Summary
There is now ample evidence to indicate that certain low-molecular-weight heparins given subcutaneously can replace continuous intravenous unfractionated heparin for the initial treatment of venous thromboembolism. The low-molecular-weight heparins have a predictably high absorption rate when given subcutaneously and a prolonged duration of action, permitting them to be given by a once or twice daily injection for the prevention or treatment of venous thrombosis. Furthermore, treatment does not require laboratory monitoring, thus eliminating the need for continuous IV infusion and permitting the early discharge of patients with venous thromboembolism. This should eventually lead to the outpatient treatment of venous thromboembolism. Studies to date indicate that low-molecular-weight heparin is more cost-effective than unfractionated heparin in the treatment of venous thromboembolism and the cost effectiveness will be increased by out-of-hospital treatment. At the present time, the findings associated with any individual lowmolecular-weight heparin preparation cannot be extrapolated to different low-molecular-weight heparins, and therefore each must be evaluated in separate clinical trials. The information to date is that low-molecular-weight heparin is safer and more effective than continuous intravenous unfractionated heparin in the treatment of proximal venous thrombosis. The decreased mortality rate seen in two clinical trials, particularly in patients with metastatic cancer, was quite unexpected. This requires further confirmation in larger prospective randomized trials.
Similar content being viewed by others
References
Salzman EW, Deykin D, Shapiro RM, et al. Management of heparin therapy: Controlled prospective trial.N Engl J Med 1986;315:1109–1114.
Wilson JR, Lampman J. Heparin therapy: A randomized prospective study.Am Heart J 1979;97:155–158.
Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis.N Engl J Med 1986;315:1109–1114.
Gallus AS, Jackaman J, Tillett J, et al. Safety and efficacy of warfarin started early after submissive venous thrombosis or pulmonary embolism.Lancet 1986;2:1293–1296.
Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis.N Engl J Med 1990;322: 1260–1264.
Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic levels of heparin therapy in patients with venous thrombosis.Arch Int Med 1992;152:1589–1595.
Hull R, Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.N Engl J Med 1982;307:1676–1681.
Basu D, Gallus A, Hirsh J, et al. A prospective study of value of monitoring heparin treatment with the activated partial thromboplastin time.N Engl J Med 1972;287: 324–327.
Raschke P, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram.Ann Intern Med 1992;327:1128–1133.
Fennerty A, Thomas P, Backhouse G, et al. Audit of control of heparin treatment.Br Med J 1985;290:27.
Wheeler AP, Jaquiss RD, Newman JH. Physician practices in the treatment of pulmonary embolism and deep-venous thrombosis.Arch Intern Med 1988;148:1321.
Hommes DW, Bura A, Mazzolai L, et al. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis.Ann Intern Med 1992;116:279–284.
Brill-Edwards P, Ginsberg S, Johnston M, et al. Establishing a therapeutic range for heparin therapy.Ann Intern Med 1993;119:104–109.
Hull R, Brant R, Pineo G, et al. Heparin (H) resistance as a predictor of recurrent venous thromboembolism (RVTE) (abstract).Blood 1993;82(10):406.
Verstraete M. Pharmacotherapeutic aspects of unfractionated and low-molecular-weight heparin.Drugs 1990;40: 498–530.
Bara L, Billaud E, Gramond G, et al. Comparative pharmacokinetics of a low-molecular-weight heparin and unfractionated heparin after intravenous and subcutaneous administration.Thromb Res 1985;39:631–636.
Bergqvist D, Hedner U, Sjorin E, et al. Anticoagulant effects of two types of low-molecular-weight heparin administered subcutaneously.Thromb Res 1983;32:381–391.
Bratt G, Tornebohm E, Wildlund L, et al. Low-molecularweight heparin (Kabi 2165; Fragmin): Pharmacokinetics after intravenous and subcutaneous administration in human volunteers.Thromb Res 1986;42:613–620.
Frydman AM, Bara L, LeRoux Y, et al. The antithrombotic activity and pharmacokinetics of enoxaparine, a lowmolecular-weight, in humans given single subcutaneous doses of 20 to 80 mg.J Clin Pharmacol 1988;28:609–618.
