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NIHR Signal Warfarin and newer anticoagulants equally effective for long-term treatment of blood clots

Published on 29 January 2019

doi: 10.3310/signal-000721

Warfarin and newer anticoagulants work equally well to prevent blood clots in extended treatment after venous thromboembolism. One clot is prevented for every 15 people receiving either anticoagulant. Aspirin is ineffective.

Following venous thromboembolism – a blood clot in the deep leg veins (deep vein thrombosis) or lungs (pulmonary embolism) – anticoagulant treatment is given for three months, as standard. Prolonged treatment may be given for patients at high risk of recurrence. However, clinicians must balance the risk of bleeding against the risk of recurrence.

This review included 16 studies and over 22,000 patients assessing evidence for extended treatment with vitamin K blockers (typically warfarin), newer anticoagulants or aspirin. There was one major bleed for every 87 people treated with standard-intensity vitamin K blockers, but this was the only treatment which reduced mortality compared with placebo.

The equivalent effectiveness of the anticoagulants suggests that individual patient factors, preferences and cost should inform choice.

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Why was this study needed?

About 1 in 1,000 people in the UK has venous thromboembolism (VTE) every year. Most occur in people with risk factors such as cancer or major surgery. Over half of all cases follow recent hospitalisation. Around a third of people continue to have related problems over the subsequent 10 years.

Extended anticoagulant treatment is recommended for patients with high risk of recurrence, such as those with an unprovoked VTE. However, it remains essentially a question of informed choice between patient and clinician, balancing the risk of recurrence against the potential bleeding risk.

The vitamin K blocker/antagonist (VKA) warfarin has been the standard treatment. Direct oral anticoagulants (DOACs) are newer alternatives believed to have similar efficacy but lower bleeding risk. Aspirin, though not recommended, may sometimes be considered in practice. 

This review and network meta-analysis compared the effectiveness and harms of oral anticoagulants and aspirin, directly within trials and indirectly across trials, enabling better-informed decisions.

What did this study do?

The researchers identified 16 randomised controlled trials (22,396 participants) comparing any oral anticoagulant regimen or aspirin for extended treatment of VTE.

Most trials were multinational and conducted after 2010. The most common within-trial (direct) comparison was between standard-intensity VKAs and placebo/observation (six trials). Others directly compared aspirin with placebo (two trials) or low-intensity VKAs with standard-intensity or placebo (one trial each). For DOACs, trials compared standard- or low-dose factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) or direct thrombin inhibitors (dabigatran) with aspirin (one trial), standard-intensity VKAs (two trials) or placebo/observation (three trials).

Six studies had low risk of bias, while three open-label studies and one post-hoc analysis had high risk of bias. Event rates for the placebo/observation group were comparable across trials, giving confidence in the findings.

What did it find?

  • All oral anticoagulant treatment regimens reduced the risk of recurrent VTE compared with placebo or observation. Fifteen people would need treatment with standard-dose VKA (95% confidence interval [CI] 7 to 34), or any DOAC (95% CI 7 to 36), to prevent one recurrent VTE. The odds ratios (OR) ranged from 0.15 to 0.17.
  • Low-intensity warfarin was less effective, with 20 needing treatment to benefit (95% CI 6 to 80) and OR 0.36 (95% CI 0.13 to 0.98). Aspirin was ineffective for preventing further clots (OR 0.62, 95% CI 0.29 to 1.28).
  • Only VKAs increased the risk of major bleeding compared with placebo or observation.  There would be one bleed for every 87 people treated with standard-intensity VKAs (95% CI 23 to 345) and every 91 treated with low-intensity VKAs (95% CI 8 to 924). The ORs were 4.43 (95% CI 1.99 to 12.24) and 4.14 (95% CI 1.09 to 18.02), respectively.
  • However, only standard-intensity VKAs reduced the risk of all-cause mortality (OR 0.44, 95% CI 0.20 to 0.87). There was a trend for DOACs to reduce mortality (particularly low dose factor Xa inhibitors: OR 0.38, 95% CI 0.12 to 0.995), though these associations fell short of statistical significance.  
  • Baseline patient characteristics, such as age, gender, whether it was an unprovoked VTE or pulmonary embolism, did not alter the risk associations.

