Low Molecular Weight Heparin versus Warfarin in the Prevention of Recurrences after Deep Vein Thrombosis

Summary

To evaluate the role of low-molecular weight heparin (LMWH) as an alternative to oral anticoagulants in the prevention of recurrent venous thromboembolism, we compared in a randomized trial conventional warfarin treatment with a three-month course of enoxaparin 4000 anti-Xa units once a day subcutaneously. 187 patients with symptomatic deep-vein thrombosis (DVT), diagnosed by strain-gauge plethysmography plus D-dimer latex assay and confirmed by venography in most cases, were treated with full-dose subcutaneous heparin for ten days and then randomized to secondary prophylaxis. During the 3-month treatment period, 6 of the 93 patients who received LMWH (6%) and 4 of the 94 patients on warfarin (4%) had symptomatic recurrence of venous thromboembolism confirmed by objective testing (p = 0.5; 95% confidence interval [Cl] for the difference, -3% to 7%). Four patients in the LMWH group had bleeding complications as compared with 12 in the warfarin group (p = 0.04; 95% Cl for the difference, 4% to 14%). In the 9-month follow-up period, during which 34 patients on warfarin prolonged treatment for other 3 months and 14 up to one year, 10 patients in the enoxaparin group and 4 patients in the warfarin group suffered a documented recurrence of venous thromboembolism. Of these 14 late recurrences, just one occurred in patients with postoperative DVT. After one year there were 16 recurrences (17%) in the LMWH group and 8 (9%) in the warfarin group (p = 0.07; 95% Cl for the difference, 1% to 16%).

These results confirm the potential of LMWH as an alternative to oral anticoagulants in this setting, and suggest to evaluate in a prospective study a slightly higher dose of enoxaparin in patients with postoperative DVT.

• References

• 1 Prandoni P, Lensing AW, Büller HR, Carta M, Cogo A, Vigo M, Casara D, Ruol A, ten Cate JW. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-445
• 2 Hull RD, Raskob GE, Pineo GF, Green D, Throwbridge AA, Elliott CG, Lemer RG, Hall J, Sparling T, Brettell H, Norton J, Carter CJ, George R, Merli G, Ward J, Mayo W, Rosenbloom D, Brant R. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-982
• 3 Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, McLaughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979; 301: 855-888
• 4 Lagerstedt CL, Olsson CG, Fagher BO, Öqvist BW, Albrechtsson U. Need for long-term anticoagulant treatment in symptomatic calf deep-vein thrombosis. Lancet 1985; ii: 515-518
• 5 Levine MN, Hirsh J, Landefeld S, Raskob GE. Hemorrhagic complications of anticoagulant treatment. Chest 1992; 102 (Suppl) 353S-363S
• 6 Hull R, Delmore T, Carter C, Hirsh J, Genton E, Gent M, Turpie G, McLoughlin D. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306: 189-194
• 7 Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79: 1-17
• 8 Planes A, Vochelle N, Mazas F, Mansat C, Zucman J, Landais A, Pascariello JC, Weill D, Butel J. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Hae-most 1988; 60: 407-410
• 9 Pini M, Quintavalla R, Pattacini C, Manotti C, Poli T, Larini P, Megha A, Tagliaferri A, Dettori AG. Combined use of strain-gauge plethysmography and D-dimer latex test in clinically suspected deep venous thrombosis. Fibrinolysis 1993; 7: 391-396
• 10 Pini M, Potì R, Poli T, Tagliaferri R, Dettori AG. Accuracy of strain-gauge plethysmography as a diagnostic test in clinically suspected deep venous thrombosis. Thromb Res 1984; 35: 149-157
• 11 Pini M, Pattacini C, Quintavalla R, Poli T, Megha A, Tagliaferri A, Manot-ti C, Dettori AG. Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis – a randomized clinical trial. Thromb Haemost 1990; 64: 222-226
• 12 Hull R, Hirsh J, Jay R, Carter C, England C, Gent M, Turpie AGG, McLoughlin D, Dodd P, Thomas M, Raskob G, Ockelford P. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-1681
• 13 Holmgren K, Andersson G, Fagrell B, Johnsson H, Ljungberg B, Nilsson E, Wilhelmsson S, Zetterquist S. One month versus six month therapy with oral anticoagulants after symptomatic deep vein thrombosis. Acta Med Scand 1985; 218: 279-284
• 14 Pocock SJ. Clinical Trials. A practical approach. Chichester: John Wiley & Sons 1983; pp 129-130
• 15 Huisman MV, Büller HR, Basart DCG, ten Cate JW. A comparison of impedance plethysmography and strain gauge plethysmography in the diagnosis of deep vein thrombosis in symptomatic outpatients. Thromb Res 1985; 40: 533-541
• 16 Hull R, Carter C, Jay R, Ockelford P, Hirsh J, Turpie AGG, Zielinsky A, Gent M, Powers P. The diagnosis of acute recurrent deep-vein thrombosis: A diagnostic challenge. Circulation 1983; 67: 901-906
• 17 Jay R, Hull R, Carter C, Ockelford P, Büller H, Turpie AGG, Hirsh J. Outcome of abnormal impedance plethysmography results in patients with proximal-vein thrombosis. Frequency of return to normal. Thromb Res 1985; 36: 259-263
• 18 Huisman MV, Büller HR, ten Cate JW. Utility of impedance plethysmography in the diagnosis of recurrent deep-vein thrombosis. Arch Intern Med 1988; 148: 681-683
• 19 Prandoni P, Lensing AW, Büller HR, Cogo A, Prins MH, Cattelan AM, Cuppini S, Noventa F, ten Cate JW. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327: 1128-1133
• 20 Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 1992; 340: 873-876
• 21 Fihn S, McDonnel M, Martin D, Henikoff J, Vermes D, Kent D, White R. Risk factors for complications of chronic anticoagulation. Ann Intern Med 1993; 118: 511-520
• 22 van der Meer FJM, Rosendaal FR, Vandenbroucke JP, Briet E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153: 1557-1562
• 23 Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-1506
• 24 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522
• 25 Green D, Hull RD, Brant R, Pineo GF. Lower mortality in cancer patients treated with low-molecular-weight heparin versus standard heparin. Lancet 1992; 339: 1476
• 26 Marciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin III. Lancet 1977; 2: 581
• 27 Bara L, Samama M. Pharmacokinetics of low molecular weight heparins. Acta Chir Scand Suppl 1988; 543: 65-72
• 28 Levine MN, Planes A, Hirsh J, Goodyear M, Vochelle N, Gent M. The relationship between anti-factor Xa level and clinical outcome in patients receiving enoxaparin low molecular weight heparin to prevent deep vein thrombosis after hip replacement. Thromb Haemost 1989; 62: 940-944
• 29 Monreal M, Lafoz E, Olive A, del Rio L, Vedia C. Comparison of subcutaneous unfractionated heparin with a low molecular weight heparin (Frag-min) in patients with venous thromboembolism and contraindications to coumarin. Thromb Haemost 1994; 71: 7-11