NIHR Signal Extending anticoagulant treatment beyond three months reduces the risk of recurrent blood clots

Published on 1 March 2016

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.

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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.

Bibliography

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.

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.

Bibliography

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.

Extended Anticoagulant and Aspirin Treatment for the Secondary Prevention of Thromboembolic Disease: A Systematic Review and Meta-Analysis

Published on 21 November 2015

Marik, P. E.,Cavallazzi, R.

PLoS One Volume 10 , 2015

BACKGROUND: Patients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended "life-long" anticoagulation has been recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a "weak provoking factor" there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event. OBJECTIVE: A systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued. DATA SOURCES: MEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles. STUDY SELECTION: Randomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy. DATA EXTRACTION: Independent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent. DATA SYNTHESIS: Seven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11-0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69-3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40-1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm. CONCLUSIONS: VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients' risk for recurrent PE as well as the patients' values and preferences.

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.

Expert commentary

These studies clearly show that anticoagulants (whether non-vitamin K antagonist oral anticoagulants or vitamin K antagonists) are more effective than aspirin for secondary prevention of VTE. Decision-making regarding life-long anticoagulation has to balance the patients’ risk for recurrent thromboembolism versus bleeding risks, as well as the patients’ values and preferences. Of note, there was a non-significant trend towards more major bleeding in the active treatment group compared to control, as seen in clinical practice.

Gregory YH Lip, Professor of Cardiovascular Medicine, University of Birmingham