Tag Archives: VTE

Abstracts, Complications, Head

Best Of EAST 2023 #12: VTE Prophylaxis In Severe TBI

Leave a comment

Time for another abstract on venous thromboembolic disease (VTE) prophylaxis, but this time in patients with severe head injury. VTE is a significant problem for trauma patients. Those with a potential source of bleeding from their injuries cause us to hesitate and consider the timing of chemical prophylaxis closely. Do we really want to cause more bleeding?

This is particularly problematic with intracranial hemorrhage, as the treatment is major brain surgery. Over recent years, the literature has been leaning toward earlier prophylaxis as soon as the intracranial blood has stopped evolving.

The EAST Multicenter Trials Group performed a seven-year retrospective review at 24 Level I and II trauma centers to assess the safety and efficacy of VTE chemoprophylaxis.  They divided patients into three groups: no prophylaxis, early prophylaxis (within 24 hours), and late prophylaxis (after 24 hours).

The authors assessed two endpoints: VTE occurrence and expansion of intracranial hemorrhage (ICH). They used several regression models to check their hypotheses.

Here are the factoids:

  • A total of 2,659 patients met the inclusion criteria. This averages out to 15 eligible patients per month per center. This is probably reasonable when combining a few high-volume centers with more lower volume centers.
  • Compared to early prophylaxis, patients who received late prophylaxis were twice as likely to develop VTE, although this was not statistically significant (p = 0.059)
  • Compared to early prophylaxis, patients who received no prophylaxis were a third less likely to develop VTE, although this, too, was not statistically significant (p = 0.39
  • About 25% of patients who received either early or late prophylaxis suffered an extension of their ICH, but only 17% of the no-prophylaxis group did
  • The regression model showed that the no prophylaxis group was 36% less likely to develop ICH extension compared to either early or late prophylaxis groups.

The workgroup concluded that the development of VTE was not dependent on the timing of the start of prophylaxis. Furthermore, patients who did not receive any prophylaxis had significantly decreased odds of ICH extension. The group recommended larger randomized studies to extend this work.

Bottom line: Shocker! This multicenter study suggests that the no prophylaxis and early prophylaxis groups had fewer VTE events than the late group, although these results were not statistically significant. This means that there wasn’t an advantage to giving the shot.

And the other major conclusion was that both early and late prophylaxis was associated with a significantly higher incidence of ICH extension. 

Roll these together, and you will find that neither early nor late prophylaxis help prevent VTE, yet they are both associated with additional bleeding in and around the brain! 

Heresy! I am trying to figure out what to make of these results. Perhaps the retrospective nature of the study and the wildcards this introduces influenced the results. It could be a study power problem, except the numbers were approaching significance that was unfavorable for prophylaxis.

I will be very interested to hear how the authors explain these findings. And yes, a well-powered randomized study would be great, but I don’t think many institutional review boards will be keen on a no-treatment group given our current fear of VTE. So don’t count on any real answers soon.

Reference: EARLY VTE PROPHYLAXIS IN SEVERE TRAUMATIC BRAIN INJURY: A PROPENSITY SCORE WEIGHTED EAST MULTICENTER TRIAL. EAST 2023 Podium paper #38.

Abstracts, Pharmacy, Solid organ

Best Of EAST 2023 #10: Early VTE Prophylaxis In Adolescents With Solid Organ Injury

Leave a comment

Chemoprophylaxis against venous thromboembolism (VTE) is routine in trauma care. In most cases, it can be initiated shortly after admission in most trauma patients. However, there are a few major exceptions, including eye injuries and brain injuries with intracranial hemorrhage.

Solid organ injury used to be cause for concern when considering prophylaxis, but most trauma centers are now comfortable beginning within 24 to 48 hours after injury. Having said that, those numbers are for adult patients. What about the younger ones?

The University of California Irvine group queried the TQIP database (3 recent years) to examine outcomes for adolescent patients (12-17 years old) given VTE prophylaxis after injury to liver, spleen, and/or kidney. They excluded patients who had TBI, anticoagulation or coagulopathy, immediate laparotomy, transfers in, and patients who died or were discharged within 48 hours. They matched patients for age, comorbidities, grade of injury, overall severity of injury, and hypotension/need for transfusion.

Eligible patients who received chemoprophylaxis early  (within 48 hours) vs. late were reviewed to identify any differences in complications, length of stay, failed non-op management, and mortality.