What does current guidance say on this issue?

The NICE guideline on venous thromboembolism (updated 2015) recommends that people with pulmonary embolism or deep vein thrombosis (DVT) are offered a VKA within 24 hours of diagnosis and that this is continued for three months. After three months, clinicians are advised to assess the risks and benefits of continuing treatment. Continued treatment is recommended for patients with unprovoked pulmonary embolism, and considered for unprovoked DVT if there is a high risk of VTE recurrence and no risk of major bleeding.

Separate NICE guidelines cover the use of the DOACs, apixaban, edoxaban, rivaroxaban and dabigatran.

NICE advise that the anticoagulants are not licensed for treatment beyond six months.

What are the implications?

There seem to be clear benefits from extended treatment after VTE with either VKAs (i.e. warfarin) or DOACs. So, which to choose? There appears no single answer from this study. VKAs increase bleeding risk, but this may be slightly offset by the reduced mortality. Costs might also seem to favour VKAs, but then the cost of monitoring INR needs to be factored into that equation.

In practice, people are likely to continue with the anticoagulant they began immediately after the VTE if it has proved suitable, rather than switching drugs for extended treatment.  This is likely to be influenced by individual patient risk factors and preferences (including the need for monitoring). 

The review seems to provide conclusive evidence that aspirin has no role for this indication.

Citation and Funding

Wang KL, van Es N, Cameron C et al. Extended treatment of venous thromboembolism: a systematic review and network meta-analysis. Heart. 2018. DOI: 10.1136/heartjnl-2018-313617.

No funding is declared.

Bibliography

Anticoagulation UK. Developing optimal standards of care for the prevention of recurrent venous thromboembolism (VTE): consensus statement. Kent: Anticoagulation UK; accessed 2018.

Anticoagulation UK. Deep vein thrombosis. Kent: Anticoagulation UK; accessed 2018.

NHS website. Deep vein thrombosis. London: Department of Health; updated 2016.

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

NICE. Key therapeutic topic. Anticoagulants, including non-vitamin K antagonist oral anticoagulants (NOACs). London: National Institute of Health and Care Excellence; 2016.

Thrombosis UK. Thrombosis statistics. Wales: Thrombosis UK; accessed 2018.

Why was this study needed?

About 1 in 1,000 people in the UK has venous thromboembolism (VTE) every year. Most occur in people with risk factors such as cancer or major surgery. Over half of all cases follow recent hospitalisation. Around a third of people continue to have related problems over the subsequent 10 years.

Extended anticoagulant treatment is recommended for patients with high risk of recurrence, such as those with an unprovoked VTE. However, it remains essentially a question of informed choice between patient and clinician, balancing the risk of recurrence against the potential bleeding risk.

The vitamin K blocker/antagonist (VKA) warfarin has been the standard treatment. Direct oral anticoagulants (DOACs) are newer alternatives believed to have similar efficacy but lower bleeding risk. Aspirin, though not recommended, may sometimes be considered in practice. 

This review and network meta-analysis compared the effectiveness and harms of oral anticoagulants and aspirin, directly within trials and indirectly across trials, enabling better-informed decisions.

What did this study do?

The researchers identified 16 randomised controlled trials (22,396 participants) comparing any oral anticoagulant regimen or aspirin for extended treatment of VTE.

Most trials were multinational and conducted after 2010. The most common within-trial (direct) comparison was between standard-intensity VKAs and placebo/observation (six trials). Others directly compared aspirin with placebo (two trials) or low-intensity VKAs with standard-intensity or placebo (one trial each). For DOACs, trials compared standard- or low-dose factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) or direct thrombin inhibitors (dabigatran) with aspirin (one trial), standard-intensity VKAs (two trials) or placebo/observation (three trials).

