Semin Vasc Med 2003; 03(3): 303-314
DOI: 10.1055/s-2003-44640
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Oral Anticoagulant Therapy in Venous Thromboembolism

Benilde Cosmi, Gualtiero Palareti
  • Cardiovascular Department, Division of Angiology, S. Orsola-Malpighi University Hospital, Bologna, Italy
Further Information

Publication History

Publication Date:
21 November 2003 (online)

ABSTRACT

The main objective of treatment of venous thromboembolism (VTE) is the prevention of the extension, embolization, and recurrence of thrombosis. The long-term aim is to prevent late recurrences and the post-thrombotic syndrome. Heparin and oral anticoagulants (OACs) have been the cornerstones of VTE treatment in the last 30 years. Low molecular weight heparins (LMWHs) have been introduced more recently in the treatment of the acute phase of VTE, and they have allowed the home treatment of deep vein thrombosis (DVT) in selected cases. The optimal duration of OAC therapy after VTE is still controversial. Several studies have been conducted, and several are ongoing with the aim to stratify patients into risk categories for recurrence. Patients at high risk are candidates for long-term oral anticoagulation as the benefits of extended oral anticoagulation would outweigh the risk of bleeding. Patients are currently stratified into risk categories on the basis of clinical characteristics of the VTE event: (1) first or recurrent event; (2) idiopathic or due to a transient risk factor such as surgery, trauma, hormonal therapy, or immobilization; (3) presence of active cancer; (4) location (proximal DVT and/or pulmonary embolism, PE, or distal DVT); and (5) presence of known hereditary or acquired thrombophilia. Patients with distal VTE or VTE due to a transient risk factor are at a low risk of recurrence and short-term anticoagulation is indicated (3 months). Patients with an idiopathic event or with known thrombophilic defects such as FV Leiden or the G20210A prothrombin mutation are candidates for a longer course of therapy (6 months). Patients with cancer, antiphospholipid antibodies syndrome, recurrent idiopathic event, antithrombin deficiency, protein C or protein S deficiency, homozygosity for FV Leiden, and double heterozygosity are candidates for extended long-term anticoagulation. More recently, studies have indicated that other factors such as D-dimer levels after the discontinuation of OAC therapy or the residual vein thrombosis could be additional predictive factors for recurrences. In patients with VTE and cancer, oral anticoagulation poses a higher risk of bleeding, and such patients are more prone to recurrences. Alternative treatment with LMWH could be safer and more effective in these patients.

