Best of EAST #8: Reversing Antithrombotic Drugs After Severe TBI

Falls are the most common mechanism of injury at a majority of trauma centers these days. And due to the escalating number of comorbidities in our older population, more and more are taking some kind of anticoagulant or antiplatelet medication. And as all trauma professionals know, falling down and failure to clot do not mix well.

A variety of reversal regimens have been developed, including Vitamin K, plasma or platelet infusion, prothrombin complex concentrate, andexxanet, or idarucizumab depending on the agent. But when it comes to evaluating the efficacy of these agents, there are two important questions that need to be answered:

  1. Does the regimen reverse or neutralize the offending agent?
    and more importantly
  2. Does the regimen have a positive effect, i.e. reduce mortality and/or complications?

This last question has been problematic, especially for the direct oral anticoagulant drugs (DOACs). They are very expensive, but there has been little, if any, evidence that they improve mortality.

A study from the University of Florida at Jacksonville, and sponsored by EAST was performed last year. It was a multi-center, prospective, observational study of data provided by 15 US trauma centers. They collected data on the agents used, reversal attempts, and comorbidities in injured patients taking these drugs, and analyzed for head injury severity and mortality.

Here are the factoids:

  • There were a total of 2913 patients in the study, 46% on aspirin (ASA), 13% taking ASA and a P2Y12 inhibitor (one of the -grels), 11% on warfarin, 4% on ASA + warfarin, 13.5% on a Factor Xa inhibitor, and 6% on a Xa inhibitor + ASA
  • Patients on platelet blockers (P2Y12 inhibitor) had the highest mean ISS at 9
  • Warfarin was associated with a higher abbreviated injury score (AIS) for head, 1.2
  • Controlling for ISS, comorbidities, ISS, and initial SBP, warfarin + ASA had the highest head ISS with an odds ratio of 2.1 (with the lower confidence interval value of 1.19)
  • Reversal of antiplatelet therapy with DDAVP was not successful, with no change in mortality (87% with reversal and 93% without)
  • Reversal of Xa inhibitors with plasma or PCC was also unsuccessful with a mortality of 100% with reversal and 95% without

The authors concluded that reversal attempts for antiplatelet therapy or Factor Xa inhibitors did not decrease mortality, and shared the observation that combination therapies posed the most risk for severity of head injury.

My comments: Remember, the first thing to do is look at the study group. The authors did not share the inclusion or exclusion criteria for the study in the abstract, so we are a little in the dark here.

The next item that makes this study difficult to interpret (and perform) is the fact that nearly a quarter are on combination therapy for their anticoagulation. So even though nearly 3,000 patients were studied, many of the medication subgroups had only a few hundred subjects. The aspirin group was the largest, with 1,338. This makes me wonder if the overall study had the statistical power to find subtle differences in their outcome measures and support the conclusions.

Now have a look at one of the results tables:

In reviewing the demographic data, the concept of statistical significance vs clinical significance quickly comes to mind. Somehow, age, ISS, head AIS, mortality, and SBP are significantly different between some of the groups. Yet if you examine the specific values across most of the rows, there is little difference (e.g SBP ranges from 137 to 147, ISS from 7-9, mortality from 2-7%). These are all clinically identical. The only row that means much to me is the top one telling how many patients are in a group.

Here are my questions for the authors and presenter:

  1. Tell us about the study design, especially the inclusion and exclusion criteria. Were there any? How might this have influenced the study group?
  2. Please comment on your perception of the statistical power of the study, especially with seven groups of patients, each with relatively small numbers.
  3. Do you have information on the variety of reversal agents used? Were there any standards? Could this have contributed to the mortality in some of the groups?
  4. Do you have any clinical recommendations based on your findings? If not, what is the next step in examining this group of patients?

My bottom line is that I’m not sure that this study has the power to show us any significant differences. And looking at the information table and logistic regression results (odds ratio confidence intervals close to 1), I’m not really able to learn anything new from it. I’m hoping to learn a lot from the live presentation!

Reference: EAST MCT: comparison of pre-injury antithrombotic use and reversal strategies among severe TBI patients. EAST 2021, Paper 19.

