## 4 Discussion  
This observational study showed that the risk of stroke and bleeding is low across a range of weight groups in patients with AF treated with edoxaban. Furthermore, while low body weight (\(\leq\)60 kg) was associated with increased overall death, weight was not associated with different rates of stroke, major bleeding, or CV death in this population. Historically, low body weight (<50 kg) has been an independent predictor of increased risk of ischaemic stroke, major bleeding, intracranial haemorrhage and death irrespective of the oral anticoagulation therapy [17]. Overall, patients with body weight <60 kg were under-represented in NOAC trials compared with those with body weight >100 kg. In the present ETNA-AF-Europe analysis, 10% of patients weighed \(\leq\)60 kg counting towards the existing evidence for the effectiveness and safety of NOACs in low body weight patients. In the individual NOAC trials, the efficacy and safety of the NOACs in patients with low body weight was consistent with the overall findings, warranting dose reduction in the case of edoxaban in participants weighing \(\leq\)60 kg and in case of apixaban when accompanied by at least one other clinical criterion [9]. A _post hoc_ analysis of ARISTOTLE demonstrated that apixaban 5 mg BID (reduced to 2.5 mg BID if patients had \(\geq\)2 of the following criteria: age \(\geq\)80 years, body weight \(\leq\)60 kg, or a serum creatinine level \(\geq\)1.5 mg/dL) is efficacious and reduced major bleeding versus warfarin across the weight categories, including low-(\(\leq\)60 kg) and high-weight patients (>120 kg) [18]. Of note, 1985 (10.9%) of the patients were in the low-weight group (\(\leq\)60 kg). Inappropriate dosing is not uncommon with NOACs. Use of off-label dosing regimen may be influenced by various factors including clinician perception of higher bleeding risk and lack of familiarity with dosing guidelines [19; 20]. More commonly, inappropriate low dosing has been reported in studies exploring daily practice of NOACs [21; 22]. Similar findings were observed in our analysis, with a limited number of patients weighing >80 kg received lower than the recommended dose. Such findings emphasise the need to explore strategies to prevent unintentional inappropriate dosing by prescribers. Limited data obtained from trials and retrospective studies available thus far advocate the need for dedicated larger studies to address the use of NOACs in low weight patients. In the present ETNA-AF-Europe analysis, no significant differences in stroke-related outcomes were observed between body weight subgroups. These findings were suggestive of consistent effectiveness of edoxaban in a wide range of weight groups. There was a trend towards lower bleeding events with increasing weight in the unadjusted analysis. In particular, there was a significantly lower risk for major and clinically relevant non-major bleeding in patients >100 kg compared with the reference weight category. However, this difference was not noticeable after adjusting for eGFR and CHA\({}_{2}\)DS\({}_{2}\)-VASC score. Our findings are coherent with the outcomes observed in the sub-analysis of the ENGAGE AF-TIMI 48 randomised clinical trial that showed a similar risk of stroke/SE between edoxaban and warfarin-treated patients across the three weight groups (low \(\leq\)55 kg, middle 79.884 kg and high \(\geq\)120 kg body weight) [3]. Major bleeding and net clinical outcome (composite of stroke, SEE, major bleeding, or death) were favourable with edoxaban versus warfarin especially in low body weight patients [3]. The evidence available so far suggests that despite the reduced risk of thromboembolic events with the use of oral anticoagulants, a high risk of CV-related deaths has been evident and requires the attention of physicians and policy makers [23]. The impact of associated comorbidities on mortality in AF patients, deserves to be tested outside of the randomised controlled trials setting.