NIHR DC Discover

Man taking medication

NIHR Signal The blood-thinner apixaban is less likely to cause major bleeding than warfarin

Published on 16 October 2018

doi: 10.3310/signal-000661

People who take apixaban to prevent blood clots are less likely to suffer major bleeding complications than those taking warfarin. Findings are similar in different groups of people, such as those with irregular heart rhythm (atrial fibrillation) and those who have had joint replacement surgery.

Warfarin has long been used as an anticoagulant but needs frequent blood test monitoring. The new class of direct-acting oral anticoagulants does not usually need monitoring and is replacing warfarin.

This large NIHR-funded study examined registry data from 196,061 people taking anticoagulants for any reason. Fewer people had intracranial bleeding on the direct acting oral anticoagulants apixaban, dabigatran and rivaroxaban than warfarin. However, the death rate was higher for people taking low dose apixaban and rivaroxaban compared with warfarin, emphasising the need to base decisions on multiple sources of evidence.

The study was observational and based on routinely collected data from general practice registries, so the selection of patients and unmeasured factors may have biased the results. However, the study is large and provides some reassurance about the use of direct-acting oral anticoagulants as an alternative to warfarin.

Share your views on the research.

Why was this study needed?

Anticoagulants are used to prevent and to treat blood clots.  These may start in the veins and may be carried in the bloodstream to end up in the lungs, or they may start in the heart and be carried to the brain causing a stroke. People who have hip or knee replacement surgery or who develop atrial fibrillation are at high risk of clots and are usually given anticoagulants.

Trials have established that direct-acting oral anticoagulants (DOACs) are as effective as warfarin but safety information on bleeding risk collected outside the research setting is lacking.

This study aimed to compare the safety of DOACs compared with warfarin for people with and without atrial fibrillation. This heart rhythm disturbance affects around one million people in the UK.

What did this study do?

This cohort study analysed UK primary care data in two databases with 196,061 people prescribed warfarin or DOACs between 2011 and 2016. It linked patient-level data to the hospital records to see if complications had been recorded here. Around half, 103,270 (53%) had atrial fibrillation, and 92,791 (47%) were prescribed anticoagulants for other indications.

Researchers followed patients on warfarin for on average six to 11 months and on DOACs for three to nine months. Adverse event rates were calculated separately for the two databases used (Qresearch and GPRD). Rates from the larger database, QResearch, are reported in this summary. Both informed risk estimates. The analysis took account of confounding factors such as other illnesses and medications.

This was a large representative study and should reflect real-world use, but it did not look at patient adherence to the prescribed medications.

What did it find?

For people with atrial fibrillation:

  • Major bleeding was less likely with apixaban (adjusted hazard ratio [aHR] 0.66, 95% confidence interval [CI] 0.54 to 0.79). It occurred at a rate of 15 per 1,000 person years (py) compared with 25 per 1,000 py for those on warfarin.
  • Intracranial bleeding was less frequent in those on apixaban, with a rate of 3 per 1,000 py (aHR 0.40, 95% CI 0.25 to 0.64) and dabigatran, rate 3 per 1,000 py (aHR 0.45, 95% CI 0.26 to 0.77) compared with 6 per 1,000 py for those on warfarin.
  • Risk of death from any cause was higher for patients taking rivaroxaban, with a rate of 55 deaths per 1,000 py compared with 45 per 1,000 py on warfarin (aHR 1.19, 95% CI 1.09 to 1.29). It was also higher for those on low-dose apixaban with a rate of 80 deaths per 1,000 py (aHR 1.27, 95% CI 1.12 to 1.45).

For people on anticoagulation for other reasons:

  • Apixaban was associated with a lower risk of: major bleeding, with a rate of less than 18 per 1,000 py compared with 29 per 1,000 py on warfarin (aHR 0.60, 95% CI 0.46 to 0.79); and gastrointestinal bleeding, 9 per 1,000 py compared with 12 per 1,000 py on warfarin (aHR 0.55, 95% CI 0.37 to 0.83). Risk of death was higher for those on low dose apixaban at 120 per 1,000 py compared with 58 per 1,000 py for warfarin (aHR 1.34, 95% CI 1.13 to 1.58).
  • Rivaroxaban was associated with a decreased the risk of intracranial bleeds, occurring at a rate of 4 per 1,000 py compared with 6 per 1,000 py on warfarin (aHR 0.54, 95% CI 0.35 to 0.82). However, the risk of death from any cause was higher at 87 per 1,000 py compared with 58 per 1,000 py for warfarin (aHR 1.51, 95% CI 1.38 to 1.66).

What does current guidance say on this issue?

Rivaroxaban, apixaban or dabigatran are recommended in the NICE 2018 guideline for the prevention of clots for people having an elective hip or knee replacement.

