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Improving Patient Outcomes in Preventing Atrial Fibrillation-related Stroke with Non-Vitamin K Antagonist Oral Anticoagulants

European Neurological Review, 2016;11(1):27–35 DOI:


The rising incidence of atrial fibrillation (AF) is increasingly resulting in a substantial worldwide increase in AF-related stroke, particularly in elderly patients and this is creating an increasingly serious healthcare burden. Guidelines recommend the use of AF-related stroke prophylaxis but adherence to these remains poor. Studies conducted in the 1990s showed that warfarin reduced the risk of AF-related stroke by an overall 64% compared with placebo. Subsequently, prophylactic treatment was further improved with the development of non-vitamin K antagonist oral anticoagulants (NOACs). More recently, a meta-analysis of four large clinical trials on NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) showed there was a relative risk reduction of 0.81 (p<0.0001) favouring NOAC treatment over warfarin for stroke or systemic embolic events in patients with AF. The largest trial of NOACs in AF-related stroke, to date, was the ENGAGE AF-TIMI 48 study (n=21,105) which showed that edoxaban was non-inferior to warfarin for ischaemic stroke reduction but significantly reduced bleeding and cardiovascular mortality. A recent subgroup analysis of this study showed that with edoxaban the incidences of intracranial haemorrhage (ICH) subtypes (all ICH, fatal ICH, fatal, subdural and epidural bleed) were significantly lower with 60 mg of edoxaban (p=0.013–<0.001). Edoxaban was also shown to be an effective option in patients with prior stroke. In addition edoxaban was shown to reduce deaths due to fatal bleeds compared with warfarin. The results of current studies, especially the ENGAGE AF-TIMI 48 subgroup analysis therefore, show that the benefits of anticoagulation therapy in patients with AF substantially outweigh the risks
Keywords: Atrial fibrillation-related stroke, outcomes, non-vitamin K oral anticoagulants (NOACs)
Disclosure: Peter Kelly has served on advisory boards or received speakers fees or benefits from the American Stroke Association, Bayer and Daiichi Sankyo, and has received research unit grants from the Health Research Board of Ireland, Irish Heart Foundation and Bayer. Carlos Molina has nothing to declare in relation to this article. Christian T. Ruff has received research support from GlaxoSmithKline, Daiichi Sankyo, Intarcia and AstraZeneca, and serves as a consultant and on the advisory boards for Boehringer Ingelheim, Bayer, Daiichi Sankyo, Portola and DrugDev. Roland Veltkamp has received speaker fees, consulting honoraria and research support from Bayer, Boehringer Ingelheim, BMS, Pfizer, Daiichi Sankyo, CSL Behring, Apoplex Medical Technologies, Morphosys, Biogen, Medtronic.
Acknowledgments: Editorial assistance was provided by James Gilbart at Touch Medical Media, London, this was supported by an unrestricted grant from Daiichi Sankyo Europe GmbH. This article reports the proceedings of a sponsored satellite symposium and as such has not been subject to the journal’s usual peer-review process
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit
Received: October 16, 2015 Accepted: February 19, 2016
Correspondence: Peter Kelly, Stroke Service and NeuroVascular Unit for Translational and Therapeutics Research, University College Dublin, Ireland E:
Support: The publication of this article was supported by Daiichi Sankyo Europe GmbH. The views and opinions expressed are those of the authors and not necessarily those of Daiichi Sankyo Europe GmbH.

In atrial fibrillation (AF), considerable harm can result from the lack of appropriate preventive therapy, and optimal prevention is critical, especially in vulnerable elderly or frail patients. AF markedly increases the risk of stroke and this condition must be monitored and potentially treated wherever it is detected.1–4 AF is an increasing concern for physicians worldwide as populations age and more people are at risk.5–7 Although guidelines for stroke prevention in AF that recommend anticoagulation have been established for many years, many at-risk patients receive inadequate anticoagulation or none at all.8–11 This ‘reluctance to treat’ stems largely from a fear of inducing intracranial haemorrhage (ICH) and other serious bleeding types that are associated with warfarin and the non–vitamin K antagonist oral anticoagulants (NOACs). This risk, however, is often over-stated and substantially less than the risks that are associated with the lack of stroke prevention treatment in AF. This review discusses the burden of AF-related stroke and evidence that supports current treatments, and considers novel insights on the use of edoxaban as provided by recent subgroup analyses of the ENGAGE AF-TIMI 48 trial results (see end of article for trial name definitions). These topics were presented at a satellite symposium convened at the European Stroke Organisation Annual Meeting in Glasgow, UK, in April 2015.

Preventing the Rise of AF-related Stroke– A Call to Action
Large-scale population-based observational studies have shown AF to be a serious factor increasing the likelihood of strokes and substantially worsening mortality and morbidity after a stroke.12 Various studies have predicted increasing incidence and prevalence of AF-related stroke and the associated heavy burden this will place on healthcare authorities worldwide. Professor Peter Kelly assessed the history and rising incidence of AF-related stroke. His message constitutes a call to action, encouraging physicians to treat all patients with AF to help stem the burgeoning number of ischaemic strokes and reduce the burden strokes impose on healthcare services.

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Keywords: Atrial fibrillation-related stroke, outcomes, non-vitamin K oral anticoagulants (NOACs)