23:2123-2129.
8. Kakkar A.K., Levine M.N., Kadziola Z., et al. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the Fragmin Advanced Malignancy Outcome Study (FAMOUS). Journal of Clinical Oncology 2004, 22:1944-1948.
9. Lebeau B., Chastang C., Brechot J.M., et al. Subcutaneous heparin treatment increases survival in small cell lung cancer. Cancer 1994, 74:38-45.
10. Altinbas M., Coskun H.S., Er O., et al. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. Journal of Thrombosis and Haemostasis 2004, 2:1266-1271.
11. Klerk C.P., Smorenburg S.M., Otten H.M., et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. Journal of Clinical Oncology 2005, 23:2130-2135.
12. Lazo-Langner A., Goss G.D., Spaans J.N., Rodger M.A. The effect of low-molecular-weight heparin on cancer survival. A systematic review and meta-analysis of randomized trials. Journal of Thrombosis and Haemostasis 2007, 5:729-737.
13. Kuderer N.M., Ortel T.L., Francis C.W. Impact of venous thromboembolism and anticoagulation on cancer and cancer survival. Journal of Clinical Oncology 2009, 27:4902-4911.
14. Mousa S.A., Petersen L.J. Anti-cancer properties of low-molecular-weight heparin: preclinical evidence. Thrombosis and Haemostasis 2009, 102:258-267.
15. Borsig L. Heparin as an inhibitor of cancer progression. Progress in Molecular Biology and Translational Science 2010, 93:335-349.
16. Cohen A.T., Tapson V.F., Bergmann J.F., et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008, 371:387-394.
17. Linhardt R.J., Gunay N.S. Production and chemical processing of low molecular weight heparins. Seminars in Thrombosis and Hemostasis 1999, 25(Suppl. 3):5-16.
18. Garcia D.A., Baglin T.P., Weitz J.I., Samama M.M. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012, 141(2 Suppl.):e24S-e43S.
19. Young E., Wells P., Holloway S., Weitz J., Hirsh J. Ex-vivo and in-vitro evidence that low molecular weight heparins exhibit less binding to plasma proteins than unfractionated heparin. Thrombosis and Haemostasis 1994, 71:300-304.
20. Lovenox [package insert] 2008, sanofi-aventis U.S. LLC, Bridgewater, NJ.
21. Depasse F., Gonzalez de Suso M.J., Lagoutte I., Fontcuberta J., Borrell M., Samama M.M. Comparative study of the pharmacokinetic profiles of two LMWHs-bemiparin (3500IU, anti-Xa) and tinzaparin (4500IU, anti-Xa)-administered subcutaneously to healthy male volunteers. Thrombosis Research 2003, 109:109-117.
22. Viskov C., Just M., Laux V., Mourier P., Lorenz M. Description of the chemical and pharmacological characteristics of a new hemisynthetic ultra-low-molecular-weight heparin, AVE5026. Journal of Thrombosis and Haemostasis 2009, 7:1143-1151.
23. Martinez-Gonzalez J., Vila L., Rodriguez C. Bemiparin: second-generation, low-molecular-weight heparin for treatment and prophylaxis of venous thromboembolism. Expert Review of Cardiovascular Therapy 2008, 6:793-802.
24. Rico S., Antonijoan R.M., Gich I., et al. Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers-a first-time-in-human single ascending dose study. Thrombosis Research 2011, 127:292-298.
25. Dubruc C., Karimi-Anderesi N., Lunven C., Zhang M., Grossmann M., Potgieter H. Pharmacokinetics of a new, ultra-low molecular weight heparin, semuloparin (AVE5026), in healthy subjects. Results from the first phase I studies. Blood 2009, 114. [abstract 1073].
26. Innohep [package insert] 2008, Celgene Corporation, Summit, NJ.
27. Fraxiparine product monograph May 25, 2011, GlaxoSmithKline, Mississauga, Ontario, Canada, Available at: http://www.gsk.ca/english/docs-pdf/Fraxiparine_2011.pdf [accessed 30.03.13].
28. Jeske W., Wolf H., Ahsan A., Fareed J. Pharmacologic profile of certoparin. Expert Opinion on Investigational Drugs 1999, 8:315-327.
29. Jeske W.P., Walenga J.M., Fareed J. Differentiating between the low-molecular-weight heparins used for venous thromboembolism treatment and prophylaxis. Thrombosis Clinic 2008, 2:8-21.
30. Zammit A., Pepper D.S., Dawes J. Interaction of immobilised unfractionated and LMW heparins with proteins in whole human plasma. Thrombosis and Haemostasis 1993, 70:951-958.
31. Vignoli A., Marchetti M., Russo L., et al. LMWH bemiparin and ULMWH RO-14 reduce the endothelial angiogenic features elicited by leukemia, lung cancer, or breast cancer cells. Cancer Investigation 2011, 29:153-161.
