Thrombolysis in Deep Vein Thrombosis: Is there still an Indication?

Summary

The most accepted therapy for DVT consists of anticoagulation with unfractionated heparin or low molecular weight heparin, followed by variable duration oral anticoagulation but thrombolytic therapy has been proposed in addition to standard anticoagulation. This paper reviews the literature on post thrombotic syndrome, the natural history of vein patency after therapy, and we perform a systematic review, using accepted standards for meta-analysis, to determine the outcomes when thrombolytic therapy is used to treat DVT. We demonstrate that thrombolytic therapy for DVT results in a significant increase in the risk of major hemorrhage and a significant increase in the rate of vein patency. However, although thrombolytic therapy is advantageous over anticoagulation as measured by early vein patency, a benefit in terms of a reduction in PTS risk, is unproven. Our review also shows that there is no evidence that there is a difference in efficacy between thrombolytic agents or that local therapy differs from systemic therapy. Finally, the potential role of catheter directed therapy is unknown since appropriate trials have not been performed but it is reasonable to use catheter directed therapy in patients with phlegmasia cerulea dolens. We conclude that more work is needed to define the role of thrombolytic therapy but it is too early to abandon this therapeutic modality.

Key words

Thrombolytics - post thrombotic syndrome - deep-vein thrombosis - treatment - bleeding, meta-analysis

^* Dr. Wells is a Canada Research Chair in Thromboembolic Diseases; Dr. Forster is the recipient of Samuel R. McLaughlin Scholarship in Medicine

