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Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients

Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients

Steph’s Note: After a midyear clinical break, we’re back with a clinical topic all of you have likely encountered on a daily basis. But did you take a moment to stop and dig into the what and why?

Along with the exciting, unusual disease states you may already be learning about, there’s also the piece I like to call “routine health maintenance” of the inpatient variety. Outpatient practitioners have all the excitement of keeping up with vaccines and preventative exams, but we inpatient people have health maintenance measures to take too! To ensure that you’re keeping track of this crucial piece of your patient workup, we’re going to take a moment to have this quick topic discussion.

You’re working up your new internal medicine patients on rotation. You’re investigating that meropenem, that sevelamer, and that pamidronate. Your patients have meningitis and pneumonia. SO much to learn. SO complex.

And then, BAM. Your preceptor asks you about VTE prophylaxis. And you’re like, ummm, but I know this cool new thing about meropenem? But they don’t let you off the hook. They want to know about that blood thinner.

Well darn.

To save you this awkwardness, let’s chat VTE prophylaxis.

What is VTE?

VTE stands for venous thromboembolism. Aka, a blood clot in the venous vasculature. VTEs may come in the form of deep venous thromboembolisms (DVTs), which may then travel from extremities to the blood vessels of the lungs and become lodged there. These are called pulmonary embolisms (PEs). No bueno.

The CDC estimates that about 900,000 Americans are affected by VTE each year, and more than 50% of these are thought to be related to a recent hospitalization or surgery (aka healthcare-associated VTE or HA-VTE). The period of risk for VTE is known to extend beyond the actual hospitalization. To add insult to injury, almost 100,000 people die each year from VTE.

And now the real kicker.

We can PREVENT these in an estimated 70% of cases. And yet, less than half of hospitalized patients receive preventative measures.

Why?!? What are we (NOT) doing, and WHY???

Risk Factors for VTE

Let’s think back to Virchow’s triad. Remember, these are the 3 big categories of patient factors that may predispose them to development of a clot.

Virchow’s Triad ( Image )

Virchow’s Triad (Image)

Within each of these categories, you can imagine all sorts of specific diseases that could contribute. For example, endothelial injury may come in the form of trauma or even damage to blood vessels from prolonged hypertension.

Hypercoagulability may be due to cancer, genetic clotting factor alterations (like factor V Leiden), medications (e.g., oral contraceptives), smoking, nephrotic syndrome, age, and so on!

Finally, stasis of blood flow may be due to immobility (the most obvious reason for this), but then there are less evident causes of blood stasis, such as obesity.

Assessing Risk of VTE in Inpatients

Does every person admitted to the hospital need VTE prophylaxis? If not, then how do we know when inpatients are at high enough risk to warrant preventative measures?

This 2017 study evaluated how often providers used formal clinical assessment tools to predict risk for VTE versus relying on clinical judgment.

Less than 60% of patients were appropriately risk-stratified when comparing scales with judgment. A whole bunch of people (182 or 240 who were low risk for VTE) received unnecessary drug, and some patients who were high risk didn’t receive any drug at all (although luckily no clinical VTEs were noted in that group).

Long story short, our judgement stinks, and we do the patient a disservice when we try to rely solely on it. We humans are faulty computers, and we should at least be trying to incorporate scales into our patient assessments.

Now which one is still the question…

We should at least  try  to do a smidge better than rolling the risk die. ( Image )

We should at least try to do a smidge better than rolling the risk die. (Image)

There are several risk factor scales that have been developed to try to make this easier to determine, including the Geneva Risk Score, the Caprini Risk Score, and the Padua Prediction Score. The Geneva Risk Score is potentially a more accurate prediction score than Padua based on this 2014 validation study, but it’s also longer and more labor intensive than the slightly older 2010 Padua Prediction Score. The Caprini Risk Score also didn’t do so hot on predicting risk of VTE in non-ICU medical patients in this 2016 study.

Clearly, this topic of risk assessment is a huge area of need! Based on the CDC’s numbers, we know our patients are at risk - and at risk for BAD outcomes - but we don’t precisely know how to pick out which patients are high enough risk for VTE to start preventative medication.

‘Tis a quandary!

