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.
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.
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Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre