In patients with non-valvular atrial fibrillation (AF), direct oral anticoagulants (DOACs) have proven to be non-inferior to vitamin K antagonists (VKAs) in preventing ischemic stroke and systemic embolism and with a better safety profile [1].

DOACs’ efficacy and safety over VKAs was first investigated in large phase III trials. In spite of their high quality, phase III trials also have limits; inclusion/exclusion criteria are very strict, therapy adherence and persistence very high, physicians are strongly motivated in following patients properly and there could be some selection bias. These specific characteristics render conclusions of phase III trials not completely applicable to real life, where things are different and comorbidities usually more relevant. To evaluate the efficacy and safety of drugs in daily practice, post-authorisation safety studies (PASS) are usually performed. The advantage of PASS trial lies in the fact that they reflect routine clinical practice and are not affected by study protocols, leaving drugs and dosages prescriptions’ decisions to the attending physicians, without any interference. In addition, control of therapy is not usually as strict as in trials. PASS studies integrate therefore the information derived from phase III studies.

ETNA-AF (Edoxaban treatment in routine clinical practice-atrial fibrillation) [2] and XANTUS (Xarelto for prevention of stroke in patients with atrial fibrillation) [3] are prospective observational post-authorisation non interventional trials, planned to collect information about safety of treatment with edoxaban and rivaroxaban, respectively, which are DOACs directly inhibiting factor Xa. ETNA-AF and XANTUS also contribute to generate information about the efficacy of these two drugs in real word. Despite the many similarities between these two studies, distinct results were observed that are worth of careful interpretation. The aim of the present manuscript was to interpret different findings in ETNA-AF and XANTUS.