As a general surgery resident more than half-way through my training career, I have taken care of my fair share of trauma patients. However, the trauma patients I’m referring to aren’t the stereotypical victims of gun-shot and stab wounds seen on TV. One of my most common trauma patients is the frail 80-something year old woman on anti-coagulation for atrial fibrillation who fell down a few stairs and hit her head, chest or hip. In the past, most of these patients had been anti-coagulated with warfarin (Coumadin) which, although inconvenient, was able to be reversed with vitamin K or fresh frozen plasma (and more recently prothrombin complex concentrate) in emergency situations. Now though, many patients are being treated with the easier-to-use novel oral anti-coagulants (NOACs) such as direct thrombin inhibitors and factor Xa inhibitors that don’t require INR monitoring and frequent blood draws. While patients enjoy many of the benefits of NOACs, these newer agents came at a cost–the absence of a rapid reversal antidote can be deadly in the setting of trauma or bleeding.
Fortunately, recent clinical trials have shown efficacy for new antidotes to some of these NOACS. First a report on idarucizumab (Praxbind) for the reversal of dabigatran (Pradaxa), a direct thrombin inhibitor, was published in NEJM this past August. This has been followed by a report on andexanet alpha for the reversal of the factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eloquis), published Online First last month in NEJM by Siegal et al.
Andexanet alpha is a recombinant modified human factor Xa decoy protein that is able to bind to factor Xa inhibitors without interacting with other coagulation factors. Andexanet represents a novel approach to reversing NOACs. These proof-of-concept trials enrolled 145 healthy volunteers aged 50-75 and randomly assigned participants to receive a factor Xa inhibitor (apixiban or rivaroxaban) and either a placebo or andexanet (as a bolus or as a bolus plus 2 hour infusion).
Anti-factor Xa activity was rapidly reduced after administration of a bolus of andexanet in both apixaban and rivaroxaban groups as compared to placebo. The reversal lasted for about 2 hours, consistent with the known half-life of andexanet, before levels gradually increased to that of the placebo recipients. For the group receiving a bolus plus 2 hour infusion, andexanet had similar effect on restoration of factor Xa activity for andexanet compared to placebo. The effect lasted for 1-2 hours after completion of the infusion. All participants who received andexanet had an 80% or greater reversal of anti-factor Xa activity compared to none in the placebo group. There were no serious adverse events or thrombotic events reported.
There are several limitations to this study including a relatively young population with minimal comorbidities and normal creatinine. And although this represents a rigorous scientific study, it does not provide us with data regarding the real time use of andexanet in bleeding patients or patients undergoing emergency surgery. Additionally, as Jean Connors, from Brigham and Women’s Hospital, explains in the accompanying editorial, dosing of andexanet is not straight forward “potentially making use in the busy ER environment challenging, and concerning for under dosing the bleeding patient if clinically obtained information is incorrect.” “Despite these current knowledge limitations,” Dr. Connors concludes, “andexanet represents a giant step forward in our ability to control anticoagulation therapy.” NEJM Deputy Editor Dr. Dan Longo concurs adding, “Andexanet will likely be a useful tool for restoring hemostasis among patients on Factor Xa inhibitors who require immediate reversal. One unresolved issue is whether the development of non-neutralizing antibodies to andexanet among 16% of recipients will alter the agents’ pharmacology sufficiently to compromise efficacy should a second or subsequent event require repeated use.”
With a phase 3b/4 study underway to assess the clinical effectiveness of andexanet in patients on factor Xa inhibitors with major bleeding, we are moving closer to approval of another potential anti-coagulant reversal agent. Perhaps before I finish residency, there will be an FDA-approved reversal agent available for me to give to my bleeding trauma patients on apixaban or rivaroxaban.