Aspirin To Prevent Recurrent VTE? Too Little, Too Late?

Patients with a history of a single unprovoked venous thromboembolism (VTE) have a 10-30% risk of a recurrence within 5 years following cessation of anticoagulation.¹ The decision to extended anticoagulation beyond 6-12 months in patients with a previous VTE must weigh the benefit of reducing recurrent VTEs versus the burdens of anticoagulation therapy (e.g. bleeding, drug costs, need for monitoring). The burdens of therapy aren’t trivial.  While 3.6% of recurrent VTEs are fatal, so are 11.6% of major bleeding events.¹ From a benefit:risk view point, the decision to extend anticoagulation rests heavily on whether we can minimize the risk of bleeding.

There are many patients who are not good candidates for extended anticoagulation and who find warfarin therapy too burdensome.  In these circumstances we are forced to consider alternatives to prevent a recurrent event.  The WARFASA and ASPIRE trials give us some insight about the use of aspirin following treatment with oral anticoagulation.^2,3

The Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study was a double-blind, randomized, placebo-controlled trial that originally aimed to enroll 3,000 subjects with a history of one unprovoked VTE.³  However, due to slow enrollment, the investigators terminated the ASPIRE study and combine the results with those from WARFASA as part of a pre-planned meta-analysis.³  Similar to WARFASA, subjects received either aspirin 100 mg once daily or placebo for 2-4 years and the primary outcome was symptomatic VTE. A secondary endpoint included major vascular events (a composite of MI, stroke, VTE, and CV death).  The trial failed to meet its target enrollment after 8 years of recruitment, randomizing only 822 patients. The primary outcome occurred at a rate of 6.5% per year in the placebo group and 4.8% per year in the aspirin group (hazard ratio with aspirin, 0.74; 95% CI, 0.52-1.05; p=0.09). Not surprisingly, major vascular events were reduced with aspirin therapy when compared to placebo (hazard ratio, 0.66; 95% CI, 0.48 – 0.92, p=0.01) with a NNT = 36 if treated with aspirin for 1 year.  Bleeding, including overt bleeding associated with a ≥2 g/dL drop in hemoglobin, OR requiring ≥ 2 units of blood or a surgical intervention, OR contributing to disabling or death, AND clinically relevant non-major bleeding, occurred at a rate of 0.6% per year with placebo versus 1.1% per year with aspirin (p=0.22).

Data from the pooled analysis of ASPIRE and WARFASA supports the role of aspirin for the prevention of recurrent VTE in patients with a unprovoked VTE after anticoagulation therapy has been given for 6-18 months.  While this is well and good, the difficulties encountered in enrolling patients in both trials highlights the limited generalizability of ASPIRE and WARFASA.  In reality, most middle-aged patients (mean age = 62 and 55 years in WARFASA and ASPIRE, respectively) with a history of vascular disease should be on aspirin for the primary prevention of stroke or MI.^2,3 Indeed, AT9 recommends aspirin for the primary prevention of cardiovascular disease in all patients 50 years or older (Grade 2B).⁴

What is the role of aspirin for the secondary prevention of VTE?  Tell us what you think.