BACKGROUND: Chronic Kidney Disease (CKD) significantly increases the risk of cardiovascular diseases, including atrial fibrillation, which usually requires anticoagulant therapy. The effectiveness and safety of direct oral anticoagulants compared to vitamin K antagonists in patients with CKD remain insufficiently studied, particularly in the more advanced stages. METHODS: This systematic review, registered in PROSPERO (CRD42023410192), adhered to PRISMA guidelines and included randomized clinical trials and cohort studies comparing direct oral anticoagulants and vitamin K antagonists in CKD patients. Major databases were searched, and studies were selected based on strict inclusion criteria. A meta-analysis was performed using random-effects models. RESULTS: Twenty-three studies with a total of 465,673 CKD patients were included. Direct oral anticoagulants showed a significant reduction in major bleeding events compared to vitamin K antagonists (Relative Risk [RR] = 0.62, 95% Confidence Interval: 0.49-0.79, p <
0.01) and a non-significant trend toward reducing thromboembolic events (RR = 0.69, 95% Confidence Interval: 0.43-1.14, p = 0.11). Furthermore, direct oral anticoagulants were associated with a significant reduction in all-cause mortality (RR = 0.63, 95% Confidence Interval: 0.43-0.91, p = 0.02). CONCLUSION: Direct oral anticoagulants may offer a safe alternative to vitamin K antagonists in CKD patients, particularly in terms of reducing bleeding risks and potentially improving survival. However, their role in preventing thromboembolic events remains uncertain, highlighting the need for further research, especially in patients with advanced CKD and kidney failure.