Category Archives: Pharmacy

Direct Oral Anticoagulant (DOAC) Reversal: Part 3

January 28, 2025 The Trauma Pro Leave a comment

In my last two posts, I reviewed some older papers on the efficacy of Andexxa (andexanet alfa) for the reversal of Factor Xa inhibitor anticoagulants. Those results were not very impressive, especially considering the high cost of this drug.

In 2021, an article was published (reference 1) that performed a systematic review of the literature from 2017 to 2020. It concluded that “available evidence does not unequivocally support the clinical effectiveness of andexanet alfa or prothrombin complex concentrate to reverse factor Xa inhibitor-associated acute major bleeding.” This is a very roundabout way of saying that it didn’t really work. The authors also set out to perform a meta-analysis but could not do so, given the data’s low quality.

However, 2024 was a banner year for systematic reviews of this type of study! Four of them with meta-analyses were published comparing andexanet alfa (AA) with 4-factor prothrombin complex concentrate (PCC). And to keep it confusing, the conclusions were highly variable. Results were evaluated based on successful anticoagulation (hemostatic efficacy), mortality, and thrombotic complications. I also closely reviewed the conflict of interest information if any of the authors had any relationship to AstraZeneca, which owns both AA and the anticoagulant it reverses (Andexxa).

The results were very interesting. Here is a table that condenses the key points.

Reference #	Hem. Effic.	Mort.	Thrombosis	Conflict
2	AA better	No diff.	AA higher	No
3	—–	No diff.	AA higher	No
4	No diff.	No diff.	AA higher.	Yes
5	AA better	AA lower	No diff.	Yes

Many of the same original studies were analyzed in more than one of these reviews. And unfortunately, the results and confidence intervals were mysteriously a bit different in each review.

I specifically highlighted the efficacy and thrombosis results in red in Paper #4 because the authors stated that the efficacy of AA was qualitatively higher and the thrombotic complications the same. But their analysis in the body of the paper suggested otherwise. These were qualitative trends and are overhyped in the section most people read in PubMed, the abstract. My red text reflects how the abstract should have read. This is very misleading.

I also find it interesting that paper #5, with five of the nine authors either employed by or speaking for the company, was the only one that found the AA mortality lower and the thrombotic events no different than PCC. I believe this represents significant bias, and I find it hard to believe that the authors would be allowed to publish a negative or even neutral study about a drug that their company owns.

Bottom line: Who to believe?

Restoring clotting: Most of these studies indicated that andexanet alfa may restore hemostasis more effectively.

Preventing death: This drug doesn’t appear to reduce mortality, which is the outcome we are most interested in when treating these patients.

Thrombotic complications. These do seem to be more common when AA is given.

And even after ten years, cost is still a major consideration. The average cost of a course of treatment in 2023 was $26,787 (ref 6). Can we justify such an expense if it doesn’t seem to save lives? This is a decision that you and your hospital administration will have to work out. At least until much, much better data comes along.

References:

Andexanet Alfa or Prothrombin Complex Concentrate for Factor Xa Inhibitor Reversal in Acute Major Bleeding: A Systematic Review and Meta-Analysis. Crit Care Med. 2021 Oct 1;49(10):e1025-e1036. doi: 10.1097/CCM.0000000000005059. PMID: 33967205.
Efficacy and Safety of Andexanet Alfa Versus Four Factor Prothrombin Complex Concentrate for Emergent Reversal of Factor Xa Inhibitor Associated Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Neurocrit Care. 2024 Oct 8. doi: 10.1007/s12028-024-02130-y. Epub ahead of print. PMID: 39379749.
Andexanet alpha versus four-factor prothrombin complex concentrate in DOACs anticoagulation reversal: an updated systematic review and meta-analysis. Crit Care. 2024 Jul 5;28(1):221. doi: 10.1186/s13054-024-05014-x. PMID: 38970010; PMCID: PMC11225147.
Andexanet Alfa versus Four-Factor Prothrombin Complex Concentrate for the Reversal of Factor Xa (FXa) Inhibitor-Associated Intracranial Hemorrhage: A Systematic Review of Retrospective Studies. J Clin Med. 2024 May 24;13(11):3077. doi: 10.3390/jcm13113077. PMID: 38892788; PMCID: PMC11173120.
Andexanet alfa versus PCC products for factor Xa inhibitor bleeding: A systematic review with meta-analysis. Pharmacotherapy. 2024 May;44(5):394-408. doi: 10.1002/phar.2925. Epub 2024 May 9. PMID: 38721837.
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Complications, Pharmacy

Direct Oral Anticoagulant (DOAC) Reversal: Part 2

December 24, 2024 The Trauma Pro Leave a comment

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

December 20, 2024 The Trauma Pro Leave a comment

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:

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.

