All posts by The Trauma Pro

Complications, Pharmacy

Direct Oral Anticoagulant (DOAC) Reversal: Part 2

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In the previous post, I reviewed some basic information on DOAC reversal. Five years ago, it was costly and questionably effective. So what has happened in the meantime?

In this post, I’ll review a big trial the pharma company was excited about and make a few comments.

ANNEXA-I Study

This study sought to evaluate the hemostatic effect of Andexanet administration in patients taking a Factor Xa inhibitor who suffered an intracranial hemorrhage.

Key points in this study:

  • It was a five-year, multicenter, randomized controlled trial
  • Subjects had to have taken their medication within 15 hours of the event, had an intracranial hemorrhage identified by CT within 12 hours of symptoms, and randomized in the study within two hours after the scan
  • There were 263 patients reversed with Andexanet and 267 with “usual care,” which was not clearly defined aside from administration of prothrombin complex concentrate (PCC)
  • Traumatic ICH was only present in about 13% of subjects, and the average volume was about 10 mL. Most were intracerebral hemorrhages (90%), with 5% or less being subdural hematomas.
  • Andexanet treatment was associated with increased “hemostatic efficacy,” a combination variable consisting of volume change, change in NIH Stroke Scale score, and no need for rescue therapy within 12 hours.   There was also decreased hematoma volume change by 3.8mm (12%), an increased number of thrombotic events (10% vs. 6%), and an increased number of ischemic strokes (6.5% vs. 1.5%) at 30 days. There was no difference in deaths at 30 days.
  • Hemostatic efficacy was highest in intracerebral hemorrhages and nearly ineffective for subdural hematomas
  • Hemostatic efficacy was significantly higher than that of patients who received PCC in the “usual care” arm, but it was no better than usual care without PCC (?)

Bottom line: Wow! That’s a lot of numbers. The company was excited because the trial was stopped early due to “superior [hemostatic] efficacy vs usual care.” Basically, what they are saying is that the combination of hematoma size, stroke scale, and lack of need for other rescue therapy was significantly lower in patients treated with andexanet alfa. 

But is this meaningful in trauma? There are several issues, IMHO:

  • The study was not powered to detect mortality or functional outcome differences, which is what we trauma people are really interested in
  • The primary outcome (hemostatic efficacy) was powered mainly by hematoma size change, which is not of any clear clinical significance
  • There were some shenanigans from company involvement in the study design, with several protocol amendments that occurred
  • It was not clear what “usual care” consisted of other than PCC administration in some patients
  • There was no information on costs

In my next post, I’ll cite several systemic reviews and meta-analyses to come to some final conclusions about this drug.

Reference: Andexanet for factor xa Inhibitor–Associated acute intracerebral hemorrhage. N Engl J Med. 2024;390(19):1745-1755.

Pharmacy

Direct Oral Anticoagulant (DOAC) Reversal: Part 1

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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.
Complications

What Is: A Morel-Lavallee Lesion?

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Anyone who takes care of blunt trauma has seen the Morel-Lavallee lesion (M-L). Here’s an obvious one because it’s acute:

The M-L lesion is essentially a closed degloving injury in which the skin remains intact. The subcutaneous tissue is sheared off of the underlying fascia, and typically blood accumulates in the potential space that is created. This picture shows a less acute lesion; the bruising and ecchymosis on the surface have resolved. Note the collection on the lateral thigh:

These injuries may take a very long time to resolve and may leave some residual deformity. The definitive management has never been very clear: needle drainage vs incision, timing, compression wraps, etc.

The Mayo Clinic reviewed their 8-year experience with 87 of these lesions to try to shed some light on proper management. They treated their patients in four different ways: needle drainage, incision and drainage, compression wraps, and debridement with vacuum drainage devices. Here are the factoids from their study:

  • Motor vehicle crash was the most common etiology for this lesion, which makes sense due to the energy needed to shear the tissues
  • The most common locations were thigh, hip, and flank
  • The incidence of pre-existing conditions that might influence outcome (diabetes, obesity, smoking history, use of anticoagulants) did not seem to influence outcomes
  • Lesion location did not change the recurrence rate (even over joints)
  • Aspiration suffered the highest recurrence rate (56%) vs only 15-19% in the other groups
  • Aspiration of more than 50cc of fluid was more common in lesions that recurred (83%) vs those that did not (33%)

Their experience led them to develop the following practice guideline:

An incision and drainage procedure is not necessarily straightforward. Many of these wounds develop a pseudo-capsule if they are long-standing. Closure of the dead space can be challenging and may require quilting sutures or use of fibrin glue in addition to low suction drains. Some surgeons use sclerosing agents, either alone or in addition to the adjuncts listed above.

Bottom line: The Morel-Lavallee lesion can be challenging to treat. Although this study has limited numbers, it provides enough guidance to suggest a consistent way of managing it. I recommend adopting this algorithm to provide a standard pathway for dealing with it.

Reference: The Mayo Clinic experience with Morel-Lavallee lesions: establishment of a practice management guideline. J Trauma 76(2):493-497, 2014.

