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Treatment of Deep Venous Thrombosis With Low-Molecular-Weight Heparins: A Meta-analysis

Treatment of Deep Venous Thrombosis With Low-Molecular-Weight Heparins: A Meta-analysis Abstract Background: An intravenous course of unfractionated heparin adjusted on the basis of the activated partial thromboplastin time is the initial treatment of choice for most patients with venous thromboembolism. Recently introduced low-molecular-weight heparin preparations can be administered subcutaneously, once or twice daily, without laboratory monitoring. We quantitatively assessed the relative efficacy and safety of low-molecular-weight heparin vs standard heparin for the initial treatment of deep venous thrombosis. Methods: English-language reports of randomized trials were identified through a MEDLINE search (1984 through 1994) and a complementary extensive manual search. Reasons for exclusion from the analysis were no heparin dosage adjustments, the lack of use of objective tests for deep venous thrombosis, duplicate reports, preliminary reports of data later presented in full, dose-ranging studies that used higher doses of low-molecular-weight heparin than are currently in use, and the failure to provide blind end-point assessment. We assessed the incidence of symptomatic recurrent venous thromboembolic disease, the incidence of clinically important bleeding, and mortality. Results: Ten of the 19 identified trials satisfied the predetermined criteria. The relative risk reductions for symptomatic thromboembolic complications (53% [95% confidence interval, 18% to 73%]), clinically important bleeding (68% [95% confidence interval, 31% to 85%]), and mortality (47% [95% confidence interval, 10% to 69%]) were all statistically significantly in favor of low-molecular-weight heparin. Conclusions: Low-molecular-weight heparins administered subcutaneously in fixed doses adjusted for body weight and without laboratory monitoring are more effective and safer than adjusted-dose standard heparin. Since low-molecular-weight heparins may not be interchangeable and the conclusions of our meta-analysis are based mainly on the findings of three trials that used two different low-molecular-weight heparins, definitive randomized controlled trials for the other low-molecular-weight heparins are required.(Arch Intern Med. 1995;155:601-607) References 1. Hirsh J. Heparin. N Engl J Med . 1991;324:1565-1574.Crossref 2. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the treatment of proximal-vein thrombosis. N Engl J Med . 1986;315:1109-1114.Crossref 3. Gallus A, Jackaman J, Tillet J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet . 1986;2:1293-1296.Crossref 4. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal-vein thrombosis. N Engl J Med . 1990;322:1260-1266.Crossref 5. Brandies DPM, Heijboer H, Büller HR, de Rijk M, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med . 1992;327:1485-1489.Crossref 6. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med . 1972;287:325-327.Crossref 7. Young E, Prins MH, Levine MN, Hirsh J. Heparin binding to plasma proteins: an important mechanism for heparin resistance. Thromb Haemost . 1992;67: 639-643. 8. Hirsh J. From unfractionated heparins to low molecular weight heparins. Acta Chir Scand Suppl . 1990;556:42-50. 9. Hirsh J, Levine MN. Low molecular weight heparin. Blood . 1992;79:1-17. 10. Nurmohamed MT, Rosendaal FR, Büller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet . 1992;340:152-156.Crossref 11. Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Deciding on best therapy. In: Clinical Epidemiology: A Basic Science for Clinical Medicine . Boston, Mass: Little Brown & Co Inc; 1985:187-248. 12. Büller HR, Lensing AWA, Hirsh J, ten Cate JW. Deep venous thrombosis: new noninvasive tests. Thromb Haemost . 1991;66:133-139. 13. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst . 1959;22:719-748. 14. Collins R, Gray R, Godwin J, Peto R. Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overviews. Stat Med . 1987;6:245-250.Crossref 15. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials . 1986;7:177-188.Crossref 16. Notarbartolo A, Salanitri G, Davi G, Averna M, Barbagallo C, Catalano I. Low molecular weight heparin in the short and long-term treatment of deep vein thrombosis in diabetic subjects. Med Prax . 1988:9:393-405. 17. 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;16:474-484. 18. Tedoldi A, Botticella F, Maloberti MR. Antithrombophilic effect of low molecular weight heparins in patients with deep vein thrombosis. Clin Trials Meta-analysis . 1993;28:215-225. 19. 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;39:107-112.Crossref 20. Lockner D, Bratt G, Tornebohm E, Aberg W, Granqvist S. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis. Haemostasis . 1986;16( (suppl) ):25-29. 21. Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Circulation . 