Niki Katsiki, MSc, PhD, MD, FRSPH
Becattini C, Agnelli G, Schenone A, et al, for the WARFASA Investigators. 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 of withdrawal from vitamin K antagonist therapy. Extending treatment with these medications reduces recurrence risk but is associated with an increased risk of bleeding and inconvenience.
The aim of the WARFASA study was to assess the clinical benefit of aspirin for the prevention of recurrence after a course of treatment with vitamin K antagonists in patients with unprovoked VTE.
Becattini et al1 compared the effect of 100 mg/d aspirin versus placebo in 402 patients with unprovoked VTE (deep vein thrombosis [DVT], pulmonary embolism [PE], or both). Patients had been on oral anticoagulant treatment for 6 to 18 months (about 55% of participants were treated for 1 year) and were randomized to aspirin
versus placebo within 2 weeks of withdrawing vitamin K antagonists. White race was reported by about 99% of the study population (mean age, approximately 62 years).
VTE recurred in 28 of 205 patients in the aspirin group and 43 of 197 patients in the placebo group [6.6% vs 11.2% per year; hazard ratio (HR) = 0.58; 95% confidence interval (CI) = 0.36-0.93; P = .02]. The median study duration was 24.6 months. Major nonfatal bleeding (1 case in each group) or clinically relevant non-major bleeding (3 cases in each group) did not differ between aspirin and placebo groups (HR = 0.98; 95% CI = 0.24-3.96; P = .97). The other adverse events were similar in the 2 groups. The study drug was discontinued prematurely in 16 patients assigned to aspirin and in 15 patients given placebo.
A recurrence of a PE was more common among the patients who entered the study with a PE than among those recruited with DVT (12.7 vs 3.2%; HR = 5.52; 95% CI = 2.29-13.30; P <.001). Independent risk factors for recurrent VTE included age >65 years (HR = 2.26; 95% CI = 1.16-4.41; P = .02) and male gender (HR = 2.02; 95% CI = 1.16-3.49; P = .01). No association was found between recurrent VTE and prior anticoagulant therapy lasting for 6 months. Death occurred in 6 patients (1.4% per year)
in the aspirin group and in 5 patients (1.3% per year) in the placebo group. Arterial events were similar in both groups (1.9 vs 1.3% per year in the aspirin and placebo groups, respectively). In this context, it is relevant that patients with symptomatic arterial disease were not included in this trial. Therefore, as the authors mention,
the study was underpowered for showing an effect of aspirin on arterial events. One advantage of this study was that its 2-year duration is longer than recent studies that evaluated treatment for VTE.
The authors concluded that aspirin reduced the rate of VTE recurrence by about 40% compared with placebo, with no apparent increase in bleeding complications. The article also considers evidence (including the Antiplatelet Trialists’ Collaboration) showing that aspirin is useful in VTE, and considers the future of aspirin use in the context of VTE prevention. New orally administered drugs (dabigatran and rivaroxaban), as well as lower-dose aspirin or warfarin, are also discussed.
1. Becattini C, Agnelli G, Schenone A, et al; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366:1959- 1967.
2. Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851-1861.
3. Paraskevas KI, Bessias N, Perdikides TP, Mikhailidis DP. Statins and venous thromboembolism: a novel effect of statins? Curr Med Res Opin. 2009;25:1807-1809.
4. Khemasuwan D, Chae YK, Gupta S, et al. Dose-related effect of statins in venous thrombosis risk reduction. Am J Med. 2011;124:852-859.
5. Squizzato A, Galli M, Romualdi E, et al. Statins, fibrates, and venous thromboembolism: a meta-analysis. Eur Heart J. 2010;31:1248-1256.
6. Glynn RJ, Ridker PM, Goldhaber SZ, et al. Effect of low-dose aspirin on the occurrence of venous thromboembolism: a randomized trial. Ann Intern Med. 2007;147:525-533.
7. Becker RC. Aspirin and the prevention of venous thromboembolism. N Engl J Med. 2012;366:2028-2030
Further Clarity on a Critical Issue
Identifying an effective way to prevent VTE after an unprovoked event is a clinically relevant issue because of the high rate of recurrence within 2 years of discontinuing oral anticoagulants1 and the increased bleeding risk and continued cost of monitoring the international normalized ratio (INR). It follows that an alternative option like aspirin is attractive, provided it is effective and associated with fewer side effects than oral anticoagulant use. Also, aspirin use does not require laboratory monitoring. These factors may ensure better adherence to treatment. For these reasons, the findings of Becattini et al1 are important. However, several issues need to
be resolved before any definitive recommendations can be made.
