Novel oral anticoagulants for the treatment of deep vein thrombosis

Background

Deep vein thrombosis (DVT) is a condition in which a blood clot forms in the deep vein of the leg or pelvis. It affects approximately 1 in 1000 people. If it is not treated, the clot can travel in the blood and block the arteries in the lungs. This life-threatening condition is called a pulmonary embolism (PE) and occurs in approximately 3 to 4 per 10,000 people. The chances of getting a DVT can be increased if people have certain risk factors. These include previous clots, prolonged periods of immobility (such as travelling on aeroplanes or bed rest), cancer, exposure to oestrogens (pregnancy, oral contraceptives or hormone replacement therapy), trauma and blood disorders such as thrombophilia (abnormal blood clotting). A DVT is diagnosed through determining the risk factors and performing an ultrasound of the leg veins. If a DVT is confirmed, people are treated with an anticoagulant. This medicine prevents further clots from forming. Until recently, the drugs of choice were heparin, fondaparinux and vitamin K antagonists. However, these drugs can cause side effects and have limitations. Two further classes of novel oral anticoagulants have been developed: these are called direct thrombin inhibitors (DTI) and factor Xa inhibitors. There are particular reasons why oral DTIs and factor Xa inhibitors might now be better medicines to use. They can be given orally, they have a predictable effect, they do not require frequent monitoring or re-dosing and they have few known drug interactions. This review measures the effectiveness and safety of these new drugs with conventional treatment.

Key results

After searching for relevant studies up to January 2015, we found 11 studies with 27,945 participants. Studies compared DTIs or factor Xa inhibitors with conventional treatment. We looked at whether they prevented blood clots and PE. The main safety outcomes included death and side effects such as bleeding. This review showed that both oral DTIs and oral factor Xa inhibitors had similar effects on preventing blood clots and PE than standard anticoagulation treatment. However, fewer people experienced bleeding who were given either of the drugs. None of the included studies measured post-thrombotic syndrome (a complication of DVT) or health-related quality of life.

Quality of the evidence

The quality of the evidence was generally high as the studies were of good quality, they answered the question we addressed directly, the results of the studies were consistent and the effect estimates were precise. We do not believe that further research will change the results we have presented.

Authors' conclusions: 

NOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

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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 strategy: 

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 generally low risk of bias. The quality of the evidence was generally 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 0.84, 95% CI 0.62 to 1.15). 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 0.84, 95% CI 0.64 to 1.11) 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.

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