Six studies had low risk of bias, while three open-label studies and one post-hoc analysis had high risk of bias. Event rates for the placebo/observation group were comparable across trials, giving confidence in the findings.

What did it find?

  • All oral anticoagulant treatment regimens reduced the risk of recurrent VTE compared with placebo or observation. Fifteen people would need treatment with standard-dose VKA (95% confidence interval [CI] 7 to 34), or any DOAC (95% CI 7 to 36), to prevent one recurrent VTE. The odds ratios (OR) ranged from 0.15 to 0.17.
  • Low-intensity warfarin was less effective, with 20 needing treatment to benefit (95% CI 6 to 80) and OR 0.36 (95% CI 0.13 to 0.98). Aspirin was ineffective for preventing further clots (OR 0.62, 95% CI 0.29 to 1.28).
  • Only VKAs increased the risk of major bleeding compared with placebo or observation.  There would be one bleed for every 87 people treated with standard-intensity VKAs (95% CI 23 to 345) and every 91 treated with low-intensity VKAs (95% CI 8 to 924). The ORs were 4.43 (95% CI 1.99 to 12.24) and 4.14 (95% CI 1.09 to 18.02), respectively.
  • However, only standard-intensity VKAs reduced the risk of all-cause mortality (OR 0.44, 95% CI 0.20 to 0.87). There was a trend for DOACs to reduce mortality (particularly low dose factor Xa inhibitors: OR 0.38, 95% CI 0.12 to 0.995), though these associations fell short of statistical significance.  
  • Baseline patient characteristics, such as age, gender, whether it was an unprovoked VTE or pulmonary embolism, did not alter the risk associations.

What does current guidance say on this issue?

The NICE guideline on venous thromboembolism (updated 2015) recommends that people with pulmonary embolism or deep vein thrombosis (DVT) are offered a VKA within 24 hours of diagnosis and that this is continued for three months. After three months, clinicians are advised to assess the risks and benefits of continuing treatment. Continued treatment is recommended for patients with unprovoked pulmonary embolism, and considered for unprovoked DVT if there is a high risk of VTE recurrence and no risk of major bleeding.

Separate NICE guidelines cover the use of the DOACs, apixaban, edoxaban, rivaroxaban and dabigatran.

NICE advise that the anticoagulants are not licensed for treatment beyond six months.

What are the implications?

There seem to be clear benefits from extended treatment after VTE with either VKAs (i.e. warfarin) or DOACs. So, which to choose? There appears no single answer from this study. VKAs increase bleeding risk, but this may be slightly offset by the reduced mortality. Costs might also seem to favour VKAs, but then the cost of monitoring INR needs to be factored into that equation.

In practice, people are likely to continue with the anticoagulant they began immediately after the VTE if it has proved suitable, rather than switching drugs for extended treatment.  This is likely to be influenced by individual patient risk factors and preferences (including the need for monitoring). 

The review seems to provide conclusive evidence that aspirin has no role for this indication.

Citation and Funding

Wang KL, van Es N, Cameron C et al. Extended treatment of venous thromboembolism: a systematic review and network meta-analysis. Heart. 2018. DOI: 10.1136/heartjnl-2018-313617.

No funding is declared.

Bibliography

Anticoagulation UK. Developing optimal standards of care for the prevention of recurrent venous thromboembolism (VTE): consensus statement. Kent: Anticoagulation UK; accessed 2018.

Anticoagulation UK. Deep vein thrombosis. Kent: Anticoagulation UK; accessed 2018.

NHS website. Deep vein thrombosis. London: Department of Health; updated 2016.

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

NICE. Key therapeutic topic. Anticoagulants, including non-vitamin K antagonist oral anticoagulants (NOACs). London: National Institute of Health and Care Excellence; 2016.

Thrombosis UK. Thrombosis statistics. Wales: Thrombosis UK; accessed 2018.

