## 4 Discussion
There was no indication for the association between high BMI and decreased NOAC effectiveness or safety, which is in line with the obesity paradox that suggests a favourable effect of higher BMI on safety and effectiveness outcomes. In the ORBIT-AF registry, all-cause death rates over the 2-year follow period decreased across increasing BMI categories, with highest rates in the normal weight group and lowest in the class III obesity group. However, it should be noted that obese patients were significantly younger than normal weight patients, and although age was included in the adjustment model, it may not have been possible to fully take the age differences into consideration [35]. Furthermore, BMI was noted to be inversely proportional to the risk for stroke/TIA/SEE in the unadjusted analysis; however, the association was no longer significant after adjustment for the risk factors. Contrary to these findings, real word data from the prospective PREFER in AF and PREFER in AF PROLONGATION registries showed no obesity paradox for thrombo-bolic events in patients with AF [36]. Obese patients were at a higher risk of TEE, and oral anticoagulation was found to reduce the risk of events. Moreover, low body weight as well as obesity were also associated with increased bleeding. Until recently, there has been a limited availability of robust clinical data to support definitive prescribing recommendations of NOACs in patients with BMI >40 kg/m\({}^{2}\) or >120 kg total body weight. NOAC-specific pharmacokinetic variations have been observed in morbidly obese patients, with different NOACs showing differences in outcomes when used in patients with a high BMI [37; 38; 39]. However, data are also emerging on the use of NOACs in these patients suggesting that NOACs may be a safe and effective alternative to warfarin for prevention of stroke or SEE in morbidly obese patients [37; 40; 41]. Recent analyses of the four pivotal NOAC trials (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48) stratified by BMI showed preserved efficacy with NOACs compared with warfarin in obese patients, with a similar risk of major bleeding [42]. Although the data for class III obese patients (BMI \(\geq\)40 kg/m\({}^{2}\)) are limited, apixaban and edoxaban demonstrated similar efficacy and safety to warfarin in patients with BMI 40-50 kg/m\({}^{2}\). In the ETNA-AF-Europe analysis, \(\sim\)20% of patients ranged between 30\(\sim\)\(\sim\)35 kg/m\({}^{2}\) and \(\sim\)9% had a BMI \(\geq\) 35 kg/m\({}^{2}\) adding to the limited evidence in patients with a very high BMI. We acknowledge the limitations of this analysis, which are typical of observational studies [43; 44]. In this ETNA-AF-Europe sub-analysis, direct comparison of casual treatment effects was not possible as it did not involve randomised selection of therapy and only patients treated with edoxaban were eligible. The open-label nature of this observational study may have introduced bias due to knowledge about treatment. Although the study included both low and high weight patients, the data on extremes of body weight are limited, with only 10% of patients weighing \(\leq\)60 kg and \(\sim\)11% weighing >100 kg. Furthermore, 90% of the patients included in our analysis are over 60 years of age. The extrapolation of these data for younger patients may not be possible because they may report somewhat different findings in comparison with older individuals.