NIHR Signal Direct acting oral anticoagulants likely to be better than warfarin for people taking them for atrial fibrillation

Published on 6 February 2018

In people with atrial fibrillation needing anticoagulant treatment, deaths were fewer in those who had direct acting oral anticoagulants compared with warfarin. The picture is less clear for the risk of stroke and complications such as bleeding in the brain or gut. Apixaban had the best efficacy and safety profile and was cost-effective compared with warfarin.

This study pooled the data in all trials reporting efficacy, safety and cost of anticoagulant prevention of stroke events in people with atrial fibrillation. Researchers used a technique called network meta-analysis to compare the different drugs used.

There is still a need for a trial directly comparing these drugs, to add to this evidence and to identify whether certain people might benefit more from one or other of the available agents.

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Why was this study needed?

Atrial fibrillation is a common irregular heart rhythm estimated to affect almost 1.4 million people in England. It carries a risk of blood clots within the heart which may dislodge into the bloodstream and block smaller blood vessels. More than one in five strokes in England and Wales is attributed to atrial fibrillation.

People with atrial fibrillation are commonly given drugs to reduce blood clotting. Warfarin was traditionally used; it is cheap but requires monitoring and has several interactions with other drugs which make it awkward for patients. The cost of warfarin and its monitoring is estimated at £90 million per year in England, Wales and Northern Ireland. Newer direct acting oral anticoagulants (DOACs) are more expensive but do not require monitoring. There is so far no trial directly comparing DOACs against one another.

This network meta-analysis compares oral anticoagulants regarding efficacy, safety and cost for prevention of stroke in patients with atrial fibrillation.

What did this study do?

This study compared four DOACs at various doses, warfarin and an antiplatelet agent for prevention of strokes in people with atrial fibrillation. It included 23 randomised trials reporting on 27 interventions and 94,656 patients. Thirteen studies included DOACs, and treatment duration ranged from three to 30 months.

The main outcomes were the number of events of stroke or systemic embolism, myocardial infarction, bleeding and mortality. The authors conducted a network meta-analysis combining results of standard meta-analyses for direct comparison. Reference treatment was warfarin to maintain an international normalised ratio 2.0-3.0.

For the cost-effectiveness analysis, the authors estimated expected total lifetime costs, quality-adjusted life years and net monetary benefit for each treatment.

The main source of bias was that in most studies participants and health professionals were aware of the treatment being given, but outcomes are objective, and this limitation is unlikely to have affected confidence in the results.

What did it find?

  • All DOACs reduced deaths from any cause compared with warfarin, although results have different levels of certainty. Apixaban 5mg twice daily, for example, reduced deaths by about 30% (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.61 to 0.81).
  • Apixaban 5mg twice daily reduced the risk of stroke or systemic embolism compared with warfarin (OR 0.79, 95% CI 0.66 to 0.94) and dabigatran 150mg twice daily did too (OR 0.65, 95% CI 0.52 to 0.81). Edoxaban 60mg daily did not significantly reduce the risk of stroke or systemic embolism compared with warfarin. Risk of clinically relevant bleeding is lower with apixaban 5mg twice daily (OR 0.67, 95% CI 0.60 to 0.75), edoxaban 30mg daily (OR 0.59, 95%CI 0.54 to 0.64) and edoxaban 60mg twice daily (OR 0.84, 95%CI 0.77 to 0.90) than with warfarin.
  • Apixaban 5mg twice daily was ranked in the indirect analysis as the most effective and safest intervention for several outcomes.
  • Despite the uncertainty around the cost estimates, all DOACs show a positive expected incremental net benefit, and apixaban 5mg twice daily is cost-effective when compared with warfarin.

What does current guidance say on this issue?

The NICE 2014 guideline on management of atrial fibrillation recommends using apixaban, dabigatran, rivaroxaban or a vitamin K antagonist (warfarin) as anticoagulant treatment. The NICE 2016 Clinical Summary Knowledge also mentions edoxaban as an option for prevention of stroke and systemic embolism.

The Technology Appraisal guidance on the use of apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation recommends considering the potential risks and benefits of all anticoagulation treatments. No guidance recommends the use of one drug over another as individual patient characteristics and preferences should be taken into consideration.

What are the implications?

The findings of this study support the use of DOACs for prevention of stroke and systemic embolism in atrial fibrillation patients. They suggest the current front runner on a range of outcomes may be apixaban 5mg twice daily.

It is hoped that the ease of taking these newer medications might improve compliance outside of clinical trials. If so, this makes them good alternatives to warfarin.

