Category Archives: Pharmacy

Early vs Late Chemoprophylaxis In Patients With Intracranial Hemorrhage

April 22, 2022 The Trauma Pro Leave a comment

In my last post, we looked at our knowledge base regarding the use of unfractionated heparin versus low molecular weight heparin. And the latter won. Today, let’s dig into the question of early versus late prophylaxis in patients with TBI and intracranial hemorrhage.

Neurosurgeons are remarkably cautious when considering anticoagulant thromboprophylaxis in these patients. Obviously, there is always concern for making the bleeding worse. This is very undesirable where there is little extra space and drainage is complicated.

But as we know, dogma about these issues tends to get spread very easily, with little scientific support. Let’s review another systematic review and meta-analysis (see last post) that examines the question.

As is usual, there have been a lot of contributions to this area over the years. Unfortunately, many are not entirely related to the question or have significant bias or design flaws. Of a total of 1,490 papers identified by the authores during PubMed searches only 29 were on topic. And of these only 11 were suitable for analysis. Early prophylaxis was defined as within 72 hours, although the authors were able to slice and dice this into shorter intervals.

Here are the results:

Progression of hemorrhage. There was no significant progression of intracranial bleeds seen at 24, 48 or 72 hours. However, this result is probably somewhat biased by the fact that fewer patients with severe injury are enrolled in studies of VTE prophylaxis. The overall odds ratio for early vs late administration was 0.86 favoring early prophylaxis. However, the confidence interval crossed the midline, so there was no difference noted in progression of bleed or mortality with early VTE prophylaxis.
Occurrence of DVT. Many of the studies indicated a decrease in VTE in the patients given early prophylaxis. This was noted at all three time intervals as well. The overall odds ratio was 0.58, which was statistically significant. This means that patients with early prophylaxis at any point had their risk of VTE reduced almost by half.
All cause mortality. Could their be other issues with early VTE prophylaxis that would increase mortality? This analysis showed that the odds ratio was 0.83 favoring early prophylaxis decreasing it. This is a 17% reduction in mortality, but unfortunately was not statistically significant. Although there is a trend toward lower mortality with early prophylaxis, it is not significant.

Bottom line: Again, this type of analysis is powerful but can suffer from the combined weaknesses of its individual papers. However, the best information we have thus far shows that early prophylaxis prior to 72 hours of admission does not appear to be harmful, does not result in progression of intracranial bleeding or excess mortality, and cuts the risk of VTE almost in half.

In my next post, I’ll explore a recent paper that examines how early we can really go with VTE prophylaxis.

Reference: Clinical outcomes following early versus late pharmacologic thromboprophylaxis in patients with traumatic intracranial hemorrhage: a systematic review and meta-analysis. Neurological review 43:861-872, 2020.

Pharmacy

Unfractionated vs Low Molecular Weight Heparin For Trauma Patients

April 19, 2022 The Trauma Pro 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.

Pharmacy

VTE Prophylaxis And TBI

April 15, 2022 The Trauma Pro Leave a comment

There has been a tremendous amount of gnashing of teeth regarding venous thromboembolism (VTE) prophylaxis in patients with blood in their head. This means any kind of blood: subarachnoid / epidural / subdural hematomas as well as intraparenchymal hemorrhage.

Trauma professionals have traditionally been hesitant to give any type of anticoagulant to a patient who has just bled, or who may be at risk for bleeding in the very near future. This becomes even more important in areas like the brain where management is a bit more difficult and adverse events can be devastating.

For this reason, our neurosurgical colleagues frequently like to steer the ship and dictate what type of VTE prophylaxis can be given, and when. Unfortunately, much of their advice may be driven by dogma and what they learned about the subject during their training. Having studied hundreds of TQIP reports over the past few years, I’ve learned to pick out hospitals that are relying on the advice of non-trauma surgeons to direct the prophylactic regimen.

Here are two dead giveaways that something is amiss. First, look at your TQIP report table titled “Pharmacologic VTE Prophylaxis Type.”

