How Long to Continue Oral Anticoagulant After Venous Thromboembolism?

ABSTRACT & COMMENTARY

Synopsis: The authors believe that prophylactic oral anti- coagulation should be continued for an indefinite period of time after a second episode of venous thromboembolism.

Source: Schulman S, et al. N Engl J Med 1997;336:393-398.

Oral anticoagulant therapy is currently recommended for virtually all patients who have suffered an acute venous thromboembolic episode because the recurrence rate is significantly reduced if such therapy is continued for 3-6 months, especially in patients who possess known risk factors such as chronic venous insufficiency.1,2 After a second thromboembolic episode, anticoagulant therapy has been recommended by some for 3-6 months and by others for up to two years;3 some physicians have strongly recommended that anticoagulation therapy be continued indefinitely.4 This disparity of recommendations is because adequate studies have heretofore not been performed in patients who have recurrent thromboembolic phenomenon.

Schulman et al in Sweden recently reported the findings of the Duration of Anticoagulation Trial Study Group. This multicenter trial in Sweden compared six months of oral anticoagulant therapy with anticoagulant therapy continued indefinitely in patients who had suffered a second episode of venous thromboembolism. Among the 227 enrolled patients, 23 in the group assigned to six months of therapy suffered a recurrent thromboembolus compared with only three in the group assigned to continuous therapy (i.e., 20.7% to 2.6%, respectively). The relative risk of recurrence in the group assigned to six months of therapy was 8.0, but the authors were quick to point out that the relative risk of major hemorrhage in the six-month group as compared to the indefinite-treatment group was 0.3. They conclude that prophylactic oral anticoagulation should be continued for an indefinite period of time after a second episode of venous thromboembolism, recognizing that there is a trend toward a higher risk of major hemorrhage when anticoagulation was continued indefinitely.

COMMENT BY HAROLD L. KARPMAN, MD

Between 1992 and 1995, three prospective randomized studies focusing on the duration of anticoagulation therapy after a first embolic event were published.1,2,5 Each study demonstrated that 3-6 months of therapy resulted in fewer thromboembolic recurrences without a significant increase in the frequency of hemorrhagic complications, suggesting that the recurrent thromboembolic tendency exists for months rather than weeks after an acute thromboembolic episode. Equally important, these reports suggested that the increase in the rate of recurrent thromboembolism occurred primarily in high-risk patients (i.e., in those patients in whom thromboembolism was idiopathic in nature and/or who were afflicted with venous insufficiency).

However, none of the three published studies discussed above included patients who had suffered more than one thromboembolic event. Therefore, the results of the Schulman et al study are extremely important. These results conclusively demonstrate that the rate of thromboembolic complications was significantly lower in the group assigned to indefinite therapy than in the six-month therapy group. Despite the trend toward an increase in hemorrhagic complications in the indefinite-therapy group, there was a significant decrease in the overall rate of complications in the six-month therapy group when one considers both hemorrhagic and thromboembolic complications. Unfortunately, there was a substantial rate of withdrawal from both treatment groups in this prolonged study. However, it is important to note that all of the thromboembolic complications in the study occurred in patients who were no longer receiving anticoagulant therapy, underscoring the high risk of recurrent disease in patients who have already suffered two thromboembolic episodes and the efficacy of long-term oral anticoagulant therapy in that group.

In conclusion, it would appear that the risk of recurrent thromboembolism is extremely low in low-risk patients (i.e., those with temporary risk factors for thromboembolic disease) who receive anticoagulants for only 4-6 weeks, whereas patients who are in the intermediate-risk group (i.e., those with recurrent venous thromboembolic disease) should receive anticoagulants for an indefinite period of time. Additional studies are necessary to determine length of therapy in special subgroups such as patients with cancer, inherited thrombophilia, etc., and it is quite probable that, as additional data are published, recommendations will change. For the time being, however, indefinite anticoagulant therapy appears to be indicated for those patients who are afflicted with recurrent thromboembolic disease.

References

1. Research Committee of the British Thoracic Society. Lancet 1992;340:873-876.

2. Schulman S, et al. N Engl J Med 1995;332:1661-1665.

3. Johansson J, et al. Lakartidningen 1982;84:22-25.

4. Hyers TM, et al. Chest 1993;103:1636.

5. Levine MN, et al. Thromb Haemost 1995;74:606-611.