###### Abstract  
Background: Extremes of body weight may alter exposure to non-vitamin K antagonist anticoagulants and thereby impact clinical outcomes. This ETNA-AF-Europe sub-analysis assessed 1-year outcomes in routine care patients with atrial fibrillation across a range of body weight groups treated with edoxaban. Methods: ETNA-AF-Europe is a multinational, multicentre, observational study conducted in 825 sites in 10 European countries. Overall, 1310, 5565, 4346 and 1446 enrolled patients were categorised into \(\leq\)60 kg, \(>\)60\(-\)\(\leq\)80 kg (reference weight group), \(>\)80\(-\)\(\leq\)100 kg and \(>\)100 kg groups. Results: Patients weighing \(\leq\)60 kg were older, more frail and had a higher CHA\({}_{2}\)DS\({}_{2}\)-VASc score vs. the other weight groups. The rates of stroke/systemic embolism, major bleeding and ICR were low at 1 year (0.82, 1.05 and 0.24%/year), with no significant differences among weight groups. The annualised event rates of all-cause death were 3.50%/year in the overall population. After adjustment for eGFR and CHA\({}_{2}\)DS\({}_{2}\)-VASc score, the risk of all-cause death was significantly higher in extreme weight groups vs. the reference group. Conclusions: Low rates of stroke and bleeding were reported with edoxaban, independent of weight. The risk of all-cause death was higher in extremes of weight vs. the reference group after adjustment for important risk modifiers, thus no obesity paradox was observed. Keywords:atrial fibrillation; edoxaban; weight; registry; effectiveness; safety; non-vitamin K antagonists oral anticoagulants; stroke +
Footnote †: journal: Clinical Medicine  
At extremes of body weight, both thrombotic and haemorrhagic risks may be increased, and the pharmacokinetics of anticoagulant drugs may be altered, with a substantial risk of overdosing in underweight and under-dosing in obese individuals [2]. The complexity of the problem is enhanced by the limited amount of pharmacokinetic/pharmacodynamic studies performed in patients at extremes of body weight [3,4]. Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred treatment option for stroke prevention in patients with AF [5]. NOACs do not require routine blood testing for measuring coagulation because of the fewer drug interactions and a wide therapeutic window. Moreover, all four phase III randomised trials comparing NOACs vs. VKAs were performed without dose adjustments based on plasma level measurements [6]. Although routine monitoring of plasma levels of NOACs and subsequent dose adjustment is generally discouraged, data are emerging for the association between NOAC plasma levels and thrombotic and bleeding complications. One observational study (START) in patients with AF treated with NOACs (dabigatran, rivaroxaban, or apixaban) reported a relationship between low C-trough levels of NOACs and the occurrence of thrombotic events whereas bleeding complications were more frequent in those with higher C-peak levels of NOACs implicating the need for a more accurate assessment of NOAC doses [7,8]. Thus, the anticoagulant effect of NOACs has been observed to be related to their plasma concentration, which is further affected by body distribution volume. Therefore, extremes of body weight (such as underweight and obesity) may alter the exposure to NOACs and thereby impact their safety and efficacy [9, 10, 11]. It is still unclear if altered pharmacokinetic parameters may lead to an increased risk of bleeding in low body weight patients or an increased risk of stroke/systemic embolism in high-body weight patients [9,12]. Due to the concerns of decreased drug exposure and risk of under-dosing in the obese population, the International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee (ISTH SSC) suggested in 2016 to avoid the use of NOACs in patients weighing >120 kg or with a BMI >40 kg/m\({}^{2}\), but also provided no clear guidance on the use of NOACs in patients with low body weight due to the paucity of data [13].