OBJECTIVES:   Guidelines suggest only 3-6 months of anticoagulant treatment in most venous thromboembolism (VTE) patients due to concerns that the bleeding risk with vitamin K antagonists (VKAs) outweighs the reduced risk of VTE recurrence in extended treatment.  However, non-VKA novel oral anticoagulants (NOACs) have been studied recently for extended VTE treatment.  Apixaban demonstrated superiority to placebo in VTE reduction without increasing risk of major bleeding in the AMPLIFY-EXT trial, justifying reassessment of the potential benefit of extending treatment.  This analysis reports cost effectiveness of lifetime treatment with apixaban versus rivaroxaban, dabigatran, and low-molecular-weight heparin (LMWH)/VKA from the perspective of the UK National Health Service (NHS). METHODS:   A Markov model was developed that includes the following health states: recurrent VTE, major bleed, clinically-relevant non-major bleed, chronic thromboembolic pulmonary hypertension, and death.  Transition rates among health states were based upon AMPLIFY and AMPLIFY-EXT clinical trial data, network meta-analyses, discontinuation due to clinical events, and UK life tables.  Costs were from UK NHS Healthcare Resource Group tables and utilities were from published literature.  The primary outcome of interest was incremental cost per quality adjusted life year (QALY) gained. RESULTS:   Compared to other anticoagulants, lifetime treatment with apixaban was projected to result in fewer bleeds and fewer recurrent VTEs. The lower bleeding risk with apixaban led to fewer treatment discontinuations, longer time on treatment, and fewer recurrent VTEs.   The reduced number of clinical events led to increased QALYs at a nominal cost increase, due primarily to longer treatment duration with apixaban.  Incremental costs per QALY gained were £2,781, £619, and £10,820 for apixaban versus dabigatran, rivaroxaban, and LMWH/VKA, respectively. Sensitivity analyses indicated that results were robust to a wide range of inputs. CONCLUSIONS:   Apixaban for lifetime treatment of VTE can offer substantial clinical benefits and is a cost-effective alternative to other NOACs and LMWH/VKA.