NICE 2014 guidelines recommend either a vitamin K antagonist such as warfarin, or apixaban, rivaroxaban or dabigatran as options for the prevention of stroke and clots in people with non-valvular atrial fibrillation at higher risk.

For ongoing treatment, and prevention of recurrence, of DVT and pulmonary embolism the NICE 2012 guideline recommended warfarin, but also suggested considering dabigatran, apixaban and rivaroxaban.

What are the implications?

This study provides further safety data which will aid shared-decision making on the use of DOACs as an alternative to warfarin. It provides information for people requiring anticoagulation for reasons other than atrial fibrillation.

DOACs have not been directly compared in randomised controlled trials, and alongside other indirect comparisons, this observational study adds to the body of evidence comparing safety and efficacy.

The increased risk in all-cause mortality with rivaroxaban and low dose apixaban is a concern but may be due to confounding or indication bias. This uncertainty could be addressed in further randomised trials.

Citation and Funding

Vinogradova Y, Coupland C, Hill T, et al. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ. 2018;362:k2505

This study was funded by National Institute for Health Research and a School for Primary Care Research grant.

Bibliography

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. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. TA275. London: National Institute for Health and Care Excellence; 2013.

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

NICE. Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. TA249. London. National Institute for Health and Care Excellence. 2012.

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 prevention of stroke and systemic embolism in people with atrial fibrillation. TA256. London. National Institute for Health and Care Excellence. 2012.

NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. CG144. London: National Institute for Health and Care Excellence. 2012 (updated 2015).

NICE. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NG89. London: National Institute for Health and Care Excellence; 2018.

Why was this study needed?

Anticoagulants are used to prevent and to treat blood clots.  These may start in the veins and may be carried in the bloodstream to end up in the lungs, or they may start in the heart and be carried to the brain causing a stroke. People who have hip or knee replacement surgery or who develop atrial fibrillation are at high risk of clots and are usually given anticoagulants.

Trials have established that direct-acting oral anticoagulants (DOACs) are as effective as warfarin but safety information on bleeding risk collected outside the research setting is lacking.

This study aimed to compare the safety of DOACs compared with warfarin for people with and without atrial fibrillation. This heart rhythm disturbance affects around one million people in the UK.

What did this study do?

This cohort study analysed UK primary care data in two databases with 196,061 people prescribed warfarin or DOACs between 2011 and 2016. It linked patient-level data to the hospital records to see if complications had been recorded here. Around half, 103,270 (53%) had atrial fibrillation, and 92,791 (47%) were prescribed anticoagulants for other indications.

Researchers followed patients on warfarin for on average six to 11 months and on DOACs for three to nine months. Adverse event rates were calculated separately for the two databases used (Qresearch and GPRD). Rates from the larger database, QResearch, are reported in this summary. Both informed risk estimates. The analysis took account of confounding factors such as other illnesses and medications.

This was a large representative study and should reflect real-world use, but it did not look at patient adherence to the prescribed medications.

What did it find?

For people with atrial fibrillation:

  • Major bleeding was less likely with apixaban (adjusted hazard ratio [aHR] 0.66, 95% confidence interval [CI] 0.54 to 0.79). It occurred at a rate of 15 per 1,000 person years (py) compared with 25 per 1,000 py for those on warfarin.
  • Intracranial bleeding was less frequent in those on apixaban, with a rate of 3 per 1,000 py (aHR 0.40, 95% CI 0.25 to 0.64) and dabigatran, rate 3 per 1,000 py (aHR 0.45, 95% CI 0.26 to 0.77) compared with 6 per 1,000 py for those on warfarin.
  • Risk of death from any cause was higher for patients taking rivaroxaban, with a rate of 55 deaths per 1,000 py compared with 45 per 1,000 py on warfarin (aHR 1.19, 95% CI 1.09 to 1.29). It was also higher for those on low-dose apixaban with a rate of 80 deaths per 1,000 py (aHR 1.27, 95% CI 1.12 to 1.45).

For people on anticoagulation for other reasons:

  • Apixaban was associated with a lower risk of: major bleeding, with a rate of less than 18 per 1,000 py compared with 29 per 1,000 py on warfarin (aHR 0.60, 95% CI 0.46 to 0.79); and gastrointestinal bleeding, 9 per 1,000 py compared with 12 per 1,000 py on warfarin (aHR 0.55, 95% CI 0.37 to 0.83). Risk of death was higher for those on low dose apixaban at 120 per 1,000 py compared with 58 per 1,000 py for warfarin (aHR 1.34, 95% CI 1.13 to 1.58).
  • Rivaroxaban was associated with a decreased the risk of intracranial bleeds, occurring at a rate of 4 per 1,000 py compared with 6 per 1,000 py on warfarin (aHR 0.54, 95% CI 0.35 to 0.82). However, the risk of death from any cause was higher at 87 per 1,000 py compared with 58 per 1,000 py for warfarin (aHR 1.51, 95% CI 1.38 to 1.66).

