Update in the Treatment of Venous Thromboembolism

ABSTRACT

This review describes recent evidence relevant to the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Because venous thromboembolism (VTE) is a spectrum of disease that includes both of these disorders, many of the therapeutic options are common to both. At the time of diagnosis, effective treatment options for patients with VTE include unfractionated heparin, low molecular weight heparins (e.g., dalteparin, enoxaparin, tinzaparin), and pentasaccharides (e.g., fondaparinux). Many patients with VTE, especially DVT, can receive most or all of their initial treatment as outpatients. Other treatment strategies such as vena caval filter placement and mechanical (or chemical) clot dissolution are discussed briefly. Anticoagulation with warfarin (or other oral vitamin K antagonists) is a highly effective strategy for the long-term prevention of VTE recurrence in most patients. In addition to presenting evidence relevant to the optimal duration of warfarin therapy, we highlight circumstances under which extended therapy with a parenteral agent such as a low molecular weight heparin might be preferable.

KEYWORDS

Deep vein thrombosis - pulmonary embolism - treatment - anticoagulation

REFERENCES

• 1 Barritt D W, Jordan S C. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled clinical trial.  Lancet. 1960;  1 1309-1312
• 2 Brandjes D P, Heijboer H, Buller H R, de Rijk M, Jagt H, ten Cate J W. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis.  N Engl J Med. 1992;  327 1485-1489
• 3 Hull R D, Raskob G E, 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
• 4 Raschke R A, Reilly B M, Guidry J R, Fontana J R, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram: a randomized controlled trial.  Ann Intern Med. 1993;  119 874-881
• 5 Gould M K, Dembitzer A D, Doyle R L, Hastie T J, Garber A M. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials.  Ann Intern Med. 1999;  130 800-809
• 6 van Dongen C J, van den Belt A G, Prins M H, Lensing A W. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.  Cochrane Database Syst Rev. 2004;  CD001100
• 7 Warkentin T E, Cook R J, Marder V J et al.. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin.  Blood. 2005;  106 3791-3796
• 8 Chong B H. Heparin-induced thrombocytopenia.  Aust N Z J Med. 1992;  22 145-152
• 9 Lee A Y, Levine M N, Baker R I et al.. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med. 2003;  349 146-153
• 10 Merli G, Spiro T E, Olsson C G et al.. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.  Ann Intern Med. 2001;  134 191-202
• 11 Simonneau G, Sors H, Charbonnier B et al.. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire.  N Engl J Med. 1997;  337 663-669
• 12 Hyers T M, Spyropoulos A C. Community-based treatment of venous thromboembolism with a low-molecular-weight heparin and warfarin.  J Thromb Thrombolysis. 2007;  24 225-232
• 13 Buller H R, Agnelli G, Hull R D, Hyers T M, Prins M H, Raskob G E. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126(3, Suppl) 401S-428S
• 14 Buller H R, Davidson B L, Decousus H et al.. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial.  Ann Intern Med. 2004;  140 867-873
• 15 Cardiovascular Disease Educational and Research Trust . Prevention and treatment of venous thromboembolism: international consensus statement.  Int Angiol. 2006;  25 101-161
• 16 Kearon C, Ginsberg J S, Julian J A et al.. Comparison of fixed-dose weight-adjusted unfractionated heparin and low-molecular-weight heparin for acute treatment of venous thromboembolism.  JAMA. 2006;  296 935-942
• 17 O'Brien B, Levine M, Willan A et al.. Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis.  Arch Intern Med. 1999;  159 2298-2304
• 18 Spyropoulos A C, Hurley J S, Ciesla G N, de Lissovoy G. Management of acute proximal deep vein thrombosis: pharmacoeconomic evaluation of outpatient treatment with enoxaparin vs inpatient treatment with unfractionated heparin.  Chest. 2002;  122 108-114
• 19 Spyropoulos A C. Outpatient-based treatment protocols in the management of venous thromboembolic disease.  Am J Manag Care. 2000;  6(20, Suppl) S1034-S1044
• 20 Elsharawy M, Elzayat E. Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis: a randomised clinical trial.  Eur J Vasc Endovasc Surg. 2002;  24 209-214
• 21 Bjarnason H, Kruse J R, Asinger D A et al.. Iliofemoral deep venous thrombosis: safety and efficacy outcome during 5 years of catheter-directed thrombolytic therapy.  J Vasc Interv Radiol. 1997;  8 405-418
• 22 Comerota A J, Throm R C, Mathias S D, Haughton S, Mewissen M. Catheter-directed thrombolysis for iliofemoral deep venous thrombosis improves health-related quality of life.  J Vasc Surg. 2000;  32 130-137
• 23 Goldhaber S Z, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).  Lancet. 1999;  353 1386-1389
• 24 Quinlan D J, McQuillan A, Eikelboom J W. Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a meta-analysis of randomized, controlled trials.  Ann Intern Med. 2004;  140 175-183
• 25 Buller H R, Davidson B L, Decousus H et al.. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.  N Engl J Med. 2003;  349 1695-1702
• 26 Kovacs M J, Anderson D, Morrow B, Gray L, Touchie D, Wells P S. Outpatient treatment of pulmonary embolism with dalteparin.  Thromb Haemost. 2000;  83 209-211
• 27 Wells P S, Anderson D R, Rodger M A et al.. A randomized trial comparing 2 low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism.  Arch Intern Med. 2005;  165 733-738
