Tag Archives: DOAC

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?

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.

AAST 2019 #6: DOACs Part 3!

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.

AAST 2019 #5: DOACs Part 2

In my last post, I reviewed a study that scrutinized reversal of direct oral anticoagulants (DOACs), and the outcomes of using various reversal agents. Today I’ll look at an abstract that compared in-hospital outcomes of elderly patients with severe TBI who were taking a variety of anticoagulant drugs, including DOACs.

The group at St. Joseph Mercy Hospital in Ann Arbor reviewed the dataset from the Michigan Trauma Quality Improvement Program database over a seven year period. To be included, patients needed to be at least 65 years old, suffer a fall, and have a significant head injury (AIS > 3). The final data consisted of records from 8312 patients treated at both Level I and II trauma centers across the state.

Here are the factoids:

  • 40% of patients were taking antiplatelet agents, 13% warfarin, 4% DOAC, and the remaining half or so were taking nothing.
  • The head injuries were severe, with mean AIS of 4.
  • After adjusting for “patient factors”, mortality or hospital outcomes were 1.6x more likely when warfarin was used
  • Complication risk increased 1.4x for warfarin and 1.3x for antiplatelet patients, but not for DOACs
  • Hospital length of stay was a day longer in the warfarin group (6.7 days) vs about 5.7 in the others

The authors concluded that elderly patients with severe TBI on DOACs fared better than those on warfarin. They stated that this could help alleviate concerns about DOACs in head trauma patients.

This is yet another interesting and surprising piece of the TBI on anticoagulants puzzle! It is obviously limited due to its retrospective database nature, which prevents us from asking even more interesting questions of this dataset. And it completely prevents us from looking at the specifics of each case including decision making, imaging, etc. But it’s a good start that should prompt us to find even better sources of data to tease out the details we must know in order to improve this patient group’s care.

Here are my questions for the presenter and authors:

  • I am very interested in the “patient factors” that were adjusted for to try to normalize the groups. Please describe in detail the specific ones that were used so we can understand how this influenced your results.
  • This information is intriguing, suggesting that warfarin is more evil that DOACs. What is the next step? What shall we do to further elucidate the problems, and how can we ameliorate the mortality and complication effects?

This is more good stuff about DOACs, and I can’t wait to hear the details.

AAST 2019 #5: DOACs Part 1

A short while ago I wrote about the proper nomenclature of the new or novel oral anticoagulant medications that are replacing warfarin in patients with atrial fibrillation (click here for details). Cut to the chase, the consensus seems to be that they should be called direct oral anticoagulants or DOACs.

These medications strike fear into the average trauma professional, primarily because there is no easy way to reverse them as there is for warfarin. We are finally accumulating enough experience with them to start to see the bigger picture with respect to complications and mortality. Today, I’ll begin the discussion with a series of three abstracts regarding these drugs.

The AAST conducted a multicenter, prospective, observational study that collected DOAC trauma patient information from 15 centers. They reviewed four years of data, specifically examining the use of reversal agents and mortality.

Here are the factoids:

  • A total of 606 patients were enrolled. They were generally elderly with an average age of 75.
  • Most were taking one of the Factor Xa inhibitors (apixaban, rivaroxaban, edoxiban), while just 8% were taking the direct thrombin inhibitor dabigatran.
  • Only 1% of patients received a reversal agent (prothrombin complex concentrate (PCC) 87%, Praxbind (12%), and Andexxa (1%)
  • Those receiving reversal tended to be older than the average and had more severe head injuries
  • Patients who were reversed with PCC had no change in mortality using a regression model
  • Patients reversed with Praxbind or Andexxa had a 15x higher probability of mortality

The author’s conclusions merely restated their results.

This is fascinating information. Unfortunately, this study was not designed to provide a comparison with patients taking warfarin. However, my next two abstract reviews will cover this very topic. 

There are two interesting tidbits here. First, reversal was only carried out in about one in eight patients. Why is this? No protocol? No product? Too pricey? Patients not hurt badly enough? And how would that be judged anyway?

The second is that reversal with PCC seems to be benign, but use of one of the specifically designed reversal agents really jacked up mortality. These agents (Praxbind and Andexxa) are very expensive ($3.5K and $50K respectively). Furthermore, there are no studies anywhere that show their effectiveness. This one actually seems to show they might be dangerous.

The devil is in the details. Here are my questions for the presenter and authors:

  • Were there any guidelines for reversal? This is key because if not, the statistics just describe “how we do it.” Yes, you can tease out higher ISS or AIS head as potential reasons, but were there directions regarding this built into the study protocol?
  • Do you have any data on the success rates of PCC reversal? Were there provisions to demonstrate lesion stability vs progression after administration?
  • Do you have an impression of why the tailored reversal agents seemed to be so deadly? Were they used as a last resort due to cost. Did the centers have a hard time getting it or authorizing its use?

This abstract could be a gold mine!

Reference: The AAST prospective, observational, multicenter study investigating the initial experience with reversal ofnovel oral anticoagulants in trauma patients. AAST 2019, Oral Paper 58.