Tag Archives: DOAC

Head

The Second Head CT In Patients Taking DOACs

November 5, 2021 The Trauma Pro Leave a comment

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.

Pharmacy

Reversing Direct Oral Anticoagulants With Andexxa

December 17, 2019 The Trauma Pro Leave a comment

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?

References:

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

Abstracts, Complications

AAST 2019 #6: DOACs Part 3!

September 13, 2019 The Trauma Pro Leave a comment

A little further down the direct oral anticoagulants (DOACs) rabbit hole please? The abstract reviewed in my last post suggested that elderly patients taking these agents actually do better than those on warfarin. So if that’s the case, do we need to be so attentive to getting followup CT scans on these patients to ensure that nothing new and unexpected is happening?

The trauma group at UCSF – East Bay performed a multi-center review of the experience at “multiple” Level I trauma centers over a three year period. They included anticoagulated patients with blunt trauma who had a negative initial head CT. Patients taking only an anti-platelet agent or a non-oral anticoagulant were excluded. They analyzed the data for new, delayed intracranial hemorrhage, use of reversal agents, neurosurgical intervention, readmission, and death.

Here are the factoids:

A total of 739 records were studied: 409 on warfarin and 330 on a DOAC. Average age was 79, and half were male.
Repeat head CT was performed only half the time (!)
Delayed hemorrhage was noted in 4% of warfarin cases (9 of 224) and 2.5% of DOAC cases (4 of 159)
There were no interventions or deaths in the DOAC group with followup CT, or in those who did not have the repeat scan
There was 1 intervention in the warfarin group and two deaths attributed to TBI
Reversal agents were administered to 2% of DOAC patients and 14% of warfarin patients
The authors performed a regression analysis that showed the two strong associations with delayed hemorrhage were male sex and AIS head > 2 (!)

The authors concluded that this “largest study” suggests that DOACs “may” have a better safety profile compared to warfarin and repeat head CT is not indicated.

Now, hold on a minute!

Rule #1: No single published paper should ever change your practice. They need to be confirmed by other, hopefully better work.

Rule #2: No single abstract should make you even think about changing your practice! These are preliminary works that always need more detail, more effort, and a lot more thought. They are meant to telegraph what the authors are working on and to raise interesting questions from the audience. They should stimulate others to try to replicate and improve upon the work. In general, if something looks really good as an abstract, the next step is successful publication. This means that peers have reviewed the data and agree that it looks promising. But then it should take several years of work by the original authors and others to prove or refute the claims.

This study was small in the first place, and became smaller because half did not have repeat CT scans. The only statistically significant result was that we confirmed that the providers were not very good about getting followup scans. Just because they didn’t do it doesn’t mean it’s not indicated, especially given the nature of the data and the very small numbers.

I consider this another very small piece in the puzzle that suggests DOACs are not as evil as warfarin. There are several of these low power studies floating around right now. But we need to hunker down and really do a big study right so we can start to get a clearer picture of what we should do. For now, it’s best to treat all anticoagulants and anti-platelet agents as evil and err on the side of overtreating.

Here are my comments and questions for the presenter and authors:

Why was the followup head CT rate so poor? Was this a “however they like to do it” thing, was there a protocol, did the trauma centers just not believe that DOACs could be bad?
What were the guidelines for reversal? If the initial head CT was normal, why ever reverse? This suggests that participating centers could do whatever they wanted based on unspecified criteria.
Was the regression analysis helpful in any way? Being male and having a mild TBI seem rather nonspecific factors and wouldn’t help select patients for reversal or repeat scan.
Please provide more information on the warfarin intervention and deaths.
Isn’t the title of this abstract rather bold for the quality of the results presented?

I’m sure there will be some lively debate at the end of this presentation!

Reference: Repeat CT head scan is not indicated in trauma patients taking novel anticoagulation: a multi-institutional study. AAST 2019, Oral Abstract #66.

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