Duration of Oral Anticoagulant Therapy after Proximal Deep Vein Thrombosis: a Decision Analysis

Summary

The optimal duration of oral anticoagulant therapy following proximal deep vein thrombosis (DVT) in the lower limbs remains controversial. To compare the risk benefit tradeoffs for different treatment durations (6 to 24 weeks) we constructed a Markov-based decision analysis model which explicitly balances the time-dependent declining risk of recurrent thrombosis and pulmonary embolism against the risk of major hemorrhagic complications. Specifically, we determined the threshold below which the risk of recurrent DVT exceeds the risk of major hemorrhage if anticoagulant therapy is discontinued, and above which the benefits provided by oral anticoagulants are outweighed by their risk.

Our model shows that for patients with a low hemorrhagic risk (0.5%/month), the benefit yielded by oral anticoagulants breaks off beyond the 4th month of therapy, while patients with moderate (1%/month) to high (2%/month) bleeding risk will no longer benefit from the therapy after 3 or 2.5 months, respectively.

In conclusion, our model supports the validity of the usually recommended duration of 3 months of oral anticoagulation after proximal vein thrombosis in the lower limbs, but suggests that this duration should be modulated between 2.5 and 4 months depending upon individual bleeding risk. Since clinical trials can hardly handle the complexity of the addressed issue, such a model may prove very helpful in daily clinical practice.

• References

• 1 Barrit DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960; 1: 1309-15
• 2 Alpert JS, Smith R, Carlson CJ, Ockene IS. et al. Mortality in patients treated for pulmonary embolism. JAMA 1976; 236: 1477-80
• 3 Gallus AS, Hirsh J. Treatment of venous thromboembolic disease. Semin Thromb Haemostas 1976; 2: 291-317
• 4 Hull R, Delmore T, Genton E. et al. Warfarin sodium versus low-dose heparin in the treatment of venous thrombosis. New Engl J Med 1979; 301: 855-8
• 5 Gallus AS, Jackson J, Tillet J. et al. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; 2: 1293-6
• 6 Hull RD, Raskob GE, Hirsh J. et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. New Engl J Med 1986; 315: 1109-14
• 7 Doyle DJ, Turpie AG, Hirsh J. et al. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Int Med 1987; 107: 441-5
• 8 Gallus A, Jackaman J, Tillet J. et al. Safety and efficacy of warfarin started early after submassive venous thrombosis or pulmonary embolism. Lancet 1986; 2: 1293-6
• 9 Hull RD, Raskob GE, Rosenbloom D. et al. Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. New Engl J Med 1990; 322: 1260-4
• 10 Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest 1992; 102 (Suppl): 408S-425S
• 11 Petiti DB, Strom BL, Melmon KL. Duration of warfarin anticoagulant therapy and the probabilities of recurrent thromboembolism and hemorrhage. Am J Med 1986; 81: 255-9
• 12 Schulman S, Lockner D, Juhlin-Dannfelt A. The duration of oral anticoagulation after deep vein thrombosis. Acta Med Scand 1985; 217: 547-52
• 13 Holmgren K, Andersson G, Fagrell B. et al. One-month versus six-month therapy with oral anticoagulants after symptomatic deep vein thrombosis. Acta Med Scand 1985; 218: 279-84
• 14 Fennerty AG, Campbell IA, Routledge PA. Anticoagulants in venous thromboembolism. BMJ 1988; 297: 1285-8
• 15 Moser KM. Venous thromboembolism. Am Rev Resp Dis 1990; 141: 235-49
• 16 Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep vein thrombosis and pulmonary embolism. Lancet 1992; 340: 873-6
• 17 Kassirer JP, Moskowitz AJ, Lau J. et al. Decision analysis: a progress report. Ann Int Med 1987; 106: 279-91
• 18 Pauker SG, Kassirer JP. Decision analysis. New Engl J Med 1987; 316: 250-8
• 19 Beck JR, Pauker SG. The Markov process in medical prognosis. Med Dec Making 1983; 3: 419-58
• 20 Moser KM, LeMoine JR. Is embolic risk conditioned by location of deep venous thrombosis?. Ann Int Med 1981; 94: 439-43
• 21 Dalen JE, Paraskos JA, Ocksene IS. et al. Venous thromboembolism, scope of the problem. Chest 1986; (suppl); 1989; 370-4
• 22 Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: Incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87: 144-52
• 23 Landefeld CS, Anderson PA. Guideline-based consultation to prevent anticoagulant-related bleeding: a randomized, controlled trial in a teaching hospital. Ann Int Med 1992; 116: 829-37
• 24 Lancaster TR, Singer DE, Sheehan MA. et al. The impact of long-term warfarin therapy on quality of life: evidence from a randomized trial. Arch Int Med 1991; 151: 1922-5
• 25 Coon WW, Willis PW, III, Symons MJ. Assessment of anticoagulant treatment of venous thromboembolism. Ann Surg 1969; 170: 559-67
• 26 Hirsh J, Hull RD. Natural history and clinical features of venous thrombosis. In: Colman RW, Hirsh J, Marder VJ, Salzman EW. Hemostasis and thrombosis; basic principles and clinical practice. J B Lipincott 1987: 1208-19
• 27 Prandoni P, Lensing AW A, Büller HR. et al. Comparison of subcutaneous low-molecular weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-5
• 28 Hull RD, Delmore T, Carter C. et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. New Engl J Med 1982; 306: 189-94
• 29 Hull RD, Hirsh J, Carter C. et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. New Engl J Med 1982; 307: 1676-81
• 30 Bell WR, Simon TL. Current status of pulmonary thromboembolic disease: Pathophysiology, diagnosis, prevention, and treatment. Am Heart J 1982; 103: 239-62
• 31 Carson JL, Kelley MA, Duff A, Weg JG. The clinical course of pulmonary embolism. New Engl J Med 1992; 326: 1240-5
• 32 Barker NW, Nygaard KK. A statistical study of postoperative venous thrombosis and pulmonary embolism. Mayo Clin Proc 1941; 16: 17-21
• 33 Hommes DW, Bura AB, Mazzolai L. et al. Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep vein thrombosis. A meta-analysis. Ann Int med 1992; 116: 279-84
• 34 Levine HJ, Hirsh J, Landefeld CS. et al. Hemorrhagic complications of anticoagulant treatment. Chest 1992; (Suppl); 102: 352s-62s
• 35 Tsevat J, Eckman MH, McNutt RA, Pauker SG. Warfarin for dilated cardiomyopathy: a bloody though pill to swallow?. Med Dec Making 1989; 9: 162-9