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Br J Clin Pharmacol. 2017 Aug;83(8):1844-1859. doi: 10.1111/bcp.13265. Epub 2017 Mar 24.

Risk of major bleeding and stroke associated with the use of vitamin K antagonists, nonvitamin K antagonist oral anticoagulants and aspirin in patients with atrial fibrillation: a cohort study.

Author information

Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands.
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands.
Radboud University Medical Centre, Nijmegen, The Netherlands.
Department of Pharmacology-Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands.
Division of Clinical Pharmacy & Toxicology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
MRC Lifecourse Epidemiology Unit, Southampton General Hospital, University of Southampton, UK.



Nonvitamin K antagonist oral anticoagulants (NOACs) are now available for the prevention of stroke in patients with atrial fibrillation (AF) as an alternative to vitamin K antagonists (VKA) and aspirin. The comparative effectiveness and safety in daily practice of these different drug classes is still unclear. The objective of this study was to evaluate the risk of major bleeding and stroke in AF patients using NOACs, VKAs or aspirin.


A retrospective cohort study was conducted among AF patients using the UK Clinical Practice Research Datalink (March 2008-October 2014). New users of VKAs, NOACs and low dose aspirin were followed from the date of first prescription of an antithrombotic drug until the occurrence of stroke or major bleeding. Analyses were adjusted for a history of comorbidities and drug use with Cox regression analysis.


A total of 31 497 patients were eligible for the study. The hazard ratio (HR) of major bleeding was 2.07 [95% confidence interval (CI) 1.27-3.38] for NOACs compared with VKAs, which was mainly attributed by the increased risk of gastrointestinal bleeding (HR 2.63, 95% CI 1.50-4.62). This increased bleeding risk was restricted to women (HR 3.14, 95% CI 1.76-5.60). Aspirin showed a similar bleeding risk as VKAs. NOACs showed equal effectiveness as VKA in preventing ischaemic stroke (HR 1.22, 95% CI 0.67-2.19). VKAs were more effective than aspirin (HR 2.18, 95% CI 1.83-2.59).


NOACs were associated with a higher risk on gastrointestinal bleeding, particularly in women. The use of NOACs in patients who are vulnerable for this type of bleeding should be carefully considered. NOACs and VKAs are equally effective in preventing stroke. Aspirin was not effective in the prevention of stroke in AF.


anticoagulants; aspirin; atrial fibrillation; gastrointestinal haemorrhage; intracranial haemorrhage; stroke

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