Compare the use of unfractionated heparin vs low molecular weight heparin (LMWH). This hospital has a huge variance from the norm compared to other comparable trauma centers. This means that “someone” is dictating its use for some subset of patients.

In my experience, this is typically a neurotrauma thing. Now take a look at the TQIP table titled “Pharmacologic VTE Prophylaxis.” Specifically, look at the “Severe TBI” cohort for time to VTE prophylaxis.

It is very clear that there is a significant delay to administering VTE prophylaxis to TBI patients. These two data points indicate that there is some reluctance to giving appropriate treatment to these patients.

The literature is clear that VTE prophylaxis is important in many trauma patients, including those with serious head injury. There are three questions that need to be answered to settle on optimal care:

Which chemoprophylaxis is best, unfractionated or low molecular weight heparin?
Is it better to give the selected agent earlier or later?
If earlier is better, how early can we give it?

I will address each of these questions in this series of posts, focusing on neurotrauma patients. In order to try to toss out dogma, the literature I cite will be recent, no more than about two years old. So join me for battle next week as we have unfractionated vs low molecular weight heparin face off.

Thanks to Jim Sargent from Beth Israel Deaconess Medical Center for suggesting this topic.

Complications, Pharmacy

Best Of EAST #6: How Long Does Risk For VTE Last After Spine Fracture?

December 24, 2021 The Trauma Pro Leave a comment

Most trauma centers use an existing venous thromboembolism (VTE) guideline or have developed their own injury-specific one. These include risk factors, contraindications, specific agent, and dosing recommendations. But one thing most do not include is duration of prophylaxis!

The length of time a patient is at risk for VTE is not well delineated yet. The group at the University of Arizona decided to tackle this program using the National Readmission Database. This dataset is a comprehensive resource for critically analyzing patients who are discharged and readmitted, even for multiple occurrences. It covers 30 states and almost two thirds of the population.

The authors focused on VTE occurring during the first six months after injury. Patients who died on the initial admission, were taking anticoagulants, had spinal surgery, or sustained a spinal cord injury were excluded. Over 41,000 records from the year 2017 met these criteria.

Here are the factoids:

The average age was 61, which shows the skew toward the elderly with these injuries
Spine areas injured were cervical in 20%, thoracic in 19%, lumbar in 29%, sacrococcygeal in 11%, and multiple levels in 21%.
During the initial admission, 1.5% developed VTE: 0.9% were DVT and 0.7% were PE
Within 1 month of discharge, 0.6% of patients were readmitted for VTE: 0.4% DVT and 0.3% PE
In the first 6 months, 1.2% had been readmitted: 0.9% DVT and 0.6% PE
Mortality in the first 6 months was 6.7%
Factors associated with readmission for VTE included older age, discharge to a skilled nursing facility, rehab center, or care facility

The authors concluded that VTE risk remains high up to 6 months after conservatively managed spinal fractures. They recommend further study to determine the ideal prophylactic agent and duration.

Bottom line: This is a creative way of examining a difficult problem. We know that VTE risk does not stop when our patient is discharged. This is one of the few ways to get a sense of readmissions, even if it is not to the same hospital. And remember, this is an underestimate because it’s possible for a patient living near a state border to be re-hospitalized in a state not in this database.

This study might prompt us to prescribe up to six months of prophylaxis, particularly in seniors who are discharged to other care facilities.

Here are my questions for the author and presenter:

Is there any way to extrapolate your data to the entire population of the US, or to compensate for the “readmission over state lines” problem?
Is the odds ratio of 1.01 for risk of VTE in the elderly age group significant in any way? It seems like a very low number that would be easily overwhelmed by the “noise” in this data set.
Is the mortality number for all causes, or just VTE?

This is an intriguing study, and one that should influence the VTE guidelines in place at many trauma centers!

Reference: THE LONG-TERM RISKS OF VENOUS THROMBOEMBOLISM AFTER NON-OPERATIVELY MANAGED SPINAL FRACTURE. EAST 35th ASA, oral abstract #28.