Harenberg J, Wurzner B, Zimmermann R, et al. Bioavailability and antagonization of the low-molecular-weight heparin CY216 in man.Thromb Res 1986;44:549–554.
Matzsch T, Bergqvist D, Hedner U. Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers.Thromb Haemost 1987;57: 97–101.
Albada J, Neuwenhuis HK, Sixma JJ. Comparison of intravenous standard heparin and Fragmin in the treatment of venous thromboembolism: A randomized double-blind study.Thromb Res 1987;XX(Suppl VI):Abstract.
Arneson KE, Handeland GF, Abildgaard U, et al. What is the optimal dosage of LMW heparin in the subcutaneous treatment of deep vein thrombosis (abstract)?Thromb Haemost 1987;58:214.
Bratt G, Aberg W, Tornebohm E, et al. Subcutaneous KABI 2165 in the treatment of deep venous thrombosis of the leg.Thromb Res 1987;7(Suppl):24.
Bratt G, Tornebohm E, Granqvist S, et al. A comparison between low-molecular-weight heparin KABI 2165 and standard heparin in the intravenous treatment of deep venous thrombosis.Thromb Haemost 1985;54:813–817.
Holm HA, Ly B, Handeland GF, et al. Subcutaneous heparin treatment of deep venous thrombosis: A comparison of unfractionated and low-molecular-weight heparin.Haemostosis 1986;16:30–37.
Aiach M, Michaud A, Balian JL, et al. A new low-molecularweight heparin derivative, in vitro and in vivo studies.Thromb Res 1983;31:611–621.
Cade JF, Buchanan MR, Boneau B, et al. A comparison of the antithrombotic and haemorrhagic effects of low molecular heparin fractions: The influence of the method of preparation.Thromb Res 1984;35:613–625.
Carter CJ, Kelton JR, Hirsh J, et al. Relationship between the antithrombotic and anticoagulant effects of low-molecular-weight heparin.Thromb Res 1981;21:169–174.
Carter CJ, Kelton JG, Hirsh J, et al. The relationship between the hemorrhagic and antithrombotic properties of low-molecular-weight heparin in rabbits.Blood 1982;59: 1239–1245.
Holmer E, Mattson C, Nilsson S. Anticoagulant and antithrombotic effects of heparin and low-molecular-weight heparin fragments in rabbits.Thromb Res 1982;25:475–485.
Nurmohamed MT, Rosendal FR, Buller HR, et al. Low-molecular-weight heparin in the prophylaxis of venous thrombosis: A meta-analysis.Lancet 1992;340:152–156.
Leizorovicz A, Haugh MC, Chapuis F-R, et al. Low-molecular-weight heparin in prevention of perioperative thrombosis.Br Med J 1992;305:913–920.
Hull RD, Raskob GE, Pineo GF, 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;329:1370–1376.
Kakkar VV, Cohen AT, Edmonson RA, et al. Low molecular weight versus standard heparin for prevention of venous thromboembolism after major abdominal surgery.Lancet 1993;341:259–265.
Thomas DP. Prevention of post-operative thrombosis by low-molecular-weight heparin in patients undergoing hip replacement.Thromb Haemost 1992;67:491–493.
A Collaborative European Multicentre Study. A randomized trial of subcutaneous low-molecular-weight heparin (CY216) compared with intravenous unfractionated heparin in the treatment of deep-vein thrombosis.Thromb Haemost 1991; 65:251–256.
Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low-molecular-weight heparin (Fragmin). Results of a double-blind randomized study.Circulation 1989;80:935–940.
Bratt G, Aberg W, Johansson M, et al. Two daily subcutaneous injections of Fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT).Thromb Haemost 1990;64:506–510.
Handeland GF, Abildgaard U, Holm HA, et al. Doseadjusted heparin treatment of deep venous thrombosis: A comparison of unfractionated and low-molecular-weight heparin.Eur J Clin Pharmacol 1990;39:107–112.
