Download PDF
Thromb Haemost 1999; 82(S 01): 139-147
DOI: 10.1055/s-0037-1615573
Commentaries
Schattauer GmbH

Low-molecular Weight Heparins in Venous and Arterial Thrombotic Disease

Nick R. Bijsterveld
1   From the Department of Vascular Medicine, Academic Medical Centre
3   Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
,
Rohan Hettiarachchi
2   Department of Clinical Epidemiology & Biostatistics, Academic Medical Centre
,
Ron Peters
3   Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
,
Martin H. Prins
2   Department of Clinical Epidemiology & Biostatistics, Academic Medical Centre
,
Marcel Levi
1   From the Department of Vascular Medicine, Academic Medical Centre
,
Harry R. Büller
1   From the Department of Vascular Medicine, Academic Medical Centre
› Author Affiliations
Further Information

Publication History

Publication Date:
14 December 2017 (online)

    Permissions and Reprints

Summary

Introduction: Since the introduction of low-molecular-weight heparins (LMWHs) in the early 1980's, the use of these compounds has been extensively investigated as a substitute for unfractionated heparin (UFH) in patients with venous and arterial thrombotic diseases. LMWHs have several advantages as compared to UFH, such as the subcutaneous route of administration, the predictable anticoagulant response and the lack of the need for laboratory monitoring. The present systematic review evaluates randomised clinical trials which investigated the efficacy and safety of LMWH in the acute treatment of venous thromboembolims, myocardial infarction, unstable coronary syndromes and ischemic stroke.

Methods: A computerised and manual search was performed to identify all relevant clinical trials. All randomised studies, with an a priori defined study population, clinical outcome measurement and adequate follow-up, were reviewed by two independent assessors. Whenever possible a common effect estimate of the included studies was calculated.

Results: Thirteen studies in approximately 4000 patients with acute venous thromboembolism revealed an odds ratio for the 3-month recurrent thromboembolism rate and major bleeding complications during exposure of 0.77 (C.I. 0.57-1.04) and 0.61 (C.I. 0.39-0.95), respectively, in favour of LMWH as compared to UFH. In patients with acute myocardial infarction, one study suggested a reduction in the incidence of reinfarction and cardiac death in LMWH recipients compared to UFH, while a placebo-controlled study revealed no beneficial effect of LMWH on these outcomes. In six studies including over 7000 patients with acute unstable coronary syndromes, there was an odds ratio for recurrent angina, myocardial infarction, urgent revascularisation and major bleedings of 0.88 (C.I. 0.76-1.01), 0.84 (C.I. 0.69-1.01), 0.83 (C.I. 0.70-0.99), 1.09 (C.I. 0.70-1.70), respectively, in favour of LMWH compared to UFH. The three studies comparing LMWH treatment with placebo in approximately 1000 patients with acute ischemic stroke revealed an odds ratio for the 10-day recurrent stroke, death or disability after 3 months and major bleeding complications of 0.68 (C.I. 0.41-1.13), 0.94 (C.I. 0.78-1.15), 2.92 (C.I. 1.88-4.55), respectively.

Conclusion: Fixed-dose subcutaneous LMWH appears to be a safe and effective alternative for dose-adjusted intravenous heparin in the treatment of patients with acute venous thrombotic disease as well as in patients with acute unstable coronary syndromes. The effectiveness of LMWH in patients with acute myocardial infarction remains unclear. There seems to be no beneficial effect of LMWH treatment as compared to placebo in patients with acute ischemic stroke, while the risk of major bleeding was clearly increased.

Key words

Venous thromboembolism - unstable coronary syndromes - cerebrovascular disorders - myocardial infarction - meta-analysis
 

