Category Archives: Complications

TXA, Thromboembolic Events, And Mortality

I’ve visited several hundred trauma centers over the past 25 years, and recently I’ve begun to appreciate that there are two camps  when it comes to the use of tranexamic acid: the TXA believers and the TXA hesitant.

There have been a number of large studies that seem to suggest a benefit with respect to survival from major hemorrhage, particularly if given soon after injury (CRASH-2, MATTERs). This drug is dirt cheap and has been around a long time, so it has a clearly defined risk profile.

However, many of those hesitant to use it point to the possibility of thromboembolic events that have been sporadically reported. Several years ago, I did my own literature review and found that the number of thrombotic events from TXA was nearly identical to that of transfusing plasma.

JAMA Surgery just published a large systematic review, meta-analysis, and meta-regression that sought to examine the association between thromboembolic events (TE) in patients of any age and involving all medical disciplines, not just trauma.

The anesthesia group at the University Hospital Frankfurt in German did a systematic search of the Cochrane Central Register of Controlled Trials, as well as MEDLINE, for randomized controlled trials involving TXA. They covered all published studies through December 2020.

The authors adhered to standard guidelines for conducting reviews and meta-analysis (PRISMA). They specifically searched for outcomes involving TEs, such as venous thromboembolism, myocardial infarction or ischemia, limb ischemia, mesenteric thrombosis, and hepatic artery thrombosis. They also tallied the overall mortality, bleeding mortality, and non-bleeding mortality.

Here are the factoids:

  • A total of 216 eligible trials were identified that included over 125,000 patients (!)
  • Total TEs in the TXA group were 1,020 (2.1%) vs 900 (2.0%) in the control group
  • Studies at lowest risk for selection bias showed similar results

Bottom line: The authors concluded that IV TXA, irrespective of the dose, does not increase the risk of thromboembolic events. Period.

Hopefully, this is the final study needed to convince the TXA hesitant that it is safe to administer. They may still argue the efficacy, but at less than $100 per vial it is becoming impossible to ignore.

Reference: Association of Intravenous Tranexamic Acid With Thromboembolic Events and Mortality A Systematic Review, Meta-analysis, and Meta-regression. JAMA Surgery 156(6):3210884, 2021.

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Best Of AAST 2021: Comparing Two Different Doses Of Enoxaparin

Oh, look, my favorite topic! Prevention of venous thromboembolism (VTE) and complications. We’ve grown accustomed to using enoxaparin at the standard 30mg bid dose for a long time.  The orthopedic surgeons like to use 40mg qd, and there is some literature that shows this is reasonable for fracture patients.

The group at OHSU in Portland wanted to show that the single dose regimen is just as safe and effective as the bid dose. They performed a seven year, prospective, randomized trial of the two dose regimens. Weekly screening duplex exams were performed. The outcome measured was the occurrence of deep venous thrombosis (DVT) in the legs. They also examined missed doses, bleeding complications, and hospital length of stay.

Here are the factoids:

  • There were 267 total patients, 139 on the single dose regimen and 128 in the bid group
  • Average age was 49 and BMI was 28 in both groups
  • DVT occurred in 15 (11%) qd patients and 12 (9%) bid patients
  • Bleeding occurred in 19% of qd patients vs 14% of bid patients
  • There were fewer missed doses in the qd patients
  • None of the differences were statistically significant

The authors concluded that the qd dose was similar to the bid dose and is equally efficacious.

Bottom line: Hold on, now. First, this is a non-inferiority study. Daily dosing is presumed to be as good as twice daily dosing since there was no statistical difference seen between groups. This assumes that you have the statistical power (enough patients) to detect a difference. Is this the case here?

I pulled out my Sample Size calculator to check this over. I work things backwards to see the magnitude of difference that would have to be present for the given number of subjects. It looks like a sample size this small would only be able to detect a difference of 2x in the DVT occurrence result!

