A blog written by retired GP, Dr Lynda Ware, for clinicians.

The novel oral anticoagulants – or NOACs – are the new kids on the block in anticoagulation. They appear to be as effective as warfarin but with a better safetyRefers to serious adverse effects, such as those that threaten life, require or prolong hospitalization, result in permanent disability, or cause birth defects. profile. A Cochrane review published in June 2015 (1) explores the role of NOACs in the treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. of deep vein thrombosis (DVT).

So what is novel about the NOACs?

DVTs  are conventionally treated with  parenteral  unfractionated heparin or subcutaneous low molecular weight heparin together with warfarin. Once therapeutic levels of warfarin have been reached, as measured by the International Normalised Ratio (INR),  heparin is discontinued. The NOACs comprise direct thrombin inhibitors (DTI) and direct Factor Xa Inhibitors  and were specifically designed to overcome the limitations of warfarin (2). They are given orally, have a predictable effect, do not require monitoring and dosing, and have few known drug interactions.

How do NOACs work?

We need to visit the dustier recesses of our medical student memories to take a look at the clotting cascade.

DTIs (eg dabigatran) and Factor Xa inhibitors (eg rivaroxaban) act directly on thrombin and factor Xa respectively, without the need for cofactors such as antithrombin.

How common is DVT?

DVT is not uncommon and affects around 1:1000 people (3). It has associations with various riskA way of expressing the chance of an event taking place, expressed as the number of events divided by the total number of observations or people. It can be stated as ‘the chance of falling were one in four’ (1/4 = 25%). This measure is good no matter the incidence of events i.e. common or infrequent. factors including immobility, smoking, obesity, surgery, trauma, cancer, thrombophilia, oestrogen in the combined oral contraceptive pill and HRT . Pulmonary embolism occurs in 3-4:10000 people, 70-80% of whom will also have a DVT, although only 15% of these DVTs will be symptomatic.

How effective and safe are NOACs compared to conventional treatment of DVT?

The Cochrane Review, which set out to answer this question, included 11 RCTs, with  27945 participants. 3 RCTS looked at oral DTIs (dabigatran in 2; ximelagatran in 1) and 8 RCTs tested Factor Xa inhibitors (rivaroxaban in 4; apixaban in 2; edoxaban in 2). The diagnosis of DVT was confirmed in each case by standard imaging techniques. The primary outcomesOutcomes are measures of health (for example quality of life, pain, blood sugar levels) that can be used to assess the effectiveness and safety of a treatment or other intervention (for example a drug, surgery, or exercise). In research, the outcomes considered most important are ‘primary outcomes’ and those considered less important are ‘secondary outcomes’. were recurrent venous thromboembolism (VTE) and fatal/non-fatal pulmonary embolism. Secondary outcomesOutcomes are measures of health (for example quality of life, pain, blood sugar levels) that can be used to assess the effectiveness and safety of a treatment or other intervention (for example a drug, surgery, or exercise). In research, the outcomes considered most important are ‘primary outcomes’ and those considered less important are ‘secondary outcomes’. included all-cause mortalitydeath, post-thrombotic syndrome (PTS), adverse effects and health-related quality of life.

The studies were found to be of high methodological standard, with high quality evidence and a low riskA way of expressing the chance of an event taking place, expressed as the number of events divided by the total number of observations or people. It can be stated as ‘the chance of falling were one in four’ (1/4 = 25%). This measure is good no matter the incidence of events i.e. common or infrequent. of biasAny factor, recognised or not, that distorts the findings of a study. For example, reporting bias is a type of bias that occurs when researchers, or others (e.g. drug companies) choose not report or publish the results of a study, or do not provide full information about a study..

A meta-analysisThe use of statistical techniques in a systematic review to combine the results of included studies. Sometimes misused as a synonym for systematic reviews, where the review includes a meta-analysis.   of the three studies (7596 participants) comparing oral DTIs with standard anticoagulation showed no difference in the rateThe speed or frequency of occurrence of an event, usually expressed with respect to time. For instance, a mortality rate might be the number of deaths per year, per 100,000 people. of recurrent VTE, recurrent DVT, fatal and non-fatal PE or all-cause mortalitydeath. Oral DTIs were, however, associated with a reduced riskA way of expressing the chance of an event taking place, expressed as the number of events divided by the total number of observations or people. It can be stated as ‘the chance of falling were one in four’ (1/4 = 25%). This measure is good no matter the incidence of events i.e. common or infrequent. of bleeding. A meta-analysisThe use of statistical techniques in a systematic review to combine the results of included studies. Sometimes misused as a synonym for systematic reviews, where the review includes a meta-analysis.   of the eight studies (16356 participants) comparing oral Factor Xa inhibitors with standard anticoagulation showed no difference in the rateThe speed or frequency of occurrence of an event, usually expressed with respect to time. For instance, a mortality rate might be the number of deaths per year, per 100,000 people. of recurrent VTE, fatal and non-fatal PE and all-cause mortalitydeath. There was a weak associationA relationship between two characteristics, such that as one changes, the other changes in a predictable way. For example, statistics demonstrate that there is an association between smoking and lung cancer. In a positive association, one quantity increases as the other one increases (as with smoking and lung cancer). In a negative association, an increase in one quantity corresponds to a decrease in the other. Association does not necessarily mean that one thing causes the other., heavily dependent on a single studyAn investigation of a healthcare problem. There are different types of studies used to answer research questions, for example randomised controlled trials or observational studies.,  with a reduced risk of recurrent DVT but this was only seen in the first three months of treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes.. Factor Xa inhibitors also had a lower riskA way of expressing the chance of an event taking place, expressed as the number of events divided by the total number of observations or people. It can be stated as ‘the chance of falling were one in four’ (1/4 = 25%). This measure is good no matter the incidence of events i.e. common or infrequent. of bleeding. None of the studies measured health-related quality of life or PTS.

