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This is a plain English summary of an original research article. The views expressed are those of the author(s) and reviewer(s) at the time of publication.

Warfarin, newer direct oral anticoagulants and aspirin all significantly reduced the rate of recurrent clots in patients treated for more than the standard three months. Aspirin was the least effective and the number of major bleeds and deaths was low in all three groups.

This review pooling seven trials found that between six and 36 months 28 in every 1000 people taking warfarin, direct oral anticoagulants or aspirin after a first blood clot developed a second clot. This was significantly fewer than the 97 per 1000 people who developed a second clot while taking placebo. The cost-effectiveness of extending treatment was not assessed.

People who have had an unexplained blood clot in a major vein, are much more likely to have another, which can be life-threatening. Normal treatment with anticoagulant drugs lasts three months with the option to extend for longer. Longer, even “life-long” treatment is also an option but based on this study the balance between effectiveness and safety is unclear beyond three years.

The systematic review suggests extending any of the three treatments can reduce VTE recurrence, but warns that close monitoring of serious side effects would be needed.

Why was this study needed?

People who have had a first clot without an obvious cause, such as surgery (an unprovoked venous thromboembolism [VTE] - see Definitions) have a higher risk of having another. Around 20-30% will have another within ten years and around 12% of these will prove fatal.

A 2005 report from the House of Commons select Committee suggests that each year over 25,000 people in England die from clots contracted in hospital and estimated that the direct and indirect costs (such as lost productivity or work) to the UK of is £640 million.

UK guidance recommends three months’ “active treatment” with anticoagulants, which can be extended for people with unprovoked clots. However, taking anticoagulants can lead to major bleeding and even death, so there is a need to carefully balance the risks and benefits over the long term.

This systematic review studied the risks and benefits of extended treatment with warfarin, direct oral anticoagulants (rivaroxaban, apixaban and dabigatran) or aspirin for people who have had an unprovoked first clot.

What did this study do?

This systematic review included seven randomised controlled trials (3815 people) evaluating the risk of recurrent clots in people who had experienced an “unprovoked” clot. Patients had received anticoagulation treatment for at least three months, and then were allocated to either long-term (at least six months) oral anti-thrombotic treatment – specifically warfarin, direct oral anticoagulation or aspirin – or a placebo.

All seven trials were high quality, scoring low for risks of bias. Three trials – all assessing direct oral anticoagulants - included a proportion of people with “provoked” clots (see Definitions) ranging from 6.8% to 26.5%. Results for provoked and unprovoked populations were not given separately. Two trials were conducted in Europe and three were international.

What did it find?

  • The risk of recurrent VTE was significantly lower in people taking prescribed oral anti-thrombotic treatment for six to 37 months (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.11 to 0.42). The average risk of VTE recurrence in this time was 2.8% in those receiving extended treatment compared with 9.7% receiving a placebo.
  • The meta-analysis would not reliably detect differences in rates of major bleeds or death because these were so rare in both groups. However, there was a non-significant trend towards a higher risk of bleeding in those receiving extended treatment (OR 1.64, CI 0.69 to 3.90). Major bleeding occurred in 0.6% of those taking active drugs compared with 0.4% in the placebo group.
  • Three trials followed people after they stopped extended treatment and found they had approximately the same annual risk of VTE recurrence as those treated for shorter periods.

What does current guidance say on this issue?

The 2012 NICE guideline recommends that people with unprovoked VTE are treated with warfarin for three months, with the option to extend treatment if their risk of VTE remains high and there is no additional risk of major bleeding. NICE recommends that people with VTE and active cancer are prescribed low molecular weight heparin for six months, then the on-going risk of VTE versus major bleeding is reviewed. Other guidance, published in 2012 recommends direct oral anticoagulants for at least three months as an option for preventing a recurrence of VTE.  Longer treatment is recommended for people with permanent risk factors, or an unprovoked deep vein thrombosis.

What are the implications?

This systematic review suggests extended anticoagulation beyond three months is effective in preventing subsequent VTE and supports current NICE guidance. The evidence was inconclusive about the risks of serious side effects and deaths long term, as there were so few events. People’s VTE risk can change over time, so NICE recommend that anyone offered extended anticoagulation is monitored to measure their VTE risk and balance that against the other risks, particularly the risk of bleeding, associated with anticoagulation.

Cost is also a major consideration in managing VTE risk. Warfarin requires regular monitoring and adjusting of the dose, involving more medical appointments. Newer drugs such as rivaroxaban require less monitoring, but are more expensive.

The decision to extend anticoagulation therapy needs to factor in evidence of what works, side effects, the cost benefits against other treatments, and patient preferences. This study addresses only what works. Other evidence is needed to better inform the other treatment decision elements.


Citation and Funding

Marik PE, Cavallazzi R. Extended Anticoagulant and Aspirin Treatment for the Secondary Prevention of Thromboembolic Disease: A Systematic Review and Meta-Analysis. PLoS One. 2015;10(11):e0143252.

No funding information was provided for this study.



NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. CG144. London: National Institute for Health and Care Excellence; 2012.

NICE. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. TA261. London: National Institute for Health and Care Excellence; 2012.

NICE. Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism. TA287. London: National Institute for Health and Care Excellence; 2013.

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Venous thromboembolism or VTE is a term that includes a blood clot event in your lung (pulmonary embolism) or elsewhere in your body (deep vein thrombosis) – usually a leg vein.

VTE can either be “provoked” – where the VTE can be connected with a specific clinical risk factor in the previous three months, such as surgery or pregnancy; or “unprovoked” – where there is no clear cause or the cause is a constant, long-term risk factor such as a blood clotting disorder.


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