• References

• 1 Salzman EW, Hirsh J. The epidemiology, pathogenesis and natural history of venous thrombosis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW. editors. Hemostasis and thrombosis: basic principles and clinical practice. Philadelphia: J. B. Lippincott Company; 1994: 1275-96.
• 2 Hyers TM, Agnelli G, Hull RD, Weg JG, Morris TA, Samama M, Tapson VF. Antithrombotic therapy for venous thromboembolic disease. IN: Dalen JE, Hirsh J. editors. Fifth ACCP consensus conference on antithrombotic therapy. Chest. 1998. 114 (supplement) 561-79.
• 3 Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000; 160: 181-8.
• 4 O’Meara JJ, McNutt RA, Evans AT, Moore SW, Downs SM. A decision analysis of streptokinase plus heparin as compared with heparin alone for deep vein thrombosis. N Engl J Med 1994; 330: 1864-9.
• 5 Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M. et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
• 6 Prandoni P, Lensing AWA, Prins M, Bagatella P, Scudeller A, Girolami A. Which is the outcome of the post-thrombotic syndrome?. Thromb Haemost 1999; 82: 1196-7.
• 7 Franzeck UK, Schalch I, Bollinger A. On the relationship between changes in the deep veins evaluated by duplex sonography and the postthrombotic syndrome 12 years after deep vein thrombosis. Thromb Haemost 1997; 77: 1109-12.
• 8 Lindner DJ, Edwards JM, Phinney ES, Taylor LM, Porter JM. Long term hemodynamic and clinical sequelae of lower extremity deep vein thrombosis. J Vasc Surg 1986; 4: 436-42.
• 9 Saarinen J, Kallio T, Lehto M, Hiltunen S, Sisto T. The occurence of the post-thrombotic changes after an acute deep venous thrombosis. A prospective two-year follow-up study. J Cardiovasc Surg 2000; 41: 441-66.
• 10 Biguzzi E, Mozzi E, Alatri A, Taioli E, Moia M, Mannucci PM. The post-thrombotic syndrome in young women: Retrospective evaluation of prognostic factors. Thromb Haemost 1998; 80: 575-7.
• 11 Brandjes DPM, Buller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H. et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349: 759-62.
• 12 Cronan JJ, Leen V. Recurrent deep venous thrombosis: limitations of US. Radiology 1989; 170: 739-42.
• 13 Mantoni M. Deep venous thrombosis: Longitudinal study with duplex US. Radiology 1991; 179: 271-3.
• 14 Meissner MH, Manzo RA, Bergelin RO, Strandness Jr DE. Venous diameter and compliance after deep venous thrombosis. Thromb Haemost 1994; 72: 372-6.
• 15 Heijboer H, Jongbloets LMM, Buller HR, Lensing AWA, ten Cate JW. Clinical utility of real-time compression ultrasonography for diagnostic management of patients with recurrent venous thrombosis. Acta Rad 1992; 33: 297-300.
• 16 Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P. et al. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation 1993; 33: 1730-5.
• 17 Schulman S, Granqvist S, Juhlin-Dannfelt A, Lockner D. Long-term sequelae of calf vein thrombosis treated with heparin or low-dose streptokinase. Acta Med Scand 1986; 219: 349-57.
• 18 Elliot MS, Immelman EJ, Jeffery P, Benatar SR, Funston MR, Smith JA. A comparative randomized trial of heparin versus streptokinase in the treatment of acute proximal venous thrombosis: an interim report of a prospective trial. Brit J Surg 1979; 66: 838-43.
• 19 Arnesen H, Heilo A, Jakobsen E, Ly B, Skaga E. A prospective study of streptokinase and heparin in the treatment of deep vein thrombosis. Acta Med Scand 1978; 203: 457-63.
• 20 Porter JM, Seaman AJ, Common HH, Rosch J, Eidemiller LR, Calhoun AD. Comparison of heparin and streptokinase in the treatment of venous thrombosis. Am Surg 1975; 41: 511-19.
• 21 Tsapogas MJ, Peabody RA, Wu KT, Karmody AM, Devaraj KT, Eckert C. Controlled study of thrombolytic therapy in deep vein thrombosis. Surg 1973; 74: 973-84.
• 22 Kakkar VV, Flanc C, Howe CT, O’Shea M, Flute PT. Treatment of deep vein thrombosis: A trial of heparin, streptokinase and arvin. Brit Med J 1969; 1: 806-10.
• 23 Robertson BR, Nilsson M, Nylander G. Value of streptokinase and heparin in treatment of acute deep vein thrombosis: A coded investigation. Acta Chir Scand 1968; 134: 203-8.
• 24 Robertson BR, Nilsson IM, Nylander G. Thrombolytic effect of streptokinase as evaluated by phlebography of deep venous thrombi of the leg. Acta Chir Scand 1970; 136: 173-80.
• 25 Common HH, Seaman AJ, Rosch J, Porter JM, Dotter CT. Deep-vein thrombosis treated with streptokinase or heparin. Follow-up of a randomized study. Angiology 1976; 27: 645-54.
• 26 Arnesen H, Hoiseth A, Ly B. Streptokinase or heparin in the treatment of deep vein thrombosis. Follow-up results of a prospective study. Acta Med Scand 1982; 211: 65-8.
• 27 Johansson L, Nylander G, Hedner U, Nilsson IM. Comparison of streptokinase with heparin: late results in the treatment of deep venous thrombosis. Acta Med Scand 1979; 206: 93-8.
• 28 Ng CM, Rivera JO. Meta-analysis of streptokinase and heparin in deep vein thrombosis. Am J Health Syst Pharm 1998; 55: 1995-2001.
• 29 Heinrich F, Heinrich U. North Baden venous lysis trial (NBVL): multi-centre prospective randomized phlebographically controlled trial on the effect of ultra-high versus conventional doses of streptokinase in fresh leg-pelvis venous thromboses. Vasc Med 1998; 3: 87-94.
• 30 Schulman S, Lockner D, Granqvist S, Bratt G, Paul C, Nyman D. A comparative randomized trial of low-dose versus high-dose streptokinase in deep vein thrombosis of the thigh. Thromb Haemost 1984; 51: 261-5.
• 31 Goldhaber SZ, Hirsch DR, MacDougall RC, Polak JF, Creager MA. Bolus recombinant urokinase versus heparin in deep vein thrombosis: a randomized controlled trial. Am Heart J 1996; 132: 314-8.
• 32 Kiil J, Carvalho A, Sakso P, Nielson HO. Urokinase or heparin in the management of patients with deep vein thrombosis?. Acta Chir Scand 1981; 147: 529-32.
• 33 Goldhaber SZ, Meyerovitz MF, Green D, Vogelzang RL, Citrin P, Heit J. Randomized controlled trial of tissue plasminogen activator in proximal deep venous thrombosis. Am J Med 1990; 88: 235-40.
• 34 Turpie AGG, Levine M, Hirsh J, Ginsberg JS, Cruikshank M, Jay R. Tissue plasminogen activator (rt-PA) vs heparin in deep vein thrombosis: results of a randomized trial. Chest 1990; 97: 172S-5S.
• 35 Verhaeghe R, Besse P, Bounameaux H, Marbet GA. Multicenter pilot study of the efficacy and safety of systemic rt-PA adminstration in the treatment of deep vein thrombosis of the lower extremities and/or pelvis. Thromb Res 1989; 55: 5-11.
• 36 Bounameaux H, Banga JD, Bluhmki E, Coccheri S, Fiessinger JN, Haar-mann W. Double-blind, randomized comparison of systemic continuous infusion of 0.25 mg vs. 0.50 mg/kg/24 h of alteplase over 3 to 7 days for treatment of deep venous thrombosis in heparinized patients: results of the European Thrombolysis with rt-PA in Venous Thrombosis (ETTT) Trial. Thromb Haemost 1992; 67: 306-9.
• 37 Schwieder G, Grimm W, Siemens H, Flor B, Hilden A, Gmelin E. Intermittent regional therapy with rt-PA is not superior to systemic thrombolysis in deep vein thrombosis (DVT): a German multicenter trial. Thromb Haemost 1995; 74: 1240-3.
• 38 Schweizer J, Elix H, Altmann E, Hellner G, Forkmann L. Comparative results of thrombolysis treatment with rt-PA and urokinase: a pilot study. Vasa 1998; 27: 167-71.
• 39 van de Loo JCW, Kriessmann A, Trubestein G, Knoch K, de Swart CAM, Asbeck F. et al. Controlled multicenter pilot study of urokinase – heparin and streptokinase in deep vein thrombosis. Thromb Haemost 1983; 50: 660-3.
• 40 Grossman C, McPherson S. Safety and efficacy of catheter-directed thrombolysis for iliofemoral venous thrombosis. Am J Roentgenol 1999; 172: 667-72.
• 41 Mewissen MW, Seabrook GR, Meissner MH, Cynamon J, Labropoulos N, Haughton SH. Catheter-directed thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999; 211: 39-49.
• 42 Comerota AJ, Throm RC, Mathias SD, Haughton S, Mewissen MW. Catheter-directed thrombolysis for iliofemerol deep venous thrombosis improves health-related quality of life. J Vasc Surg 2000; 32: 130-7.
• 43 Tarry WC, Makhoul RG, Tisnado J, Posner MP, Sobel M, Lee HM. Catheter-directed thrombolysis following vena cava filtration for severe deep venous thrombosis. Ann Vasc Surg 1994; 8: 583-90.
• 44 Patel NH, Plorde JJ, Meissner M. Catheter directed thrombolysis in the treatment of phlegmasia cerulea dolens. Ann Vasc Surg 1998; 12: 471-5.
• 45 Centeno RF, Nguyen AH, Ketterer C, Stiller G, Chait A, Fallahnejad M. An alternative approach: antegrade catheter-directed thrombolysis in a case of phlegmasia coerulea dolens. Am Surg 1999; 65: 229-31.