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Thromb Haemost 2013; 110(01): 14-22
DOI: 10.1160/TH12-12-0931
Review Article
Schattauer GmbH

Long-term treatment of deep-vein thrombosis with low-molecular-weight heparin: An update of the evidence

Russell D. Hull
1   University of Calgary, Calgary, Alberta, Canada
,
Grace Townshend
2   Watermeadow Medical, Witney, UK
› Author Affiliations
Further Information

Publication History

Received: 19 December 2012

Accepted after major revision: 21 March 2013

Publication Date:
30 November 2017 (online)

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Summary

This article reviews updated evidence-based knowledge on long-term treatment of deep-vein thrombosis (DVT) with low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs). Eleven trials were identified comparing the two treatments in a broad spectrum of patients with DVT and with >100 study participants. Four comparative trials were identified in patients with cancer and DVT (in whom anticoagulation treatment is more complex and bleeding complications more frequent). In the 11 trials in broad patient populations, LMWHs were as effective as VKAs in preventing recurrent venous thromboembolism (VTE), and there were no consistent differences in the incidence of bleeding complications during long-term treatment. In patients with cancer, VTE recurrence was significantly reduced with LMWH versus VKA in two studies, while major bleeding complications did not differ between groups in any of the four trials. Current evidence-based European and American guidelines recommend LMWH over VKA for the long-term treatment of DVT in patients with cancer. LMWH and VKA are recommended over the new oral anticoagulant drugs, for which there are limited data on use in long-term treatment. Post-thrombotic syndrome (PTS), a common complication of DVT, causes considerable morbidity. Long-term use of tinzaparin reduced the risk of PTS compared with VKA in one trial, and a meta-analysis of nine studies in total demonstrated a consistently favourable effect of LMWHs versus VKA on PTS-related outcomes. Given the limited treatment options available for PTS, this suggests that LMWHs provide a useful therapeutic option in any patient particularly at risk of developing PTS.

Keywords

Deep-vein thrombosis - low-molecular-weight heparin - tinzaparin - post-thrombotic syndrome
 

