Dec 292012
(image: Rex Parker)

Among people with unprovoked deep venous thrombosis (DVT) or pulmonary embolism (PE), 1 in 5 will experience another DVT or PE within 2 years after stopping anticoagulation with warfarin (Coumadin). For this reason, the ACCP's recommendations for treatment of unprovoked proximal DVT or PE suggest consideration of an "indefinite" period of anticoagulation -- a soft way of saying "lifelong." That's a burdensome prescription, committing patients to the continual elevated risk of bleeding and a requirement for periodic monitoring with blood draws or finger-sticks.

New anticoagulants rivaroxaban (Xarelto) and dabigatran (Pradaxa) may eventually become standard-of-care alternatives for long-term anticoagulation to reduce risk for recurrent DVT or PE. But these drugs are expensive, and their full, real-world safety profiles will have to emerge over time.

What about good old fashioned aspirin? In a randomized trial published in the May 24 New England Journal of Medicine, a single daily 100 mg aspirin, begun after completing 6-18 months of warfarin, reduced the risk of recurrent venous thromboembolism (VTE) by an impressive 40% compared to placebo.

What They Did

Cecilia Becattini, Giancarlo Agnelli, Paolo Prandoni et al (the WARFASA investigators) randomized 402 patients with an unprovoked DVT or PE to begin taking aspirin 100 mg daily or placebo for 2 years, after completing 6-18 months of warfarin therapy.

Primary outcomes were symptomatic recurrent DVT or PE, and major bleeding (defined as either being in a critical location like intracranial, or >= 2 g/dL drop in hemoglobin, or >= 2 units transfused).

Patients were ~62 years old. 34-40% of the patients had had pulmonary embolism as their VTE; 60-66% had had deep venous thrombosis. More people in the group randomized to aspirin had had first PEs (34 vs. 40%). Most (>50%) had been treated with warfarin for at least 12 months; about one-third in each group had only been treated for 6 months. Patients randomized to placebo had been treated with warfarin for slightly longer as a group (a priori, this should have biased toward the null and made a positive result for aspirin harder to achieve).

What They Found

Aspirin reduced the risk of recurrent VTE by a relative 42%, and by an absolute 5% -- a number needed to treat of less than 20 to prevent one recurrent episode of venous thromboembolism with daily aspirin.

The numbers broke down as follows:

  • There were 71 total recurrent VTEs among 403 patients (8.6% per year). 27 were recurrent PEs and 44 were recurrent DVTs.
  • 28 of 205 patients taking aspirin had recurrent DVT or PE (6.6% per year)
  • 43 of 197 patients taking placebo had recurrent DVT or PE (11.2% per year)
  • 11 of 83 taking aspirin for previous PE had a recurrent pulmonary embolism (6.7%), compared to 16 of 67 placebo-taking patients (13.5%).

This last figure -- potentially the most important -- suggests daily aspirin provides an absolute ~7% risk reduction (60% relative risk reduction) for recurrent pulmonary embolism after a first PE that was properly treated with warfarin. That's a number needed to treat of only 15 to prevent a symptomatic pulmonary embolism with daily aspirin. (I know, this wasn't a prespecified endpoint ... but it's impressive nonetheless, to me.)

The new anticoagulants dabigatran (Pradaxa) and rivaroxaban (Xarelto), by comparison, reduced risk by more than a relative 80% in clinical trials. Low-intensity warfarin is believed to provide a ~65% relative risk reduction.

There was one episode of major (nonfatal) bleeding in the placebo group, due to a gastric ulcer, and one in the aspirin-treated group, due to bowel angiodysplasia.

Authors report their study was funded by their home institution of University of Perugia (Italy), and by a "grant-in-aid" from Bayer HealthCare (makers of rivaroxaban/Xarelto, and of course Aspirin®), and Aventis (who help fund Dr. Becattini through a fellowship).

Clinical Takeaway: With the new anticoagulants poised to dislodge warfarin as first-line treatment for a first DVT or PE, and this study suggesting aspirin as a reasonable option for "indefinite" secondary prevention after a first unprovoked DVT or PE, it looks like warfarin's days as the treatment for venous thromboembolism may be numbered.

Becattini C et al (WARFASA Investigators). Aspirin for Preventing the Recurrence of Venous Thromboembolism. N Engl J Med 2012;366:1959-1967.

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An aspirin a day keeps recurrent DVT and PE away (RCT)