ObjectivesTo demonstrate how health technology assessment (HTA) methods can be used to support Medicare’s price negotiations for apixaban and rivaroxaban. MethodsFollowing the statutory outline of evidence that will be considered by Medicare, we conducted a systematic literature review, network meta-analyses (NMAs), and decision analyses to evaluate the health outcomes and costs associated with apixaban and rivaroxaban compared to warfarin and dabigatran for patients with non-valvular atrial fibrillation. Our methods inform discussions about the therapeutic impact of apixaban and rivaroxaban and suggest price premiums above their therapeutic alternatives over a range of cost-effectiveness thresholds. ResultsNMAs found apixaban resulted in a lower risk of major bleeding compared to warfarin and dabigatran, and a lower risk of stroke/systemic embolism compared to warfarin, but not compared to dabigatran. Rivaroxaban resulted in a lower risk of stroke/systemic embolism versus warfarin but not dabigatran, and there was no difference in major bleeding. Decision-analytic modeling of apixaban suggested annual price premiums up to $4,350 above the price of warfarin and up to $530 above the price for dabigatran at cost-effectiveness thresholds up to $200,000 per equal value of life years gained. Analyses of rivaroxaban showed an annual price premium of up to $3,920 above warfarin, and no premium above that paid for dabigatran. ConclusionsAlthough HTA is typically performed near the time of regulatory approval, with modifications, we produced comparative clinical and relative cost-effectiveness findings to help guide negotiations on a “fair” price for drugs on the market for over a decade.