Oops, I’ve got to backtrack a little. I just ran across a newly published study from the authors mentioned in Part 1 of this series a few days back. I pointed out some of the issues that surfaced as they tried to “hit the numbers” for factor anti-Xa levels in patients from their hospital. Here’s a breakdown of the new study.

First, I love the beginning of the title:

“If some is good, more is better”

Really?

Recognizing that 30% of patients had low anti-Xa trough levels when given the standard 30mg bid dosing regimen for enoxaparin, the authors engaged in some fancy predictive and statistical models to come up with a new one. A good portion of the methods section of the paper is devoted to explaining the machinations of exactly how they did this.

They used a patient dataset that was a little fresher than from Part 1. Three years of data from 2011 to 2014 were reviewed, and 275 patients were used to generate the new models. They selected one of seven candidates, based on a combination of simplicity and fewer supranormal levels of anti-Xa. They used this model to guide dosing to the next 145 patients. Here is the new regimen:

And here are the factoids:

• Of the 275 patients used to create the model, 70% were subtherapeutic. (This is exactly the same number as in the first paper, but a different number of patients. Hmm.)
• With the new dosing regimen in place, only 21% were subtherapeutic
• Patients with supratherapeutic anti-Xa levels increased from 2 to 5% using the new routine
• VTE was the same, at about 3-4%
• Four patients developed VTE on the new regimen, and 3 of them had therapeutic anti-Xa levels (!)

Bottom line: A lot of modeling and statistical work went into the production of this paper. I still wonder why the number of patients included over 3 years is so low for such a busy center. But the authors certainly showed that they could improve the rate at which they “hit the number.” But how important is this, really?

The concluding sentence of the abstract reads, “further studies are needed to determine whether such dosing decreases venous thromboembolism rates.” Perhaps we should figure that out before continuing to spend lots of time playing with dosing changes and blood tests.

• Enoxaparin And anti-Xa Levels: Who Cares? Part 1
• Enoxaparin And anti-Xa Levels: Who Cares? Part 1.5
• Enoxaparin And anti-Xa Levels: Who Cares? Part 2
• Enoxaparin And anti-Xa Levels: Who Cares? Part 3

Reference: If some is good, more is better: an enoxaparin dosing strategy to improve pharmacologic venous thromboembolism prophylaxis. J Trauma 81(6):1095-1100, 2016.

In my last post, I reviewed a study that looked at monitoring factor anti-Xa for the purpose of just “hitting the number.” Not very convincing. Today, I’ll review one that studied a reasonable outcome, the actual occurrence of VTE in patients.

This was another small, prospective study at a busy Level I trauma center. The outcomes that were analyzed included LOS, transfusion requirement, hematocrit on discharge, and diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE). Only the last two of these make sense, especially for this small study. (205 patients in two 10 month periods).

At this center, all trauma patients are started on enoxaparin, regardless of injury severity. And all patients have sequential compression devices applied unless contraindicated by their injuries. Patients were included if the were administered 3 consecutive enoxaparin doses and had a trough anti-Xa level measured an hour before the fourth dose. If the trough was less than 0.1 IU/ml, dosing was adjusted until it rose to > 0.2 IU/ml. Outcomes were compared to historical controls from the prior year.

Here are the factoids:

• A total of 87 study patients were enrolled in 10 months.  However, this represents only about 15% of trauma admissions to the center. Why were so few eligible for inclusion?
• 84% of study patients did not “hit the number” with 30mg bid dosing (again!)
• They were compared to 118 control patients who received enoxaparin during the same 10 month period, a year earlier
• Screening by duplex ultrasound was only done for “clinical suspicion” of DVT or PE. No routine screening. And we know how reliable clinical suspicion can be.
• 84% of patients were not at their anti-Xa goal when the first trough was done. Most of these patients needed 40mg bid to “hit the number.”
• DVT and PE occurrences were “significantly lower” in the dose adjusted group compared to historical controls (1.1% vs 7.6%). Now this is a difference between only 1 adjusted patient and 9 controls, and the p value barely made it at 0.046.
• Proximal DVT occurred  in no adjusted patients vs 2 controls (not significant)
• PE occurred in no adjusted patients and 1 control (not significant)
• Distal DVT occurred in 1 adjusted patient and 6 controls (not significant

Bottom line: This is yet another (very) small study. It also demonstrates why you must read the study, not just the abstract! The study group was a fraction of all of the patient admitted, even though all patients supposedly received prophylaxis. The attending physicians decided when to start dosing, and this varied from 0 to 4 days. Screening was ordered only if there was some kind of clinical suspicion for DVT or PE, and the details were not spelled out. 

