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Aims: Data on non-vitamin K antagonist oral anticoagulants (NOACs) use in patients with atrial fibrillation (AF) and frailty are scarce. Therefore, the impact of frailty on AF-related outcomes and benefit-risk profiles of NOACs in patients with frailty were investigated., Methods and Results: AF patients initiating anticoagulation between 2013 and 2019 were included using Belgian nationwide data. Frailty was assessed with the Claims-based Frailty Indicator. Among 254 478 anticoagulated AF patients, 71 638 (28.2%) had frailty. Frailty was associated with higher all-cause mortality risks [adjusted hazard ratio (aHR) 1.48, 95% confidence interval (CI) (1.43-1.54)], but not with thromboembolism or bleeding. Among subjects with frailty (78 080 person-years of follow-up), NOACs were associated with lower risks of stroke or systemic embolism (stroke/SE) [aHR 0.77, 95%CI (0.70-0.86)], all-cause mortality [aHR 0.88, 95%CI (0.84-0.92)], and intracranial bleeding [aHR 0.78, 95%CI (0.66-0.91)], a similar major bleeding risk [aHR 1.01, 95%CI (0.93-1.09)], and higher gastrointestinal bleeding risk [aHR 1.19, 95%CI (1.06-1.33)] compared with VKAs. Major bleeding risks were lower with apixaban [aHR 0.84, 95%CI (0.76-0.93)], similar with edoxaban [aHR 0.91, 95%CI (0.73-1.14)], and higher with dabigatran [aHR 1.16, 95%CI (1.03-1.30)] and rivaroxaban [aHR 1.11, 95%CI (1.02-1.21)] compared with VKAs. Apixaban was associated with lower major bleeding risks compared with dabigatran [aHR 0.72, 95%CI (0.65-0.80)], rivaroxaban [aHR 0.78, 95%CI (0.72-0.84)] and edoxaban [aHR 0.74, 95%CI (0.65-0.84)], but mortality risk was higher compared with dabigatran and edoxaban., Conclusion: Frailty was an independent risk factor of death. Non-vitamin K antagonist oral anticoagulants had better benefit-risk profiles than VKAs in patients with frailty, especially apixaban, followed by edoxaban., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: Conflicts of interest T.H. has received grants and consulting and/or speaking fees from AbbVie, Johnson & Johnson, Pfizer, BMS, Boehringer Ingelheim, Celgene, Lilly, MSD, Biogen, LEO Pharma, Amgen and UCB. S.V. has received grants from AbbVie, Johnson & Johnson, Pfizer, Galápagos and Takeda, and has received consulting and/or speaking fees from AbbVie, AbolerIS Pharma, Agomab, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galápagos, Genentech-Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, Johnson & Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrM Health, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma and Zealand Pharma.

Aims: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated., Methods and Results: AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding [adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)] and all-cause mortality risks [aHR 1.07, 95% CI (1.02-1.11)], but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone [aHR 1.27, 95% CI (1.21-1.34)], diltiazem [aHR 1.28, 95% CI (1.13-1.46)], verapamil [aHR 1.36, 95% CI (1.03-1.80)], ticagrelor [aHR 1.50, 95% CI (1.20-1.87)], and clarithromycin [aHR 1.55, 95% CI (1.14-2.11)]; and in edoxaban [aHR 1.24, 95% CI (1.06-1.45)], rivaroxaban [aHR 1.25, 95% CI (1.16-1.34)], and apixaban users [aHR 1.27, 95% CI (1.16-1.39)], but not in dabigatran users [aHR 1.07, 95% CI (0.94-1.23)]. Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk [aHR 1.31, 95% CI (1.03-1.68)], but not with bleeding or all-cause mortality., Conclusion: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Atrial fibrillation (AF) is associated with cognitive decline, with anticoagulated subjects potentially having a reduced risk compared with non-anticoagulated subjects. However, whether non-vitamin K antagonist oral anticoagulants (NOACs) may reduce the risk of dementia compared with vitamin K antagonists (VKAs) is unclear yet. Therefore, the risk of dementia was compared between AF subjects on NOACs versus VKAs., Methods: AF subjects initiating anticoagulation between 2013 and 2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate cognitive outcomes., Results: Among 237,012 AF subjects (310,850 person-years (PYs)), NOAC use was associated with a significantly lower risk of dementia (adjusted hazard ratio (aHR) 0.91, 95% confidence interval (CI) (0.85-0.98)) compared with VKAs. A trend towards a lower risk of vascular dementia (aHR 0.89, 95% CI (0.76-1.04)) and significantly lower risk of other/unspecified dementia (aHR 0.91, 95% CI (0.84-0.99)) were observed with NOACs compared with VKAs, whereas the risk of Alzheimer's disease was similar (aHR 0.99, 95% CI (0.88-1.11)). Apixaban (aHR 0.91, 95% CI (0.83-0.99)) and edoxaban (aHR 0.79, 95% CI (0.63-0.99)) were associated with significantly lower risks of dementia compared with VKAs, while risks were not significantly different with dabigatran (aHR 1.02, 95% CI (0.93-1.12)) and rivaroxaban (aHR 0.97, 95% CI (0.90-1.05)). Comparable risks of dementia were observed between individual NOACs, except for significantly lower risks of dementia (aHR 0.93, 95% CI (0.87-0.98)) and other/unspecified dementia (aHR 0.90 (0.84-0.97)) with apixaban compared with rivaroxaban., Conclusion: NOACs were associated with a significantly lower risk of dementia compared with VKAs, likely driven by apixaban and edoxaban use., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: Non-vitamin K antagonist oral anticoagulants (NOACs) are effective and safe alternatives compared with vitamin K antagonists (VKAs) for thromboembolic prevention in atrial fibrillation (AF), while antiplatelets are no longer recommended. However, to which extent NOAC introduction and guideline updates have increased OAC use in AF, is unclear. Therefore, worldwide trends in real-life prescribing of OACs, NOACs, VKAs, and antiplatelet monotherapy in AF patients were investigated., Methods and Results: Using PubMed and Embase, observational nationwide cohort studies on annual prevalent and/or incident OAC use in non-selected AF patients since 2010 were included. A meta-analysis of single proportions was performed. Twenty-one studies were included assessing prevalent and incident use among 9 758 637 and 197 483 OAC-eligible AF patients, respectively. Worldwide prevalence and incidence of OAC users increased from 0.42 [95% confidence interval (CI) 0.22-0.65] and 0.43 (95% CI 0.37-0.49) in 2010 to 0.78 (95% CI 0.77-0.78) and 0.75 (95% CI 0.74-0.76) in 2018, respectively. Prevalent and incident NOAC users increased globally from 0 in 2010 to 0.45 (95% CI 0.45-0.46) and 0.68 (95% CI 0.67-0.69) in 2018, respectively, whereas prevalent and incident VKA use decreased from 0.42 (95% CI 0.22-0.65) and 0.42 (95% CI 0.36-0.49) in 2010 to 0.32 (95% CI 0.32-0.32) and 0.06 (95% CI 0.06-0.07) in 2018, respectively. Prevalent antiplatelet monotherapy use decreased from 0.37 (95% CI 0.32-0.42) in 2010 to 0.09 (95% CI 0.09-0.10) in 2018., Conclusion: The proportion of OAC users worldwide almost doubled following NOAC introduction. As one-quarter of OAC-eligible AF subjects were not anticoagulated and 9% were only treated with antiplatelets in 2018, there is still room for improvement., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)