Category Archives: Pharmacy

Is Daily Enoxaparin Dosing As Good As Twice Daily?

Venous thromboembolism (VTE) remains a big problem for trauma professionals and the patients they take care of.  Every trauma center has some sort of VTE prophylaxis protocol for stratifying risk, prescribing mechanical or pharmacologic prophylaxis, and monitoring effectiveness.

This is all well and good for patients in the hospital. But what happens once they go home?  Who needs to continue chemoprophylaxis? For how long? And what product? These are all tough questions, and are not usually part of the protocol. It is an important issue, and I’d like to address the last question in this post.

Typically, patients who need ongoing chemical prophylaxis after trauma are sent home on a low molecular weight heparin product. This is usually enoxaparin. As you know, this drug has two possible dosing regimens for prophylaxis: 30 mg subq twice a day or 40 mg subq once a day.

Now, nobody likes to give themselves a shot, ever. But if one has the choice between once a day vs twice, I think it’s safe to say everyone would pick the single dose. But it just doesn’t seem right that 60 mg spread out over two doses is just as effective as 40 mg once a day. Unless, of course, we are radically overdosing on the twice a day regimen.

So is the one-a-day regimen as good as twice a day? There is older support in the orthopedic surgery literature that it is. However, general trauma patients are probably at higher risk than those old studies would suggest. The trauma group in Gainesville FL looked at this question. They had been using the once a day dose for years, then changed to twice daily administration. They performed a retrospective study of their experience.

Here are the factoids:

  • The authors excluded the extremes of injury: patients admitted for < 2 days, or death within 2 days
  • There were 409 patients in the once daily group and 278 patients with twice daily dosing
  • About 3% of patients with once daily dosing developed VTE vs only 1% in the twice daily group
  • Bleeding complications occurred in 1.8% of the once daily group vs 2.7% in the twice daily group
  • Neither of these results was statistically significantly different

Bottom line: Although the authors try to imply that twice daily dosing “may be more effective” than once daily, they do admit that the statistics don’t show that. Unfortunately, the study design makes it nearly impossible to derive any firm results. It is a retrospective study designed long after the actual patient care, and does not take into account anything other than rudimentary risk stratification. 

My take on the topic is that it is unlikely that once daily dosing is as good as twice daily. Unfortunately, we just don’t have any literature to support that yet. Until we do, I recommend that you take a close look at your individual patient’s risk for VTE, and err on the side of giving enoxaparin twice daily until we know better.

Reference: Once- Versus Twice-Daily Enoxaparin for Venous Thromboembolism Prophylaxis in High-Risk Trauma Patients. J Intensive Care Med 26(2):111-115, 2011.

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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?


  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.
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How Many Salt Tabs In A Liter Of Saline?

Seems like a simple, silly question, right? I dare you to figure it out without reading this post!


On occasion, our brain injured trauma patients have sodium issues. You know, cerebral salt wasting. Trying to maintain or regain the normal range, without making any sudden moves can be challenging. There are a lot of tools available to the trauma professional, including:

  • Saline
  • Hypertonic saline
  • Salt tablets
  • Fluid restriction
  • Some combination thereof

Fun times are had trying to figure out how much extra sodium we are giving with any of the first three items. This is important as you begin to transition from the big guns (hypertonic), to regular saline, and then to oral salt tabs.

Below is a quick and dirty conversion list. I won’t make your heads explode by trying to explain the math involved changing between meq, mg, moles, sodium and sodium chloride.

  • The “normal saline” bags we use are actually 0.9% saline (9 gm NaCl per liter)
  • Hypertonic saline can be 3% or 5% (30 gm or 50 gm per liter)
  • Salt tabs are usually 1 gm each (and oh so yummy)

Therefore, a liter of 0.9% normal saline is the same as 9 salt tabs.

A liter of 3% hypertonic saline is the same as 30 salt tabs. The usual 500cc bag contains 15.

A liter of  5% hypertonic saline is the same as 50 salt tabs. The usual 500cc bag contains 30.

To figure out how many tablets you need to give to match their IV input, calculate the number of liters infused, then do the math! And have fun!