For all these reasons, there are many, many opportunities for bias. But probably the most important problem is the statistics. I always worry when the p value for a numerical difference barely reaches 0.05, especially when the actual numbers look to be far apart. It is usually an indicator of small study size.

But in this case, the breakdown of VTE location is critical. The sums of the distal, proximal, and pulmonary occurrences show a p value difference just under 0.05. But when you compare study vs control for each, the bulk of the numbers are due to distal DVT.  The literature does not convincingly support prophylaxis for distal DVT, and we do not even treat it at my center. We continue surveillance to make sure it doesn’t creep up into the popliteal arteries.

This is yet another weak study trying to make the case for anti-Xa monitoring that doesn’t pass muster. Again, we see that 30mg bid doesn’t “hit the number” without adjustment. But we also haven’t shown that hitting that magic number of 0.2 IU/ml (peak or trough) by adjusting the dose makes a difference either.

But we continue to try. In my next post, we’ll look at another recently published study on the same topic.

Related posts:

• Enoxaparin And anti-Xa Levels: Who Cares? Part 1
• Enoxaparin And anti-Xa Levels: Who Cares? Part 1.5
• Enoxaparin And anti-Xa Levels: Who Cares? Part 2
• Enoxaparin And anti-Xa Levels: Who Cares? Part 3
• How long are trauma patients at risk for VTE?
• How long does VTE risk last in TBI patients?

Reference: Association between enoxaparin dosage adjusted by anti-factor Xa trough level and clinically evident venous thromboembolism after trauma. Jama Surg. Published online ahead of print July 6, 2016.

Several papers have been published in recent years analyzing the process of fine-tuning venous thromboembolism (VTE) prophylaxis with enoxaparin. My own hospital has (or had) a protocol in place to automatically draw anti-Xa levels after the third enoxaparin dose in select patients. What is the science behind this concept? It looks like that’s a popular question these days.

Enoxaparin interacts with antithrombin III, turning off a number of factors further down in the clotting cascade. As part of the process, it inactivates Factor Xa, which is easily measurable by a simple blood test. This is very helpful, since PT and PTT are not affected by enoxaparin.

The paper I will discuss today postulated that many patients are “sub-therapeutic” given the usual dosing regimen of 30mg bid. They primarily focused on “hitting the number”, meaning achieving an anti-Xa level > 0.2 IU/ml.

Patients at a single Level I trauma center were enrolled, receiving standard dose enoxaparin and undergoing duplex screening within 48 hours of admission, and again during the first week in hospital. Anti-Xa levels were drawn four hours after the third dose (peak level) and one hour before the fourth dose (trough level).

Here are the factoids:

• Of 164 patients enrolled, only 61 patients remained in the study. A total of 103 (63%) were excluded because blood draws or screening studies were not done correctly. (!!)
• 70% of patients had sub-therapeutic enoxaparin dosing based on anti-Xa peak levels
• The subtherapeutic patients tended to be males, with “higher body weight.” The reality was that the therapeutic patients weighed 71kg and the non-therapeutic men 88kg. But BMI was only 25 and 29, respectively, and was not significantly different.
• There were 3 VTEs detected during the study, all receiving the initial 30mg dose of enoxaparin. Two of the three had therapeutic anti-Xa levels.
• No bleeding complications were observed in patients who had their enoxaparin dose adjusted upward

Bottom line: It’s really hard to take anything away from this study at all! Well, we can certainly see that the research group had a tough time adhering to their own protocol, losing two thirds of their study group. This throws the accuracy of the data on the remaining subjects into doubt given the very low numbers.

It would appear that many patients did not achieve their magic number of 0.2 IU/ml for anti-Xa when receiving the standard enoxaparin dose. So what? VTE occurred essentially equally in both groups, but really can’t be interpreted either due to the low numbers.

So basically, this paper is just telling us how many of their patients don’t hit the magic number. Not if that number has any implications on real outcomes, like DVT, PE, or mortality. But if you only read the title or abstract, you might think so!

Tomorrow, I’ll review a paper on anti-Xa that takes a different approach. Just about as successfully.

Related posts:

• Enoxaparin And anti-Xa Levels: Who Cares? Part 1
• Enoxaparin And anti-Xa Levels: Who Cares? Part 1.5
• Enoxaparin And anti-Xa Levels: Who Cares? Part 2
• Enoxaparin And anti-Xa Levels: Who Cares? Part 3
• DVT and PE in trauma
• Aspirin for DVT prophylaxis??
• DVT in children: how old is old enough to worry?

Reference: Dose adjusting enoxaparin is necessary to achieve adequate venous thromboembolism prophylaxis in trauma patients. J Trauma 745(1):128-135, 2013.