Pharmacy

Best Of EAST #4: 4-Factor PCC vs Andexanet Alfa For Factor Xa Inhibitor Reversal

December 22, 2021 The Trauma Pro Leave a comment

Falls are by far the most common mechanism of injuries in US trauma centers these days. They typically occur in elderly patients, and a growing number are on some type of oral anticoagulant for their medical conditions. And the number of these patients who are taking a DOAC (direct thrombin inhibitor or factor Xa antagonist) is rising quickly.

Unfortunately, most of the DOACs do not have good reversal agents, and they are very, very expensive. Specifically, Andexanet Alfa, the antidote for rivaroxaban and apixaban used to cost in excess of $50,000 per dose. This has come down over time to “only” $22,000 per dose. Unfortunately, the half-life is much shorter than the agent it is neutralizing, frequently requiring two doses. And the kicker is that there are no studies definitively showing that Andexanet Alfa improves mortality when used for CNS hemorrhage.

Prothrombin complex concentrate (PCC) has been used for reversal of these agents as well. Its efficacy is also not well known. The group at George Washington University is presenting an abstract comparing it against Andexanet Alfa (AA) for reversal of either of the Factor Xa inhibitors (rivaroxaban, apixaban). They performed a multicenter study involving 10 trauma centers. The endpoints studied were number of transfusions, mortality, and ICU length of stay.

Here are the factoids:

From a total of 263 patients, 77 received AA and 186 received PCC
Only 4% of patients received a second dose of AA despite its short half-life
There was no significant difference in the number of PRBCs transfused
The authors stated that the mortality was significantly lower with PCC but the p value in the data table provided was = 0.05
They also stated that the ICU LOS was significantly lower with PCC (1.2 vs 1.5 days, p = 0.04)

The authors concluded that PCC is non-inferior to AA for reversal in bleeding trauma patients. They recommended a randomized study be done.

Bottom line: The first thing for you to know is that I have never been impressed with the data on Andexanet Alfa. Which means I have to be very careful and aware of my own cognitive bias. In practice, this means I can’t just look at the study title or abstract and be happy that it meets my confirmation bias. I have to make a conscious effort to critically read the paper or abstract and see if it really does mean what I want it to mean, or if I need to change my opinion.

This abstract doesn’t really satisfy my confirmation bias. The title states that PCC is not inferior to AA. I would certainly like to believe that. But in order to safely say that, it is vitally important that a power analysis is performed to ensure that enough patients are present in both treatment groups to confidently state that there was no difference. If the number of patients is too small, significance can’t be detected and non-inferiority cannot be confirmed.

The body of the abstract claims that mortality was significantly lower in the PCC group, although the table states that the p value was 0.05, which technically is not significant. The difference in mortality numbers is impressive (PCC mortality 20% vs 32% for AA) so why the significance issue?

And one note about significance. Be careful not to conflate statistical significance with real-life significance. ICU length of stay in this study was statistically significantly shorter in the PCC group (1.2 vs 1.5 days) but I doubt that a difference of 7 hours in the ICU is clinically relevant.

Here are my questions for the authors and presenter:

Did you have enough patients in the study to assure that the PCC treatment was actually non-inferior? Please show us your power analysis.
What were the inclusion criteria for the study? This will help us understand the patient group better. Were these primarily head bleeds, actual external or intra-cavity hemorrhage?
Please clarify the significance claim for mortality. The raw percentages are impressively different, but the P value is not significant.
Could the low rate of administering a second dose of AA have influenced the outcomes? As mentioned above, the half-life of the antidote is much shorter than that of the DOAC. Perhaps giving a second dose is actually needed and could have moved the results in favor of AA.

This is a thought-provoking abstract for me. Let’s see if you can either confirm or refute my opinion on AA!

Reference: 4-FACTOR PROTHROMBIN COMPLEX CONCENTRATE IS NOT INFERIOR TO ANDEXANET ALFA FOR THE REVERSAL OF FACTOR XA INHIBITORS: AN EAST MULTICENTER STUDY. EAST 25th ASA, oral abstract #15.

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