NIHR DC Discover

NIHR Signal New drugs for deep vein thrombosis may offer a safe alternative to warfarin

Published on 20 October 2015

doi: 10.3310/signal-000137

This Cochrane systematic review found that two new types of drugs taken by mouth for deep vein thrombosis were as effective as standard treatment, which most commonly involves treatment by injection followed by warfarin tablets for at least three months. The new drugs have the advantage that they do not require monitoring or dose changes and were associated with a lower risk of bleeding.

This high quality review was based on evidence from 11 good quality trials and can be considered reliable. This review did not look at overall cost or cost-effectiveness. NICE has conducted some assessments of individual drugs and is conducting further assessments. Each assessment has a costing tool or statement that can be used by clinicians and commissioners weighing up the benefits and costs of potential changes to current treatment pathways (see Bibliography below for links).

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Why was this study needed?

Deep vein thrombosis (DVT) describes a blood clot that has formed in the deep veins of the legs or pelvis, that is, not the ones you can see near the surface of the skin. It is relatively common and affects about one in a 1,000 people in the UK each year. There is a risk the clot could move and travel to one of the lung arteries causing a life threatening condition called pulmonary embolism. Pulmonary embolism is estimated to affect 3 to 4 per 10,000 people.

DVT is usually treated first of all by injections of a drug called heparin, followed by an anti-clotting drug taken by mouth, mostly commonly warfarin. But warfarin has several drawbacks. It interacts with other drugs and needs frequent monitoring and dose control to ensure the right balance between clotting and bleeding risk is achieved.

NICE has carried out individual assessments for some of the new drugs that act slightly differently to warfarin. This Cochrane systematic review was conducted to summarise all the available evidence on the effectiveness and safety for the two new types of drugs for people with or at risk of DVT.

What did this study do?

The review searched for published and unpublished randomised controlled trials where one of the two new types of oral anti-clotting drug had been used. These two types are called direct thrombin inhibitors (dabigatran, ximelagatran) and factor Xa inhibitors (rivaroxaban, apixaban and edoxaban).

These drugs were compared with the standard treatments of heparin injections, warfarin or one of the similar drugs. They identified 11 trials including 27,945 people. There were two dabigatran trials, one ximelagatran, four rivaroxaban, two apixaban, and two edoxaban trials. All included studies were rated as high quality. The assessors in 10 of the trials were not aware of which treatment had been given. Six studies were not blinded as the comparison treatment was given by an injection. The results were pooled using meta-analyses where possible to give an overall result.

As there were no trials directly comparing the new drugs with each other this review cannot help in the decision about which drug to prescribe.

What did it find?

  • There was no difference in risk of recurrent DVT in those using direct thrombin inhibitors compared with standard treatment (odds ratio [OR] 1.08, 95% confidence interval [CI] 0.74 to 1.58). But factor Xa inhibitors were associated with a significantly reduced risk of recurrent DVT compared with standard treatment (OR 0.75, 95% CI 0.57 to 0.98). However this association was weak and dependent on the results of one study.
  • There was no difference in the risks of pulmonary embolism or death from any cause with either of the new drug groups compared with standard treatment.
  • Both of the new drug groups were associated with significantly lower risk of bleeding compared with standard treatment: risk was 32% lower using direct thrombin inhibitors (OR 0.68, 95% CI 0.47 to 0.98), and 43% lower using factor Xa inhibitors (OR 0.57, 95% CI 0.43 to 0.76).

What does current guidance say on this issue?

NICE guidelines (2010, 2012) recommend the use of heparin, fondaparinux (another injected drug) and warfarin - or one of its related drugs - for most people with DVT or pulmonary embolism.

The newer drugs dabigatran (a direct thrombin inhibitor), apixaban and rivaroxaban (both factor Xa inhibitors) have been assessed individually by NICE (2013, 2014, 2015). All are currently recommended as options for all people with DVT or pulmonary embolism, having previously been restricted to certain groups, such as those having hip or knee replacement surgery.

What are the implications?

The newer oral drugs were found to be as effective as the standard treatment, which most commonly involves injections followed by warfarin, but were linked to a lower risk of bleeding, so may be safer.

Unlike warfarin, the new oral drugs do not require frequent monitoring or dose changes to try and maintain the delicate balance between clotting and bleeding risk. This would be more convenient for patients and also reduce the resources needed for monitoring clinics.

The lack of a reversal agent is of concern to some clinicians and patients. Fortunately, the need is relatively rare as the newer drugs have a short half-life (if renal function is good). Reversal agents to each of the new drugs are currently under trial and results are awaited.

The ease of use, in the short term, may also provide clinical and economic benefits in the avoidance of the warfarin loading phase of treatment. This is a step which needs injected anticoagulants and frequent blood tests, and is sometimes undertaken in hospital.

Overall the review supports the current recommendations of NICE (2013, 2014, 2015) that these drugs may be considered for the treatment of DVT or pulmonary embolism. The review did not look at overall cost or cost-effectiveness, but the NICE assessments include costing statements and tools that give further information on the individual drugs and could be useful to commissioners seeking cost data relevant to their populations. All these drugs are more expensive per day than warfarin.

