The Great Reveal of Andexanet Alfa

The brave new world of “bleeding that doesn’t stop” is a little closer to ending today.  However, this is definitely just the smallest of baby steps in that direction – and hardly as straightforward and simple as the authors’ conclusion:

“Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects.”

This is ANNEXA-A and ANNEXA-R, two healthy-volunteer studies evaluating the utility of Andexanet Alfa for reversal of Factor Xa inhibitors.  Andexanet is a recombinant Xa decoy protein with a higher afinity for the Xa inhibitors than endogenous Factor Xa, having the net effect of restoring thrombin production.  In these studies, the 40-odd participants in each were housed at the study site for 8 days, loaded with either apixaban or rivaroxaban, and then assigned in a 3:1 or 2:1 ratio to receive either Andexanet or placebo.  Then, the participants were assigned to single-bolus dosing or bolus plus infusion.

The general gist of the outcomes is best visualized by the following graphic:

Andexanet, as expected, rapidly binds circulating Factor Xa.  However, there are two quite obvious, clinically important considerations.  First, reversal is very short-acting if only the bolus is given.  Then, it seems clear while the Factor Xa inhibitor is bound, it cannot be eliminated – and there is a rebound phenomenon to near-baseline levels once the infusion is stopped.  It appears this may be a very tricky drug to use in certain clinical scenarios, considering the duration of required reversal – especially if full and permanent effects are desired.

And, as noted before, this is just baby steps.  This handful of healthy volunteers did not have any specific adverse events related to the infusion, but the small numbers prevent any reliable conclusions regarding safety.  This is also just a pharmacokinetic study without clinical outcomes, and we don’t truly know its real-world effectiveness based on this publication.

It is quite an interesting innovation, but it still lands somewhere between “promising” and “minimally useful” – and almost certainly expensive.

“Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity”
http://www.nejm.org/doi/full/10.1056/NEJMoa1510991

1 thought on “The Great Reveal of Andexanet Alfa”

  1. There was, actually, one adverse event. one patient developed hives in response to this. Are we looking at a Vitamin K similar anaphylactoid response? How many people will react to this in the next trial? We'll see soonish.

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