Complications, Solid organ

Low Grade Spleen Injury With Contrast Blush

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It is almost a given that low-grade solid organ injuries are relatively benign and seldom require any intervention. In fact, some trauma centers actually discharge these patients home from the emergency department.

But what about low-grade isolated spleen injuries with a contrast blush? Apparently, a few authors believe that this may be a benign condition that doesn’t require any specific management. This didn’t sit well with some, and a multicenter study was launched to look at this group more closely.

A retrospective cohort study involving 21 trauma centers was organized via the Eastern Association for the Surgery of Trauma. It enrolled adults (>18 years) with a grade I or II injury on CT scan after blunt trauma, which also demonstrated a contrast blush. Hemodynamically unstable patients and those who had clotting disorders or were taking any anticoagulant other than aspirin were excluded.

Here are the factoids:

  • Although 209 patients were enrolled over a nearly six-year period, 64 were removed due to meeting exclusion criteria or undergoing some intervention or laparotomy for other injuries
  • The remaining 145 patients were 66% men with an average age of 47
  • About one-third had a grade I injury, and two-thirds had grade II
  • 20% of these patients failed nonoperative management
  • These results were unchanged between grade I (18%) and grade II (21%)
  • Those who failed had a longer hospital stay (8 days vs. 5 days), had a higher likelihood of blood transfusion (55% vs. 26%) and MTP activation (14% vs. 3%)
  • There was no difference in discharge disposition or mortality

Bottom line: This study was conducted between 2014 and 2019. During that period, the AAST spleen and liver injury grading scales did not consider vascular injury. The 2018 update automatically upgrades injuries with blush or extravasation to Grade IV. This has a significant impact on how we view these injuries.

I have always said that any patient with contrast extravasation is bleeding to death until we stop it. The only exception is pediatric patients, who seem to clot these on their own. The 2018 update bore this out, and this paper confirms that low-grade anatomic injuries become dangerous if extravasation is present. I would also extend this to patients with a CT showing significant pseudoaneurysm formation.

So what should you do? If you have a patient with a spleen or liver injury that has contrast extravasation or a pseudoaneurysm, consider this a patient that needs hemorrhage control by interventional radiology under Standard 4.15 in the 2022 ACS Resources for Optimal Care of the Injured Patient. This means that you must let your IR team know that you have a patient who needs an intervention within 60 minutes, or you will need to transfer to a center with those capabilities as soon as possible.

Reference: Failure rates of nonoperative management of low-grade splenic injuries with active extravasation: an Eastern Association for the Surgery of Trauma multicenter study. Trauma Surg Acute Care Open. 2024 Mar 7;9(1):e001159. doi: 10.1136/tsaco-2023-001159. PMID: 38464553; PMCID: PMC10921525.

Complications

Incidental Appendectomy During Trauma Laparotomy?

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The debate over incidental appendectomy has waxed and waned over the years. And for the most part, it has nearly permanently waned in general surgical cases for now. But every once in a while, I am asked about incidental appendectomy during trauma laparotomy. Is it a good idea? What reasons could there possibly be for doing it?

In the old days, we would frequently do an incidental appendectomy because… well, just because we were there. The surgeon was in the midst of a general surgical case, typically an open one, and this normal little appendix was staring us in the face. The justification was usually, “We’ll save him/her another operation in the future in case he develops acute appendicitis.”

Legitimate reason? It took many years for the literature to develop, but it finally did. Here are the reasons we figured out not to do it:

  • Despite how innocuous a procedure seems, there is a measurable uptick in complication rates. This is true in the usual clean contaminated general surgery cases. Some papers also noted an increased mortality when the appendectomy was added to a cholecystectomy case. In a trauma procedure with bowel injury and contamination, it’s a bit harder to see the correlation. But any time we cut or staple something out, there is always the possibility that it might break down.
  • Cost increases in laparoscopic cases if additional ports and equipment are needed for the appendectomy. This doesn’t apply to major trauma cases since we better not be doing them laparoscopically!
  • The appendix is not the useless vestigial structure we initially thought. Evidence shows that it is a repository for the gut microbiome, which can help repopulate the colon with bacteria after a serious insult like prolonged antibiotic administration. Unnecessary removal may ultimately interfere with gut health and disease.

Can acute appendicitis develop after trauma laparotomy? Sure, at any time. Thankfully, it’s not very common. The presenting complaints are the same as we learned in the doctor books. However, the location of the pain and tenderness may not be in the classic location, depending on the post-trauma anatomy and presence of adhesions.

Bottom line: Incidental appendectomy is no longer indicated for just about anything, including trauma laparotomy. If one of your patients presents with abdominal pain at any time, both post-traumatic and other causes must be considered. CT has become the standard for appendicitis workup and is extremely helpful in sorting out causes in the post-op trauma patient. Use it, and if it is one of the rare cases where appendicitis is actually present, then proceed with the usual and appropriate operative on nonoperative management.

References:

  • Incidental appendicectomy with laparotomy for trauma. Br J Surg 62(6):487-9, 1975
  • Appendicitis following blunt abdominal trauma. Am J Emerg Med 35(9):1386.e5-1386, 2017.
  • Systematic review of blunt abdominal trauma as a cause of acute appendicitis. Ann R Coll Surg Engl 92(6):477-82, 2010.