Tag Archives: DOAC

Best Of EAST #4: 4-Factor PCC vs Andexanet Alfa For Factor Xa Inhibitor Reversal

Falls are by far the most common mechanism of injuries in US trauma centers these days. They typically occur in elderly patients, and a growing number are on some type of oral anticoagulant for their medical conditions. And the number of these patients who are taking a DOAC (direct thrombin inhibitor or factor Xa antagonist) is rising quickly.

Unfortunately, most of the DOACs do not have good reversal agents, and they are very, very expensive. Specifically, Andexanet Alfa, the antidote for rivaroxaban and apixaban used to cost in excess of $50,000 per dose. This has come down over time to “only” $22,000 per dose. Unfortunately, the half-life is much shorter than the agent it is neutralizing, frequently requiring two doses. And the kicker is that there are no studies definitively showing that Andexanet Alfa improves mortality when used for CNS hemorrhage.

Prothrombin complex concentrate (PCC) has been used for reversal of these agents as well. Its efficacy is also not well known. The group at George Washington University is presenting an abstract comparing it against Andexanet Alfa (AA) for reversal of either of the Factor Xa inhibitors (rivaroxaban, apixaban). They performed a multicenter study involving 10 trauma centers. The endpoints studied were number of transfusions, mortality, and ICU length of stay.

Here are the factoids:

  • From a total of 263 patients, 77 received AA and 186 received PCC
  • Only 4% of patients received a second dose of AA despite its short half-life
  • There was no significant difference in the number of PRBCs transfused
  • The authors stated that the mortality was significantly lower with PCC but the p value in the data table provided was = 0.05
  • They also stated that the ICU LOS was significantly lower with PCC (1.2 vs 1.5 days, p = 0.04)

The authors concluded that PCC is non-inferior to AA for reversal in bleeding trauma patients. They recommended a randomized study be done.

Bottom line: The first thing for you to know is that I have never been impressed with the data on Andexanet Alfa. Which means I have to be very careful and aware of my own cognitive bias. In practice, this means I can’t just look at the study title or abstract and be happy that it meets my confirmation bias. I have to make a conscious effort to critically read the paper or abstract and see if it really does mean what I want it to mean, or if I need to change my opinion.

This abstract doesn’t really satisfy my confirmation bias. The title states that PCC is not inferior to AA. I would certainly like to believe that. But in order to safely say that, it is vitally important that a power analysis is performed to ensure that enough patients are present in both treatment groups to confidently state that there was no difference. If the number of patients is too small, significance can’t be detected and non-inferiority cannot be confirmed.

The body of the abstract claims that mortality was significantly lower in the PCC group, although the table states that the p value was 0.05, which technically is not significant. The difference in mortality numbers is impressive (PCC mortality 20% vs 32% for AA) so why the significance issue?

And one note about significance. Be careful not to conflate statistical significance with real-life significance. ICU length of stay in this study was statistically significantly shorter in the PCC group (1.2 vs 1.5 days) but I doubt that a difference of 7 hours in the ICU is clinically relevant.

Here are my questions for the authors and presenter:

  • Did you have enough patients in the study to assure that the PCC treatment was actually non-inferior? Please show us your power analysis.
  • What were the inclusion criteria for the study? This will help us understand the patient group better. Were these primarily head bleeds, actual external or intra-cavity hemorrhage?
  • Please clarify the significance claim for mortality. The raw percentages are impressively different, but the P value is not significant.
  • Could the low rate of administering a second dose of AA have influenced the outcomes? As mentioned above, the half-life of the antidote is much shorter than that of the DOAC. Perhaps giving a second dose is actually needed and could have moved the results in favor of AA.

This is a thought-provoking abstract for me. Let’s see if you can either confirm or refute my opinion on AA!


The Second Head CT In Patients Taking DOACs

Direct oral anticoagulant drugs (DOACs) are here to stay. When they were first released, I was very concerned with our inability to reverse them. I feared that we would have a rash of our elders presenting with severe head bleeds that we could do nothing about.

Well, that has not materialized. In fact, it appears that the probability of serious bleeding is more likely with our old reversible workhorse drug, warfarin.

