The structure of the model is appropriate, and all data sources are valid and reasonable. Thus, limitations with the submission relate mainly to whether the decision problem at hand was adequately addressed:

• According to clinical experts, anticoagulation is appropriate in all patients with AF and a CHADS₂ (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, and prior stroke or transient ischemic attack or thromboembolism) score ≥ 1. However, the patient population in ENGAGE AF-TIMI 48 was restricted to AF patients with CHADS₂ ≥ 2. Thus, the submission does not address the cost-effectiveness of edoxaban in AF patients with CHADS₂ = 1.
• The submitted report highlights the separate comparisons of edoxaban with warfarin and rivaroxaban. According to the manufacturer’s economic submission, rivaroxaban was selected as the main NOAC comparator because the trials of edoxaban and rivaroxaban were most comparable to one another. This permitted a more robust indirect comparison of these two agents than of edoxaban versus apixaban or dabigatran. Nevertheless, the latter two agents are relevant comparators for edoxaban given their current funding status. Thus, a single, sequential analysis should have been performed of all six alternatives for nonvalvular AF: edoxaban, warfarin, rivaroxaban, apixaban, and dabigatran (110 mg and 150 mg).
• The current effective prices for rivaroxaban, apixaban, and dabigatran are unknown, which may limit the ability to accurately interpret the results of this submission.

The first and last of these issues cannot be addressed but should be considered in making funding recommendations and decisions for edoxaban. The second issue is addressed below.