TXA in Pre-Hospital Care

I don't think it's correct to say that there is no relationship between TXA and VTE's. In the MATTERS trial there was a significant increase in both PE and DVT in those who received TXA. Is there any medicine that doesn't have any side effects? I would otherwise say "no", but the CRASH-2 trial couldn't find any, which is fishy in its own right.

Overall I'm still skeptical of TXA. This article didn't get enough play in the FOAMed-verse, although it was mentioned in a Maryland CCP Project: http://www.ncbi.nlm.nih.gov/pubmed/23694890

That being said, this segment came right after the section by Orman on negative cognitive biases, so perhaps I'm guilty of that.

-Matt

MATTERS trial: http://archsurg.jamanetwork.com/article.aspx?articleid=1107351

Matthew,

I appreciate your listening. I'd like to clear up a couple of points. TXA is hardly a new drug. It has been used in cardiothorasic, orthopedic and OB/GYN surgery for many years. The safety and efficacy (and lack of DVTs / PEs) is well proven.

http://www.ncbi.nlm.nih.gov/pubmed/?term=21412876
http://www.ncbi.nlm.nih.gov/pubmed/?term=25430635
http://www.ncbi.nlm.nih.gov/pubmed/?term=25116268
http://www.ncbi.nlm.nih.gov/pubmed/?term=23440847

We also know how TXA works in the body. At the molecular level, TXA binds to a lysine-binding site on plasminogen. When this TXA-bound plasminogen combines with endogenous tissue plasminogen activator (tPA), the plasmin that is created is inactive and cannot break down fibrin clots. Thus, TXA augments the body’s natural response to bleeding. So TXA is not thrombogenic - it does not create clots. Thus, it cannot create a deep venous thrombosis or pulmonary embolism.

So what about MATTERs? Well, there are a few things to look at. First of all, MATTERs was an observational trial. As such, there were imperfections in the matching of the controls and observational groups. In the overall cohort, the TXA group had a higher ISS and a higher percentage of patients with severe extremity injury. Additionally, the TXA group had a lower Revised Trauma Score and a greater percentage of patients presenting with a depressed GCS score and hypotension. So, to quote the authors, “The higher rate of DVT and PTE in the TXA group should be taken in the context of a higher injury burden, which is associated with thrombotic events.” Second, the authors suggest these events may represent a “survivors benefit” saying “the increased rate of these events may reflect a survivorship phenomenon in the TXA group that has a relative risk reduction of mortality of 27% in the overall cohort and 49% in the massive transfusion cohort”. So even if we accept that TXA would have been the cause of these DVTs / PEs, the all cause mortality at 28 days was significantly reduced in the TXA group. If this is true, the choice would be die without a PE or survive with one! Fortunately, when more randomized studies are done, this issue disappears.

There is nothing fishy about the lack of DVTs / PEs in CRASH-2. When MATTERs 2 was performed (a randomized, placebo control study) there was no increase in VTEs. Nor has any been demonstrated in the literature from other surgical uses (outside of trauma – see above). The British National Health Service and most of Western Europe have been using TXA in trauma care for a few years and there has not been an increase in VTEs in their population. As a side note, they did come up with one of the most unique training tools for TXA (check it out here: http://www.npr.org/blogs/health/2012/11/29/166154251/wham-doctor-tries-comic-book-to-boost-trauma-drug or https://t.co/4jX4o19M - google docs required)

The article you mentioned (http://www.ncbi.nlm.nih.gov/pubmed/23694890) is a nice opinion piece, but again, I think TXA comes down to public health and patient selection. Is TXA always the best agent to use in the trauma bay? Probably not. But is it the best adjunct we have on the side of the road, an hour away from the trauma center, with the bleeding trauma patient? Damn Skippy it is!

- HKM

Here are the contents of the Newark Fire Department TXA "kit":

1 50cc bag Normal Saline
1 10cc syringe
1 filter needle
1 18g needle
1 set of 10 gtt/cc IV tubing
1 1g/10mL ampule of TXA
1 Tyvek bracelet to identify TXA was given.