32. Young E., Podor T.J., Venner T., Hirsh J. Induction of the acute-phase reaction increases heparin-binding proteins in plasma. Arteriosclerosis, Thrombosis, and Vascular Biology 1997, 17:1568-1574.
33. Young E., Prins M., Levine M.N., Hirsh J. Heparin binding to plasma proteins, an important mechanism for heparin resistance. Thrombosis and Haemostasis 1992, 67:639-643.
34. Jeske W.P., Hoppensteadt D., Gray A., et al. A common standard is inappropriate for determining the potency of ultra low molecular weight heparins such as semuloparin and bemiparin. Thrombosis Research 2011, 128:361-367.
35. Ansell J., Hirsh J., Hylek E., Jacobson A., Crowther M., Palareti G. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008, 133:160S-198S.
36. Spyropoulos A.C. Current and emerging anticoagulation therapies for the management of venous thromboembolism in nonsurgical patients. Thrombosis Clinic 2008, 2:31-46.
37. Linkins L.A., Dans A.L., Moores L.K., et al. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012, 141:e495S-e530S.
38. Gray E., Mulloy B., Barrowcliffe T.W. Heparin and low-molecular-weight heparin. Thrombosis and Haemostasis 2008, 99:807-818.
39. Shaughnessy S.G., Young E., Deschamps P., Hirsh J. The effects of low molecular weight and standard heparin on calcium loss from fetal rat calvaria. Blood 1995, 86:1368-1373.
40. Holmer E., Kurachi K., Soderstrom G. The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin. Biochemical Journal 1981, 193:395-400.
41. Carter C.J., Kelton J.G., Hirsh J., Cerskus A., Santos A.V., Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982, 59:1239-1245.
42. Maddineni J., Walenga J.M., Jeske W.P., et al. Product individuality of commercially available low-molecular-weight heparins and their generic versions: therapeutic implications. Clinical and Applied Thrombosis/Hemostasis 2006, 12:267-276.
43. Walenga J.M., Jackson C.M., Kessler C.M. Low molecular weight heparins differ substantially: impact on developing biosimilar drugs. Seminars in Thrombosis and Hemostasis 2011, 37:322-327.
44. US Food and Drug Administration Guidance for industry Scientific considerations in demonstrating biosimilarity to a reference product February 2012, Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf [accessed 30.03.13].
45. Arixtra (fondaparinux sodium) solution for subcutaneous injection [package insert] 2011, GlaxoSmithKline, Research Triangle Park, NC.
46. Eliquis [package insert] 2012, Bristol-Myers Squibb Company, Princeton, NJ.
47. Xarelto [package insert] 2013, Janssen Pharmaceuticals, Inc., Titusville, NJ.
48. Kearon C., Akl E.A., Comerota A.J., et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012, 141:e419S-e494S.
49. Ansell J. Factor Xa or thrombin: is factor Xa a better target?. Journal of Thrombosis and Haemostasis 2007, 5 Suppl. 1:60-64.
50. Gomez-Outes A., Suarez-Gea M.L., Lecumberri R., Rocha E., Pozo-Hernandez C., Vargas-Castrillon E. New parenteral anticoagulants in development. Therapeutic Advances in Cardiovascular Disease 2011, 5:33-59.
51. Falkon L., Gari M., Barbanoj M., Amiral J., Fontcuberta J. Tissue factor pathway inhibitor and anti-FXa kinetic profiles of a new low-molecular-mass heparin, Bemiparin, at therapeutic subcutaneous doses. Blood Coagulation and Fibrinolysis 1998, 9:137-141.
52. Lassen M.R., Fisher W., Mouret P., et al. Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVE-KNEE. Journal of Thrombosis and Haemostasis 2012, 10:822-832.
53. Kakkar A.K., Agnelli G., Fisher W.D., et al. The ultra-low-molecular-weight heparin semuloparin for preventions of venous thromboembolism in patients undergoing major abdominal surgery. Blood 2010, 116:188. [abstract 188; oral presentation].
54. Griffiths G.O., Burns S., Noble S.I., Macbeth F.R., Cohen D., Maughan T.S. FRAGMATIC: a randomised phase III clinical trial investigating the effect of fragmin added to standard therapy in patients with lung cancer. BMC Cancer 2009, 9:355.
55. Riess H., Pelzer U., Deutschinoff G., et al. A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): results of the CONKO 004 trial. 2009 Annual Meeting of the American Society of Clinical Oncology 2009, [abstract LBA4506].
56. Riess H., Pelzer U., Hilbig A., et al. Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy. BMC Cancer 2008, 8:361.
57. Samama M.M., Cohen A.T., Darmon J.Y., et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. New England Journal of Medicine 1999, 341:793-800.
58. Alikhan R., Cohen A.T., Combe S., et al. Prevention of venous thromboembolism in medical patients with enoxaparin: a subgroup analysis of the MEDENOX study. Blood Coagulation and Fibrinolysis 2003, 14:341-346.
59. Palumbo A., Cavo M., Bringhen S., et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. Journal of Clinical Oncology 2011, 29:986-993.
