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Vol. 163 No. 11, June 9, 2003 TABLE OF CONTENTS
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Duration of Anticoagulation in Venous Thromboembolism

Arch Intern Med. 2003;163:1265-1266.

ORAL ANTICOAGULATION with a vitamin K (phytonadione) antagonist has always been a problematic therapy. The risk of serious bleeding is substantial (2%-3% yearly) and does not decrease over time. In fact, as patients undergoing long-term therapy age, the bleeding risk increases. The therapeutic effect of oral anticoagulation falls in a narrow range between increased risk of thrombosis when the international normalized ratio (INR) is too low and increased bleeding risk when it is too high.

Because of multiple drug and dietary interactions with vitamin K antagonists, therapy must be frequently monitored and the dose of drug adjusted. Patients must make substantial lifestyle changes to cope with the increased bleeding risk and the need for monitoring. Patients with atrial fibrillation or a mechanical heart valve have a permanent risk of thrombotic stroke, and the bleeding risk and inconvenience of oral anticoagulation must be accepted. However, in patients with venous thromboembolism (VTE), the risk of recurrent thromboembolism seems to decline with time after the index event. Caregivers and patients wrestle continuously with the question of duration of therapy. Unfortunately, evidence-based recommendations on duration of therapy are often long on recommendations and short on evidence.1

In this issue of the ARCHIVES, van Dongen and colleagues2 publish a meta-analysis that attempts to give some scientific rationale for the duration of therapy for VTE. Their effort is admirable but is hamstrung by the dearth of suitable studies on duration of therapy. This statement is illustrated by the fact that 83 of 118 studies initially deemed appropriate for analysis had to be discarded because of absence of information on the timing of recurrence after cessation of anticoagulation. A further hindrance is the fact that many of the remaining studies did not adequately characterize the risk status of the patients included. These studies offered only general descriptions of risk status such as history of VTE, the presence of cancer, other permanent risk factors, or transient risk factors.

Nevertheless, some useful generalizations can be derived. First, van Dongen and colleagues confirm that the risk of recurrence decreases over time after cessation of anticoagulation, becoming quite low after 9 months. This statement applies to durations of anticoagulation the authors classify as short (4-6 weeks), medium (3 months), and long (4-6 months). Second, with few exceptions, recurrence of VTE is inversely related to duration of anticoagulation, being highest in the group that receives the shortest duration of anticoagulation.

Although the authors do not describe the individual risk factors that contribute to recurrence, other researchers have shown that patients with idiopathic or primary disease are at high risk of recurrence.3-4 From these findings, general recommendations can be made about duration of anticoagulation. First, patients with an initial episode of VTE secondary to a transient risk factor such as surgery, trauma, immobilization, or estrogen use need undergo only a short period of anticoagulation. Although the precise duration is unknown, 3 to 6 months is a useful approximation. Second, patients with idiopathic disease require a longer period of anticoagulation, although the precise duration is again unknown. Furthermore, recent studies suggest that longer periods of anticoagulation only delay the time to recurrence.5-6 Despite this caveat, a useful approximation for a first event of idiopathic VTE is at least 6 months, although some authorities recommend even longer periods of anticoagulation. In this regard, a recent study indicates that after 6 months of anticoagulation to an INR of 2.0 to 3.0, subsequent anticoagulation to an INR of 1.5 to 2.0 results in a very low incidence of recurrent VTE with negligible bleeding.7

These 2 recommendations have some rational basis, but thereafter the medical evidence on duration of therapy is quite deficient. Patients with recurrent VTE usually undergo anticoagulation therapy for longer than 6 months.8 Patients with a first event and familial thrombophilia such as antithrombin deficiency or protein C or S deficiency usually undergo anticoagulation therapy for a year or longer.9-10 Patients with a first event and an antiphospholipid antibody manifested as a lupus anticoagulant are at high risk of recurrence and seem to require extended or permanent anticoagulation.11 In contrast, patients with a first episode who are heterozygous for factor V Leiden or the prothrombin mutation and have a transient risk factor such as surgery seem to require only 3 to 6 months of therapy. However, there are few controlled studies of treatment duration in any of these subgroups.

What can be done to address this lack of knowledge? Controlled trials are needed on duration of therapy in individual risk groups, particularly in patients with cancer. Furthermore, investigators who perform future treatment trials in VTE should carefully characterize the individual risk status of their study patients and observe them for at least a year after cessation of anticoagulation to determine the rate and timing of recurrent disease. Only with this information can we make stronger recommendations about the duration of anticoagulation in individual patients with VTE. In the meantime, decisions about duration of therapy must incorporate full discussion of risks and benefits of anticoagulation and consideration of individual patient preferences in this regard.

Thomas M. Hyers, MD
St Louis University School of Medicine
CARE Clinical Research
533 Couch Ave, Suite 140
St Louis, MO 63122
(e-mail: thyers@careinternet.com)


REFERENCES

1. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119:176S-193S. FULL TEXT
2. van Dongen CJJ, Vink R, Hutten BA, Büller HR, Prins MH. The incidence of recurrent venous thromboembolism after treatment with vitamin K antagonists in relation to time since first event: a meta-analysis. Arch Intern Med. 2003;163:1285-1293. ABSTRACT/FULL TEXT
3. Schulman S, Rhedin AS, Lindmarker P, et al, for the Duration of Anticoagulation Trial Study Group. 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. ABSTRACT/FULL TEXT
4. 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. ABSTRACT/FULL TEXT
5. Agnelli G, Prandoni P, Santamaria MG, et al, for the Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med. 2001;345:165-169. ABSTRACT/FULL TEXT
6. Pinede L, Ninet J, Duhaut P, et al. 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 deep vein thrombosis. Circulation. 2001;103:2453-2460. ABSTRACT/FULL TEXT
7. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348:1425-1434. ABSTRACT/FULL TEXT
8. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med. 1997;336:393-398. ABSTRACT/FULL TEXT
9. van den Belt AG, Sanson BJ, Simioni P, et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med. 1997;157:2227-2232. ABSTRACT
10. Hirsh J, Kearon C, Ginsberg J. Duration of anticoagulant therapy after first episode of venous thrombosis in patients with inherited thrombophilia. Arch Intern Med. 1997;157:2174-2177. CrossRef | ISI | MEDLINE
11. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332:993-997. ABSTRACT/FULL TEXT

RELATED ARTICLES IN ARCHIVES OF INTERNAL MEDICINE

The Incidence of Recurrent Venous Thromboembolism After Treatment With Vitamin K Antagonists in Relation to Time Since First Event: A Meta-analysis
Carlo J. J. van Dongen, Roel Vink, Barbara A. Hutten, Harry R. Büller, and Martin H. Prins
Arch Intern Med. 2003;163:1285-1293.
ABSTRACT | FULL TEXT  




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