1989;80: 935-940.Crossref 22. Harenberg J, Huck K, Bratsch H, et al. Therapeutic application of subcutaneous low-molecular-weight heparin in acute venous thrombosis. Haemostasis . 1990;20:205-219. 23. Momanmäki K, Hallen C, Kim H, Finnish Multicentre Group. Low molecular weight heparin (Fragmin) once daily versus continuous infusion of standard heparin in the treatment of DVT. Haemostasis . 1994;24( (suppl 1) ):248. Abstract. 24. Fiessinger JN, Fernandez ML, Gatterer E, Ohlsson CG. Fragmin once daily versus continuous infusion heparin in the treatment of DVT: a European multicentre trial. Haemostasis . 1994;24( (suppl 1) ):44. Abstract. 25. 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 . 1985:85: 813. 26. 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) ):30-37. 27. Faivre R, Neuhart E, Kieffer Y, Toulemonde F, Bassand JP, Maurat JP. Subcutaneous administration of a low molecular weight heparin (CY 222) compared with subcutaneous administration of standard heparin in patients with acute deep vein thrombosis. Thromb Haemost . 1987;58( (suppl) ):120. Abstract 430. 28. 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;64:506-510. 29. Duroux P. 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. 30. Prandoni P, Lensing AWA, Büller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deepvein thrombosis. Lancet . 1992;339:441-445.Crossref 31. 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 . 1992:68:14-18. 32. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximalvein thrombosis. N Engl J Med . 1992;326:975-982.Crossref 33. Simonneau G, Charbonnier B, Decousus H, et al. Subcutaneous low molecular weight heparin compared with continuous intravenous unfractionated heparin in the initial treatment proximal vein thrombosis. Arch Intern Med . 1993;153: 1541-1546.Crossref 34. Lindmarker P, Holmström M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemost . 1994;72:186-190. 35. Anderson DR, O'Brien BJ, Levine MN, Roberts R, Wells PS, Hirsh J. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med . 1993;119:1105-1112.Crossref 36. Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ . 1994;309: 299-304.Crossref 37. Oxman AD. Checklist for review articles. BMJ . 1994;309:648-651.Crossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Treatment of Deep Venous Thrombosis With Low-Molecular-Weight Heparins: A Meta-analysis

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American Medical Association
Copyright
Copyright © 1995 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.1995.00430060059007
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Abstract

Abstract Background: An intravenous course of unfractionated heparin adjusted on the basis of the activated partial thromboplastin time is the initial treatment of choice for most patients with venous thromboembolism. Recently introduced low-molecular-weight heparin preparations can be administered subcutaneously, once or twice daily, without laboratory monitoring. We quantitatively assessed the relative efficacy and safety of low-molecular-weight heparin vs standard heparin for the initial treatment of deep venous thrombosis. Methods: English-language reports of randomized trials were identified through a MEDLINE search (1984 through 1994) and a complementary extensive manual search. Reasons for exclusion from the analysis were no heparin dosage adjustments, the lack of use of objective tests for deep venous thrombosis, duplicate reports, preliminary reports of data later presented in full, dose-ranging studies that used higher doses of low-molecular-weight heparin than are currently in use, and the failure to provide blind end-point assessment. We assessed the incidence of symptomatic recurrent venous thromboembolic disease, the incidence of clinically important bleeding, and mortality. Results: Ten of the 19 identified trials satisfied the predetermined criteria. The relative risk reductions for symptomatic thromboembolic complications (53% [95% confidence interval, 18% to 73%]), clinically important bleeding (68% [95% confidence interval, 31% to 85%]), and mortality (47% [95% confidence interval, 10% to 69%]) were all statistically significantly in favor of low-molecular-weight heparin. Conclusions: Low-molecular-weight heparins administered subcutaneously in fixed doses adjusted for body weight and without laboratory monitoring are more effective and safer than adjusted-dose standard heparin. Since low-molecular-weight heparins may not be interchangeable and the conclusions of our meta-analysis are based mainly on the findings of three trials that used two different low-molecular-weight heparins, definitive randomized controlled trials for the other low-molecular-weight heparins are required.(Arch Intern Med. 1995;155:601-607) References 1. Hirsh J. Heparin. N Engl J Med . 1991;324:1565-1574.Crossref 2. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the treatment of proximal-vein thrombosis. N Engl J Med . 1986;315:1109-1114.Crossref 3. Gallus A, Jackaman J, Tillet J, Mills W, Wycherley A. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet . 1986;2:1293-1296.Crossref 4. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal-vein thrombosis. N Engl J Med . 1990;322:1260-1266.Crossref 5. Brandies DPM, Heijboer H, Büller HR, de Rijk M, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med . 1992;327:1485-1489.Crossref 6. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med . 1972;287:325-327.Crossref 7. Young E, Prins MH, Levine MN, Hirsh J. Heparin binding to plasma proteins: an important mechanism for heparin resistance. Thromb Haemost . 1992;67: 639-643. 8. Hirsh J. From unfractionated heparins to low molecular weight heparins. Acta Chir Scand Suppl . 1990;556:42-50. 9. Hirsh J, Levine MN. Low molecular weight heparin. Blood . 1992;79:1-17. 10. Nurmohamed MT, Rosendaal FR, Büller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet . 1992;340:152-156.Crossref 11. Sackett DL, Haynes RB, Guyatt GH, Tugwell P. Deciding on best therapy. In: Clinical Epidemiology: A Basic Science for Clinical Medicine . Boston, Mass: Little Brown & Co Inc; 1985:187-248. 12. Büller HR, Lensing AWA, Hirsh J, ten Cate JW. Deep venous thrombosis: new noninvasive tests. Thromb Haemost . 1991;66:133-139. 13. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst . 1959;22:719-748. 14. Collins R, Gray R, Godwin J, Peto R. Avoidance of large biases and large random errors in the assessment of moderate treatment effects: the need for systematic overviews. Stat Med . 1987;6:245-250.Crossref 15. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials . 1986;7:177-188.Crossref 16. Notarbartolo A, Salanitri G, Davi G, Averna M, Barbagallo C, Catalano I. Low molecular weight heparin in the short and long-term treatment of deep vein thrombosis in diabetic subjects. Med Prax . 1988:9:393-405. 17. 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;16:474-484. 18. Tedoldi A, Botticella F, Maloberti MR. Antithrombophilic effect of low molecular weight heparins in patients with deep vein thrombosis. Clin Trials Meta-analysis . 1993;28:215-225. 19. 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;39:107-112.Crossref 20. Lockner D, Bratt G, Tornebohm E, Aberg W, Granqvist S. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis. Haemostasis . 1986;16( (suppl) ):25-29. 21. Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Circulation . 1989;80: 935-940.Crossref 22. Harenberg J, Huck K, Bratsch H, et al. Therapeutic application of subcutaneous low-molecular-weight heparin in acute venous thrombosis. Haemostasis . 1990;20:205-219. 23. Momanmäki K, Hallen C, Kim H, Finnish Multicentre Group. Low molecular weight heparin (Fragmin) once daily versus continuous infusion of standard heparin in the treatment of DVT. Haemostasis . 1994;24( (suppl 1) ):248. Abstract. 24. Fiessinger JN, Fernandez ML, Gatterer E, Ohlsson CG. Fragmin once daily versus continuous infusion heparin in the treatment of DVT: a European multicentre trial. Haemostasis . 1994;24( (suppl 1) ):44. Abstract. 25. 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 . 1985:85: 813. 26. 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) ):30-37. 27. Faivre R, Neuhart E, Kieffer Y, Toulemonde F, Bassand JP, Maurat JP. Subcutaneous administration of a low molecular weight heparin (CY 222) compared with subcutaneous administration of standard heparin in patients with acute deep vein thrombosis. Thromb Haemost . 1987;58( (suppl) ):120. Abstract 430. 28. 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;64:506-510. 29. Duroux P. 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. 30. Prandoni P, Lensing AWA, Büller HR, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deepvein thrombosis. Lancet . 1992;339:441-445.Crossref 31. 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 . 1992:68:14-18. 32. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximalvein thrombosis. N Engl J Med . 1992;326:975-982.Crossref 33. Simonneau G, Charbonnier B, Decousus H, et al. Subcutaneous low molecular weight heparin compared with continuous intravenous unfractionated heparin in the initial treatment proximal vein thrombosis. Arch Intern Med . 1993;153: 1541-1546.Crossref 34. Lindmarker P, Holmström M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep venous thrombosis. Thromb Haemost . 1994;72:186-190. 35. Anderson DR, O'Brien BJ, Levine MN, Roberts R, Wells PS, Hirsh J. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty. Ann Intern Med . 1993;119:1105-1112.Crossref 36. Leizorovicz A, Simonneau G, Decousus H, Boissel JP. Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis. BMJ . 1994;309: 299-304.Crossref 37. Oxman AD. Checklist for review articles. BMJ . 1994;309:648-651.Crossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Mar 27, 1995

References