OBJECTIVES: The novel oral anti-coagulants (NOACs) have not been compared directly in a randomised controlled trial (RCT) examining the initial treatment of venous thromboembolism (VTE). A systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of the NOACs in this indication. Safety with respect to bleeding is a major concern for physicians and patients. METHODS: Electronic databases were systematically searched (July 2014) to identify randomised controlled trials (RCTs) evaluating apixaban, dabigatran, rivaroxaban, and edoxaban versus standard care. Eligible adult patients had objectively confirmed deep vein thrombosis (DVT), pulmonary embolism (PE) or both. A fixed-effect Bayesian NMA was conducted for relevant outcomes. RESULTS: Six phase III RCTs were included: apixaban (AMPLIFY [n=5,395]); rivaroxaban (EINSTEIN-DVT/PE pooled [n=4,832+3449]); dabigatran (RE-COVER I/II [n=2,539/2568]); edoxaban (Hokusai-VTE [n=8,292]). The relative risk of ‘VTE and VTE-related death’ was lower with apixaban compared with both dabigatran (↓24%, 0.76 [0.46, 1.26]), rivaroxaban (↓7%, 0.93 [0.59, 1.45]) and edoxaban (↓6%, 0.94 [0.62, 1.42]). Apixaban was associated with the most favourable safety profile, showing a statistically significant reduction in the risk of ‘major or clinically relevant non-major (CRNM) bleed’ compared with rivaroxaban (↓53%, 0.47 [0.36, 0.61]), dabigatran (↓31%, 0.69 [0.51, 0.94]) and edoxaban (↓46%, 0.69 [0.51, 0.94]). The relative risks of all-cause mortality for apixaban versus dabigatran, rivaroxaban and edoxaban were comparable (21%, 0.79 [0.44, 1.40]; 18%, 0.82 [0.50, 1.34]; 25%, 0.75 [0.47, 1.21], respectively). CONCLUSIONS: While the NOACs have similar efficacy in terms of reduction in VTE or VTE-related death, apixaban had a significantly better safety profile versus other NOACs in terms of reduction in ‘major or CRNM bleed’ for initial/long term treatment of VTE.