  • References

  • 1 Kearon C, Akl EA, Comerota AJ. 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 (Suppl. 02) e419S-94S.
    CrossrefPubMedSearch in Google Scholar
  • 2 van der Heijden JF, Hutten BA, Büller HR. et al. Vitamin K antagonists or low-molecular-weight heparin for the long-term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev 2002; 01: CD002001.
    PubMedSearch in Google Scholar
  • 3 Andras A, Sala ATenna, Crawford F. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev 2012; Oct 17; 10: CD002001. doi:10.1002/14651858.CD002001.pub2.
    PubMedSearch in Google Scholar
  • 4 Cardiovascular Disease Educational and Research Trust. et al. Prevention and treatment of venous thromboembolism. International Consensus Statement (Guidelines according to scientific evidence). Int Angiol 2006; 25: 101-161.
    PubMedSearch in Google Scholar
  • 5 Hull RD, Liang J, Townshend G. Long-term low-molecular-weight heparin and the post-thrombotic syndrome: A systematic review. Am J Med 2011; 124: 756-765.
    CrossrefPubMedSearch in Google Scholar
  • 6 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: 191-197.
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Das SK, Cohen AT, Edmondson RA. et al. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial. World J Surg 1996; 20: 521-526.
    CrossrefPubMedSearch in Google Scholar
  • 8 Lopaciuk S, Bielska-Falda H, Noszczyk W. et al. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb Haemost 1999; 81: 26-31.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Gónzalez-Fajardo JA, Arreba E, Castrodeza J. et al. Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 1999; 30: 283-292.
    CrossrefPubMedSearch in Google Scholar
  • 10 Veiga F, Escriba A, Maluenda M P. 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: 559-564.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 López-Beret P, Orgaz A, Fontcuberta J. et al. Low molecular weight heparin versus oral anticoagulants in the long-term treatment of deep venous thrombosis. J Vasc Surg 2001; 33: 77-90.
    CrossrefPubMedSearch in Google Scholar
  • 12 Kakkar VV, Gebska M, Kadziola Z. et al. Bemiparin Investigators. Low-molecular-weight heparin in the acute and long-term treatment of deep vein thrombosis. Thromb Haemost 2003; 89: 674-680.
    PubMedSearch in Google Scholar
  • 13 Daskalopoulos ME, Daskalopoulou SS, Tzortzis E. et al. Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): a prospective randomized trial. Eur J Vasc Endovasc Surg 2005; 29: 638-650.
    CrossrefPubMedSearch in Google Scholar
  • 14 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: 72-82.
    CrossrefPubMedSearch in Google Scholar
  • 15 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: 762-769.
    CrossrefPubMedSearch in Google Scholar
  • 16 Romera A, Cairols MA, Vila-Coll R. et al. A randomised open-label trial comparing long-term sub-cutaneous low-molecular-weight heparin compared with oral-anticoagulant therapy in the treatment of deep venous thrombosis. Eur J Vasc Endovasc Surg 2009; 37: 349-356.
    CrossrefPubMedSearch in Google Scholar
  • 17 Romera-Villegas A, Cairols-Castellote MA, Vila-Coll R. et al. Long-term use of different doses of low-molecular-weight heparin versus vitamin K antagonists in the treatment of venous thromboembolism. Ann Vasc Surg 2010; 24: 628-639.
    CrossrefPubMedSearch in Google Scholar
  • 18 Laporte S, Bertoletti L, Romera A. et al. Long-term treatment of venous thromboembolism with tinzaparin compared to vitamin K antagonists: A meta-analysis of 5 randomized trials in non-cancer and cancer patients. Thromb Res 2012; 130: 853-858.
    CrossrefPubMedSearch in Google Scholar
  • 19 Pérez-de-Llano LA, Leiro-Fernández V, Golpe R. et al. Comparison of tinzaparin and acenocoumarol for the secondary prevention of venous thromboembolism: a multicentre, randomized study. Blood Coagul Fibrinolysis 2010; 21: 744-749.
    PubMedSearch in Google Scholar
  • 20 Hutten BA, Prins MH, Gent M. et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000; 18: 3078-3083.
    CrossrefPubMedSearch in Google Scholar
  • 21 Prandoni P, Lensing AW, Piccioli A. et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484-3488.
    CrossrefPubMedSearch in Google Scholar
  • 22 Lee AY, Levine MN, Baker RI. et al CLOT investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-153.
    CrossrefPubMedSearch in Google Scholar
  • 23 Meyer G, Marjanovic Z, Valcke J. et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162: 1729-1735.
    CrossrefPubMedSearch in Google Scholar
  • 24 Hull RD, Pineo GF, Brant RF. et al LITE Trial Investigators. Long-term LMWH versus usual-care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119: 1062-1072.
    CrossrefPubMedSearch in Google Scholar
  • 25 Deitcher SR, Kessler CM, Merli G. et al ONCENOX Investigators. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 2006; 12: 389-396.
    CrossrefPubMedSearch in Google Scholar
  • 26 Akl EA, Labedi N, Barba M. et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2011; Jun 15; (6) CD006650. doi:10.1002/14651858.CD006650.pub3.