Lets look at this in simple terms. The absolute number of DVTs was actually higher in the qd group (11% vs 9%). So let’s say it is actually inferior to bid, meaning that the higher occurrence of DVT is real. Using the number of subjects here, the incidence could rise to 20% in the qd group and still not reach significance. 

The other major issue is the potential for selection bias. This study took place over 7 years. Yet only 267 were enrolled, or 38 patients per year. But this trauma center admits several thousand patients annually. If the enrollment criteria were so strict, the subjects probably don’t represent the general population. And if they weren’t, where did all the patients go? This is most likely a skewed study group.

I have lots of questions for the presenter and authors on this one!

  • Please show us your power calculations. Are you sure you have the statistical oomph to show non-inferiority?
  • Why did it take so long to accumulate 267 subjects? Show us the statistics for your overall trauma population to make sure they look the same.
  • Were you able to detect any other complications like pulmonary embolism?

Lots of questions here! Hopefully there’s much more information in the presentation!

Reference: A PROSPECTIVE RANDOMIZED TRIAL COMPARING TWO
STANDARD DOSES OF ENOXAPARIN FOR PREVENTION OF
THROMBOEMBOLISM IN TRAUMA. AAST 2021, Oral abstract 40.

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Best Of AAST: Delayed Treatment Of Blunt Carotid And Vertebral Injury

I recently published a series on blunt carotid and vertebral artery injury (BCVI). Today, I’ll review an AAST abstract that details the results of a multicenter study on the timing of medical treatment of this condition. This typically takes the form of anti-platelet agents, usually aspirin.

The trial collected prospective, observational data from 16 trauma centers. Patients had to receive medical therapy at some time after their injury or they were excluded. The stroke consequences of early vs late medical therapy were evaluated, where late was defined at > 24 hours.

Here are the factoids:

  • There were 636 BCVI included in the study
  • Median time to first medical therapy was 11 hours in the early group and 62 hours in the late group
  • ISS was higher in the delayed group (26 vs 22); although this was “statistically significant”, it is probably not a clinically significant difference
  • There was no increase in stroke rate with later administration of medical treatment

Bottom line: This is a very interesting study. We always worry about missing BCVI (see my previous post here), and now we know a little more about what happens if we do. The authors suggest that the stroke rate does not go up if medical management is delayed, say for some other potential bleeding issue.

This is a reasonably large data set, but the key thing to consider is the time frame observed. The median delay to medical management was only about 2.5 days. Were there any strokes involved in the patients with much longer delays? That is the real question. And were there any strokes that occurred despite early/immediate medical management?

The descriptive statistics and simple analyses presented do not provide all of the information we need. A stoke is a very significant adverse event for the patient. Statistical means are fine, but information on the specific patients who suffered one is necessary to truly understand this issue.

Here is my question for the presenter and authors:

  • Please break down the details on all patients who suffered a stroke. It will be very interesting to see if there were any in the early group and if there was a trend toward stroke in the very late tail data.

Reference: DOES TREATMENT DELAY FOR BLUNT CEREBROVASCULAR INJURY AFFECT STROKE RATE?: AN EAST MULTICENTERTRIAL. AAST 2021, Oral abstract #23.

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Treatment Of BCVI

In my last post, I reviewed the grading system for blunt carotid and vertebral artery injury (BCVI). Today, we’ll wrap up and discuss treatment.

There are basically three modalities at our disposal for managing BCVIantithrombotic medication (heparin and/or antiplatelet agents), surgery, and endovascular procedures. The choice of therapy is usually based on surgical accessibility and patient safety for anticoagulation. We do know that a number of studies have shown a decrease in stroke events in patients who are heparinized. Unfortunately, this is not always possible due to associated injuries. Antiplatelet agents are usually tolerated after acute trauma, especially low-dose aspirin. Several studies have shown little difference in outcomes in patients receiving heparin vs aspirin/clopidogrel for BCVI.