Best of EAST #7: Whole Blood Plus 4-Factor Prothrombin Complex Concentrate

In my last post, I went through some of the basics of whole blood transfusion. However, the focus was more on compatibility than function. Today, I’ll review an abstract that explored functionality of that blood transfused.

In theory, whole blood contains the usual array of clotting factors. It has been shown that high factor levels persist in whole blood, even when stored at room temperature. So in theory, additional clotting factor infusion should not be necessary.

The group at the University of Arizona explored adding 4-factor prothrombin complex concentrate (4-PCC) to whole blood transfusion. The scanned three years of data in the TQIP database. They identified two groups of patients, those who received whole blood alone and those who received 4-PCC in addition to it. They were interested in the impact on total product transfused and the usual crude outcomes of hospital / ICU length of stay and mortality.

Here are the factoids:

  • Only 252 patients in this entire database (tens of thousands of records in three years) received whole blood, and 84 of them also received 4-PCC
  • The patients tended to be young (average age 47), 63% male, with moderate (median ISS 27), and blunt injury in 85%
  • Administration of 4-PCC was associated with a significantly decreased transfusion requirement of both blood (5 vs 8 units) and plasma (3 vs 6 units), but not platelets
  • ICU LOS was significantly lower in the 4-PCC group (5 vs 8 days), but there was no difference in hospital stay or in-hospital mortality

The authors concluded that 4-PCC given with whole blood was associated with a decrease in transfusion requirements and ICU length of stay, and that further studies were needed.

My comments: Well, this is certainly interesting and unexpected.  Why would a clinician even think of giving 4-PCC when giving whole blood? It looks like a very rare occurrence in the dataset. Unfortunately, we can never find out. We can’t just go back and look in the charts. Perhaps these centers were using TEG or ROTEM during the resuscitation?

As always in these big databank analyses, the researchers can only control for the variables they can think of that are already present in the database. Although they were able to match the patient groups for the usual demographics, vital signs, injury patterns, comorbidities, and trauma center level, it is entirely possible that there were other factors in play.

Here are some questions for the authors and presenter:

  • Why did you choose to do this study? Was there some clinical question that arose that triggered it? Something you found in the literature that suggested it?
  • How do you explain the results, given that the factors in 4-PCC have been shown to persist at functional levels in whole blood? Why do you think less blood and plasma were needed?
  • What needs to happen next? I agree that more research is needed to see if this association is real. How would you go about doing it?

Thanks for a very intriguing paper! Details will follow, I’m sure.

Reference: Four factor prothrombin complex concentrate in adjunct to whole blood in trauma-related hemorrhage: does whole blood replace the need of factors? EAST 2021, Paper 18.

Best of EAST #6: Does Rh Status Matter In Whole Blood Transfusion?

What goes around comes around. Fifty plus years ago, the only transfusion product available was whole blood. Then the major blood banks discovered that more patients could be treated for specific problems if the blood were fractionated. Packed red cells then became the standard for trauma transfusion and persists to this day.

But there is a move afoot to re-explore the use of whole blood. There are many theoretical advantages, since our trauma patients are bleeding whole blood, not packed cells. Unfortunately, combining a unit of packed red cells, plasma, and platelets does not give you a reconstituted unit of whole blood by a long shot. Check out this diagram:

The challenge is that we are used to only thinking about universal donor red cells (group O Rh-). This is the safest packed cell product to give a patient with an unknown blood type. But unfortunately, it is also one of the hardest to find, present in about 7% of the population.

Packed red cells are nearly plasma free. What we don’t think about with whole blood is the level of antibodies to blood groups that are present in the plasma. Group O blood will have plasma with anti-A and anti-B antibodies. So if we include the plasma with those universal donor red cells, these antibodies may attack the patient’s red cells if he or she is group A, B, or AB and cause a reaction.

Theoretically, this issue can be avoided by using universal donor plasma (group AB+). Since the donor has all of the major group antigens, they will have no antibodies in their plasma. Unfortunately again, this is a rare type and tough to get donors (about 3% of the population).

To avoid potential transfusion reactions, group O whole blood is tested for antibody titers, and only low titer blood is selected for transfusion. Typically Rh- whole blood has been selected to avoid any issues with Rh incompatibility, even though reactions to this antigen are usually mild.