Pharmacy

What’s With Those Capital Letters In Drug Names?

May 31, 2024 The Trauma Pro Leave a comment

Call me slow. I’ve subconsciously seen those capital letters in drug names for years. But I never really paid attention or thought much about them. For whatever reason, I just now realized that they are EVERYwhere!

So I decided to investigate. Technically, they are called tall man letters. Here are some examples:

Certain parts of the drug name are capitalized to highlight differences from a drug with similar spelling. Note the similarities of the drugs in each row, and how the capital letters set them apart.

Studies from 20 years ago have shown that drug names are easier to distinguish using tall man letters. From a practical standpoint, fewer medication errors occur when tall man letters are used.

This technique is now used on preprinted pharmacy labels, and in electronic medical record systems. Surveys have shown that half of respondents have used tall man lettering in conjunction with pharmacy labels and medical records. Those found on labels were considered most effective, and those on preprinted order forms was least effective.

The use of tall man characters is now so pervasive that they are just part of the background. But a very important part. Now you (and I) know!

Reference:Tall man letters are gaining wide acceptance. P T. 2012 Mar;37(3):132-48. PMID: 22605902; PMCID: PMC3351881.

Abstracts, Pharmacy

Best Of AAST #5: Door-To-Prophylaxis Time

September 18, 2023 The Trauma Pro Leave a comment

Today’s abstract continues the theme of VTE prophylaxis. The authors introduce another timing parameter in this one: the “door-to-prophylaxis” time. Just as it sounds, this is the time interval between admission to the ED and initiating chemo-prophylaxis. Just like some centers struggle with how long to wait to start it after a solid organ injury (see previous post here), many find it challenging to get it ordered in the first place.

The authors retrospectively reviewed their registry data over four years. They compared adult patients who arrived as a highest-level of activation and received blood during their resuscitation. They were divided into two groups: those with DVT or pulmonary embolism (VTE group) and those without (no VTE group). The door-to-prophylaxis time was defined as the time from hospital arrival to the first dose of medication.

Here are the factoids:

Just over 2,000 patients met inclusion criteria, with 106 experiencing VTE and 1,941 without it
VTE patients had higher ISS (29 vs. 24), higher lactate levels (4.6 vs. 3.9), and more post-ED blood transfusions (8 vs. 2)
There was no difference in the need for dose adjustment or missed doses between the groups
Door-to-prophylaxis time was significantly longer in the VTE group (35 vs. 25 hours)
When controlling for age, sex, ISS, lactate, and post-ED transfusions, each hour of delay increased the likelihood of VTE by 1.5%

The authors concluded that the door-to-prophylaxis time was significantly associated with increased incidence of VTE. They suggest that the door-to-prophylaxis time should be utilized as a performance improvement metric for this condition.

Bottom line: Unfortunately, we need a lot more information here. There was not enough room for details about the statistical analysis in the abstract, but they will be essential to know. And the authors remind us that this study shows association, not causation.

Severe injury and blood transfusion are already known to be associated with a higher likelihood of VTE. The fact that the longer door-to-prophylaxis group had more frequent VTE may very well be due to their higher ISS and greater number of transfusions. Those events themselves may have led to the hesitation in starting a heparin.

Early prophylaxis is certainly a desirable goal in any trauma patient. But we need more than a new metric. We need more concrete information on the specific reasons for the delay and to prove that it is safe to give the drug early in patients who have those potential delaying factors.

Reference: “Door-to-prophylaxis” time as a novel quality improvement metric in preventing venous thromboembolism following traumatic injury. AAST 2023, Plenary paper #38.

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