Here are the factoids:

  • A total of 1,022 cases were isolated from the TQIP database, and 417 adolescent cases were matched to adults
  • VTE rate was statistically the same, 0.6% in the early group vs. 1.7% in the delayed group
  • Failed non-op management was identical at 5.9% vs. 5.6%
  • There was one death in the delayed group and none in the early group (not significant)
  • ICU LOS was the same at 3-4 days
  • One item not mentioned in the body of the abstract: hospital length of stay was significantly longer in the early group: 9 days vs. 6 days

The authors concluded that early VTE prophylaxis in adolescent trauma patients did not increase failure of nonoperative management, nor did it decrease the incidence of VTE.

Bottom line: This is a study that needed to be done. Due to IRB restrictions, it is typically more challenging to perform actual studies on children and adolescents. Retrospective use of databases helps overcome this problem, although it always introduces a few unwanted wrinkles.

We frequently assume that adolescents behave physiologically like adults. Although often true, you can’t always count on it. Those of us who take care of children and young adults know that they tend to do better than adults by most measures. But again, this is an assumption and needed to be studied.

This database study was limited to three years of data and only produced 417 matched cases for study. This is a small number, and I always worry about statistical power. If the results of such a study are negative, one is left wondering if a proper power analysis was done.

One puzzling result left me wondering about the power question. Patients who received early prophylaxis had exactly the same rate of VTE as those who received it late. Adult data indicates that early use should decrease this complication. Is this another indication of a statistical power problem? Would the inclusion of more patients have shown a real difference?

The other result that struck me (and was not commented upon in the body of the abstract) was the statistically significant 50% increase in hospital length of stay for the early prophylaxis group. Is there some unknown variable that was not matched that caused it? This is one of the known pitfalls of these retrospective database studies.

Here are my questions and comments for the presenter/authors:

  • Broken record question: Did you have enough cases to provide adequate statistical power? This study showed a negative result. Did you have enough matched cases to actually be able to detect a difference if there was one? Why not add a few more years of data and recalculate?
  • How do you explain the failure of early VTE prophylaxis to protect these patients from DVT or PE? Is this also a statistical power problem?
  • Why is the hospital length of stay significantly longer in the early prophylaxis group?

This intriguing paper follows my bias toward treating these patients exactly the same as adults with early chemoprophylaxis. I just need a few of the loose ends tied up.

Reference: SIMILAR RATE OF VENOUS THROMBOEMBOLISM AND FAILURE OF NON-OPERATIVE MANAGEMENT FOR EARLY VERSUS DELAYED VTE CHEMOPROPHYLAXIS IN ADOLESCENT BLUNT SOLID ORGAN INJURIES: A PROPENSITY-MATCHED ANALYSIS. EAST 2023 Podium paper #27.

Abstracts, Prevention

Best of AAST 2022 #3: VTE Risk After Spinal Cord Injury

Leave a comment

Venous thromboembolism (VTE) is always a concern in trauma patients. But patients with spine fractures are at much higher risk and those with spinal cord injuries on top of it even more so. The best tool we have right now for prevention is chemoprophylaxis with some type of heparin. Unfortunately, VTE prophylaxis is commonly interrupted or delayed due to concern for causing bleeding. These concerns may relate to concomitant injuries (e.g. solid organ injury) or necessary surgical procedures.

About five years ago, the Army provided a $4.25M grant to fund the Coalition of Leaders in Thromboembolism (CLOTT) study group. It involved contributions from 17 Level I trauma centers attempting to look at the incidence, treatment, and prevention of VTE after trauma. Additional phases are now under way to look at offshoot discoveries from the original research.

A group from the University of California – Sand Diego performed a secondary analysis of a subset of the CLOTT study in patients age 18-40 over a three year period. Patients with a diagnosis of spinal cord injury who were admitted for at least 48 hours were analyzed. The authors focused on timing of the start of VTE prophylaxis, VTE rates, and missed prophylactic dosing. They also reviewed any bleeding complications.

Here are the factoids:

  • From the entire CLOTT study group, 343 met criteria and had sustained a spinal cord injury
  • Most subjects were young (mean 29) and male (77%) and had sustained blunt injury (79%)
  • A total of 44 patients (13%) developed VTE – 30 DVT, 3 pulmonary embolism, and 11 pulmonary thrombus
  • Only one in five patients started chemo-prophylaxis prior to 24 hours, and this increased to about 50% at 48 hours (!)
  • VTE rate overall was 9.6% (?)
  • The rate trended lower in patients who received their prophylaxis within 48 hours (7% vs 13% but not significant)
  • Missed doses of chemo-prophylaxis were common (30%) and were associated with higher VTE rates

The authors concluded that VTE rates are high in these patients and early chemoprophylaxis is critical in limiting thrombotic events.