The group at the University of Texas – Houston reviewed their experience using Rh+ low titer group O blood in trauma resuscitations. Their two-year study substituted Rh+ whole blood when Rh- product was not available. They monitored patients for transfusion reactions, renal failure, sepsis, VTE, and ARDS.

Here are the factoids:

  • A total of 637 patients received low titer group O blood during the study period; 448 received Rh+ product and 189 received Rh-
  • Those receiving Rh+ blood were more likely to be male, had lower initial SBP, and a significantly lower GCS (7 vs 12)
  • Overall there were no differences in hemolysis labs, transfusion reaction, complications or mortality
  • The patient groups were then sliced and diced by their own Rh antibody status to see if Rh- patients had an increased likelihood of problems from Rh+ plasma
  • Once again, the Rh- subgroup was significantly different for sex (57% female vs 26% in the Rh+ group), and blunt trauma mechanism (92% vs 70%)
  • And once again no differences were seen in hemolysis, transfusion reaction, complications or mortality

The authors then concluded that Rh+ low titer whole blood is a safe alternative in either Rh+ or Rh- patients.

My comments: Sounds good, right? But wait a minute! This was a non-randomized observational study. It appears that Rh+ whole blood was used when Rh- was unavailable, which was quite a bit of the time. This is clear when you see the demographic differences listed above between the two recipient groups, as well as the subgroups stratified by their own Rh status.

This is the first thing that makes me a bit more skeptical of the recommendation. The other one is something you’ve heard me harp about before… non-inferiority studies. This abstract tries to say that since they did not detect a difference, then the two products are equivalent.

That is only true if there is adequate power in the number of patients studied. If not, you may not be able to show a statistically significant difference. By my own calculations, if the incidence of transfusion reaction in the Rh- group is 1% and the ratio of the patient groups is 0.42, the reported sample size could only show a significant difference if the Rh+ patients had a 5% transfusion reaction rate.

So is it truly non-inferior, or does the study need include a lot more patients? 

Here are my questions for the authors and presenter:

  • What is the impact of the non-randomized patient selection process on your results? The groups and subgroups appear to be very different. Couldn’t this influence your results?
  • Exactly what type of statistical analysis did you use? Your abstract merely lists the software package, not the specific tests applied.
  • Do you believe that your study is sufficiently powered? What assumptions did you use to calculate this?

As we move toward more use of whole blood, the Rh question will be an important one. I look forward to questioning the authors on this one!

Reference: Can Rh+ whole blood be safely used as an alternative to Rh- product? An analysis of efforts to improve the sustainability of a hospital’s low titer group O whole blood program. EAST 2021, Paper 17.

Best of EAST #5: Elderly Falls And Vision Problems

Elderly falls have become a huge problem. There isn’t a night that goes by that we don’t admit at least two or three at our trauma center. There are at least a dozen factors that have been identified that are associated with falls, including:

  • Medications
  • Bone and muscle loss
  • Underlying medical conditions
  • Gait problems
  • Throw rugs and other environmental hazards
  • Visual problems

And many more! But let’s focus on that last one. Vision problems can be due to primary disease, such as glaucoma, or from lack of adequate correction of those problems, such as decreased visual acuity.

The group at West Virginia University is presenting a prevention paper next week. They prospectively studied patients older than 60 years who were admitted to their trauma service over a one year period. They wanted to determine the prevalence of undertreated or undiagnosed eye disease in the population, and to find out if using readily available screening tests could detect this and assist in prevention efforts.

A dilated ophthalmic exam was performed and used as the gold standard. The results were compared to a screening app administered by a trauma provider via an iPad (the eyeTests Easy app). This app can be used to test for visual acuity, macular degeneration, near vision, and astigmatism.

Here are the factoids:

  • A total of 96 patients were enrolled, with an average age of 75 and a predominant mechanism of fall in 79%
  • Significant abnormal vision was undiagnosed in 39% of patients and undertreated in 14%
  • The trauma provider app exam was 94% sensitive and 92% specific
  • Correlation was best on pupil exam (86%), visual fields (58%), and the macular degeneration test (52%)
  • A combination of visual fields and the Amsler grid were associated with significant abnormal vision

The authors concluded that unrecognized visual problems are common, and are present in 53% of their elderly trauma admissions. They also state the the trauma provider exam can identify abnormalities in “most cases” and can identify those who should be screened by an ophthalmologist.

