Aspirin After Warfarin Prevents Recurrence of VTE
Abstract & Commentary
By Andrew J. Boyle, MBBS, PhD, Assistant Professor of Medicine, Interventional Cardiology, University of California, San Francisco. Dr. Boyle reports no financial relationships relevant to this field of study.
Source: Becattini C, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366:1959-1967.
Approximately 20% of patients with unprovoked venous thromboembolism (VTE) have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy. Extending anticoagulation prevents VTE recurrence but is associated with an increased risk of bleeding. The benefit of aspirin for the prevention of recurrent VTE is unknown. Therefore, Becattini and colleagues performed a multicenter, double-blind study of aspirin vs placebo for 2 years in patients with first-ever unprovoked VTE who had completed 6 to 18 months (at the discretion of their physician) of oral anticoagulation with warfarin. Inclusion criteria included symptomatic imaging-proven proximal deep venous thrombosis (DVT), pulmonary embolism (PE) or both, in the absence of any known precipitating cause for VTE. Exclusion criteria included cancer, known major thrombophilia, an indication for long-term anticoagulant therapy other than venous thromboembolism (such as atrial fibrillation or prosthetic heart valve), previous symptomatic complications of atherosclerosis requiring treatment with aspirin or other antiplatelet agents, active (or recent) bleeding or high risk for bleeding, allergy or intolerance to aspirin, life expectancy shorter than 6 months, pregnancy or breast-feeding, or the use of estrogen-progestin therapy. After completion of their clinically-indicated course of warfarin, 403 patients were randomly assigned to receive aspirin 100 mg daily (n = 205) or placebo (n = 198) for 2 years, with the option of extending the study treatment. The study was investigator-initiated, but was funded by Bayer.
Baseline demographics were similar between treatment groups. The primary efficacy outcome, recurrence of VTE, occurred in 6.6% of the aspirin group and 11.2% of the placebo group per year (hazard ratio [HR] 0.58; P = 0.02). Interestingly, those who initially presented with PE were more likely to have PE as their recurrent event. In a post-hoc subgroup analysis, the reduction in event rate was of a similar order of magnitude whether the initial presentation was PE or DVT, although only PE reached statistical significance. The authors performed a multivariable analysis to account for age, sex, index event (PE or DVT), and duration of initial anticoagulant treatment. The HR was still in favor of aspirin over placebo (HR 0.53; P = 0.009). They found two independent predictors of recurrence of VTE: age > 65 years (HR 2.26; P = 0.02) and male gender (HR 2.02; P = 0.01). Major bleeding was rare, occurring in only one patient in each group. Death occurred in 1.4% and 1.3% of the aspirin and placebo groups, respectively (P = NS). Minor bleeding and other adverse events were not different between groups. The authors conclude that aspirin reduced the risk of recurrence when given to patients with unprovoked VTE who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding.
Commentary
The optimal duration of warfarin therapy for VTE has been difficult to define because of the heterogeneous nature of VTE and the patients in whom it occurs. The high recurrence rate in patients with "unprovoked" VTE suggests there may actually be predisposing factors in some patients that we are currently unable to diagnose. In the absence of identifying the patients who are at most risk, we are left with the conundrum of short vs longer duration of oral anticoagulation in all patients. The excess bleeding associated with longer oral anticoagulation could pose a significant risk to some patients. An approach that can reduce the risk of recurrence in all-comers with no excess bleeding is most welcome. Aspirin appears to be an inexpensive and safe method to reduce recurrence by approximately 40%.
Where this study fits with the new generation of oral factor Xa inhibitors and direct thrombin inhibitors remains to be determined. The newer agents have lower bleeding rates compared to warfarin, and prolonged therapy with them may further reduce the recurrence rate of VTE over aspirin with no excess bleeding, but this remains to be tested in future clinical trials. Aspirin, prolonged lower intensity warfarin, or prolonged use of the newer agents may all have a place in treating different patients, based on their bleeding risk and comorbidities.
This study is limited by excluding many patient groups, such as those with arterial disease who would require aspirin. It should be remembered that this study only applies to unprovoked VTE, and those with provoked VTE may not have the same response to aspirin. However, the study is strengthened by its rigorous design, the placebo-controlled design, the multicenter cohort that was enrolled, and independent adjudication of events. Aspirin may represent an alternative long-term strategy to prolonged anticoagulation or no treatment at all.
Approximately 20% of patients with unprovoked venous thromboembolism (VTE) have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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