Bottom line: Hmm. This abstract confuses me a little. Actually, I had expected a higher VTE rate in this patient group. I’ve seen reports 2x to 3x higher than reported here. But yes, I do believe that these patients are at high risk.

And looking at the chart, it appears that there is a trend toward higher rates in patients who missed doses rather than those who did not. But the real questions are:

  1. Is it real? That is, are those differences significant? The only analysis in the abstract compares early vs late administration and that is trending toward significance but didn’t quite make it there. And remember that the graph you are looking at cuts off at 18% which makes the differences look much bigger.
  2. What can we do about it? Many trauma professionals are still uncomfortable giving prophylaxis early because of fear of bleeding. This is probably unwarranted, but we just don’t have enough hard data to say so. Anecdotal data about surgeons operating uneventfully through chemoprophylaxis is growing, though.

My impression of this study is that it shows some interesting trends, but probably doesn’t include enough subjects to know the real answer for sure. 

Here are my questions for the authors / presenter:

  1. Tell us about the statistics. How did you calculate the rates that are cited in the paper? I can’t figure out the math.
  2. What is the difference between a pulmonary embolism and pulmonary thrombus? Is it merely the presence or absence of concomitant clot in the legs or pelvis? Why distinguish between the two if you are lumping them all together as “VTE?”
  3. What are we to do with this data? Obviously, everyone wants to provide VTE prophylaxis in a timely manner. But there are a raft of reasons why clinicians are “not comfortable” doing it. Any suggestions?

Reference: VENOUS THROMBOEMBOLISM RISK AFTER SPINAL CORD INJURY: A SECONDARY ANALYSIS OF THE CLOTT STUDY. Plenary Paper 23, AAST 2022.

 

Pharmacy

How Early Can We Start Chemoprophylaxis In TBI Patients?

Leave a comment

We’ve learned a couple of things in the last two posts by reviewing recent systematic review / meta-analysis studies. First, low molecular weight heparin provides better prophylaxis against venous thromboembolism (VTE) than unfractionated heparin. And giving prophylaxis within the first 72 hours of admission significantly decreases the incidence of VTE with no increase in existing intracranial bleeds or mortality.

So the only remaining question is, how low can you go? That is, how soon can you safely start chemoprophylaxis? The trauma group at George Washington University in DC put together a study to examine this question.

They, and one other Level I trauma center, performed a retrospective cohort study of adult, blunt TBI patients over a three year period. Patients with penetrating brain injury, and those with any other body region with significant injury (AIS >1) were excluded so this group truly represented isolated brain injury. Other exclusion criteria were progression of blood on CT within 6 hours, and crani or death within 24 hours. Early VTE prophylaxis was defined as occurring within 24 hours, and late was > 24 hours.

All patients had hourly neuro evaluations and a repeat head CT at six hours after admission. All had compression devices applied to their legs, and received either low molecular weight (LMWH) or unfractionated heparin (UH) at a fixed dose regarding of body habitus. Anti-Factor Xa levels were not measured.

Here are the factoids:

  • Between the two centers, 264 met inclusion criteria
  • About 40% received early prophylaxis and the remaining ones received their drug after 24 hours
  • ISS was higher (18 vs 15) and GCS was lower (13 vs 14) in the late therapy group
  • About 88% of patients in the early prophylaxis group received LMWH vs only 63% in the late group
  • Average time to prophylaxis start in the early group was 17 hours vs 47 hours in the late group
  • There were no differences in bleed progression between early and late groups (5.6% vs 7%)
  • The craniotomy / craniectomy rates were the same in early and late groups (1.9% vs 2.5%)
  • VTE rate was the same in early vs late groups (0% vs 2.5%)

Bottom line: The authors concluded that there was no additional risk in giving early VTE prophylaxis in TBI patients with a stable CT seven hours after arrival. This was true for patients with subdural, epidural, subarachnoid, and intraparenchymal bleeds.

But there are some limitations to consider. This was a retrospective study, and was a “how we do it” study” as well in terms of the choice of LMWH vs UH. This means there was not protocol for the form of heparin used; that was determined by surgeon preference. 

There was also a difference in ISS and GCS between groups. However, the difference may not have been clinically significant, and it could have made the late group look worse if it were. Statistically, it did not.

And finally, the numbers are small and there was no power analysis. So there is the question of whether a significant difference could have even been detected.