REFERENCES

  • 1 Ansell J E. Oral anticoagulant therapy-50 years later.  Arch Intern Med . 1993;  153 586-596
  • 2 Stenflo J, Fernlund P, Egan W, Roepstortf P. Vitamin K dependent modifications of glutamic acid residues in prothrombin.  Proc Natl Acad Sci USA . 1974;  71 2730-2733
  • 3 Nelsestuen G L, Zytkovicz T H, Howard J B. The mode of action of vitamin K: identification of gamma carboxyglutamic acid as a component of prothrombin.  J Biol Chem . 1974;  249 6347-6350
  • 4 Barrit D W, Jordan S C. Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial.  Lancet . 1960;  1 1309-1312
  • 5 Hirsh J, Dalen J E, Anderson D R. Oral anticoagulants: mechanism of action, clinical effectiveness and optimal therapeutic range.  Chest . 1998;  114 445S-469S
  • 6 Gallus A, Jackman J, Mills W, Tillett J, Wicherley A. safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism.  Lancet . 1986;  6 1293-1296
  • 7 Hull R D, Raskob G E, Rosenbloom D. Heparin for 5 days as compared with 10 days in the initial treatment of proximal vein thrombosis.  N Engl J Med . 1990;  322 1260-1264
  • 8 Harrison L, Johnston M, Massicotte M P. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy.  Ann Intern Med . 1997;  126 133-136
  • 9 Crowther M A, Ginsberg J B, Kearon C, Harrison L, Johnson J, Massicotte M P, Hirsh J. A randomized trial comparing 5-mg and 10-mg warfarin loading doses.  Arch Intern Med . 1999;  159 46-48
  • 10 Hull R D, Delmore T, Genton E. Warfarin sodium versus low dose heparin the long term treatment of venous thrombosis.  N Engl J Med . 1979;  302 855-858
  • 11 Hull R D, Delmore T, Carter C. Adjusted subcutaneous heparin versus warfarin sodium in the long term treatment of venous thrombosis.  N Engl J Med . 1982;  306 189-194
  • 12 Hull R D, Hirsh J, Jay R M. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis.  N Engl J Med . 1982;  307 1676-1681
  • 13 Doyle D J, Turpie A G, Hirsh J. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial.  Ann Intern Med . 1987;  107 441-445
  • 14 Brandjes D PM, Hejboer H, Buller H R. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal vein thrombosis.  N Engl J Med . 1992;  327 1485-1489
  • 15 Levine M, Gent M, Hirsh J. A comparison of low molecular weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis.  N Engl J Med . 1996;  334 677-681
  • 16 Koopman M MW, Prandoni P, Piovella F. Treatment of venous thrombosis with intravenous heparin administered in the hospital as compared with subcutaneous low molecular weight heparin administered at home.  N Engl J Med . 1996;  334 682-687
  • 17 Ten Cate W J, Buller H R, Gent M. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism by The Columbus Investigators.  N Engl J Med . 1997;  337 657-662
  • 18 Simonneau G, Sors H, Charbonnier B. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism.  N Engl J Med . 1997;  337 663-669
  • 19 Ginsberg J, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest . 1998;  114 524S-530S
  • 20 Hyers T M, Agnelli G, Hull R D, Morris T A, Samama M, Tapson V, Weg J G. Antithrombotic therapy for venous thromboembolic disease.  Chest . 2001;  119 176S-193S
  • 21 Garabedian-Ruffalo S M, Gary D R, Sax M J. Retrospective evaluation of a pharmacist-managed warfarin anticoagulation clinic.  Am J Hosp Pharm . 1985;  42 304-308
  • 22 Cortelazzo S, Finazzi G, Viero P. Thrombotic and hemorrhagic complications in patients with mechanical heart valve prostheses attending an anticoagulation clinic.  Thromb Haemost . 1993;  69 316-320
  • 23 Wilt V M, Gums J G, Ahmed O I. Pharmacy operated anticoagulation service: improved outcomes in patients on warfarin.  Pharmacotherapy . 1995;  15 732-739
  • 24 Chiquette E, Amato M G, Bussey H I. Comparison of an anticoagulation clinic and usual medical care: anticoagulation control, patient outcomes and health care costs.  Arch Intern Med . 1998;  158 1641-1647
  • 25 Poller L, Wright D, Rowlands M. Prospective comparative study of computer programs used for management of warfarin.  J Clin Pathol . 1993;  46 299-303
  • 26 Poller L, Shiach C R, MacCallum P. The European Concerted Action on Anticoagulation (ECAA): multicentre randomized study of computerized anticoagulant dosage.  Lancet . 1998;  352 1505-1509
  • 27 Manotti C, Moia M, Palareti G, Pengo V, Ria L, Dettori A G. Effect of computer-aided management on the quality of treatment in anticoagulated patients: a prospective, randomized, multicenter trial of APROAT (Automated PRogram for Oral Anticoagulant Treatment).  Haematologica . 2001;  86 1060-1070
  • 28 Coon W W, Willis P W. Recurrence of venous thromboembolism.  Surgery . 1973;  73 823-827
  • 29 Lagerstedt C I, Fagher B O, Albrechtsson U. Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis.  Lancet . 1985;  2 515-518
  • 30 O'Sullivan E F. Duration of anticoagulant therapy in venous thromboemebolism.  Med J Aust . 1972;  2 1104-1107
  • 31 Holmgren K, Andersson G, Fagrell B. 1 month versus 6 months therapy with oral anticoagulants after symptomatic deep vein thrombosis.  Acta Med Scand . 1985;  218 279-284
  • 32 Schulman S, Lockner D, Juhlin-Dannfelt A. The duration of oral anticoagulation after deep vein thrombosis-a randomized study.  Acta Med Scand . 1985;  217 547-552
  • 33 Fennerty A G, Dolben J, Thomas P, Backhouse G, Bentley D P, Campbell I A, Routledge P A. A comparison of 3 and 6 weeks' anticoagulation in the treatment of venous thromboembolism.  Clin Lab Haematol . 1987;  9 17-21
  • 34 Sudlow M F, Campbell I A, Angel J H. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism.  Lancet . 1992;  340 873-876
