Aspirin After Six Months or One Year of Oral Anticoagulants for the Prevention of Recurrent Venous Thromboembolism in Patients With Idiopathic Venous Thromboembolism. The WARFASA Study.

Background

Venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism, is a common disease with an annual incidence of 0.5-1.6 per 1000 in the general population.1-4 Standard treatment with intravenous or subcutaneous heparin or low molecular heparin relayed with oral anticoagulants is highly effective in preventing recurrent episodes of venous thromboembolism.5 However, oral anticoagulant therapy has a number of limitations including an increased risk of major bleeding and the need for laboratory monitoring to adjust dose. Because of these limitations, venous thromboembolism is usually treated with oral anticoagulants for a limited period of time. Anticoagulants are generally discontinued when the risks and inconvenience of remaining on treatment outweigh the risk of recurrent venous thromboembolism. Indeed, recent studies showed that after discontinuation of anticoagulant treatment, the risk of recurrent venous thromboembolism remains high in patients with idiopathic venous thromboembolism.

Recently, four major randomized trials have evaluated extended-duration treatment with oral anticoagulants in patients with venous thromboembolism. In each of these trials more than 90% of recurrences occurred after oral anticoagulants had been discontinued 6-9. The rate of recurrence after discontinuation of oral anticoagulants was similar in patients assigned long-term therapy compared with short-term therapy (about 15% in the 2-3 years after warfarin discontinuation) which indicates that although oral anticoagulants are highly effective to prevent recurrence, it have no impact on the natural history of idiopathic venous thromboembolism. Taken together, these data suggest that effective therapy should be continued indefinitely in patients with idiopathic venous thromboembolism if recurrence is to be avoided. Indeed, once oral anticoagulants are discontinued, there are currently no established safe and effective alternatives to prevent recurrence in patients with idiopathic venous thromboembolism. However, the long-term use of oral anticoagulants is not only inconvenient because of the need for close laboratory monitoring but also is constrained by an increased risk of major bleeding, including fatal and intracranial bleeding. In randomized trials of extended-duration oral anticoagulants (target INR 2.0-3.0) for the treatment of venous thromboembolism,6-9 the annual incidence of intracranial bleeding was 0.3%, major bleeding 3%, and the case-fatality rate of major bleeding approximately 10%. In addition, 5-15% of patients experienced minor bleeding each year. These data highlight the need to identify simple, safe, effective, and widely applicable strategies for the long-term prevention of recurrent deep vein thrombosis or pulmonary embolism in patients with idiopathic venous thromboembolism.

About 3% of patients with venous thromboembolism experience an arterial cardiovascular event (myocardial infarction, stroke, sudden otherwise unexplained death) in the 2-3 years after the first episode of venous thromboembolism10. The long-term use of oral anticoagulants could potentially prevent these adverse events. Barriers to the more widespread appropriate use of oral anticoagulants include physician concerns regarding the risk of bleeding, particularly in the elderly, as well as the need for close monitoring and regular blood tests to measure the INR. A simple, safe, effective, and widely applicable pharmacological approach is needed for the prevention of these events.

The clinical utility of aspirin in the management of venous thromboembolism is a matter of debate. The Pulmonary Embolism Prevention Study 11 demonstrated that 35 days of low-dose aspirin (160 mg daily) compared with placebo reduced the risk of symptomatic venous thromboembolism, including fatal pulmonary embolism, by about one-third (RRR 36%, 95% CI: 19-50%, p=0.0003) in patients undergoing emergency surgery for hip fracture or elective joint arthroplasty. There was no excess of fatal or intracranial bleeding. In the Heart and Estrogen/progestin Replacement Study (HERS)12 2800 postmenopausal women with coronary artery disease were randomized to hormonal replacement therapy or placebo. A secondary analysis showed that the use of aspirin was independently associated with a 50% reduction (95% CI: 20-80%) in risk of venous thromboembolism during an average of 4.1 years of follow-up. Taken together, these data suggest that aspirin reduces the risk of a first episode of venous thromboembolism by about one-quarter (i.e., 25% risk reduction).