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Thromb Haemost 2003; 89(04): 674-680
DOI: 10.1055/s-0037-1613574
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis

Vijay V. Kakkar
1   Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, U.K.
,
Milena Gebska
1   Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, U.K.
,
Zbigniew Kadziola
1   Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, U.K.
,
Neelam Saba
1   Thrombosis Research Institute, Emmanuel Kaye Building, Chelsea, London, U.K.
,
Pilar Carrasco
2   Laboratorios Farmaceuticos Rovi S.A., Madrid, Spain
,
on behalf of the Bemiparin Investigators › Author Affiliations Financial support: Supported by a grant from Laboratorios Farmaceuticos Rovi S.A., Madrid, Spain.
Further Information

Publication History

Received 14 November 2002

Accepted after revision 28 January 2003

Publication Date:
07 December 2017 (online)

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Summary

Low molecular weight heparins (LMWHs) are frequently used during acute treatment of deep vein thrombosis, but their utility for long-term treatment needs to be defined.

In this multi-centre trial, 378 patients with acute deep vein thrombosis were randomised to intravenous unfractionated heparin (group A), once daily subcutaneous LMWH (bemiparin) for one week (group B) or once daily bemiparin in a therapeutic dose for one week followed by a maintenance dose for 12 weeks (group C).

Fifty-two per cent of patients in group A, 72% of group B and 72% of group C showed venographic reduction in thrombus size assessed objectively on day 14; 20% greater improvement in group B and C indicates not only non-inferiority of bemiparin (p = 0.00003) but also superiority (p = 0.004) compared to UFH. Day 84 venographic or Doppler sonographic recanalisation of the affected veins was demonstrated in 75.3%, 79.8% and 81.5% in groups A, B and C respectively. Mortality, recurrent thromboembolic events and bleeding were similar in the three groups.

Both bemiparin regimens were more effective than UFH in reducing thrombus size during the acute phase of treatment. The efficacy in terms of recurrence of venous thromboembolism and safety of Bemiparin is similar to UFH. Bemiparin is also an effective alternative to warfarin for long-term treatment.

