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We have used a series of economic models to evaluate the differences in medical costs associated with the use of each of the four targeted-specific oral anticoagulants (TSOACs), dabigatran, rivaroxaban, apixaban, and edoxaban vs. warfarin for the treatment of nonvalvular atrial fibrillation (NVAF) and venous thromboembolism (VTE). All economic models were based on clinical event rates reported in published randomized phase III clinical trials, except one model used real-world data among patients with VTE. Incremental annual medical costs among NVAF and VTE patients with clinical events from a U.S. payer perspective were obtained from the literature and inflation adjusted to 2013 cost levels. The economic model for NVAF patients estimated that in a year the total medical cost differences associated with TSOAC use relative to warfarin at $204, $140, $495, and -$340 per patient for dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. The economic model for patients with acute symptomatic VTE estimated that in a year the total medical cost differences associated with TSOAC use relative to warfarin at -$146, -$482, -$918, and -$344 per patient for dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. In all cases, univariate and multivariable sensitivity analyses were conducted to establish the robustness of the results of the economic models. Additionally, we extrapolated the results of our economic models to a combined population of NVAF patients and acute VTE patients among a hypothetical cohort of 1 million insured lives. Our economic evaluations have consistently shown that medical costs are reduced when TSOACs are used instead of warfarin for the treatment of NVAF or VTE, with apixaban being associated with the greatest reduction in medical costs. This review describes the execution of these economic evaluations and their results.