My comments: This is an interesting study that compares a simple, app-based screen with a more sophisticated ophthalmology exam. However, it is not clear what “significant abnormal vision (SAV)” really is. The sensitivity and specificity numbers cited depend on this definition. Is it a positive answer to one of the screening questions? Evidence of macular degeneration? If so, how much? I’m sure that a lot of the elderly (and younger) population have some small irregularities in their vision, but what makes it significant?

The study does show that the app can be used as a screening tool due to the congruence with the “gold standard” ophthalmologic exam. And given that vision is one of the major factors associated with falls risk, it may be a cost-effective tool for reducing it.

Here are my questions for the authors and presenter:

  • What is you exact definition of “significant abnormal vision?” This is critical, because it determines the significance of the rest of your results. If the threshold is set too low, you will detect many anomalies but they may not be clinically significant. This definition needs to be as objective as possible so others can duplicate and take advantage of your work.
  • What do you recommend for workflow to incorporate this tool? Who should do it and when? Should the user focus on particular portions of the app (e.g. Amsler and visual fields, acuity)?
  • Describe your future plans for the longitudinal study mentioned in the abstract.

This is very interesting prevention work. I look forward to the nitty gritty details next week!

Reference: Stop the fall: identifying the 50% of geriatric trauma patients with significant vision loss. EAST 2021, Paper 11.

Best of EAST #4: Futile Trauma Transfers

Level I and II trauma centers are regularly on the receiving end of what may be termed as “futile transfers.” These are patients who have sustained unsalvageable injuries and are initially seen at a lower level center. They are then transferred upstream where they succumb shortly (0-48 hours) after arrival.

As you might imagine, these patients can place a significant burden on resources at the Level I or II center. This is an even more acute situation given the large numbers of COVID patients who also require hospitalization and palliative care services these days.

The group at the University of Kansas sought to put some numbers on this phenomenon. They examined their own experience as one of two Level I trauma centers in the Kansas City metro area. They defined futile care as patients who died or were discharged to hospice care within 48 hours of arrival and who did not undergo operative, endoscopic, or interventional radiology procedures.

Here are the factoids:

  • A total of 1,241 patients were transferred in during the two year study period
  • Of these, 407 had stays of 48 hours or less, and 18 (1.5%) were deemed futile care according to their definition
  • The futile care patients tended to be much older (75 vs 61 years) and were much more severely injured (ISS 21 vs 8)
  • When transport and hospital charges were combined, the average total cost was $56,000
  • Total cost to this hospital was $1.7 million, and this was extrapolated to an annual cost of 27 million for the entire US

The authors concluded that these futile transfers are a small yet costly patient population. They suggested that accurately identifying these patients and providing resources to help referral hospitals figure out how to care for them would be helpful.

My comments: This is a very straightforward descriptive paper that details a problem that every high level trauma center sees on a regular basis. Older patients, typically those with critical head injuries that are beyond treatment, are transferred to the “big house.” The families are frequently told that there are no local resources to provide the care needed, and that the higher level center is their only chance. 

The families then have unrealistic expectations, and are inconvenienced by the travel involved. Wouldn’t it be better to just tell the family that the injury is a really bad one, and provide palliative / hospice care in the local community? Unfortunately, it’s not that simple. Many small hospitals do not have providers who are well-versed in this type of care. Thus, the suggestion to provide resources (people? training?) is a sound one.

This abstract highlights a problem we all face but seldom publicize. Hopefully this one will get us talking. And acting.

Here are my questions for the authors and presenter:

  1. What kind of resources do you think are needed to allow referral hospitals to care for these patients?
  2. How will these hospitals know when care is futile? Will there be an expectation to work with the receiving center to help determine this?

I enjoyed this paper and can’t wait to hear the details!

Reference: Futile trauma transfers: an infrequent but costly component of regionalized trauma care. EAST 2021, paper 9.