    PubMedSearch in Google Scholar
  • 27 Farge D, Debourdeau P, Beckers M. et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11: 56-70.
    CrossrefPubMedSearch in Google Scholar
  • 28 Lyman GH, Khorana AA, Falanga A. et al American Society of Clinical Oncology. American Society of Clinical Oncology Guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007; 25: 5490-5505.
    CrossrefPubMedSearch in Google Scholar
  • 29 Mandalà M, Falanga A, Roila F. ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol 2011; 22 (Suppl. 06) vi85-92.
    PubMedSearch in Google Scholar
  • 30 Imberti D, Agnelli G, Ageno W. et al. Clinical characteristics and management of cancer-associated acute venous thromboembolism: findings from the MASTER registry. Haematologica 2008; 93: 273-278.
    CrossrefPubMedSearch in Google Scholar
  • 31 Debourdeau P, Beckers M, Gérome P. et al. How to improve the implementation of guidelines on cancer-related thrombosis. Expert Rev Anticancer Ther 2011; 11: 473-483.
    CrossrefPubMedSearch in Google Scholar
  • 32 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedSearch in Google Scholar
  • 33 Bauersachs R, Berkowitz SD, Brenner B. et al. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499-2510.
    CrossrefPubMedSearch in Google Scholar
  • 34 Buller HR, Prins MH, Lensing AWA. et al. EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedSearch in Google Scholar
  • 35 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 (Suppl. 06) 454S-545S.
    CrossrefPubMedSearch in Google Scholar
  • 36 Kahn SR, Shrier I, Julian JA. et al. Determinants and time course of the post-thrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008; 149: 698-707.
    CrossrefPubMedSearch in Google Scholar
  • 37 Kahn SR, Partsch H, Vedantham S. et al. on behalf of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of post-thrombotic syndrome of the leg for use in clinical investigations: a recommendation for standardization. J Thromb Haemost 2009; 07: 879-883.
    CrossrefPubMedSearch in Google Scholar
  • 38 Nicolaides AN, Allegra C, Bergan J. et al. Consensus Statement. Management of chronic venous disorders of the lower limbs: Guidelines according to scientific evidence. Int Angiol 2008; 27: 1-59.
    PubMedSearch in Google Scholar
  • 39 Chitsike RS, Rodger MA, Kovacs MJ. et al. Risk of post-thrombotic syndrome after subtherapeutic warfarin anticoagulation for a first unprovoked deep vein thrombosis: results from the REVERSE study. J Thromb Haemost 2012; 10: 2039-2044.
    CrossrefPubMedSearch in Google Scholar
  • 40 Daskalopoulos ME, Daskalopoulou SS, Prezas L. et al. Three-year follow-up of long-term deep venous thrombosis treatment with the low molecular weight heparin tinzaparin. Angiology 2006; 25 (Suppl. 01) 76.
    PubMedSearch in Google Scholar
  • 41 Daskalopoulos ME, Daskalopoulou SS, Liapis CD. Tinzaparin in longterm treatment of deep venous thrombosis. Eur J Vasc Endovasc Surg 2007; 34: 353-354.
    CrossrefPubMedSearch in Google Scholar
  • 42 González-Fajardo JA, Martin-Pedrosa M, Castrodeza J. et al. Effect of the anticoagulant therapy in the incidence of post-thrombotic syndrome and recurrent thromboembolism: Comparative study of enoxaparin versus coumarin. J Vasc Surg 2008; 48: 953-959.
    CrossrefPubMedSearch in Google Scholar
  • 43 Hull R, Butcher P. Value of patient self-assessment in the diagnosis and monitoring of post-thrombotic syndrome: the Patient-Tracked Symptoms questionnaire. Clin Appl Thromb Hemost 2012; 18: 345-350.
    CrossrefPubMedSearch in Google Scholar
  • 44 Cook DJ, Guyatt GH, Juniper E. et al. Interviewer versus self-administered questionnaires in developing a disease-specific, health-related quality of life instrument for asthma. J Clin Epidemiol 1993; 46: 529-534.
    CrossrefPubMedSearch in Google Scholar
  • 45 Cohen SB, Strand V, Aguilar D. et al. Patient- versus physician-reported outcomes in rheumatoid arthritis patients treated with recombinant interleukin-1 receptor antagonist (anakinra) therapy. Rheumatology 2004; 43: 704-711.
    CrossrefPubMedSearch in Google Scholar
  • 46 Ballard KD, Seaman HE, de Vries CS. et al. Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study—Part 1. Br J Obst Gynecol 2008; 115: 1382-1391.
    CrossrefPubMedSearch in Google Scholar
  • 47 Fransen GA, Janssen MJ, Muris JW. et al. Measuring the severity of upper gastrointestinal complaints: does GP assessment correspond with patients’ self-assessment?. Fam Pract 2007; 24: 252-258.
    CrossrefPubMedSearch in Google Scholar
  • 48 Evangelou E, Tsianos G, Ioannidis J P. Doctors’ versus patients’ global assessments of treatment effectiveness: empirical survey of diverse treatments in clinical trials. Br Med J 2008; 336: 1287-1290.
    CrossrefPubMedSearch in Google Scholar
  • 49 Noble S, Finlay I. Is long-term low-molecular-weight heparin acceptable to palliative care patients in the treatment of cancer related venous thromboembolism? A qualitative study. Palliat Med 2005; 19: 197-201.
    CrossrefPubMedSearch in Google Scholar