Trial Information

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).

A systematic overview including more than 8000 patients from randomized trials on
antiplatelet primary thromboprophylaxis suggested that antiplatelet therapy was effective to
prevent deep vein thrombosis and pulmonary embolism in high risk patients (Antiplatelet
Trialists' Collaboration).13 Antiplatelet therapy was associated with a relative risk
reduction [RRR] of 39%; (p=0.00001) in the incidence of venous thromboembolism in high-risk
medical patients or undergoing orthopedic or general surgery. There was no excess in
cerebral or fatal bleeding.

The European Stroke Prevention Study 2 (ESPS 2)14 evaluated the efficacy and safety of
aspirin, dipyridamole (extended-release preparation), or aspirin and dipyridamole, versus
placebo, for the secondary prevention of ischemic stroke in 6,600 patients. Prespecified
secondary analyses found that aspirin resulted in a 30% reduction in venous thromboembolism.

Bleeding, particularly within the gastrointestinal tract, is the only important side effect
of low-dose aspirin therapy in patients that are not already known to be aspirin intolerant
(e.g., allergy). Long term, low-dose aspirin therapy (i.e., 160 mg per day), is associated
with about a two-fold increase in the risk of bleeding.15-17 This increase of bleeding is
small in patients without known contraindications to aspirin. Evidences from randomized
trials of aspirin in asymptomatic subjects, patients with vascular risk factors, or patients
with a past history of vascular disease (more than 250,000 patient-years of follow-up),
showed an absolute excess of major bleeding with aspirin from 0.3 to 1.7 episodes per 1000
patient-years, equivalent to an absolute risk of 1 event for every 1000 patients treated.15
Increasing doses of aspirin, even within the range of 100-300 mg per day, were associated
with an increasing risk of gastrointestinal bleeding, with the lowest risk occurring in
patients receiving 100 mg daily.15;18-19

In summary, aspirin could achieve a risk reduction of 30 to 40 episodes of deep vein
thrombosis or pulmonary embolism for every 1000 patients treated, at a cost of 1 bleed
requiring transfusion in high-risk patients with idiopathic venous thromboembolism. Aspirin
is simple to administer and does not require laboratory monitoring.

In the present study we propose to evaluate the use of low-dose aspirin for the prevention
of recurrent venous thromboembolism in patients with previous idiopathic venous
thromboembolism who have received initial 6-month treatment with oral anticoagulants.