Category Archives: Pharmacy

Andexanet Alfa – The Final Nail In The Coffin

January 5, 2026 The Trauma Pro Leave a comment

The number of patients requiring chronic anticoagulation has been increasing over the past five years. It was estimated that 7-8 million people were taking these drugs in 2020. Since then, the number of patients taking direct oral anticoagulants (DOACs) has skyrocketed, tripling. At the same time, the use of warfarin has dropped by nearly half.

There was significant concern in the early years of DOACs that they were irreversible agents. If an anticoagulated patient developed a bleed in a critical area (the brain, for example), it could become a fatal problem. Fortunately, the literature has borne out the fact that they appear to be safer than good old warfarin.

A reversal agent for rivaroxaban and apixaban was developed and approved in 2018 based on preliminary studies. A series of studies, named ANNEXA, was performed. The first two were ANNEXA-A and ANNEXA-R. These were Phase 3 trials conducted in healthy volunteers who were pre-treated with apixaban (ANNEXA-A) or rivaroxaban (ANNEXA-R). They showed reversal of “anticoagulation biomarkers” but did not assess clinical hemostasis.

Then came ANNEXA-4, which assessed patients with GI or intracranial bleeding. It monitored the same biomarker (anti-FXa) as before and noted decreased activity, with about 80% of patients achieving “excellent” or “good” hemostasis within 12 hours. However, 30-day mortality was high (15% for intracranial hemorrhage), and the incidence of thrombotic events such as stroke, DVT, PE, or MI was 10% over 30 days.

Finally, ANNEXA-I was a randomized study that examined spontaneous intracranial hemorrhage treated with andexanet alfa or the usual care (usually prothrombin complex concentrate). It found similar reductions in antiFX-a activity, and higher “effective hemostasis.” This is a fudgy number that allowed a comparison between the drug and usual care, yielding a 67% vs 53% efficacy in favor of andexanet alfa. This example was statistically significant but does not appear clinically significant. Offsetting this possible benefit was a higher number of thrombotic strokes and no change in 30-day functional outcome.

Andexanet alfa was approved based on its demonstrated effect on anti-FXa activity, not on efficacy. The company withdrew this drug just a few months ago because the series of ANNEXA studies showed minimal benefit and significant risk.

Bottom line: So what went wrong? We all focused on the mechanism. The drug clearly reduced anti-FXa activity, so it must be working, right? All too often, though, we find that treating the numbers doesn’t always solve the problem and may create more serious ones. Think tight glucose control in the ICU.

When we finally had enough data to see the high complication rates and lack of survival or functional outcome benefit, we could see it was time to pull the plug on this drug. The other major downside was its cost: about $20,000 per dose, and a second dose was nearly always required.

So it’s time to say goodbye to Andexanet alfa. Always remember: in clinical care, outcomes are more important than whether some arbitrary lab number is “fixed.”

Related posts:

Pharmacy

Drugs And Their Side Effects

July 22, 2025 The Trauma Pro Leave a comment

One of the cornerstones of allopathic medicine is the use of drugs to treat disease conditions. And unfortunately, one of the side effects of using drugs to treat problems is the production of side effects(!).

In trauma care, even something as simple as treating pain from an injury can create major problems. Give a narcotic pain medication. The patient gets nauseated and vomits. Try a different narcotic. The patient develops constipation. Give stool softeners and cathartics. Diarrhea. Then, pseudo-obstruction develops. Give neostigmine. The patient becomes bradycardic. Give… well, you get the picture.

How common are side effects? Very! Did anyone see the first TV commercials for Chantix, the smoking cessation drug? It was approximately 3 minutes long due to the lengthy list of side effects that were described. I’m surprised anyone was willing to risk them just to stop smoking cigarettes. Fortunately, it was pulled from the market in 2021.

A study looked at the number of side effects listed on the labels of 5,602 medications approved by the FDA. There was a grand total of 534,125 adverse drug effects described in the packaging. Some interesting statistics:

The number of adverse effects ranged from 0 to 525(!) for a single drug
The median number of adverse effects was 49, and the average was 70
Drugs with the most side effects are used in neurology, psychiatry, and rheumatology
Newer drugs had significantly more adverse effects than older ones

It’s certainly easy to bash pharmaceutical companies on their products. But some of these findings may be due to more rigorous testing and monitoring, as well as nuances in the populations in which these drugs are used.

Bottom line:

“There are no side effects, merely effects.”

Drugs are chemicals! Each chemical has a number of effects, some of which are desirable and some of which are not. Drug companies choose to market a drug based on one desired effect (e.g., control of nausea). Just remember, when you give that medication, you will probably get the desired effect, but you will just as likely also get some of the other 69 possible side effects. Be prepared, and prescribe sensibly.

Reference: A quantitative analysis of adverse events and “overwarning” in drug labeling. Arch Int Med 171(10):944-946, 2011.

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.

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