Harenberg J, Huck K, Bratsch H, et al. Therapeutic application of subcutaneous low-molecular-weight heparin in acute venous thrombosis.Haemostasis 1990;20(Suppl 1): 205–219.
Huet Y, Janvier G, Bendriss PH, et al. Treatment of established venous thromboembolism with Enoxaparin: Preliminary report.Acta Chir Scand 1990;556(Suppl):116–120.
Lockner D, Bratt G, Tornebohm E, et al. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis.Haemostasis 1986;16:25–29.
Prandoni P, Vigo M, Cattelan AM, et al. Treatment of deep venous thrombosis by fixed doses of a low-molecular-weight heparin (CY216).Haemostasis 1990;20(Suppl 1): 220–223.
Siegbahn A, Y-Hassan S, Boberg J, et al. Subcutaneous treatment of deep venous thrombosis with low-molecular-weight heparin. A dose finding study with LMWH-Novo.Thromb Res 1989;55:767–778.
Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intra-venous heparin in the treatment of proximal-vein thrombosis.N Engl J Med 1992;326:975–983.
Prandoni P, Lensing AW, Buller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis.Lancet 1992;339:411–415.
Simonneau G, Charbonnier B, Decousus H, et al. Subcuta-neous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis.Arch Int Med 1993;153: 1541–1546.
Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous low-molecular-weight heparin versus subcutaneous unfrac-tionated heparin in the treatment of deep vein thrombosis: A Polish multicentre trial.Thromb Haemost 1992;68:14–18.
Arnesen H, Heilo A, Jakobsen E, et al. A prospective study of streptokinase and heparin in the treatment of deep vein thrombosis.Acta Med Scand 1978;203:457–463.
Marder VJ, Soulen RL, Atchartakarn V, et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy.J Lab Clin Med 1977;89:1018–1029.
Hull RD, Rosenbloom D, Pineo GF, et al. A cost-effectiveness analysis of low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis (abstract).Circulation 1993;88: 1–516.
Harenberg J, Leber G, Dempfle CE, et al. Long-term anticoagulation with low-molecular-weight heparin in outpatients with side effects on oral anticoagulants.Nouv Rev Fr Hematol 1988;31:363–369.
Omri A, Delaloye JF, Andersen H, et al. Low-molecular-weight heparin Novo (LHN-1) does not cross the placenta during the second trimester of pregnancy.Thromb Haemost 1989;61:55–56.
Bergqvist D, Hedner U, Sjorin E, et al. Anticoagulant effects of two types of low-molecular-weight heparin administered subcutaneously.Thromb Res 1983;32:381–391.
Forestier F, Daffos F, Capella-Pavlovsky M. Lowmolecular-weight heparin (PK 10169) does not cross the placenta during the second trimester of pregnancy. Study by direct fetal blood sampling under ultrasound.Thromb Res 1984;34:557–560.
Forestier F, Daffos F, Rainaut M, et al. Low-molecularweight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy.Thromb Haemost 1987; 57:234.
Andrew M, Cade J, Buchanan MR, et al. Low-molecularweight heparin does not cross the placenta (abstract).Thromb Haemost 1983;50:225.
Mohr VD, Lenz J. Heparin-assoziierte thrombocytopenie, thrombose und embolie. Unerwünschte Wirkung der thromboembolieprophylaxe mit dem niedermolekularen heparin Enoxaparin?Chirurg 1991;62:686–690.
Monreal M, Lafoz E, Salvador R, et al. Adverse effects of three different forms of heparin therapy: Thrombocytopenia, increased transaminases, and hyperkalemia.Eur J Clin Pharmacol 1989;37:415–418.
Matzsch T, Bergqvist D, Hedner U, et al. Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers.Thromb Haemost 1987;57:97–101.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hull, R.D., Pineo, G.F. Treatment of venous thromboembolism with low-molecular-weight heparin. J Thromb Thrombol 1, 279–284 (1995). https://doi.org/10.1007/BF01060737
Issue Date:
DOI: https://doi.org/10.1007/BF01060737