• Aspirin dose: Becattini et al1 compared aspirin 100 mg/d versus placebo. It is widely accepted that 70 mg/d is a common dose of aspirin for the prevention of arterial
events. Whether the lower dose of aspirin will be as effective as the higher dose in preventing VTE recurrence (while being associated with fewer side effects) can only be established by large trials lasting several years.
• Warfarin dose: As shown in 2 previous studies, the bleeding risk associated with lower-intensity warfarin treatment is approximately 1%.1 In contrast, the risk of bleeding in the Becattini et al1 study was 0.3% per year in both groups (ie, aspirin and placebo) and the bleeding rate for conventional VTE prevention with warfarin (INR 2-3) is estimated at 2.0% per year.1 The effect of lower-intensity warfarin treatment in preventing a recurrence of VTE is estimated at 64%, which is greater than
the 40% reported by Becattini et al1 for aspirin. In evaluating these options it is relevant to consider that lower-intensity warfarin treatment requires INR monitoring.
• “New” oral anticoagulants: dabigatran and rivaroxaban were evaluated for recurrent VTE prevention, with an estimated risk reduction of 80%1: approximately
twice as effective as aspirin in the Becattini et al1 study. Although dabigatran and rivaroxaban do not require monitoring, they are considerably more expensive than aspirin. There are also other new oral anticoagulants that will need to be evaluated (eg, apixaban, darexaban, edoxaban), preferably in matched comparisons with other drugs in prolonged trials.
• Risk of arterial events: patients with symptomatic arterial disease were not included in the Becattini et al1 study. However, there may be an increased risk of arterial events in patients who had a VTE.1 Any treatment offered for recurrent VTE prevention will become more cost-effective if it also reduces arterial events. For example, in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial the effectiveness of primary prevention increased when arterial and venous events were pooled.2 This prediction will be especially true if patients at high risk of arterial events are included in VTE trials.2-4
• Combination therapy (statin + aspirin or 2 antiplatelet agents administered together): There is no mention of statin use in the Becattini et al1 study. The use of these drugs was probably low due to the absence of participants with established arterial disease. There is evidence that the aspirin + statin combination is more effective than aspirin alone when oral anticoagulants are discontinued after a VTE.4 In a retrospective cohort study4 (n = 1100), 6.3% (54/861) of statin users developed VTE compared with 22.2% (53/239) of nonusers (HR = 0.24; P <.001). After controlling for confounding factors, statin use remained associated with a lower risk of VTE (HR = 0.29; P <.001). Furthermore, high-dose statin was more effective (HR = 0.25; P <.001) than standard-dose statin use (HR = 0.38; P <.001). A statin and antiplatelet combination further reduced the occurrence of VTE (HR = 0.16; P <.001). A synergism between statins and aspirin is not all that surprising since both drugs exert anti-inflammatory actions.2-4 Statins also beneficially affect hemostasis.4 Both inflammation and thrombotic diathesis are involved in the pathogenesis of VTE and arterial thrombosis.4 The effect of statins on VTE is also supported by the Squizzato et al meta-analysis of.5 Both aspirin and clopidogrel monotherapy significantly reduced VTE events in a recent analysis (HR = 0.47; 95% CI = 0.28-0.79 and HR = 0.3; 95% CI = 0.11-0.82, respectively).4 Dual antiplatelet therapy with aspirin and clopidogrel further decreased the occurrence of VTE (HR 0.19; 95% CI = 0.1-0.34; P < .001).4 However, not all trials have shown a beneficial effect of aspirin on VTE.6
Clearly, preventing unprovoked VTE recurrence is a clinically relevant issue. More trials are needed to address the important issues discussed. The editorial7 accompanying the Becattini et al1 study describes the ongoing Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study, expected to report in 2012. In the ASPIRE trial, patients who received warfarin for 3 to 6 months for VTE are randomly assigned to either aspirin (100 mg/d) or placebo for a median of
3 years. It is hoped that this trial will provide further clarity about this very important issue.
About the Authors
Niki Katsiki, MSc, PhD, MD, FRSPH, is a specialist in internal medicine and a researcher at the Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece. Her clinical and research interests involve cardiovascular disease prevention and treatment, with a special focus on dyslipidemias. Dr Katsiki serves as a reviewer for several cardiovascular journals and is the Editorial Manager of Angiology and Section Editor of Archives of Medical Science. She was assisted in the writing of this article by Dimitri P. Mikhailidis, BSc, MSc, MD, FRSPH, FCP, FFPM, FRCP, FRCPath, Academic Head of the Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), and Department of Surgery, Royal Free Campus, University College London Medical School, UCL, London, UK. He is Editor-in-Chief of several journals including Current Medical Research and Opinion, Current Vascular Pharmacology, and Expert Opinion on Pharmacotherapy.