Keywords

Heparin - deep vein thrombosis - treatment
 

  • References

  • 1 Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin): results of a double-blind randomised study. Circulation 1989; 80: 935-40.
    CrossrefPubMedGoogle Scholar
  • 2 A randomised trial of subcutaneous low molecular weight heparin (CY216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis: a collaborative European multicentre study. Thromb Haemost 1991; 65: 251-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Holmstrom MC, Berglund MC, Granquist BS, Bratt G, Tornebohm E, Lockner D. Fragmin once or twice daily subcutaneously in the treatment of deep venous thrombosis of the leg. Thromb Res 1992; 67: 49-55.
    CrossrefPubMedGoogle Scholar
  • 4 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: 975-82.
    CrossrefPubMedGoogle Scholar
  • 5 Lindmarker P, Holmstrom M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1994; 72: 186-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Prandoni P, Lensing AWA, Buller HR. et al. Comparison of subcutaneous low molecular weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-5.
    CrossrefPubMedGoogle Scholar
  • 7 Lopaciuk S, Meissner AJ, Filipecki S. et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis; a Polish multicenter trial. Thromb Haemost 1992; 68: 14-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 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: 1541-6.
    CrossrefPubMedGoogle Scholar
  • 9 Fiessinger JN, Lopez-Fernandez M, Gatterer E. et al. Once-daily sub-cutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost 1996; 76: 195-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Partsch H, Kechavarz B, Mostbeck A, Kohn H, Lipp C. Frequency of pulmonary embolism in patients who have iliofemoral deep vein thrombosis and are treated with once or twice daily low molecular weight heparin. J Vasc Surg 1996; 24: 774-82.
    CrossrefPubMedGoogle Scholar
  • 11 The Columbus Investigators. Low molecular weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med 1997; 337: 657-62.
    CrossrefPubMedGoogle Scholar
  • 12 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: 677-81.
    CrossrefPubMedGoogle Scholar
  • 13 Koopman MMW, 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. N Engl J Med 1996; 334: 682-7.
    CrossrefPubMedGoogle Scholar
  • 14 Charbonnier BA, Fiessinger JN, Banga JD, Wenzel E, d’Azemar P, Sagnard L. Comparison of a once daily with a twice daily subcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. Thromb Haemost 1998; 79: 897-901.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Spiro TE. A multicenter clinical trial comparing once and twice daily subcutaneous exoxaparin and intravenous heparin in the treatment of acute deep vein thrombosis. Thromb Haemost 1997; 77 suppl 373-4. abstract
    PubMedGoogle Scholar
  • 16 Kirchmaier CM, Wolf H, Schafer H, Ehlers B, Breddin HK. Efficacy of low molecular weight heparin administered intravenously or subcutaneously in comparison with intravenous unfractionated heparin in the treatment of deep venous thrombosis. Int Angiol 1998; 17: 135-45.
    PubMedGoogle Scholar
  • 17 Breddin HK, Hach-Wunderle V, Nakov R, Kakkar VV. Effects of low molecular weight heparin on thrombus regression and recurrent thromboembolism in patients with deep vein thrombosis. N Engl J Med 2001; 344: 628-31.
    PubMedGoogle Scholar
  • 18 Bratt G, Rornebohm E, Granqvist S, Aberg W, Lockner D. A comparison between low molecular weight heparin (Kabi 2165) and standard heparin in the intravenous treatment of deep vein thrombosis. Thromb Haemost 1985; 54: 813-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Holm HA, Ly B, Handeland GF. et al. Subcutaneous heparin treatment of deep venous thrombosis: a comparison of unfractionated and low molecular weight heparin. Haemostasis 1986; 16 (Suppl. 02) Suppl 30-7.
    PubMedGoogle Scholar
  • 20 Faivre R, Neuhart Y, Kieffer Y. et al. A new treatment of deep venous thrombosis: low molecular weight heparin fractions. Randomised study. Presse Med 1988; 17: 197-200.
    PubMedGoogle Scholar
  • 21 Bratt G, Aberg W, Johnansson M, Tornebohm E, Granqvist S, Lockner D. Two daily subcutaneous injections of Fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT). Thromb Haemost 1990; 64: 506-10.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Duroux P. A Collaborative European Multicentre Study: a randomised trial of subcutaneous low molecular weight heparin (CY216) compared with intravenous unfractioanted heparin in the treatment of deep vein thrombosis. Thromb Haemost 1991; 65: 251-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Luomanmaki K, Granqvist S, Hallert C. et al. A multicentre comparison of once-daily subcutaneous dalteparin (low molecular weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Intern Med 1996; 240: 85-92.
    CrossrefPubMedGoogle Scholar
  • 24 Harenberg J, Schmidt JA, Koppenhagen K. et al. Fixed-dose, body weight-independent subcutaneous LMW heparin versus adjusted dose unfractionated intravenous heparin in the initial treatment of proximal venous thrombosis. Thromb Haemost 2000; 83: 652-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Merli G, Spiro TE, Olsson CG. et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001; 134: 191-202.
    CrossrefPubMedGoogle Scholar
  • 26 Pini M, Aiello S, Manotti C. et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 1994; 72: 191-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Das SK, Cohen AT, Edmonson RA, Melissari E, Kakkar VV. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomised trial. World J Surg 1996; 20: 521-7.
    CrossrefPubMedGoogle Scholar
  • 28 Lopaciuk S, Bielska-Falda H, Noszczyk W, Bielawiec M, Witkiewicz W, Filipecki S. et al. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb Haemost 1999; 81: 26-31.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Veiga F, Escriba A, Maluenda MP, Lopez Rubio M, Margalet I, Lezana A, Gallego J, Ribera JM. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomised trial. Thromb Haemost 2000; 84: 559-64.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Lopez-Beret P, Orgaz A, Fontcuberta J, Doblas M, Martinez A, Lozano G, Romero A. Low molecular weight heparin versus oral anticoagulants in the long-term treatment of deep venous thrombosis. J Vasc Surg 2000; 33: 77-90.
    PubMedGoogle Scholar
  • 31 Farrington CT, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non zero risk difference or non-unity relative risk. Stat Med 1990; 9: 1447-54.
    CrossrefPubMedGoogle Scholar
  • 32 Marder VJ, Soulen RL, Atichartakarn V. et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018-29.
    PubMedGoogle Scholar
  • 33 Blackwelder WC. “Proving the null hypothesis” in clinical trials. Control Clin Trials 1982; 3: 345-53.
    CrossrefPubMedGoogle Scholar
  • 34 Yanagawa T, Tango T, Hicjima Y. Mantel-Haenszel-type tests for testing equivalence or more than equivalence in comparative clinical trials. Biometrics 1994; 50: 859-64.
    CrossrefPubMedGoogle Scholar
  • 35 Van Dreden P, Grasley M, Cost H. Total and free levels of tissue factor pathway inhibitor: a risk factor in patients with factor V Leiden?. Blood Coagul Fibrinolysis 1999; 10: 115-6.
    CrossrefPubMedGoogle Scholar
  • 36 Kakkar VV, Hoppenstead D, Fareed J, Kadziola Z. et al. Randomised trial of different regimens of heparin and in-vivo thrombin generation in acute deep vein thrombosis. Blood 2002; 15.99 (06) 1965-70.
    PubMedGoogle Scholar
  • 37 Westmuckett AD, Lupu F, Kakkar VV, Hanuso J, Lupu C. Bemiparin and fluid flow modulates the expression, activity and release of Tissue Factor Pathway Inhibitor in human endothelium. Thromb Haemost 2001; 6: 1547-54.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Breddin HK, Kadziola Z, Scully M, Nakov R, Misselwitz F, Kakkar VV. Risk factors and coagulation parameters to phlebographic response and clinical outcome in the treatment of acute deep vein thrombosis. Thromb Haemost 2003; 89: 272-7.
    Article in Thieme ConnectPubMedGoogle Scholar