Andexanet Alfa for Factor Xa Inhibitor Reversal

To the Editor: In their interim report on the Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors (ANNEXA-4) study, Connolly et al. (Sept.22 issue) 1 report on the potential utility of andexanet alfa in reversing three factor Xa inhibitors.We understand the difficulty in conducting such studies but wonder how the efficacy of andexanet alfa can be reliably assessed without a comparator group.We also observed that the data on anti-factor Xa activity do not appear as a single pooled outcome.Consequently, the subgroup analyses of anti-factor Xa activity may be misconstrued as coprimary outcomes for rivaroxaban, apixaban, and enoxaparin and may lead readers to overestimate the importance of the results.Moreover, the interpretation and translation of these results to emergencycare settings will be further complicated by the median 4.8-hour delay from presentation in the emergency department to the administration of andexanet alfa, the reversal of the short half-lives of the agents in plasma, 2,3 and the use of adjunct hemostatic interventions as they also relate to the coprimary outcomes.We agree with the authors' call for placebo-controlled trials to assess the antidotal efficacy of andexanet alfa and only hope that their preliminary report will not diminish the ethical feasibility of such studies.