60. Sakon M., Kobayashi T., Shimazui T. Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: results from a multicenter, randomized, open-label study. Thrombosis Research 2010, 125:e65-e70.
61. Hull R.D., Schellong S.M., Tapson V.F., et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Annals of Internal Medicine 2010, 153:8-18.
62. Simonneau G., Laporte S., Mismetti P., et al. A randomized study comparing the efficacy and safety of nadroparin 2850IU (0.3mL) vs. enoxaparin 4000IU (40mg) in the prevention of venous thromboembolism after colorectal surgery for cancer. Journal of Thrombosis and Haemostasis 2006, 4:1693-1700.
63. Goldhaber S.Z., Dunn K., Gerhard-Herman M., Park J.K., Black P.M. Low rate of venous thromboembolism after craniotomy for brain tumor using multimodality prophylaxis. Chest 2002, 122:1933-1937.
64. Bergqvist D., Agnelli G., Cohen A.T., et al. Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. New England Journal of Medicine 2002, 346:975-980.
65. Baykal C., Al A., Demirtas E., Ayhan A. Comparison of enoxaparin and standard heparin in gynaecologic oncologic surgery: a randomised prospective double-blind clinical study. European Journal of Gynaecological Oncology 2001, 22:127-130.
66. Dickinson L.D., Miller L.D., Patel C.P., Gupta S.K. Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery 1998, 43:1074-1081.
67. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. British Journal of Surgery 1997, 84:1099-1103. ENOXACAN Study Group.
68. Gondret R., Dominici L., Angelard B., et al. Safety of preoperative enoxaparin in head and neck cancer surgery. Head & Neck 1995, 17:1-6.
69. Larocca A., Cavallo F., Bringhen S., et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012, 119:933-939.
70. Agnelli G., Gussoni G., Bianchini C., et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncology 2009, 10:943-949.
71. Perry S.L., Bohlin C., Reardon D.A., et al. Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients. Journal of Neuro-Oncology 2009, 95:129-134.
72. Perry J.R., Julian J.A., Laperriere N.J., et al. PRODIGE: a randomized placebo-controlled trial of dalteparin low molecular weight heparin (LMWH) thromboprophylaxis in patients with newly diagnosed malignant glioma. Journal of Thrombosis and Haemostasis 2010, 8:1959-1965.
73. Robins H.I., O'Neill A., Gilbert M., et al. Effect of dalteparin and radiation on survival and thromboembolic events in glioblastoma multiforme: a phase II ECOG trial. Cancer Chemotherapy and Pharmacology 2008, 62:227-233.
74. Sideras K., Schaefer P.L., Okuno S.H., et al. Low-molecular-weight heparin in patients with advanced cancer: a phase 3 clinical trial. Mayo Clinic Proceedings 2006, 81:758-767.
75. Leizorovicz A., Cohen A.T., Turpie A.G., Olsson C.G., Vaitkus P.T., Goldhaber S.Z. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004, 110:874-879.
76. Maxwell G.L., Synan I., Dodge R., Carroll B., Clarke-Pearson D.L. Pneumatic compression versus low molecular weight heparin in gynecologic oncology surgery: a randomized trial. Obstetrics and Gynecology 2001, 98:989-995.
77. Maraveyas A., Waters J., Roy R., et al. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. European Journal of Cancer 2012, 48:1283-1292.
78. Haas S.K., Freund M., Heigener D., et al. Low-molecular-weight heparin versus placebo for the prevention of venous thromboembolism in metastatic breast cancer or stage III/IV lung cancer. Clinical and Applied Thrombosis-Hemostasis 2012, 18:159-165.
79. Kakkar V.V., Balibrea J.L., Martinez-Gonzalez J., Prandoni P. Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. Journal of Thrombosis and Haemostasis 2010, 8:1223-1229.
80. Agnelli G., George D.J., Kakkar A.K., et al. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. New England Journal of Medicine 2012, 366:601-609.
81. Lyman G.H., Khorana A.A., Kuderer N.M., et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: american society of clinical oncology clinical practice guideline update. Journal of Clinical Oncology 2013, 31:2189-2204.
82. Streiff M.B., Bockenstedt P.L., Cataland S.R., et al. Venous thromboembolic disease. Journal of the National Comprehensive Cancer Network 2011, 9:714-777.
83. Kahn S.R., Lim W., Dunn A.S., et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012, 141(2 Suppl.):e195S-e226S.
84. Hanna D.L., White R.H., Wun T. Biomolecular markers of cancer-associated thromboembolism. Critical Reviews in Oncology/Hematology 2013, March 20, epub ahead of print.
85. Khorana A.A., Kuderer N.M., Culakova E., Lyman G.H., Francis C.W. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008, 111:4902-4907.
86. Ay C., Dunkler D., Marosi C., et al. Prediction of venous thromboembolism in cancer patients. Blood 2010, 116:5377-5382.
87. Bijsterveld N.R., Moons A.H., Boekholdt S.M., et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002, 106:2550-2554.