So what to do? Here are some broad guidelines:

  • Grade I (intimal flap). Heparin or antiplatelet agents should be given. If heparin can be safely administered, it may be preferable in patients who will need other surgical procedures since it can be rapidly reversed just by stopping the infusion. These lesions generally heal completely on their own, so a followup CT angiogram should be scheduled in 1-2 weeks. Medication can be stopped when the lesion heals.
  • Grade II (flap/dissection/hematoma). These injuries are more likely to progress, so heparin is preferred if it can be safely given. Stenting should be considered, especially if the lesion progresses. Long-term anti-platelet medication may be required.
  • Grade III (pseudoaneurysm). Initial heparin therapy is preferred unless contraindicated. Stable pseudoaneurysms should be followed with CTA every 6 months. If the lesion enlarges, then surgical repair should be carried out in accessible injuries or stenting in inaccessible ones.
  • Grade IV (occlusion). Heparin therapy should be initiated unless contraindicated. Patients who do not suffer a catastrophic stroke may do well with followup antithrombotic therapy. Endovascular treatment does not appear to be helpful.
  • Grade V (transection with extravasation). This lesion is frequently fatal, and the bleeding must be addressed using the best available technique. For lesions that are surgically accessible, the patient should undergo the appropriate vascular procedure. Inaccessible injuries should undergo angiographic treatment and may require embolization to control bleeding without regard for the possibility of stroke.

References:

  1. Scott WW, Sharp S, Figueroa SA, et al. Clinical and radiographic outcomes following traumatic Grade 1 and 2 carotid artery injuries: a 10-year ret-rospective analysis from a Level I trauma center. J Neurosurg 122:1196, 2015.
  2. Scott WW, Sharp S, Figueroa SA, et al. Clinical and radiographic outcomes following traumatic Grade 3 and 4 carotid artery injuries: a 10-year ret-rospective analysis from a Level 1 trauma center. J Neurosurg 122:610, 2015.
  3. Scott WW, Sharp S, Figueroa SA, et al. Clinical and radiological outcomes following traumatic Grade 1 and 2 vertebral artery injuries: a 10-year retrospective analysis from a Level 1 trauma cen-ter. J Neurosurg 121:450, 2015.
  4. Scott WW, Sharp S, Figueroa SA, et al. Clinical and radiological outcomes following traumatic Grade 3 and 4 vertebral artery injuries: a 10-year retrospective analysis from a Level I trauma center. The Parkland Carotid and Vertebral Artery Injury Survey. J Neurosurg 122:1202, 2015.
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How To Grade BCVI

In my last post, I reviewed the three screening systems for blunt carotid and vertebral artery injury (BCVI). Today, we’ll look at grading them.

Only 10 years ago, it was a major production to identify BCVI. CT angiography was still in its early days, and scanner resolution and radiologist experience were major issues that impacted accuracy.

We’ve come a long way in a relatively short period of time, and current day scanners now have more than adequate resolution. It’s also more common to have a radiologist with special skills reading these studies, the neuroradiologist. For these reasons, CT angiography has become the standard for diagnosis. It is also the most cost-effective. Only in very rare cases do we need to obtain a conventional contrast angiogram.

Once the study has been obtained, it’s time to identify and classify the injury. The Denver group is also responsible for bringing us the grading system for BCVI. See the diagram below.

Here are the details:

Grade I: A mild intimal irregularity is seen. Note the abnormally narrowed area, representing a small intimal injury, possibly with a small amount of clot.

Grade II: This grade has several presentations. There may be an intraluminal thrombosis/hematoma with (left) or without (right) an intimal flap, or a flap alone (center).

Grade III: There is a full-thickness injury to the vessel with a contained extraluminal extravasation (pseudoaneurysm)

Grade IV: The vessel is completely occluded by flap or thrombus

Grade V: The artery is transected and freely extravasating

Here’s a nice diagram:

Remember, we always grade things for a reason! Ultimately, the injury grade will translate into the selection of treatment. We’ll cover that in my next post.

Reference: Blunt carotid arterial injuries: implications of a new grading scale. J Trauma. 1999;47(5): 845-53.

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