  • References

  • 1 Weitz J. Low-molecular weight heparins. N Engl J Med 1997; 377 (10) 688-98.
    PubMedGoogle Scholar
  • 2 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
  • 3 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
  • 4 Moher D, Pham B, Jones A. et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analysis?. Lancet 1998; 352: 609-13.
    CrossrefPubMedGoogle Scholar
  • 5 Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719-48.
    PubMedGoogle Scholar
  • 6 Faivre R, Neuhart Y, Kieffer Y. et al. Un nouveau traitement des thromboses veineuses profondes: les fractions d'heparine de bas poids moleculaire. Etude randomisee. Presse Med 1988; 17: 197-200.
    PubMedGoogle Scholar
  • 7 Duroux P. 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 Multi-centre Study: Thromb Haemost 1991; 65: 51-6.
    PubMedGoogle Scholar
  • 8 Hull RD, Raskob GL, 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
  • 9 Prandoni P, Lensing AWA, BYller 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
  • 10 Lopaciuk S, Meissner J, 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
  • 11 Simonneau G, Charbonnier B, Decousus H. et al. Subcutaneous fixed dose of enoxaparine versus intravenous adjusted dose of unfractionated heparin in the treatment of deep vein thrombosis. Arch Intern Med 1993, 153 541-6.
    PubMedGoogle Scholar
  • 12 Lindmarker P, Holmstrom M, Granqvist S, Johnson H, Lockner D. Comparison of oncedaily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemost 1994; 72: 186-90.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Fiessinger JN, LopezFernandez M, Gatterer E. et al. Oncedaily subcutaneous 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
  • 14 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
  • 15 Simonneau G, Sors H, Charbonnier B. et al. A comparison of low-molecular weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med 1997; 337: 663-9.
    CrossrefPubMedGoogle Scholar
  • 16 Decousus H, Leizorovicz A, Parent F. et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 1998; 338: 409-15.
    CrossrefPubMedGoogle Scholar
  • 17 Hettiarachchi RJK, Prins MH, Lensing AWA, Buller HR. Low molecular weight heparin versus unfractionated heparin in the initial treatment of venous thromboembolism. Curr Op Pulm Med 1998; 4: 220-5.
    PubMedGoogle Scholar
  • 18 Handeland GF, Abildgaard U, Holm HA, Arnesen KE. Dose adjusted heparin treatment of deep venous thrombosis. a comparison of unfractionated and low molecular weight heparin. Eur J Clin Pharmacol 1990; 39: 107-12.
    PubMedGoogle Scholar
  • 19 Lockner D, Bratt G, Tornebohm E, Aberg W, Granqvist S. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis. Haemostasis 1986; 16 (suppl) 25-9.
    PubMedGoogle Scholar
  • 20 Luomanmaki K. and the Finnish multicentre group Low molecular weight heparin (Fragmin) once daily vs continuous infusion of standard heparin in the treatment of DVT. Haemostasis. 1994 24. (suppl.1) abstract 248.
    PubMedGoogle Scholar
  • 21 Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Circulation 1989; 80: 935-40.
    CrossrefPubMedGoogle Scholar
  • 22 Harenberg J, Huck K, Bratsch H. et al. Therapeutic application of subcutaneous low-molecular-weight heparin in acute venous thrombosis. Haemostasis 1990; 20: 205-19.
    PubMedGoogle Scholar
  • 23 Notarbartolo A, Salanitri G, Davi G, Averna M, Barbagallo C, Catalano I. Low molecular weight heparin in the short and longterm treatment of deep vein thrombosis in diabetic subjects. Med Prax 1988; 9: 393-405.
    PubMedGoogle Scholar
  • 24 Zanghi M, Morici V, Costanzo M, Astuto L, Salanitri G. Deep vein thrombosis of the legs: new therapy by means of low molecular weight heparins. J Intern Med Res 1988; 16: 474-84.
    PubMedGoogle Scholar
  • 25 Tedoldi A, Botticella F, Maloberti MR. Antithrombophilic effect of low molecular weight heparins in patients with deep vein thrombosis. Clin Trials Metaanalysis 1993; 28: 215-25.
    PubMedGoogle Scholar