Citation and Funding

Lopez-Lopez JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058.

This project was funded by the National Institute for Health Research.

Bibliography

Public Health England. Atrial fibrillation prevalence estimates in England: Application of recent population estimates of AF in Sweden. London: Public Health England; 2017.

NHS Choices. Atrial fibrillation. London: Department of Health; 2015.

NICE. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. London: National Institute for Health and Clinical Excellence; 2017.

NICE. Atrial fibrillation: management. CG180. London: National Institute for Health and Clinical Excellence; 2014.

NICE. Clinical Knowledge Summaries: Anticoagulation - oral. London: National Institute for Health and Clinical Excellence; 2016.

Why was this study needed?

Atrial fibrillation is a common irregular heart rhythm estimated to affect almost 1.4 million people in England. It carries a risk of blood clots within the heart which may dislodge into the bloodstream and block smaller blood vessels. More than one in five strokes in England and Wales is attributed to atrial fibrillation.

People with atrial fibrillation are commonly given drugs to reduce blood clotting. Warfarin was traditionally used; it is cheap but requires monitoring and has several interactions with other drugs which make it awkward for patients. The cost of warfarin and its monitoring is estimated at £90 million per year in England, Wales and Northern Ireland. Newer direct acting oral anticoagulants (DOACs) are more expensive but do not require monitoring. There is so far no trial directly comparing DOACs against one another.

This network meta-analysis compares oral anticoagulants regarding efficacy, safety and cost for prevention of stroke in patients with atrial fibrillation.

What did this study do?

This study compared four DOACs at various doses, warfarin and an antiplatelet agent for prevention of strokes in people with atrial fibrillation. It included 23 randomised trials reporting on 27 interventions and 94,656 patients. Thirteen studies included DOACs, and treatment duration ranged from three to 30 months.

The main outcomes were the number of events of stroke or systemic embolism, myocardial infarction, bleeding and mortality. The authors conducted a network meta-analysis combining results of standard meta-analyses for direct comparison. Reference treatment was warfarin to maintain an international normalised ratio 2.0-3.0.

For the cost-effectiveness analysis, the authors estimated expected total lifetime costs, quality-adjusted life years and net monetary benefit for each treatment.

The main source of bias was that in most studies participants and health professionals were aware of the treatment being given, but outcomes are objective, and this limitation is unlikely to have affected confidence in the results.

What did it find?

  • All DOACs reduced deaths from any cause compared with warfarin, although results have different levels of certainty. Apixaban 5mg twice daily, for example, reduced deaths by about 30% (odds ratio [OR] 0.71, 95% confidence interval [CI] 0.61 to 0.81).
  • Apixaban 5mg twice daily reduced the risk of stroke or systemic embolism compared with warfarin (OR 0.79, 95% CI 0.66 to 0.94) and dabigatran 150mg twice daily did too (OR 0.65, 95% CI 0.52 to 0.81). Edoxaban 60mg daily did not significantly reduce the risk of stroke or systemic embolism compared with warfarin. Risk of clinically relevant bleeding is lower with apixaban 5mg twice daily (OR 0.67, 95% CI 0.60 to 0.75), edoxaban 30mg daily (OR 0.59, 95%CI 0.54 to 0.64) and edoxaban 60mg twice daily (OR 0.84, 95%CI 0.77 to 0.90) than with warfarin.
  • Apixaban 5mg twice daily was ranked in the indirect analysis as the most effective and safest intervention for several outcomes.
  • Despite the uncertainty around the cost estimates, all DOACs show a positive expected incremental net benefit, and apixaban 5mg twice daily is cost-effective when compared with warfarin.

What does current guidance say on this issue?

The NICE 2014 guideline on management of atrial fibrillation recommends using apixaban, dabigatran, rivaroxaban or a vitamin K antagonist (warfarin) as anticoagulant treatment. The NICE 2016 Clinical Summary Knowledge also mentions edoxaban as an option for prevention of stroke and systemic embolism.

The Technology Appraisal guidance on the use of apixaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation recommends considering the potential risks and benefits of all anticoagulation treatments. No guidance recommends the use of one drug over another as individual patient characteristics and preferences should be taken into consideration.

What are the implications?

The findings of this study support the use of DOACs for prevention of stroke and systemic embolism in atrial fibrillation patients. They suggest the current front runner on a range of outcomes may be apixaban 5mg twice daily.

It is hoped that the ease of taking these newer medications might improve compliance outside of clinical trials. If so, this makes them good alternatives to warfarin.

