In our Executive Summary examining the use of novel oral anticoagulants (NOACs) as a substitute for warfarin, we highlighted the lack of reversal agents or antidotes as a potentially significant disadvantage to their use. This lack was quickly appreciated by the medical community because NOACs were used more and more frequently and reports of adverse events emerged. Consequently, two possible reversal agents-andexanet alfa (andexanet) and ciraparantag-are now in various stages of development. In a phase III trial, andexanet alfa was shown to reverse the effects of two factor Xa inhibitors, apixaban and rivaroxaban.

It is important for neuroscience nurses to fully understand the scope and outcome of drug studies to place the results in clinical context. For example, in the andexanet alfa study, 145 healthy and mostly male (61%) adults with a mean age of 57.9 years enrolled in the study. Patients were randomized to the apixaban (ANNEXA-A) or the rivaroxaban (ANNEXA-R) arm. Patients received 3 days of factor Xa inhibition and then, again using randomization, received either intravenous andexanet alfa or placebo. The primary study outcomes, reduction of antifactor Xa and regeneration of thrombin, achieved statistical significance (p < .001) compared with placebo. On the basis of this study, and the mechanism of the drug, andexanet alfa received breakthrough therapy designation by the Food and Drug Administration. Yet, what is worth noting is that none of the study participants had atrial fibrillation, the main indication for the NOACs, nor bleeding, the most worrisome complication. A subsequent study enrolling 270 patients between now and 2022 attempts to answer the effectiveness of andexanet alfa in treating major bleeding events in adults receiving factor Xa inhibitors for therapeutic purposes. In this study, the primary outcome is termination of a bleeding event within 24 hours of andexanet alfa administration.

Three important points are worth noting about these and many other drug studies. First, most drugs are approved after testing on a very small subset of those for whom the drug is indicated. Second, postmarketing surveillance (phase IV) is designed to detect effects not apparent during new drug development. Finally, study outcomes must be carefully scrutinized, because proxy measures, such as the level of reduction of antifactor Xa, are imprecise measures of clinical effectiveness. Finally, we recommend that neuroscience nurses who are curious about publically and privately funded research around the world explore the clinical trials site of the National Institutes of Health (https://clinicaltrials.gov/) as well as the sources included in supplemental content that specifically address the development of NOAC antidotes (see Supplemental Digital Content 1, available at http://links.lww.com/JNN/A67).