• 28 Nendaz M R, Bandelier P, Aujesky D et al.. Validation of a risk score identifying patients with acute pulmonary embolism, who are at low risk of clinical adverse outcome.  Thromb Haemost. 2004;  91 1232-1236
• 29 Aujesky D, Obrosky D S, Stone R A et al.. A prediction rule to identify low-risk patients with pulmonary embolism.  Arch Intern Med. 2006;  166 169-175
• 30 Aujesky D, Roy P M, Le Manach C P et al.. Validation of a model to predict adverse outcomes in patients with pulmonary embolism.  Eur Heart J. 2006;  27 476-481
• 31 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. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group.  N Engl J Med. 1998;  338 409-415
• 32 PREPIC Study Group . Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study.  Circulation. 2005;  112 416-422
• 33 Anderson R C, Bussey H I. Retrievable and permanent inferior vena cava filters: selected considerations.  Pharmacotherapy. 2006;  26 1595-1600
• 34 Streiff M B. Vena caval filters: a review for intensive care specialists.  J Intensive Care Med. 2003;  18 59-79
• 35 Kahn S R. The post-thrombotic syndrome: the forgotten morbidity of deep venous thrombosis.  J Thromb Thrombolysis. 2006;  21 41-48
• 36 Prandoni P, Lensing A W, Prins M H et al.. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial.  Ann Intern Med. 2004;  141 249-256
• 37 Brandjes D P, Buller H R, Heijboer H et al.. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis.  Lancet. 1997;  349 759-762
• 38 van Dongen C J, Prandoni P, Frulla M, Marchiori A, Prins M H, Hutten B A. Relation between quality of anticoagulant treatment and the development of the postthrombotic syndrome.  J Thromb Haemost. 2005;  3 939-942
• 39 Agnelli G, Prandoni P, Santamaria M G et al.. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators.  N Engl J Med. 2001;  345 165-169
• 40 Kearon C, Gent M, Hirsh J et al.. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med. 1999;  340 901-907
• 41 Kovacs M J, Rodger M, Anderson D R et al.. Comparison of 10-mg and 5-mg warfarin initiation nomograms together with low-molecular-weight heparin for outpatient treatment of acute venous thromboembolism: a randomized, double-blind, controlled trial.  Ann Intern Med. 2003;  138 714-719
• 42 Garcia D, Regan S, Crowther M, Hughes R A, Hylek E M. Warfarin maintenance dosing patterns in clinical practice: implications for safer anticoagulation in the elderly population.  Chest. 2005;  127 2049-2056
• 43 Levine M N, Hirsh J, Gent M et al.. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.  Thromb Haemost. 1995;  74 606-611
• 44 Schulman S, Rhedin A S, Lindmarker P et al.. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.  N Engl J Med. 1995;  332 1661-1665
• 45 Eichinger S, Weltermann A, Minar E et al.. Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism.  Arch Intern Med. 2004;  164 92-96
• 46 Christiansen S C, Cannegieter S C, Koster T, Vandenbroucke J P, Rosendaal F R. Thrombophilia, clinical factors, and recurrent venous thrombotic events.  JAMA. 2005;  293 2352-2361
• 47 den Heijer M, Willems H P, Blom H J et al.. Homocysteine lowering by B vitamins and the secondary prevention of deep vein thrombosis and pulmonary embolism: a randomized, placebo-controlled, double-blind trial.  Blood. 2007;  109 139-144
• 48 Kearon C, Ginsberg J S, Kovacs M J et al.. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.  N Engl J Med. 2003;  349 631-639
• 49 Ridker P M, Goldhaber S Z, Danielson E et al.. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism.  , [comment] N Engl J Med. 2003;  348 1425-1434
• 50 McRae S, Tran H, Schulman S, Ginsberg J, Kearon C. Effect of patient's sex on risk of recurrent venous thromboembolism: a meta-analysis.  Lancet. 2006;  368 371-378
• 51 Agnelli G, Prandoni P, Becattini C et al.. Extended oral anticoagulant therapy after a first episode of pulmonary embolism.  Ann Intern Med. 2003;  139 19-25
• 52 Palareti G, Cosmi B, Legnani C et al.. D-dimer testing to determine the duration of anticoagulation therapy.  N Engl J Med. 2006;  355 1780-1789
• 53 Palareti G, Legnani C, Cosmi B, Guazzaloca G, Cini M, Mattarozzi S. Poor anticoagulation quality in the first 3 months after unprovoked venous thromboembolism is a risk factor for long-term recurrence.  J Thromb Haemost. 2005;  3 955-961
• 54 Beyth R J, Quinn L M, Landefeld C S. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin.  Am J Med. 1998;  105 91-99
• 55 Kuijer P M, Hutten B A, Prins M H, Buller H R. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism.  Arch Intern Med. 1999;  159 457-460
• 56 Shireman T I, Mahnken J D, Howard P A, Kresowik T F, Hou Q, Ellerbeck E F. Development of a contemporary bleeding risk model for elderly warfarin recipients.  Chest. 2006;  130 1390-1396
• 57 Hull R D, Pineo G F, Brant R F et al.. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer.  Am J Med. 2006;  119 1062-1072
• 58 Deitcher S R, Kessler C M, Merli G, Rigas J R, Lyons R M, Fareed J. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period.  Clin Appl Thromb Hemost. 2006;  12 389-396
• 59 Dentali F, Manfredi E, Crowther M, Ageno W. Long-duration therapy with low molecular weight heparin in patients with antiphospholipid antibody syndrome resistant to warfarin therapy.  J Thromb Haemost. 2005;  3 2121-2123
• 60 Hull R D, Pineo G F, Brant R F et al.. Self-managed long-term low-molecular-weight heparin therapy: the balance of benefits and harms.  Am J Med. 2007;  120 72-82
• 61 van der Heijden J F, Hutten B A, Buller H R, Prins M H. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism.  Cochrane Database Syst Rev. 2002;  CD002001