  • 35 Schulman S, Rhedin A S, Lindmarker P. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism.  N Engl J Med . 1995;  332 1661-1665
  • 36 Schulman S, Wiman B, Duration of Anticoagulation (DURAC) trial study group. The significance of hypofibrinolysis for the risk of recurrence of venous thromboembolism. Thromb Haemost .  1996;  75 607-611
  • 37 Crowther M A, Roberts J, Roberts R. Fibrinolytic variables in patients with recurrent venous thrombosis: a prospective cohort study.  Thromb Haemost . 2001;  85 390-394
  • 38 Schulman S, Granqvist S, Holmstrom M. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism.  N Engl J Med . 1997;  336 393-398
  • 39 Prandoni P, Lensing A WA, Cogo A. The long term clinical course of acute deep vein thrombosis.  Ann Intern Med . 1996;  125 1-7
  • 40 Levine M N, Hirsh J, Gent M. 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
  • 41 Kearon C, Gent M, Hirsh J. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thrombosis.  N Engl J Med . 1999;  340 901-907
  • 42 Agnelli G, Prandoni P, Santamaria M G. Three months versus one year of oral anticoagulation therapy for idiopathic deep venous thrombosis.  N Engl J Med . 2001;  345 165-169
  • 43 Pinede L, Ninet J, Duhaut P. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf-vein thrombosis.  Circulation . 2001;  103 2453-2460
  • 44 Hutten B A, Prins M H. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism (Cochrane Review). In: Cochrane Library Oxford: Update Software 2003 issue 1
  • 45 Ridker P M, Goldhaber S Z, Danielson E. Long-term, low intensity warfarin therapy for the prevention of recurrent venous thromboembolism.  N Engl J Med . 2003;  348 1425-1434
  • 46 Bauer K A. Management of patients with hereditary defects predisposing to thrombosis including pregnant women.  Thromb Haemost . 1995;  74 94-100
  • 47 Hirsh J, Lee A. How we diagnose and treat deep vein thrombosis.  Blood . 2002;  99 3102-3110
  • 48 Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, Coccheri S. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost .  2002;  87 7-12
  • 49 Piovella F, Crippa L, Barone M. Normalization of compression ultrasonography in patients with a first episode of deep vein thrombosis of the lower limbs: association with DVT recurrence and new thrombosis.  Haematologica . 2002;  87 515-522
  • 50 Prandoni P, Lensing A W, Prins M H. Residual venous thrombosis as a predictive factor for recurrent venous thromboembolism.  Ann Intern Med . 2002;  137 955-960
  • 51 Das S K, Cohen A T, Edmondson R A, Melissari E, Kakkar V V. Low-molecular-weight heparin versus warfarin for prevention of recurrent venous thromboembolism: a randomized trial.  World J Surg . 1996;  20 521-526
  • 52 Gonzalez-Farajardo J A, Arreba E, Castrodeza J. Venographic comparison of subcutaneous low-molecular-weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis.  J Vasc Surg . 1999;  30 283-290
  • 53 Hamann H. Rezidivprophylaxe nach Phlebothrombose-orale Antikoagulatin oder niedermolekulares Heparin subkutan [Low molecular weight heparin versus coumarin in the prevention of recurrence after deep vein thrombosis].  Vasomed . 1998;  10 133-136
  • 54 Lopaciuk S, Bielska-Falda H, Noszczyk W. Low molecular weight heparin versus acenocoumarol in the secondary prophylaxis of deep vein thrombosis.  Thromb Haemost . 1999;  81 26-31
  • 55 Lopez-Beret P, Orgaz A, Fontcuberta J, Doblas M, Martinez A, Lozano G, Romero A. Low molecular weight heparin versus oral anticoagulants in the long-term treatment of deep venous thrombosis.  J Vasc Surg . 2001;  33 77-90
  • 56 Pini M, Aiello S, Manotti C. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.  Thromb Haemost . 1994;  72 191-197
  • 57 Veiga F, Escriba A, Maluenda M P. Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial.  Thromb Haemost . 2000;  84 559-564
  • 58 van der Heijden J F, Hutten B A, Büller H R, Prins M H. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism (Cochrane Review). In: The Cochrane Library. Oxford: Update Software 2002 issue 3
  • 59 Palareti G, Manotti C, D'Angelo A. Thrombotic events during anticoagulant treatment: results of the inception cohort, prospective, collaborative ISCOAT study.  Thromb Haemost . 1997;  78 1438-1443
  • 60 Hutten B A, Prins M H, Gent M, Ginsberg J, Tijssen J, Buller H R. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved International Normalized Ratio: a retrospective analysis.  J Clin Oncol . 2000;  18 3078-3083
  • 61 Palareti G, Legnani C, Lee A. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy.  Thromb Haemost . 2000;  84 805-810
  • 62 Prandoni P, Lensing A W, Piccioli A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.  Blood . 2002;  100 3484-3488
  • 63 Meyer G, Marjanovic Z, Valcke J. Comparison of low-molecular weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study.  Arch Intern Med . 2002;  162 1729-1735
  • 64 Monagle P, Michelson A D, Bovill E, Andrew M. Antithrombotic therapy in children.  Chest . 2001;  119 344S-370S
  • 65 Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant.  Am J Pediatr Hematol Oncol . 1990;  12 95-104
  • 66 Andrew M, Vegh P, Johnston M. Maturation of the hemostatic system during childhood.  Blood . 1992;  80 1998-2005
  • 67 Streif W, Andrew M, Marzinotto V. Analysis of warfarin therapy in paediatric patients: a prospective cohort study.  Blood . 1999;  94 3007-3014
  • 68 Andrew M, Marzinotto V, Brooker L. Oral anticoagulant therapy in pediatric patients: a prospective study.  Thromb Haemost . 1994;  71 265-269