By Harold L. Karpman, MD, FACC, FACP
Clinical Professor of Medicine, UCLA School of Medicine
Dr. Karpman reports no financial relationships relevant to this field of study.
Patients with unprovoked venous thromboembolism (VTE) are at high risk of recurrence after discontinuation of vitamin K antagonist (such as warfarin) therapy, with an approximately 10% risk of recurrence within the first year and 5% risk per year thereafter.1-6 Extending treatment with warfarin or similar agents reduces the risk of recurrence while treatment continues,1-7 but such therapy is, of course, associated with an increased risk of bleeding and the inconvenience of laboratory monitoring and dose adjustment.8 Several studies have evaluated the efficacy of the new oral anticoagulants for the prevention of recurrent VTE as part of the initial or the extended treatment regimen, but these drugs still carry a risk of bleeding and are expensive.9-14 Therefore, aspirin, as a low-cost and relatively safe drug, was recently evaluated in the Aspirin for the Prevention of Recurrent Venous Thromboembolism (WARFASA)15 and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials.16 These trials demonstrated that aspirin reduced the risk of recurrent VTE, but they were not sufficiently powered to detect moderate treatment effects for particular outcomes or subgroups.
Simes and associates performed an analysis of the two trials15-16 in order to more accurately estimate the effects of aspirin therapy overall, on individual outcomes, and in prespecified subgroups of patients.17 The major bleeding rate was low for both the placebo group and for the aspirin-treated group, and aspirin was found to reduce VTE by 42% in the broad cross-section of patients with a first unprovoked VTE.
Fewer than 50% of the patients in the United States and around the world with unprovoked VTE are routinely treated with long-term anticoagulant therapy.18–20 The prospectively planned analysis of the WARFASA and ASPIRE trials using individual patient data provides strong evidence that in patients with a prior unprovoked VTE, aspirin, after any initial anticoagulation therapy had been completed, was effective in reducing the rate of VTE recurrence. It has been estimated that there are 1 million patients worldwide with unprovoked VTE and that if they were to remain on aspirin therapy long term, 100,000 events might be prevented with only a minimal increase in bleeding. Besides being cost-effective, more importantly, aspirin therapy in this group of patients is medically effective and should be continued long term.
In summary, the prospective combined analysis of the WARFASA and ASPIRE trials provides clear evidence that long-term aspirin therapy reduces the risk of recurrent VTE events by approximately 40% and is both very safe and effective. Even though it does not reduce the rate of recurrent VTE as much as warfarin or the newer oral anticoagulants, among patients for whom these therapies are not considered appropriate or have been discontinued for any reason, aspirin therapy should be strongly considered.
- Prandoni P, et al. The risk of recurrence of venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. Hematologica 2007;92:199-205.
- Boutitie F, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: Analysis of individual participant’s data from seven trials. BMJ 2011;342:d3036.
- Agnelli G, et al; Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep vein thrombosis. N Engl J Med 2001;345:165-169.
- Kearon C, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907.
- Heit JA, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism. Arch Intern Med 2000;160:761-768.
- Agnelli G, et al; Warfarin Optimal Duration Italian Trial Investigators. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003;139:19-25.
- Eikelboom JW, et al. Anticoagulation for venous thromboembolism. BMJ 2007;334:645.
- Linkins LA, et al. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: A meta-analysis. Ann Intern Med 2003;139:893-900.
- The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-2510.
- The EINSTEIN Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-1297.
- Schulman S, et al. Dibigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2013;368:709-718.
- Agnelli G, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708.
- Agnelli G, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808.
- Becattini C, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366:1959-1967.
- Brighton TA, et al; ASPIRE Investigators. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012;367:1979-1978.
- Simes J, et al. Aspirin for the prevention of recurrent venous thromboembolism. The INSPIRE collaboration. Circulation 2014;130:1062-1071.
- Computerized Registry of Patients with Venous Thromboembolism (RIETE). Madrid: S&H Medical Science Service. 2001–2013. Available at: https://www.riete.org. Accessed Nov. 13, 2014.
- Liu X, et al. Persistence on warfarin therapy in patients with venous thromboembolism: A large US insurance database analysis. Circulation 2013; 128:A12664.
Cohen A, et al. Vitamin K antagonist treatment patterns and persistence after venous thromboembolism in noncancer patients VTE Epidemiology Group (VEG) Study.
J Thromb Haemost 2013;11(suppl 2):84.