Citation

Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database Syst Rev. 2015 Jun 30;6:CD010956.

Bibliography

NHS Choices. Deep vein thrombosis [internet]. London: Department of Health; 2014.

NICE. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. CG144. London: National Institute for Health and Care Excellence; 2012.

NICE. Venous thromboembolism in adults admitted to hospital: reducing the risk. CG92. London: National Institute for Health and Care Excellence; 2010.

NICE. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. TA245. London: National Institute for Health and Care Excellence; 2012.

NICE. Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. TA341. London: National Institute for Health and Care Excellence; 2015.

NICE. Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. TA157. London: National Institute for Health and Care Excellence; 2008.

NICE. Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. TA327. London: National Institute for Health and Care Excellence; 2014.

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 the prevention of venous thromboembolism after total hip or total knee replacement in adults. TA170. London: National Institute for Health and Care Excellence; 2013.

Why was this study needed?

Deep vein thrombosis (DVT) describes a blood clot that has formed in the deep veins of the legs or pelvis, that is, not the ones you can see near the surface of the skin. It is relatively common and affects about one in a 1,000 people in the UK each year. There is a risk the clot could move and travel to one of the lung arteries causing a life threatening condition called pulmonary embolism. Pulmonary embolism is estimated to affect 3 to 4 per 10,000 people.

DVT is usually treated first of all by injections of a drug called heparin, followed by an anti-clotting drug taken by mouth, mostly commonly warfarin. But warfarin has several drawbacks. It interacts with other drugs and needs frequent monitoring and dose control to ensure the right balance between clotting and bleeding risk is achieved.

NICE has carried out individual assessments for some of the new drugs that act slightly differently to warfarin. This Cochrane systematic review was conducted to summarise all the available evidence on the effectiveness and safety for the two new types of drugs for people with or at risk of DVT.

What did this study do?

The review searched for published and unpublished randomised controlled trials where one of the two new types of oral anti-clotting drug had been used. These two types are called direct thrombin inhibitors (dabigatran, ximelagatran) and factor Xa inhibitors (rivaroxaban, apixaban and edoxaban).

These drugs were compared with the standard treatments of heparin injections, warfarin or one of the similar drugs. They identified 11 trials including 27,945 people. There were two dabigatran trials, one ximelagatran, four rivaroxaban, two apixaban, and two edoxaban trials. All included studies were rated as high quality. The assessors in 10 of the trials were not aware of which treatment had been given. Six studies were not blinded as the comparison treatment was given by an injection. The results were pooled using meta-analyses where possible to give an overall result.

As there were no trials directly comparing the new drugs with each other this review cannot help in the decision about which drug to prescribe.

What did it find?

  • There was no difference in risk of recurrent DVT in those using direct thrombin inhibitors compared with standard treatment (odds ratio [OR] 1.08, 95% confidence interval [CI] 0.74 to 1.58). But factor Xa inhibitors were associated with a significantly reduced risk of recurrent DVT compared with standard treatment (OR 0.75, 95% CI 0.57 to 0.98). However this association was weak and dependent on the results of one study.
  • There was no difference in the risks of pulmonary embolism or death from any cause with either of the new drug groups compared with standard treatment.
  • Both of the new drug groups were associated with significantly lower risk of bleeding compared with standard treatment: risk was 32% lower using direct thrombin inhibitors (OR 0.68, 95% CI 0.47 to 0.98), and 43% lower using factor Xa inhibitors (OR 0.57, 95% CI 0.43 to 0.76).

What does current guidance say on this issue?

NICE guidelines (2010, 2012) recommend the use of heparin, fondaparinux (another injected drug) and warfarin - or one of its related drugs - for most people with DVT or pulmonary embolism.

The newer drugs dabigatran (a direct thrombin inhibitor), apixaban and rivaroxaban (both factor Xa inhibitors) have been assessed individually by NICE (2013, 2014, 2015). All are currently recommended as options for all people with DVT or pulmonary embolism, having previously been restricted to certain groups, such as those having hip or knee replacement surgery.

What are the implications?

The newer oral drugs were found to be as effective as the standard treatment, which most commonly involves injections followed by warfarin, but were linked to a lower risk of bleeding, so may be safer.

Unlike warfarin, the new oral drugs do not require frequent monitoring or dose changes to try and maintain the delicate balance between clotting and bleeding risk. This would be more convenient for patients and also reduce the resources needed for monitoring clinics.

The lack of a reversal agent is of concern to some clinicians and patients. Fortunately, the need is relatively rare as the newer drugs have a short half-life (if renal function is good). Reversal agents to each of the new drugs are currently under trial and results are awaited.

The ease of use, in the short term, may also provide clinical and economic benefits in the avoidance of the warfarin loading phase of treatment. This is a step which needs injected anticoagulants and frequent blood tests, and is sometimes undertaken in hospital.