But, since the 2012 CHEST Guidelines for VTE Prophylaxis in Non-surgical Patients references the Padua Prediction Score and it’s a little more user-friendly, that’s generally the one reached for first for medical non-ICU patients. Just know that it is not a perfect answer by any means, and it’s entirely possible for institutions to adopt alternative tools.

At this point, reading all of this about risk of VTE while hospitalized, you may be wondering why we don’t just give EVERYBODY preventative medications when they’re admitted… With that kind of incidence, what could possibly be the downfall??

VTE Prophylaxis

First think drugs, right!? We’re pharmacists, we like drugs!!!

No. Just no. Not always true.

Sequential compression devices (SCDs aka “scuds” aka “Ess Cee Dees”. We can’t make up our mind on pronunciation. ( Image )

Sequential compression devices (SCDs aka “scuds” aka “Ess Cee Dees”. We can’t make up our mind on pronunciation. (Image)

The first form of VTE prophylaxis is mechanical. Sequential compression devices (or pneumatic compression devices) are essentially booties that patients wear on their lower legs. They inflate and deflate in cycles to help move blood through the vasculature, thereby (hopefully) preventing clots.

Pretty low risk overall, so we generally use these if patients are at high risk of bleeding.

You can imagine just how much patients looooove wearing these while lying in a bed that’s also inflating and deflating all day. I’m sure people feel like science experiments with all the wires, tubes, people staring at them, and air compressors making noise. #rememberthepatientexperience

But still, if it helps to prevent a blood clot, maybe worth wearing…

Ok, now we can move to the drugs.

Speaking of, have you seen our handy Anticoagulant/Antiplatelet Cheat Sheet?

There are several options for VTE chemoprophylaxis. We’ll discuss each of them in terms of mechanism and then go through some of the pros and cons of each.

DISCLAIMER: Please note that dosing does in part depend on what population of patients you’re serving - medical or surgical - and here we’re just talking about your good ol’ gen med patients. We’re not going to get into all the different options for VTE prophylaxis after knee or hip surgery or after trauma because those are whole other blog posts!

The 3 options for VTE chemoprophylaxis in medical hospitalized patients are: unfractionated heparin (UFH), low-molecular weight heparin (LMWH), and fondaparinux.

Let’s just get a few principles straight.

  • All of these are anticoagulants. (I know, durrr, but I’m just setting the record straight in case anyone got lost in risk scales discussion above.)

  • All of these depend on a substance called antithrombin III (ATIII) to work, and all of them potentiate the action of antithrombin III. Just as its name implies, antithrombin works against blood clotting factors, most importantly thrombin (factor II) but also factors Xa, IXa, and XIa. So it’s basically a naturally-occurring anticoagulant (but not vitamin K dependent like proteins C and S) that helps to regulate the clotting cascade.

  • All of these have the same basic chemical structure: a core pentasaccharide sequence +/- a polysaccharide tail (more in a moment). The presence or absence of that tail affects the range of factor inhibition exhibited by each anticoagulant.

Alright, now that we have those things straight, let’s talk about mechanisms of action.

LMWH doesn’t have the lassoing skills that UFH does for capturing thrombin. And fondaparinux just isn’t in the roping game at all!  Also, win for finding a way to get a horse image into this post :) ( Image )

LMWH doesn’t have the lassoing skills that UFH does for capturing thrombin. And fondaparinux just isn’t in the roping game at all!

Also, win for finding a way to get a horse image into this post :) (Image)

The pentasaccharide core sequence of UFH binds to ATIII, increasing its affinity for binding (aka neutralizing) factor Xa - up to 1000 fold! But because UFH also has that really long polysaccharide tail, it can also wrap around and effectively capture/neutralize thrombin. (See panel A in the below pic). So UFH inhibits both thrombin and factor Xa in pretty equal ratios (aka 1:1).

Now let’s cut off some of that polysaccharide tail and make LMWH. This class includes enoxaparin and dalteparin. (But really, enoxaparin is the workhorse at most institutions.)

These products still have the pentasaccharide core sequence, so they’re still going to increase ATIII’s affinity for binding and neutralizing factor Xa.

