Alternative anticoagulants to warfarin (dabigatran, rivaroxaban and apixaban) are becoming available for the prevention of thromboembolic stroke in atrial fibrillation, but there is a lack of information on their comparative effectiveness. We evaluated this using a discrete event simulation with a lifetime horizon of analysis, based on an indirect comparison of the RE-LY, ROCKET-AF and ARISTOTLE trial results for patients with the characteristics of the US atrial fibrillation population. Over a lifetime, apixaban, dabigatran and rivaroxaban accrued 0.130 (95% central range [CR] -0.030 to 0.264), 0.106 (95% CR -0.048 to 0.248) and 0.095 (95% CR -0.052 to 0.242) more quality-adjusted life-years than warfarin, respectively, with apixaban having a 55% probability of accruing the highest total lifetime QALYs. In the absence of a definitive trial, and acknowledging the limitations of an indirect comparison, the available evidence suggests apixaban to be the more effective anticoagulant.Clinical Pharmacology & Therapeutics (2013); accepted article preview online 25 April 2013; doi:10.1038/clpt.2013.83.