What does it all mean? Well, it suggests that early (within 24 hours) chemoprophylaxis does not cause harm compared to later administration. But the study is not definitive enough to change practice yet. It should definitely prompt discussions and practice guideline development for starting prophylaxis after 24 hours of CT scan stability now. And hopefully these authors (or others) are planning a better prospective study to help us start even sooner!

Reference: Early chemoprophylaxis against venous thromboembolism in patients with traumatic brain injury. Am Surgeon 88(2):187-193, 2021.

Pharmacy

Unfractionated vs Low Molecular Weight Heparin For Trauma Patients

Leave a comment

In my last post, I described some of the telltale signs that could be seen in a trauma center’s TQIP report that might suggest there are issues with how they go about providing prophylaxis for venous thromboembolism for their patients. Today, I will analyze a systematic review and meta-analysis of a collection of research that compared the efficacy and safety of unfractionated heparin (UFH) to low molecular weight heparin (LMWH) specifically for trauma patients.

First, it’s important to understand the concept of research quality. There is a huge amount of research published these days, and it varies considerably in how well it is designed, executed, and analyzed. Here is a diagram that illustrates the levels of quality and the volume of research published at each level. By quality, I mean the applicability to clinical treatment of actual humans. For this reason, test tube and animal research are low on the pyramid.

The research that most people consider to be the “gold standard” (randomized, controlled, double blind) is very close to the top. There is one class that, if conducted properly, may even be better. That is the systematic review and meta-analysis.

Most people have heard of meta-analysis, and it can be very good by itself. This combines lots of smaller studies into one larger one. However, it may hampered by the quality of the studies included in the meta-analysis. The tenet of “garbage in equals garbage out” certainly holds. But a systematic review takes that one step further.

The systematic review compiles all possible studies related to a small set of research questions, and usually concentrates on the ones with the highest quality research design. The quality of each of the studies is evaluated, and a meta-analysis is then performed on the best. Results are usually represented in a forest plot. This is an easy way to illustrate the estimated results from a number of studies that address the same question. There is also an entry that shows the relative strength of all of the studies combined. Here’s an example:

There are seven studies included, and each is displayed with its risk ratio (RR) and confidence interval (CI). The final diamond is the combined RR and CI for the entire group of studies. In the example above, note that most of the studies have CI bars that extend over the risk ratio = 1 line, meaning they may not be significant. But when taken together, the final risk ratio of the group is well under 1.0 and does not cross over it, denoting significance.

Let’s now apply this concept to a group of studies comparing UFH and LMWH for prevention of VTE for trauma patients. Based on keyword search, the authors identified 1,227 records for screening. Of those, only 40 were tentativley found to directly address the question. After in-depth analysis, only 12 were eligible for final review. For various reasons, only about 1 in 100 papers could be used to try to analyze the question. This always shocks me.

Here are the efficacy results. All are statistically significant, and all but mortality were stated with moderate certainty. The mortality number had low certainty due to the fact there were only three studies and confidence intervals were very wide.

  • Deep venous thrombosis: LMWH reduced by about 35% compared to UH
  • Pulmonary embolism: LMWH reduced by 44% although certainty was low
  • Any VTE: LMWH reduced by about 30%
  • Mortality: LMWH reduced by 56% (low to very low certainty)

Safety was also analyzed, including bleeding events, unexpected return to OR, heparin induced thrombocytopenia (HIT), and “any adverse events.” All of the Total Confidence Interval diamonds were situated on the risk ratio = 1 line, denoting no significant change when comparing LMWH vs UH.  However, quality of this data was noted to be low due to the quality of the individual studies. This means that we do not really know the answer to the safety question with any certainty yet.

Bottom line: This is one of the best summaries of our research on UH vs LMHW to date. It broadly reviewed the available literature and found only a small subset to analyze. It is clear that LMWH is superior for prevention of DVT and VTE overall. However, the impact on pulmonary embolism and death is still unclear.

As far as safety, the studies are still of quality that is too low to use for a decent analysis. Although this study did not detect any increase in complications, we still can’t say with any degree of certainty.

So what does it all mean? We have been using LMWH for decades now. Most likely, if there were regular complications like bleeding, unexpected return to OR, or HIT we would have definitely noticed it by now. Fortunately, we only have a few anecdotes and case reports to scare us off.

Overall, there is good support for the use of LMWH exclusively in most trauma patients. However, the prescribing provider should always assess patient factors that may suggest that UH might be better is a specific case. But remember that using UH trades an unclear/unlikely safety advantage for a recognized decrease in efficacy.

Reference: Efficacy and safety of low molecular weight heparin versus unfractionated heparin for prevention of venous thromboembolism in trauma patients. Ann Surgery 275(1):19-28, 2022.