Using Low-Dose Aspirin to Prevent Recurrent Venous Thromboembolism

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationships relevant to this field of study.

Synopsis: Aspirin therapy, as compared with placebo, significantly reduced the rate of major vascular events with improved net clinical benefit and also reduced the rate of recurrent venous thromboembolism.

Source: Brighton TA, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012;367: 1979-1987.

It is well known that patients who have had an episode of unprovoked venous thromboembolism are at high risk for recurrence after anticoagulant therapy is discontinued.1-2 Long-term warfarin anticoagulant therapy has proven to be very effective in preventing a recurrence of venous thromboembolism, but is associated with an increased risk of bleeding and is inconvenient from the patient’s point of view.3-6 As a result, many patients will discontinue their warfarin therapy after 3-6 months despite recommendations for prolonged therapy.5

Brighton and his colleagues evaluated the efficacy of low-dose aspirin compared to placebo in preventing a recurrence of venous thromboembolism in patients who had completed initial anticoagulation therapy with warfarin after a first unprovoked episode of venous thromboembolism. They performed the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study,7 which was a double-blind, randomized, placebo-controlled study of 822 patients who had completed initial anticoagulation therapy with heparin followed by warfarin or another effective anticoagulant therapy after the first episode of unprovoked venous thromboembolism. A target INR of 2.0-3.0 was recommended while on warfarin therapy that was maintained for 6 to 12 months. Subjects were randomly assigned to receive a 100 mg dose of aspirin or placebo. The patients on aspirin demonstrated a large, although not significant, reduction in the rate of recurrence of venous thromboembolism. Most importantly, the patients also demonstrated a significant reduction in the rate of occurrence of other major vascular events, including myocardial infarction, stroke, or cardiovascular death.

Commentary

Although the results of the trial performed by Brighton et al did not demonstrate a significant reduction in the primary outcome of recurrent venous thromboembolism with aspirin as compared to placebo therapy in patients who had suffered a first unprovoked venous thromboembolic incident and had been treated with 6-12 months of warfarin therapy, they did demonstrate that aspirin therapy significantly reduced the secondary composite outcome of major vascular events by 34% without increased bleeding. With fewer patients recruited than originally planned, the trial by itself was not sufficiently powered to show a significant reduction in the primary outcome, but when combined with the WARFASA study8 results, in which patients had baseline characteristics that were similar, a clear effect was evident. The combined results of the two trials revealed a highly significant reduction of 32% in the rate of recurrent venous thromboembolism and a reduction of 34% in the rate of major vascular events with no excess bleeding.

It is well known that the risk of late reoccurrence of venous thromboembolism after a first unprovoked event remains high at approximately 10% in the first year.1,2 Therefore, it is important to have an alternative form of medical therapy for the many patients who are unwilling to accept extended warfarin therapy because of its inconvenience and the increased risk of developing significant bleeding. Although aspirin is less effective than warfarin, this study by Brighton et al suggests that aspirin therapy is an attractive alternative to warfarin because it is simple, inexpensive, and has a well-documented safety profile. Aspirin has now been demonstrated to be effective by producing a significant overall reduction in the risk of major thrombotic events and cardiovascular death and a large, although not statistically significant, reduction in the rate of recurrent venous thromboembolism.

In summary, low-dose aspirin therapy appears to be beneficial in preventing recurrent venous thromboembolism and major vascular events in patients who had a first episode of unprovoked venous thromboembolism. It also appears to be an attractive therapeutic option for these patients after they have completed an initial course of warfarin therapy.

References

1. Prandoni P, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7.

2. Rodger M, et al. Unprovoked venous thromboembolism: Short-term or indefinite anticoagulation? Balancing long-term risk and benefit. Blood Rev 2010;24:171-178.

3. Kearon C, et al. Antithrombotic therapy for VTE: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141: e419S-e494S.

4. Schulman S, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1999;341:298.

5. Agnelli G, et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep vein thrombosis. N Engl J Med 2001;345:165-169.

6. Agnelli G, et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003;139:19-25.

7. Brighton TA, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012; 367:1979-1987.

8. Prandoni P, et al. An association between atherosclerosis and venous thrombosis. N Engl J Med 2003;348: 1435-1441.