We thank Drs. Li and Zhao for their interest in our paper (1). They are correct that indirect comparisons cannot address all the heterogeneity between trials, as well as the underlying pathogenic mechanisms that they allude to. However, it is not very likely that there would be major differences in stroke subtypes among the 3 studies. Also, the inclusion and exclusion criteria are broadly the same in the 3 trials, except for the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial, wherein more patients may possibly have a different stroke type than thromboembolism-related, because of the higher-risk profile.

The only way to definitively address this issue would be to perform a large head-to-head randomized trial, and with the current agents, this would need to be a 4-arm noninferiority randomized trial of dabigatran (2 doses), apixaban, and rivaroxaban, which would probably require a massive number of atrial fibrillation patients (probably >50,000) and require >5 years of follow-up.

In the absence of head-to-head comparisons, indirect comparisons allow the opportunity to have some insight into how these novel anticoagulants would perform against each other for the main efficacy and safety endpoints (2). To that end, our analysis (1) concludes that there are no profound differences in the major efficacy and safety endpoints between the novel oral anticoagulants. This is consistent with other recent papers on the same topic ((3),4), although 1 analysis by Kansal et al. (5) did highlight some differences with fewer incidents of ischaemic stroke and intracranial hemorrhage, as well as cost effectiveness, when dabigatran was compared against rivaroxaban.