  • 26 Bratt G, Aberg W, Johansson 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. Thromb Haemost 1990; 64: 506-10.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Holm HA, Ly B, Handeland GF. et al. subcutaneous heparin treatment of deep vein thrombosis: a comparison of unfractionated and low molecular weight heparin. Haemostasis. 1986 16. (suppl) 307.
    PubMedGoogle Scholar
  • 28 Bratt G, Tornebohm 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 (4) 813-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Vogel G, Machuik M. Efficacy and safety of a low molecular weight heparin (LMW-heparin Sandoz) in patients with deep vein thrombosis. Thromb Haemost. 1987 58. (suppl) abstract 427.
    PubMedGoogle Scholar
  • 30 Fragmin during instability in coronary artery disease (FRISC) study group. Low-molecular-weight heparin during instability in coronary artery disease. Lancet 1996; 347: 561-8.
    CrossrefPubMedGoogle Scholar
  • 31 Klein W, Buchwald A, Hillis SE. et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation 1997; 96 (1) 61-8.
    PubMedGoogle Scholar
  • 32 The Thrombolysis in Myocardial Infarction (TIMI) IIB Trial Investigators. TIMI II B. Presented at the XXth Congress of the European Society of Cardiologie, Vienna, Austria 1998
    PubMedGoogle Scholar
  • 33 Kay R, Wong KS, Yu YL. et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333 (24) 1588-93.
    CrossrefPubMedGoogle Scholar
  • 34 FISS-bis investigators. Double blind placebo-controlled study of two dosages of nadroparin calcium (Fraxiparin) in the treatment of acute ischemic stroke (FISS-BIS). Submitted 1998
    PubMedGoogle Scholar
  • 35 Nilsen DW, Goransson L, Larsen AI, Hetland O, Kierulf P. Systemic thrombin generation and activity resistant to low molecular weight heparin administered prior to streptokinase in patients with acute myocardial infarction. Thromb Haemost 1997; 77 (1) 57-61.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Strandberg LE, Kahan T, Lundin P, Svensson J, Erhardt L. Anticoagulant effects of low-molecular-weight heparin following thrombolytic therapy in acute myocardial infarction: a dose-finding study. Haemostasis 1996; 26 (5) 247-57.
    PubMedGoogle Scholar
  • 37 Nesvold A, Kontny F, Abildgaard U, Dale J. Safety of high doses of low molecular weight heparin (Fragmin) in acute myocardial infarction. A dose-finding study. Thromb Res 1991; 64 (5) 579-87.
    PubMedGoogle Scholar
  • 38 Scala PJ, Thiollet M, Midavaine M. et al. Deep venous thrombosis and left ventricular thrombosis prophylaxis by low molecular weight heparin in acute myocardial infarction. Haemostasis 1990; 20 6 368-9.
    PubMedGoogle Scholar
  • 39 Frostfeldt G, Ahlberg G, Gustafsson G. et al. Low molecular weight heparin (dalteparin) as adjuvant treatment of thrombolysis in acute myocardial infarction; a pilot study: biochemical markers in acute coronary syndromes (BIOMACS II).
    PubMedGoogle Scholar
  • 40 Glick A, Kornowski R, Michowich Y, Koifman B, Roth A, Laniado S, Keren G. Reduction of reinfarction and angina with use of low-molecular-weight heparin therapy after streptokinase (and heparin) in acute myocardial infarction. Am J Cardiol 1996; 77 (14) 1145-8.
    CrossrefPubMedGoogle Scholar
  • 41 Melandri G, Branzi A, Semprini F, Cervi V, Magnani B. Effects of two dosages of subcutaneous low molecular weight heparin (Parnaparin) and of unfractionated heparin on fibrin formation and lipolysis in acute myocardial infarction. Throm Res 1992; 66 (2-3) 141-50
    CrossrefPubMedGoogle Scholar
  • 42 Baird SH, Mc Bride SJ, Trouton TG, Wilson C. Low molecular weight heparin versus unfractionated heparin following Trombolysis for acute myocardial infarction. Presented at the 47th annual scientific session of the American College of Cardiology, Atlanta, USA 1998
    PubMedGoogle Scholar
  • 43 Kontny F, Dale J, Abildgaard U, Pedersen TR. Randomised trial of low molecular weight heparin (dalteparin) in prevention of left ventricular thrombus formation and arterial embolism after acute anterior myocardial infarction: the Fragmin in Acute Myocardial Infarction (FRAMI) Study. J Am Coll Cardiol 1997; 30 (4) 962-9.