But we are still spooked by DOACs. Nearly every center that has a practice guideline for managing patients with TBI on blood thinners includes a repeat CT scan after a given time interval. This is typically 6, 12, or even 24 hours.

Given the evolving safety profile of DOACs, is this even necessary? The surgical group at the Henry Ford Wyandotte Hospital in Michigan performed a retrospective registry review for their Level III trauma center. They reviewed the data for all adult patients who had suspected or confirmed blunt head trauma (any mechanism), were taking a DOAC, and received at least one CT scan.

Here are the factoids:

  • There were 400 patients with 498 encounters (yes, 15% came back with another TBI)
  • Patients were elderly (mean age 76) and nearly evenly split by sex
  • Fall was the most common mechanism (97%)
  • The first scan was negative in 96% of patients;12% of them did not have a repeat scan
  • Of the 420 patients who had a second scan, 418 were negative (99.5%). The two with positive scans were discharged uneventfully.
  • There were no differences based on specific DOAC, presenting GCS or mechanism

Bottom line: This is a relatively small, single institution study. However, it does appear that the authors have a large population of elderly patients suffering falls. This paper suggests that, indeed, a second scan may not be necessary. This parallels data from my own hospital. But to be on the safe side, keep an eye out for bigger, multi-institutional studies to be sure.

Reference: The utility of a second head CT scan af-ter a negative initial CT scan in head trauma patients on new direct oral anticoagulants (DOACs). Injury, article in press, June 13, 2021.

The July 2021 Trauma MedEd Newsletter Is Live! Yet More Potpourri

I’ve put together another issue of miscellaneous, interesting stuff!

In this issue, learn about:

  • The effect of ambulance deceleration on ICP in head injury patients
  • An interesting technique for sealing vacuum systems applied around external fixators
  • An analysis of thrombotic events following TXA administration
  • The utility of a second head CT in patients taking DOACs

To download the current issue, just click here!

Or copy this link into your browser: https://www.traumameded.com/courses/more-potpourri-july-21/

This newsletter was released to subscribers over a week ago. If you would like to be the first to get your hands on future newsletters, just click here to subscribe!


In The Next Trauma MedEd Newsletter: More Potpourri!

The July issue of Trauma MedEd will be sent out to subscribers near the end of the month. It will review some topics that I find very interesting, and I hope you will to.

This issue is being released to subscribers by July 30. If you sign up any time before then, you will receive it, too. Otherwise, you’ll have to wait until it goes out to the general public at the end of next week. Click this link right away to sign up now and/or download back issues.

In this issue, learn about:

  • The effect of ambulance deceleration on ICP in head injury patients
  • An interesting technique for sealing vacuum systems applied around external fixators
  • An analysis of thrombotic events following TXA administration
  • The utility of a second head CT in patients taking DOACs
  • And one or two more depending on space available!

As always, this month’s issue will go to all of my subscribers first. If you are not yet one of them, click this link right away to sign up now and/or download back issues.

Reversing Direct Oral Anticoagulants With Andexxa

I just finished a summary of the Australian consensus paper regarding anticoagulants (and anti-platelet agents) in patients with hemorrhagic TBI. One of the issues addressed was reversal of these agents. Today I’m going to provide more specific information on one of the new reversal agents, Andexxa (recombinant Factor Xa, inactivated-zhzo).

First, maybe someone can help me here. What does zhzo mean? I’ve done a deep dive including a review of the FDA filings, and still can’t figure out what this is. I have a hard enough time with the thousands of something-umab monoclonal antibody products out there. Now we’re adding on a bunch of z’s to the end of drug names?

There are currently two classes of direct oral anticoagulant drugs (DOACs) available, direct thrombin inhibitors 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 in patients taking apixaban or rivaroxaban if it was not possible to show that the drugs were non-therapeutic. This means that if your lab could not measure anti-Factor Xa levels in a timely manner and the patient was known to be taking one of these agents, reversal should be considered.

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 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 control of hemorrhage. 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 such time 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 but this has been revised downward. Effective in October 2019, Medicare agreed to reimburse a hospital about $18,000 for Andexxa over and above the DRG for the patient’s care. Remember, due to the half life of the Factor Xa inhibitors, two doses may be needed. 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 of the factors listed above and do the math for themselves. Given the growing number of patients being 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?


  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.