So what conclusions can we draw from these results?

The authors conclude:

 ‘NOACs such as DTIs and Factor Xa inhibitors may be an effective and safe alternative to conventional treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. for DVT.’
‘We do not believe that further research will change the results we have presented.’

Implications for practice

The studies included in the Cochrane Review were large and of high quality. The National Institute for Health and Care Excellence (NICE) has given its stamp of approval to rivaroxaban (2012), dabigatran (2014) and apixaban (2015) as options to be considered in the treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. of VTE in adults. Edoxaban awaits pronouncement  in August 2015.
NOACs have clear benefits in terms of ease of use and lower risks of major bleeding. Caution must be exercised in people with compromised renal function since the NOACs are all to some extent excreted via the kidneys.

What more do we need to know?

At present there is no blood monitoring test available for NOACs as there is for warfarin. This would be of particular use and relevance, for example, in patients with impaired renal function or those requiring surgery or presenting with major bleeding.
The search is on for an antidote to the NOACs. One hopeful candidate is idarucizumab for reversing dabigatran (4).
It is not yet known what role NOACs have in the treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. of other categories of VTE such as those associated with malignancy and thrombophilia. Further studies are needed to look at head-to-head comparisons of individual NOACs.
A further Cochrane Review is underway looking at the effectivenessThe ability of an intervention (for example a drug, surgery, or exercise) to produce a desired effect, such as reduce symptoms. of NOACs in the treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. of PE.
NICE has approved the use of dabigatran, rivaroxaban and apixaban for patients with non-valvular AF to prevent stroke and systemic embolism (5).

 

Treating deep vein thrombosis: novel ways to anti coagulate by Lynda Ware is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.
Based on a work at http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010956.pub2/abstract.
Permissions beyond the scope of this license may be available at http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD010956.pub2/abstract.
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Links:

1. Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database of Systematic ReviewsIn systematic reviews we search for and summarize studies that answer a specific research question (e.g. is paracetamol effective and safe for treating back pain?). The studies are identified, assessed, and summarized by using a systematic and predefined approach. They inform recommendations for healthcare and research. 2015, Issue 6. Art. No.: CD010956. DOI: 10.1002/14651858.CD010956.pub2.
2. AssociationA relationship between two characteristics, such that as one changes, the other changes in a predictable way. For example, statistics demonstrate that there is an association between smoking and lung cancer. In a positive association, one quantity increases as the other one increases (as with smoking and lung cancer). In a negative association, an increase in one quantity corresponds to a decrease in the other. Association does not necessarily mean that one thing causes the other. of the British Pharmaceutical Industry Stroke in Atrial Fibrillation Initiative. NOACS: innovation in anticoagulation: optimising the prevention of AF-related stroke. London: AssociationA relationship between two characteristics, such that as one changes, the other changes in a predictable way. For example, statistics demonstrate that there is an association between smoking and lung cancer. In a positive association, one quantity increases as the other one increases (as with smoking and lung cancer). In a negative association, an increase in one quantity corresponds to a decrease in the other. Association does not necessarily mean that one thing causes the other. of the British Pharmaceutical Industry; 2014.
3. Scottish Intercollegiate Guidelines Network (SIGN). Prevention and management of venous thromboembolism. Edinburgh: SIGN; 2010. (SIGN publication no. 122). [issued 10 Dec 2010]. Available from: http://www.sign.ac.uk/guidelines/fulltext/122/index.htmlNEJM  June 22 2015 Pollack C
4. Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA,Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW,Stangier J, Steiner T, Wang B, Kam CW, Weitz JI. Idarucizumab for Dabigatran Reversal. N Engl J Med 2015;373(6):511-20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26095746
5. National Institute for Health and Care Excellence. Atrial fibrillation: treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. and management. London: National Institute for Health and Care Excellence; 2015, July. (NICE Quality Standard 93). [Issued July 2015]. Available from: https://www.nice.org.uk/