Picture:
https://www.dropbox.com/s/pdaokz2xn69ja14/TXAkit.jpeg?dl=0

Current cost: appx $107 (USD)

We just approved TXA for use by prehospital providers in NC. One of the caveats is that for a EMS system to have state permission to carry TXA they must have a letter from their receiving trauma center stating that they agree with its use and will give the follow up dose. The trauma centers do not have to give the go ahead for each individual use of TXA. They just that they agree that their local EMS agencies can give the drug in general. That way we can insure that the trauma centers can watch for any possible complications and give the 2nd dose.

JE "Tripp" Winslow, MD MPH
Medical Director NC Office of EMS

Thank you for this talk. what about the more recent article in JOT: http://www.ncbi.nlm.nih.gov/pubmed/24854303 which showed increased mortality irrespective of when it was administered?

Hmm, i looked at the Valle study a little more:

TXA patients appear to be more sick (so it's expected they'd have higher mortality).
-more sick cohort based on: going to the OR more rapidly (mean time 24 min vs. 35 min) as well as receiving more blood products over the first 24hours (2.25L vs 1.99L).
-Mortality difference was not statistically significant until subgroup analysis excluding certain groups (highly suspect then to draw conclusions) such as those that died within the first 2 hours of arrival (if non-TXA patients died at a higher rate within 2hours they wouldn't be counted), TBI pts, received < 2L blood (TXA patients may have required less blood products), those with BP > 120 (TXA patients may not be hypotensive given less bleeding).
-No reasonable explanation is given by authors of why there was increased mortality (DVT/PE physiologically shouldn't be increased with TXA as it's not thrombogenic).

Actually, the Valle study had a lot of problems. First, it was an observational case control study. By the authors own statement: "TXA did not become available at our trauma center until March 2011. There were patients from before and after this date included in the matching procedure to obtain propensity scores." Second, they actually found TXA worked! In patients who didn't need the OR, mortality was reduced by 40% with TXA (but didn't reach statistical significance). Additionally, in patients who received less than 2000 mL of pRBCs (6.67 units) the mortality was 5.7% with TXA vs. 12.7% with no TXA however, again, the study was underpowered and the p-value was only 0.0959.

But most telling was when and how their fatalities happened: "The fact is that, in our hands, most of the time, TXA was administered in the OR after the patient had already received a transfusion." So, they gave TXA, with an average time of 97 minutes after admission (not injury), to patients in the OR, who required more than 6 units of blood and had SBP less than 120 on presentation. And they usually gave it at the end of surgery. In that setting, I agree, TXA is not needed. But in most other settings even the Valle paper suggests it works!

Where TXA is needed is in the setting of presumed severe hemorrhage from trauma when the OR is not readily available within one hour of injury and no alternative exists in that time frame to effect an anti-hemorrhagic resuscitation. I.e., it should be given by EMS and/or non-trauma centers before transfer.

Is there an advantage to starting the second dose for a prolonged transport of patient scenario?

In my case, often is the situation where a potential transport time can easily be an hour and a half or more.

Is there a disadvantage to starting the drip after the initial dose is given, and is there a time frame between the two doses that should be respected / observed?

Sorry for being late to the conversation.

David.

David,

No worries, welcome to the party! In any event, the studies of TXA have really been silent to this issue. In fact, MATTERs - 1 included patients who had only gotten the first dose. For us in Newark, the delay to the second dose was going to only be an hour (at maximum), so the Trauma Pharmacist at the Ohio State University (yes, they have a specific Trauma Pharmacist - how cool is that?!?) felt that we were o.k. to hold the second dose in the field. This was very helpful as we did not have the funds available for pumps nor the training time to teach their use. If you do, I don't see a problem with EMS giving the second dose. That said, I wouldn't want to wait beyond the 3 hour safety window to initiate the second dose.

Doc Mell,
Jumping in on the conversation late and on David W's question, for guys in prolonged field care (PFC) situations, do you have a SOP at Newark for giving it? Any accelerated protocols that you know of (pushing the first 1g dose or giving it over 1-2 minutes)? We'd be doing it without a pump (i.e setting drip rate to 1gtt/40sec with a 60cc & 10gtt/cc tubing).

Ian
iancmay@gmail.com