A new class of anticoagulants, the direct oral anticoagulants (DOACs), were introduced in 2010.  I started writing about them more than five years ago and was initially pessimistic about their safety profile in patients with head injuries. However, reversal agents and/or protocols were introduced, and the literature has borne out the fact that they appear to be safer than the old stand-by warfarin.

The most recent DOAC reversal agent, Andexxa (andexanet alfa), was approved in 2018. Today, I will republish a post on this agent five years ago and a year after the FDA approved it.  In my next post, I’ll refresh and update the trial data and cost, and review several systemic reviews with meta-analyses to come up with a consensus on its usefulness.

Here’s the repost:

Two classes of direct oral anticoagulant drugs (DOACs) are currently available: direct thrombin and Factor Xa inhibitors. Andexxa was designed to reverse the latter by providing a lookalike of Factor Xa to selectively bind to apixaban (Eliquis) and rivaroxaban (Xarelto).

The Austrian consensus paper I previously discussed recommended giving Andexxa to patients taking apixaban or rivaroxaban if it was not possible to show that the drugs were non-therapeutic. This means that reversal should be considered if your lab could not measure anti-Factor Xa levels promptly and the patient was known to be taking one of these agents.

Sounds cut and dried, right? Your patient is taking a Factor Xa inhibitor, and they are bleeding, so give the reversal agent. Unfortunately, it’s much more complicated than that.

• The half-life of Andexxa is much shorter than that of the drugs it reverses. The reversal effect of Andexxa begins to wear off two hours after administration and is gone by four hours. On the other hand, the half-life of rivaroxaban is 10+ hours in the elderly. The half-life of apixaban is even longer, 12 hours. This means that it is likely that multiple doses of Andexxa would be necessary to maintain reversal.
• There are no studies comparing the use of Andexxa with the current standard of care (prothrombin complex concentrate, PCC). The ANNEXA-4 study tried to do this. It was a single-arm observational study with 352 subjects. These patients were given Andexxa if major bleeding occurred within 18 hours of their DOAC dose. Two-thirds of the patients had intracranial bleeding. All were given a bolus followed by a two-hour drip. All showed dramatic drops in anti-Factor Xa levels, and 82% of patients had good or excellent hemorrhage control. However, 15% died, and 10% developed thrombotic complications.
• The FDA clinical reviewers recommended against approval due to the lack of evidence for clinical efficacy. The director for the Office of Tissues and Advanced Therapies overruled the reviewers and allowed approval until a definitive study was completed. So far, there have been no justifiable claims that Andexxa is superior to PCC.
• To be fair, PCC has not been compared to placebo either. So, we don’t really know how useful it is when treating bleeding after DOAC administration.
• Andexxa is very expensive. Old literature showed a single dose price of $49,500, which has been revised downward. Effective October 2019, Medicare agreed to reimburse a hospital about $18,000 for Andexxa over and above the DRG for the patient’s care. Remember, two doses may be needed due to the long half-life of the Factor Xa inhibitors. This comes to about $36,000, which is much higher than the cost for PCC (about $4,000).

Bottom line: Any hospital considering adding Andexxa to their formulary should pay attention to all the factors listed above and do the math for themselves. Given the growing number of patients placed on DOACs, the financial and clinical impact will continue to grow. Is the cost and risk of this therapy justified by the meager clinical efficacy data available?

References:

1. Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors. NEJM 380(14):1326-1335, 2019.
2. Key Points to Consider When Evaluating Andexxa for Formulary Addition. Neurocrit Care epub ahead of print, 22 Oct 2019.