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Background: Chronic kidney disease (CKD) is associated with a high prevalence of atrial fibrillation (AF), but in this population the risk/benefit ratio of anticoagulant therapy with vitamin K antagonists (VKA) for thromboprophylaxis is uncertain. Summary: In end-stage renal disease (ESRD) patients undergoing hemodialysis, VKA seem less effective in stroke prevention than in the general population, with an increased risk of major bleeding. Recently, novel oral anticoagulant agents (NOACs) have proven to be effective for stroke prevention in AF and have demonstrated an improved safety profile compared to VKA. Limited data from post hoc analyses of controlled clinical trials suggest the safe and effective use of NOACs in patients with moderate renal impairment (i.e., estimated glomerular filtration rate, eGFR, between 30 and 50 mL/min). The question still remains whether NOACs can be used in patients with an eGFR <30 mL/min, since there are no studies addressing this subject. In fact, patients with CKD stage 4 and 5 were excluded from controlled clinical trials on anticoagulation therapy for stroke prevention in AF. Left atrial appendage (LAA) occlusion represents a nonpharmacological alternative for stroke prevention in patients with AF who are difficult to manage medically. Preliminary data indicate a similar efficacy and safety profile in patients with CKD compared to patients with normal renal function. Key Messages: Stroke prevention in patients with ESRD and AF represents a clinical challenge with poor evidence. LAA occlusion may become the standard of care for stroke prevention in patients with ESRD and AF.