But they don’t have the super long polysaccharide tail for capturing thrombin. Still sooooome action, but not quite so much (panel B below).

Therefore, the ratio of thrombin to factor Xa inhibition changes to be more like 1:2 or 1:4 depending on the product.

Then, finally we have fondaparinux. It is a synthetic version of the core pentasaccharide sequence. There is NO polysaccharide tail at all. What this means is that it neutralizes factor Xa ONLY because there’s no tail to wrap around thrombin (panel C below).

See how much structure-function relationship matters?! Not to mention it also just makes it way easier to remember how they work if you can recall their structures!

Yes, I left this mechanism of action image ginormous. Because if you take nothing else away from this post, remember this! ( Image )

Yes, I left this mechanism of action image ginormous. Because if you take nothing else away from this post, remember this! (Image)

Now that we know how they work, let’s move to comparing the options and talking pros and cons.

For more info, check out  this article  about dosing in extremes of weight and  this article  about pharmacology.  SC = subcutaneously  HIT = heparin-induced thrombocytopenia

For more info, check out this article about dosing in extremes of weight and this article about pharmacology.

SC = subcutaneously

HIT = heparin-induced thrombocytopenia

There are a few major points to pull out from this chart when considering pros and cons:

  • Dosing according to weight is necessary for all options to ensure optimal protection.

  • They are all injections. As such, patients can and will refuse them throughout their admissions. Which takes us back to SCDs, if patients are willing to wear them. You can see how this can get complicated.

  • Heparin is our drug of choice for prophylaxis in the setting of renal impairment. It’s also the quickest on, quickest off of all the meds, which can be useful in the setting of anticipated procedures or surgeries. (Unfortunate with the current drug shortage, eh?)

  • Heparin also carries the highest risk of a potentially serious adverse effect: heparin-induced thrombocytopenia or HIT. So if a patient qualifies based on weight and renal function for an alternative, why not switch them to a lower risk medication. Also, watch those platelets… And if your patient has a noted history of HIT, avoid both heparin and enoxaparin in favor of using synthetic fondaparinux.

  • Heparin requires more injections/day. #rememberthepatientexperience and save those sticks! (Not to mention that drug shortage again too…)

  • Anti-Xa levels are a way to gauge anticoagulant effect (not concentration of the medication itself). Although they’re not routinely necessary for most patients on enoxaparin or fondaparinux, consider obtaining when concerned about adequate protection (or over-treatment) in extremes of body weight or borderline renal function scenarios. Each medication has a specific goal range for protective anti-Xa levels.

  • This isn’t in the chart, but to make sure you’re still reading… Heparin and enoxaparin are both biologically sourced, which is a nice way of saying they’re made from pig intestines. So if your patient has a pork allergy, a history of alpha-gal, or even a cultural/religious desire to avoid porcine products, you’ll need to (again) look to fondaparinux.

    • See how much potential reliance there is on fondaparinux because it’s synthetic? But also notice its particular limitations in extremes of body weight or diminished renal function? So what do we do if a patient has an alpha gal allergy but also has an acute kidney injury?? And you thought VTE prophylaxis was straight-forward…

Wrapping Up VTE Prophylaxis

So as you hopefully can see by now, VTE prophylaxis isn’t necessarily the routine, straight-forward entity we’d all like it to be in comparison to the other complex medical issues our patients face while admitted. It’s imperative that you actively keep this on your radar when monitoring your inpatients to ensure that you’re adequately protecting from VTE without exposing to unnecessary or excessive bleeding risks.

( Image )

As you may also have noticed, we still have many unanswered questions about this topic.

In particular, who should receive chemoprophylaxis?

How do we ensure we choose these patients in a thoughtful, standardized, evidence-based way? (This isn’t duck duck goose!)

How do we dose and monitor in patients that don’t fit the studied populations?

What do we do when a patient’s characteristics preclude use of certain medications and force us to evaluate either no therapy or escalated therapy?

How long should we continue VTE prophylaxis - just in the hospital or even after discharge?

As a final teaser (since this post focuses really on the period of inpatient stay), check out the 2017 APEX trial about extended duration of betrixaban VTE prophylaxis after hospital discharge.

What will we see next?

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