    CrossrefPubMedGoogle Scholar
  • 44 The Thrombolysis in Myocardial Infarction (TIMI) 11A Trial Investigators. Dose-ranging trial of enoxaparin for unstable angina: results of TIMI 11A. J Am Coll Cardiol 1997; 29 (7) 1474-82.
    CrossrefPubMedGoogle Scholar
  • 45 Klein W, Buchwald A, Hillis WS. et al. Fragmin in unstable angina pectoris or in non-Q wave acute myocardial infarction (the FRIC study). Fragmin in unstable coronary artery disease. Am J Cardiology 1997; 80 (5A) 30-4E.
    PubMedGoogle Scholar
  • 46 Cohen M, Demers C, Gurfinkel EP. et al. Low-molecular-weight heparins in non-ST-segment elevation ischemia: The ESSENCE trial. Am J Cardiol 1998; 82 (5 B) 19-24L.
    PubMedGoogle Scholar
  • 47 Swahn E, Walletin L. Low-molecular-weight heparin (Fragmin) during instability in coronary artery disease (FRISC). FRISC Study group. Am J Cardiology 1997; 80 (5A) 25-9E.
    PubMedGoogle Scholar
  • 48 Xiao Z. Theroux P.Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998; 97 (3) 251-6.
    CrossrefPubMedGoogle Scholar
  • 49 Lindahl B, Andren B, Ohlsson J, Venge P, Wallentin L. Risk stratification in unstable coronary artery disease. Additive value of troponin T determinations and pre-discharge exercise tests. FRISK Study Group. Eur Heart J 1997; 18 (5) 762-70.
    PubMedGoogle Scholar
  • 50 Cohen M, Demers C, Gurfinkel EP. et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group (ESSENCE). N Engl J Med 1997; 337 (7) 447-52.
    PubMedGoogle Scholar
  • 51 Gurfinkel EP, Manos EJ, Mejail RI, Cerda MA, Duronto EA, Garcia CN, Daroca AM, Mautner B. Low molecular weight heparin versus regular heparin or aspirin in the treatment of unstable angina and silent ischemia. J Am Coll Cardiol 1995; 26 (2) 313-8.
    CrossrefPubMedGoogle Scholar
  • 52 The FRAXIS study group. The FRAXIS study. Presented at the XXth Congress of the European Society of Cardiology, Vienna, Austria 1998
    PubMedGoogle Scholar
  • 53 Suvarna TT, Parikh JA, Keshav R, Pillai MG, Pahlajani DB, Gandhi MJ. Comparison of clinical outcome of fixed-dose subcutaneous low molecular weight heparin (tinzaparin) with conventional heparin in unstable angina: a pilot study. Indian Heart J 1997; 49: 159-62.
    PubMedGoogle Scholar
  • 54 The publication Committee for the Trial ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (Danaparoid), and outcome after acute ischemic stroke. JAMA 1998; 279: 1265-72.
    CrossrefPubMedGoogle Scholar
  • 55 Sandset PM, Dahl T, Stiris M, Rostad B, Scheel B, Abildgaard U. A double-blind and randomised placebo-controlled trial of low molecular weight heparin once daily to prevent deep-vein thrombosis in acute ischemic stroke. Semin Thromb Hemost 1990; 16 Suppl 25-33.
    PubMedGoogle Scholar
  • 56 Prins MH, Gelsema R, Sing AK, van Heerde LR, den Ottolander GJ. Prophylaxis of deep venous thrombosis with a low-molecular-weight heparin (Kabi 2165/Fragmin) in stroke patients. Haemostasis 1989; 19 (5) 245-50.
    PubMedGoogle Scholar
  • 57 Turpie AGG, Hirsh J, Jay RM. et al. Double blind randomised trial of ORG 10172 low-molecular-weight heparinoid in prevention of deep vein thrombosis in thrombotic stroke. Lancet 1987; 523-6.
    PubMedGoogle Scholar
  • 58 Dumas R, Woitinas F, Kutnowski M. et al. A multicenter, double-blind, randomized study to compare the safety and efficacy of once-daily ORG 10172 and twice-daily low-dose heparin in preventing deep-vein thrombosis in patients with acute ischaemic stroke. Age and Ageing 1994; 23: 512-6.
    CrossrefPubMedGoogle Scholar
  • 59 Kay R, Wong KS, Woo J. Pilot study of low-molecular-weight heparin in the treatment of acute ischemic stroke. Stroke 1994; 25 (3) 684-5.
    CrossrefPubMedGoogle Scholar
  • 60 Van den, Belt AGM, Prins MH, Lensing AWA. et al. Fixed dose subcutaneous low molecular weigth heparins versus adjated dose unfractionated heparin in the treatment of venous thromboembolism. The Conchrane Library April 1998
    PubMedGoogle Scholar
  • 61 Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Int Med 1995; 155: 601-7.
    PubMedGoogle Scholar