Citation and Funding

Lopez-Lopez JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017;359:j5058.

This project was funded by the National Institute for Health Research.

Bibliography

Public Health England. Atrial fibrillation prevalence estimates in England: Application of recent population estimates of AF in Sweden. London: Public Health England; 2017.

NHS Choices. Atrial fibrillation. London: Department of Health; 2015.

NICE. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. London: National Institute for Health and Clinical Excellence; 2017.

NICE. Atrial fibrillation: management. CG180. London: National Institute for Health and Clinical Excellence; 2014.

NICE. Clinical Knowledge Summaries: Anticoagulation - oral. London: National Institute for Health and Clinical Excellence; 2016.

Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis

Published on 1 December 2017

Lopez-Lopez, J. A.,Sterne, J. A. C.,Thom, H. H. Z.,Higgins, J. P. T.,Hingorani, A. D.,Okoli, G. N.,Davies, P. A.,Bodalia, P. N.,Bryden, P. A.,Welton, N. J.,Hollingworth, W.,Caldwell, D. M.,Savovic, J.,Dias, S.,Salisbury, C.,Eaton, D.,Stephens-Boal, A.,Sofat, R.

Bmj Volume 359 , 2017

Objective To compare the efficacy, safety, and cost effectiveness of direct acting oral anticoagulants (DOACs) for patients with atrial fibrillation.Design Systematic review, network meta-analysis, and cost effectiveness analysis. Data sources Medline, PreMedline, Embase, and The Cochrane Library.Eligibility criteria for selecting studies Published randomised trials evaluating the use of a DOAC, vitamin K antagonist, or antiplatelet drug for prevention of stroke in patients with atrial fibrillation.Results 23 randomised trials involving 94 656 patients were analysed: 13 compared a DOAC with warfarin dosed to achieve a target INR of 2.0-3.0. Apixaban 5 mg twice daily (odds ratio 0.79, 95% confidence interval 0.66 to 0.94), dabigatran 150 mg twice daily (0.65, 0.52 to 0.81), edoxaban 60 mg once daily (0.86, 0.74 to 1.01), and rivaroxaban 20 mg once daily (0.88, 0.74 to 1.03) reduced the risk of stroke or systemic embolism compared with warfarin. The risk of stroke or systemic embolism was higher with edoxaban 60 mg once daily (1.33, 1.02 to 1.75) and rivaroxaban 20 mg once daily (1.35, 1.03 to 1.78) than with dabigatran 150 mg twice daily. The risk of all-cause mortality was lower with all DOACs than with warfarin. Apixaban 5 mg twice daily (0.71, 0.61 to 0.81), dabigatran 110 mg twice daily (0.80, 0.69 to 0.93), edoxaban 30 mg once daily (0.46, 0.40 to 0.54), and edoxaban 60 mg once daily (0.78, 0.69 to 0.90) reduced the risk of major bleeding compared with warfarin. The risk of major bleeding was higher with dabigatran 150 mg twice daily than apixaban 5 mg twice daily (1.33, 1.09 to 1.62), rivaroxaban 20 mg twice daily than apixaban 5 mg twice daily (1.45, 1.19 to 1.78), and rivaroxaban 20 mg twice daily than edoxaban 60 mg once daily (1.31, 1.07 to 1.59). The risk of intracranial bleeding was substantially lower for most DOACs compared with warfarin, whereas the risk of gastrointestinal bleeding was higher with some DOACs than warfarin. Apixaban 5 mg twice daily was ranked the highest for most outcomes, and was cost effective compared with warfarin.Conclusions The network meta-analysis informs the choice of DOACs for prevention of stroke in patients with atrial fibrillation. Several DOACs are of net benefit compared with warfarin. A trial directly comparing DOACs would overcome the need for indirect comparisons to be made through network meta-analysis.Systematic review registration PROSPERO CRD 42013005324.

Expert commentary

This is one of some published network meta-analyses that tries to compare one newer direct-acting oral anticoagulant versus another in relation to their relative efficacy and safety, given the absence of head to head randomised trials. 

These analyses are no substitute for randomised controlled trials, but since we now have warfarin and four newer drugs available, we can fit the drug to the patient’s clinical profile (and vice versa). After all, patients with atrial fibrillation are elderly and often heterogeneous in relation to comorbidities and risk profile, so a ‘one drug fits all’ approach is probably inappropriate.

Gregory Y H Lip, Professor of Cardiovascular Medicine, University of Birmingham, UK; National Institute for Health Research (NIHR) Senior Investigator