What does current guidance say on this issue?

Rivaroxaban, apixaban or dabigatran are recommended in the NICE 2018 guideline for the prevention of clots for people having an elective hip or knee replacement.

NICE 2014 guidelines recommend either a vitamin K antagonist such as warfarin, or apixaban, rivaroxaban or dabigatran as options for the prevention of stroke and clots in people with non-valvular atrial fibrillation at higher risk.

For ongoing treatment, and prevention of recurrence, of DVT and pulmonary embolism the NICE 2012 guideline recommended warfarin, but also suggested considering dabigatran, apixaban and rivaroxaban.

What are the implications?

This study provides further safety data which will aid shared-decision making on the use of DOACs as an alternative to warfarin. It provides information for people requiring anticoagulation for reasons other than atrial fibrillation.

DOACs have not been directly compared in randomised controlled trials, and alongside other indirect comparisons, this observational study adds to the body of evidence comparing safety and efficacy.

The increased risk in all-cause mortality with rivaroxaban and low dose apixaban is a concern but may be due to confounding or indication bias. This uncertainty could be addressed in further randomised trials.

Citation and Funding

Vinogradova Y, Coupland C, Hill T, et al. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care. BMJ. 2018;362:k2505

This study was funded by National Institute for Health Research and a School for Primary Care Research grant.

Bibliography

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. Apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial fibrillation. TA275. London: National Institute for Health and Care Excellence; 2013.

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

NICE. Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. TA249. London. National Institute for Health and Care Excellence. 2012.

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 prevention of stroke and systemic embolism in people with atrial fibrillation. TA256. London. National Institute for Health and Care Excellence. 2012.

NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. CG144. London: National Institute for Health and Care Excellence. 2012 (updated 2015).

NICE. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NG89. London: National Institute for Health and Care Excellence; 2018.

Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: cohort study in primary care

Published on 4 July 2018

Y Vinogradova, C Coupland, T Hill, J Hippisley-Cox

The BMJ , 2018

Objective To investigate the associations between direct oral anticoagulants (DOACs) and risks of bleeding, ischaemic stroke, venous thromboembolism, and all cause mortality compared with warfarin. Design Prospective open cohort study. Setting UK general practices contributing to QResearch or Clinical Practice Research Datalink. Participants 132 231 warfarin, 7744 dabigatran, 37 863 rivaroxaban, and 18 223 apixaban users without anticoagulant prescriptions for 12 months before study entry, subgrouped into 103 270 patients with atrial fibrillation and 92 791 without atrial fibrillation between 2011 and 2016. Main outcome measures Major bleeding leading to hospital admission or death. Specific sites of bleeding and all cause mortality were also studied. Results In patients with atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (adjusted hazard ratio 0.66, 95% confidence interval 0.54 to 0.79) and intracranial bleeding (0.40, 0.25 to 0.64); dabigatran was associated with a decreased risk of intracranial bleeding (0.45, 0.26 to 0.77). An increased risk of all cause mortality was observed in patients taking rivaroxaban (1.19, 1.09 to 1.29) or on lower doses of apixaban (1.27, 1.12 to 1.45). In patients without atrial fibrillation, compared with warfarin, apixaban was associated with a decreased risk of major bleeding (0.60, 0.46 to 0.79), any gastrointestinal bleeding (0.55, 0.37 to 0.83), and upper gastrointestinal bleeding (0.55, 0.36 to 0.83); rivaroxaban was associated with a decreased risk of intracranial bleeding (0.54, 0.35 to 0.82). Increased risk of all cause mortality was observed in patients taking rivaroxaban (1.51, 1.38 to 1.66) and those on lower doses of apixaban (1.34, 1.13 to 1.58). Conclusions Overall, apixaban was found to be the safest drug, with reduced risks of major, intracranial, and gastrointestinal bleeding compared with warfarin. Rivaroxaban and low dose apixaban were, however, associated with increased risks of all cause mortality compared with warfarin.

Expert commentary

This is one of an increasing number of ‘real world’ data comparing direct acting oral anticoagulants (DOACs) with warfarin. All consistently show that the DOACs show improved effectiveness and safety compared with warfarin. They also have relative convenience, without the need for anticoagulation intensity monitoring as we would do for warfarin.

Real-world data are no substitute for randomised trials, and in the absence of head to head trials, we can see associations from such real-world analyses. However, residual confounding is likely, due to many factors. Thus, these real-world data would only be supportive of randomised trials, and not replacing them.

Overall, the DOACs have transformed the landscape for stroke prevention in atrial fibrillation. New treatment guidelines have expressed a preference for the DOACs over warfarin, and the default is to offer stroke prevention unless the patient is found to be low risk (CHA2DS2-VASc score 0 in males, or 1 in females).

Gregory Y H Lip, Price-Evans Chair of Cardiovascular Medicine, University of Liverpool