It is now 4 years since the introduction of the new direct oral anticoagulants into clinical practice. Therefore, the Italian Association of Hospital Cardiologists (ANMCO) has deemed necessary to update the previous position paper on the prevention of thrombo-embolic complications in patients with non-valvular atrial fibrillation, which was published in 2013. All available scientific evidence has been reviewed, focusing on data derived from both clinical trials and observational registries. In addition, all issues relevant to the practical clinical management of oral anticoagulation with the new direct inhibitors have been considered. Specific clinical pathways for optimal use of oral anticoagulation with the new directly acting agents are also developed and proposed for clinical implementation. Special attention is finally paid to the development of clinical algorithms for medium and long-term follow-up of patients treated with new oral direct anticoagulants.