Overall the review supports the current recommendations of NICE (2013, 2014, 2015) that these drugs may be considered for the treatment of DVT or pulmonary embolism. The review did not look at overall cost or cost-effectiveness, but the NICE assessments include costing statements and tools that give further information on the individual drugs and could be useful to commissioners seeking cost data relevant to their populations. All these drugs are more expensive per day than warfarin.

Citation

Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database Syst Rev. 2015 Jun 30;6:CD010956.

Bibliography

NHS Choices. Deep vein thrombosis [internet]. London: Department of Health; 2014.

NICE. Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing. CG144. London: National Institute for Health and Care Excellence; 2012.

NICE. Venous thromboembolism in adults admitted to hospital: reducing the risk. CG92. London: National Institute for Health and Care Excellence; 2010.

NICE. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. TA245. London: National Institute for Health and Care Excellence; 2012.

NICE. Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. TA341. London: National Institute for Health and Care Excellence; 2015.

NICE. Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. TA157. London: National Institute for Health and Care Excellence; 2008.

NICE. Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. TA327. London: National Institute for Health and Care Excellence; 2014.

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 the prevention of venous thromboembolism after total hip or total knee replacement in adults. TA170. London: National Institute for Health and Care Excellence; 2013.

Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis

Published on 1 July 2015

Robertson, L.,Kesteven, P.,McCaslin, J. E.

Cochrane Database Syst Rev Volume 6 , 2015

BACKGROUND: Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately 1 in 1,000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of novel oral anticoagulants (NOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the treatment of DVT. OBJECTIVES: To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the treatment of DVT. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). We searched clinical trials databases for details of ongoing or unpublished studies and the reference lists of relevant articles retrieved by electronic searches for additional citations. SELECTION CRITERIA: We included randomised controlled trials in which people with a DVT confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor for the treatment of DVT. DATA COLLECTION AND ANALYSIS: Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third review author (PK). We performed meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent VTE and PE. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). MAIN RESULTS: We included 11 randomised controlled trials of 27,945 participants. Three studies tested oral DTIs (two dabigatran and one ximelagatran), while eight tested oral factor Xa inhibitors (four rivaroxaban, two apixaban and two edoxaban). We deemed all included studies to be of high methodological quality and low risk of bias. The quality of the evidence was graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the ORs. Meta-analysis of three studies (7596 participants) comparing oral DTIs with standard anticoagulation groups showed no difference in the rate of recurrent VTE (OR 1.09; 95% CI 0.80 to 1.49), recurrent DVT (OR 1.08; 95% CI 0.74 to 1.58), fatal PE (OR 1.00; 95% CI 0.27 to 3.70), non-fatal PE (OR 1.12; 95% CI 0.66 to 1.90) or all-cause mortality (OR 0.82; 95% CI 0.60 to 1.13). However, oral DTIs were associated with reduced bleeding (OR 0.68; 95% CI 0.47 to 0.98). Meta-analysis of eight studies (16,356 participants) comparing oral factor Xa inhibitors with standard anticoagulation demonstrated a similar rate of recurrent VTE between the two treatments (OR 0.89; 95% CI 0.73 to 1.07). Oral factor Xa inhibitors were associated with a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57 to 0.98). However, this was a weak association, heavily dependent on one study. The rate of fatal (OR 1.20; 95% CI 0.71 to 2.03), non-fatal PE (OR 0.94; 95% CI 0.68 to 1.28) and all-cause mortality (OR 0.90; 95% CI 0.65 to 1.23) was similar between the two treatment groups. Oral factor Xa inhibitors were also associated with reduced bleeding (OR 0.57; 95% CI 0.43 to 0.76). None of the included studies measured post-thrombotic syndrome or health-related quality of life. AUTHORS' CONCLUSIONS: NOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

Deep vein thrombosis (DVT) occurs when a blood clot forms in the deep veins of the body, usually in the leg or pelvis. Venous thromboembolism is a more general name referring to a blood clot in any vein. The most serious complication of DVT is when the blood clot moves and travels in the bloodstream to block the artery taking blood from the heart to the lungs. This is called pulmonary embolism, and can be life threatening. There are a number of risk factors for DVT including hereditary factors, having a cancer or another serious medical condition, or being immobile for a period of time, for example after surgery. Aside from anti-clotting drugs, compression stockings are often used for people who have had a DVT or are thought to be at risk of one.

Expert commentary

The management of patients with suspected deep venous thrombosis has proved challenging for NHS resources because of the limitations of existing drugs. The treatment pathway typically involves a difficult mixture of primary and secondary care consultations whereby patients receive injections for a few days whilst warfarin is titrated to target based on frequent blood tests. This is a hassle for patients and healthcare professionals, and the complexity of the process means that plenty of things can go wrong. There is now strong evidence from a Cochrane systematic review that newer, more convenient oral anticoagulants are safe and effective in management of patients with deep venous thrombosis. The big question now is whether NHS pathways are able to innovate so that patients can be efficiently managed in a one-stop fashion at primary care level, given that there is no longer the need for injections or regular blood tests.

Yoon K Loke, Professor of Medicine and Pharmacology, Norwich Medical School