The Hematologist

September-October 2012, Volume 9, Issue 5

Take One and Call Me in the Morning?

Margaret V. Ragni, MD, MPH

Published on: September 01, 2012

Dr. Ragni indicated no relevant conflicts of interest.

Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366:1959-1967.

In patients who have experienced an episode of unprovoked venous thromboembolism (VTE), recurrence is observed in as many as 20 percent following discontinuation of anticoagulant therapy. Yet, extending anticoagulation longer than the recommended six months1 would increase cost, inconvenience patients, and put them at risk for bleeding complications. Thus, the need for uncomplicated, safe, inexpensive therapy for long-term VTE prevention is apparent.

What is the role of aspirin in VTE prevention? From a biologic standpoint, the question is reasonable. Coagulation reactions occur on the surface of activated platelets in three different ways: platelets fuse with tissue factor-bearing microparticles to initiate coagulation;2 platelets form venous thrombi together with fibrin, red cells, and leukocytes;3 and platelets release mediators that promote thrombin generation.4 Further, while atherosclerotic cardiovascular disease and VTE are considered separate processes, patients with VTE have an increased risk of atherosclerotic cardiovascular disease, and patients with atherosclerotic cardiovascular disease have an increased risk of VTE.5 Also, aspirin has been used for secondary prevention of cardiovascular events and, in the last decade, for prevention of VTE in medical, surgical, and stroke patients. For example, low-dose aspirin provided a relative risk reduction in VTE of 36 percent in a study involving more than 13,000 patients undergoing elective hip fracture or joint arthroplasty surgery5 and 39 percent in patients at high risk for VTE.6

The aim of the trial by Becattini and colleagues from the University of Perugia was to determine if aspirin is beneficial in preventing VTE recurrence in patients with unprovoked VTE after completing a standard course of treatment with an oral vitamin K antagonist. Together with investigators from the Warfarin and Aspirin Study, Becattini et al. conducted a double-blind, placebo-controlled trial comparing 100 mg of aspirin daily with a placebo over a two-year period in 402 patients who had completed at least six months of oral anticoagulant therapy for a first-time, unprovoked VTE. They reported that aspirin reduced VTE recurrence by nearly half, 11.2 percent versus 6.6 percent (95% CI, 0.36-0.93). No correlation between duration of prior anticoagulation and VTE event rates was observed, and no difference was found in the incidence of major bleeding (one episode in each arm, 0.5%), non-major bleeding, (three episodes in each arm, 1.5%), or deaths (1.4% vs.1.3% per year, treatment arm vs. placebo arm, respectively).

By providing evidence that, following standard oral anticoagulation, low-dose aspirin safely and significantly reduces the incidence of thrombosis recurrence, the current study suggests a new standard of care for patients who experience a first-time, unprovoked VTE event. Further, the results of the study by Becattini can be seen as verification of the hypothesis that platelets contribute to the pathobiology of VTE.

Patients with cancer or a thrombophilic condition were excluded from the study. Whether the findings of Becattini and colleagues apply to such patients and other groups requires further investigation.

How do these findings using low-dose aspirin compare with extended use of oral anticoagulant therapy or with extended use of one of the new oral anticoagulants (the thrombin inhibitor [dabigatran] or the Xa inhibitor [rivaroxaban])? Continuing oral vitamin K inhibition beyond six months provides modest risk reduction, but such therapy necessitates monitoring and increases the incidence of bleeding. The oral thrombin and Xa inhibitors reduce the risk of VTE recurrence by 80 percent,7,8 but treatment is expensive, and, importantly, the relatively long half-life of these drugs together with the lack of an effective antidote puts patients at risk for serious morbidity and even death from bleeding complications. Such adverse effects are being increasingly recognized, especially among elderly patients. The extent of these problems will need to be carefully documented, but for now, the study by Becattini and colleagues bestows respectability upon the wag’s advice to “take an aspirin and call me in the morning.”

1. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S-e494S.

2. del Conde I, Shrimpton CN, Thiagarajan P, et al. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulation. Blood. 2005;106:1604-1611.

3. Brill A, Fuchs TA, Savchenko AS, et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. 2012;10:135-44.

4. Sørensen HT, Horvath-Puho E, Søgaard KK, et al. Arterial cardiovascular events, statins, low-dose aspirin and subsequent risk of venous thromboembolism: a population-based case-control study. J Thromb Haemost. 2009;7:521-528.

5. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000;355:1295-1302.

6. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86.

7. Schulman S, Baanstra D, Eriksson H, et al. Dabigatran vs. placebo for extended maintenance therapy of venous thromboembolism. J Thromb Haemost. 2011;9:Suppl 2:22, abstract.

8. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.

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