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What Should We Call Them? NOAC vs DOAC

They are the bane of trauma professionals, the anticoagulants that cannot be easily or cheaply reversed. Yes, I’m talking about the direct thrombin inhibitors and the Factor Xa inhibitors. They were originally called NOACs, or novel oral anticoagulants since they were newer than the old standard, warfarin. But they’ve also been listed as DOACs (direct) or TSOACS (target-specific, just rolls off the tongue doesn’t it?).

Here’s a nice table I put together recently showing the all the common oral agents available. Click the image for a full-size, more readable image.

Dabigatran was the first of the newer oral agents, and it is the only direct thrombin inhibitor in the group. The rest are Factor Xa inhibitors. This is easy to remember if you look at their generic name. Each will contain “xaban.” Get it? Xa ban.

The daily cost of warfarin is about $7, while the daily cost of the others is around $16 per day. However, that does not take into account the cost of blood work to monitor INR in those taking warfarin, so it’s cost will be higher.

What I found most interesting was the cost of the reversal agents, if any. For warfarin it’s either a hit of 4-factor prothrombin complex concentrate or many bags of plasma. Praxbind for the DTI dabigatran appears to be a bargain! But look at the agent for the Xa inhibitors, Andexxa! Almost $50K per pop!

And what about the asterisk, you ask? That means that there is no literature available that shows that these expensive drugs are clinically effective! But they seem like they should work. Hmm.

Anyway, back to the nomenclature. NOACs or DOACs? Opinion is moving away from NOAC because it can be misinterpreted as “no anticoagulants.” The International Society on Thrombosis and Haemostasis polled their members, and the consensus opinion was that DOAC should be adopted for common use.  They add that the specific mechanism of action (direct thrombin vs Xa inhibitor) should be specified in addition to the DOAC acronym when clinically relevant.

Bottom line: DOAC wins! So hopefully we can all converge on using one common term for this group of drugs. Yet I still shudder when I have a head injured patient that tells me they are taking any of them!

Reference: Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH.  J Thrombosis Haemostasis 13(6):1154-1156, 2015.

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Platelet Transfusion In Patients Taking Anti-Platelet Drugs

These days, trauma professionals see quite a few patients who take antiplatelet agents for cardiovascular comorbidities. These drugs can be problematic when the patients sustain injuries that result in bleeding in problematic areas like the cranial vault.

Aspirin and clopidogrel are the most common medications, and they irreversibly inhibit platelet aggregation.  All exposed platelets essentially quit working for the remainder of their 10-day lifespan. Platelet aggregation improves slowly over time after cessation of the drug as new platelets are added to the circulation from the bone marrow.

But what can you do if you are concerned that your patient is bleeding after injury because their platelets are not working? It seems logical that you would just transfuse some new platelets. But you should know by now that not everything that makes sense really works. A group in France designed a study to test this premise in patients taking either aspirin or clopidogrel. They performed a prospective, observational study on patients presenting with potentially life-threatening hemorrhage.

The authors used the Verify Now device to measure platelet response to the two drugs. Patients who had normal platelet function in the first place (not compliant or not a responder to the therapy) were excluded. All patients had initial platelet counts greater than 100K/ml. They underwent platelet transfusion for management of hemorrhagic shock, intracranial hemorrhage, or an emergent neurosurgical procedure.

Here are the factoids:

  • Only 25 patients were enrolled during the three year study; 13 were receiving only aspirin, 8 clopidogrel only, and 4 combined therapy
  • Average transfusions were 1-2 apheresis packs of platelets (6-12 units)
  • For aspirin patients, all showed significant platelet dysfunction before transfusion, and all but one showed recovery of function post-transfusion
  • For clopidogrel patients, platelet function remained impaired; the percent of inhibited platelets decreased but remained above the study threshold for “normal” of 20%

Bottom line: This is a very small study, but drives home the point that clopidogrel and its relatives may be problematic in bleeding patients. The active metabolites of this drug class are not well understood. But they are most likely still circulating in the blood in patients actively taking them, and deactivate new platelets as soon as they are transfused (assuming that the transfused platelets have good function in the first place). 

This issue requires further study so we can really tease out the actions of the drugs and their effect on transfused platelets. Until then, carefully consider whether platelet transfusion will be helpful in your bleeding patients, and if it is even worthwhile giving them or waiting for them to finish prior to going to the operating room.

Reference: Is platelet transfusion efficient to restore platelet reactivity in patients who are responders to aspirin and/or clopidogrel before emergency surgery? J Trauma 74(5):1367-1369, 2013.

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