Extended treatment of venous thromboembolism: a systematic review and network meta-analysis

Published on 18 October 2018

Wang, K. L.,van Es, N.,Cameron, C.,Castellucci, L. A.,Buller, H. R.,Carrier, M.

Heart , 2018

OBJECTIVE: To evaluate efficacy and safety of oral anticoagulant regimens and aspirin for extended venous thromboembolism (VTE) treatment. METHODS: We searched MEDLINE, Embase, CENTRAL and conference proceedings for randomised controlled trials studying vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or aspirin for secondary prevention of VTE beyond 3 months. ORs (95% credible intervals) between treatments were estimated using random-effects Bayesian network meta-analysis. RESULTS: Sixteen studies, totaling more than 22 000 patients, were included. Compared with placebo or observation and with aspirin, respectively, the risk of recurrent VTE was lower with standard-intensity VKAs (0.15 (0.08 to 0.24) and 0.23 (0.09 to 0.54)), low-dose factor Xa inhibitors (0.16 (0.06 to 0.38) and 0.25 (0.09 to 0.66)), standard-dose factor Xa inhibitors (0.17 (0.08 to 0.33) and 0.27 (0.11 to 0.65)) and the direct thrombin inhibitor (0.15 (0.04 to 0.37) and 0.23 (0.06 to 0.74)) although the risk of major bleeding was higher with standard-intensity VKAs (4.42 (1.99 to 12.24) and 4.14 (1.17 to 18.86)). Effect estimates were consistent in male patients and those with index pulmonary embolism or with unprovoked VTE and in sensitivity analyses. In addition, compared with placebo or observation, the risk of all-cause mortality was reduced with standard-intensity VKAs (0.44 (0.20 to 0.87)) and low-dose factor Xa inhibitors (0.38 (0.12 to 0.995)). CONCLUSIONS: Standard-intensity VKAs and DOACs are more efficacious than aspirin for extended VTE treatment. Despite a higher risk of major bleeding, standard-intensity VKAs was associated with a lower risk of all-cause mortality. Since overall efficacy and safety of standard-intensity VKAs and DOACs are in equipoise, patient factors, costs and patient preferences should be considered when recommending extending anticoagulation treatment.

Standard-intensity vitamin K antagonists (VKAs) aim for a target blood level international normalised ratio (INR) of 2.0-3.0. Low-intensity VKAs aim for an INR of 1.5-2.0.

Expert commentary

Many studies have aimed to clarify long term strategies to prevent blood clots (venous thromboembolism) without risking increased bleeding. When the results are pooled, giving data from over 22,000 patients, it is difficult not to sit up and take notice:  standard dose long term treatment with a vitamin K antagonist (eg warfarin) appears to remain the best option, and the temptation to use aspirin should be avoided.

The problem is that aspirin is not the only antiplatelet currently used, and information on newer anticoagulants is constantly accruing. With luck, the same researchers will repeat this study in a few years to take in to account new developments in this important and rapidly changing area of medicine.

Mr Harvey Chant, Consultant Vascular Surgeon, Royal Cornwall Hospitals

The commentator declares no conflicting interests

Expert commentary

For a patient in whom extended venous thromboembolism (VTE) prophylaxis is contemplated, clinicians are faced with a variety of treatment options. Standard intensity vitamin K antagonists (VKAs) (INR 2.0-3.0) and direct oral anticoagulants are both effective in reducing the risk of recurrent VTE and all-cause mortality; aspirin less so. As a personal choice, reduced-dose Factor Xa inhibitors seem to tick the most boxes, with less risk of clinically relevant bleeding than VKAs.

Ideal treatment regimens for patients at higher risk of recurrent VTE (thrombophilia and cancer), and those in whom treatment is to be undertaken beyond one year, still require further investigation.

Frank CT Smith, Professor of Vascular Surgery and Surgical Education, University of Bristol and North Bristol NHS Healthcare Trust

The commentator declares no conflicting interests