SGEM#293: CRASH in the US, CRASH in the US, CRASH-2 in the USA

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Date: May 29th, 2020

Reference: Erramouspe et al. Mortality and Complication Rates in Adult Trauma Patients Receiving Tranexamic Acid: A Single-center Experience in the Post–CRASH-2 Era. AEM May 2020

Guest Skeptic: Dr. Corey Heitz is an emergency physician in Roanoke, Virginia. He is also the CME editor for Academic Emergency Medicine.

Case: A 44-year-old male presents to your level 1 trauma center by EMS after a motor vehicle collision. He is hypotensive and tachycardic. You suspect abdomen and pelvic trauma and calculate his injury severity score (ISS) to be 22. Your hospital protocol is to give tranexamic acid (TXA) 1g IV over 10 minutes followed by a 1g infusion over eight hours. You wonder what his over-all chance of dying or developing a thromboembolic event when treated with TXA.

Background: TXA is synthetic derivative of lysine that controls bleeding by inhibiting fibrinolysis and thus stabilizing clots that are formed. We have covered TXA as a treatment modality a number of times on the SGEM. The evidence for TXA providing a patient-oriented outcome (POO) has been mixed. It seems to work for epistaxis (SGEM#53 and SGEM#210), failed to demonstrate a decrease in all-cause mortality in post-partum hemorrhage (SGEM#214), and did not result in an improved neurologic outcome in hemorrhagic strokes (SGEM#236).

REBEL EM has looked at using TXA for those conditions plus a few others (we will include a table in the show notes). It is unclear if it provides a benefit for gastrointestinal bleeds (GIB). Nebulized TXA shows promise for both post-tonsillectomy bleeding and hemoptysis. However, better studies are needed to confirm these observations.

Dr. Anand Swaminathan and I covered the classic CRASH-2 Trial (SGEM#80). This study published in 2010 showed an absolute mortality reduction of 1.5% in adult trauma patients giving a number needed to treat to prevent one death of 67 (Shakur et al. Lancet 2010)

CRASH-3 was a well-designed, large, multi-centred randomized placebo controlled trial published in October 2019 (The Lancet). It asked if TXA had a mortality benefit in patients with isolated head trauma (SGEM#270)? While there was a suggestion of benefit in a secondary subgroup analysis, the primary outcome demonstrated no statistical difference in head-injury related mortality with TXA compared to placebo (18.5% TXA vs. 19.8% placebo, RR 0.94 [95% CI 0.86 to 1.02]).

One of the limitations to both CRASH-2 and CRASH-3 was the external validity. The majority of sites involved were in middle to low income countries. CRASH-3 had one Canadian site and the USA had no participating centres. Transfusion practices and identification of adverse events may differ in developing countries compared to the USA.

Clinical Question: What is the mortality and thromboembolic events in adult trauma patients receiving TXA an American Level 1 Trauma Center?

Reference: Erramouspe et al. Mortality and Complication Rates in Adult Trauma Patients Receiving Tranexamic Acid: A Single-center Experience in the Post–CRASH-2 Era. AEM May 2020

Population: Adults (18 years or older) who received TXA after an acute traumatic injury
- Excluded: Patients who received oral TXA, received it for elective surgery or nontrauma indications, received TXA 8 hours or longer after the injury, and patients with cardiac arrest at time of ED arrival.
Intervention: TXA 1g IV over 10 minutes and maintenance infusion of 1g IV over 8 hours
Comparison: None
Outcome:
- Primary Outcome: In-hospital mortality
- Safety Outcome: Thromboembolic event within 28 day

Dr. Erramousepe

This is an SGEMHOP episode and we are pleased to have both the lead author and senior author on the episode.

Dr. Joaquin Erramouspe is a medical doctor, who finished medical school in Uruguay, moved to the USA for further training and research, and now, is working as a researcher at Queensland University of Technology while obtaining his masters in science.

Dr. Daniel Nishijima

Dr. Daniel Nishijima is an emergency medicine physician at University of California Davis. His research focus is on trauma and neurological emergencies, particularly those with coagulation disorders.

Authors’ Conclusions: “Adult trauma patients receiving TXA had similar incidences of death but higher incidences of thromboembolic events compared to the CRASH-2 trial. Variation in patient characteristics, injury severity, TXA dosing, and surgery and transfusion rates could explain these observed differences. Further research is necessary to provide additional insight into the incidence and risk factors of thromboembolic events in TXA use.”

Quality Checklist for Observational Study:

1. Did the study address a clearly focused issue? Yes
2. Did the authors use an appropriate method to answer their question? Yes
3. Was the cohort recruited in an acceptable way? Yes
4. Was the exposure accurately measured to minimize bias? Yes
5. Was the outcome accurately measured to minimize bias? Yes
6. Have the authors identified all-important confounding factors? Yes
7. Was the follow up of subjects complete enough? Yes
8. How precise are the results? Fairly precise
9. Do you believe the results? Yes
10. Can the results be applied to the local population? Unsure
11. Do the results of this study fit with other available evidence? Yes

Key Results: This retrospective study included 273 patients with a mean age of 43.8 years and 74% male.

All-cause mortality was 12.8% and thromboembolic events were 6.6%

Difference between the current study and the previously published CRASH-2 study.

We have five nerdy question to ask Joaquin and Daniel to better understand their teams study. Listen to the podcast on iTunes to hear his responses.

1) Chart Review: You referenced Kaji et al. Looking through the retro-spectoscope: reducing bias in emergency medicine chart review studies (Annals of EM 2014). What additional benefit does this publication add to the quality check list for observational studies published by my EBM mentor Dr. Andrew Worster? (Annals of EM 2005).

2) External Validity: This study was conducted at a single Level 1 trauma center. How do you think it would compare to other Level 1 Trauma Centers in the USA?

None of our trauma centres in Canada see the volumes that you do in the large US trauma centres. This is because of the lack of penetrating trauma. I have worked full time for 25 years in an ED and never seen a gunshot injury. Most of the trauma we see is from blunt force injury. Do you think the results would be similar in a Canadian trauma centre?
What about non-level 1 trauma centers in the USA?
I thought that CRASH-2 and CRASH-3 had a lot of external validity to where I work in a rural/critical access hospital. We don’t have a CT scanner or a surgeon and our massive transfusion protocol is both units of O-negative blood. We usually give TXA to our trauma patients but transfer them quickly to our local trauma centre. Did your study include or exclude patients transferred to your hospital who had TXA provided prior to arrival?

3) Lack of Control: There was no control group in this study, but you did compare your results to the CRASH-2 study. Let’s go through some of the differences and comment on how that may have impacted your results or explain your findings:

Demographic Differences – The patients were older and there were less men in your cohort.
Mortality Differences – There was less all-cause mortality and less bleeding mortality in your study compared to CRASH-2.
Differences in Any Surgeries and Blood Products Transfused – You had more patients taken to the operating room for surgery and more transfusions of blood products.
Thromboembolism – Previous studies have reassured that the risk of thromboembolism is low. However, in your study you had more than three times the events as CRASH-2 (6.6% vs 2.0%). Is this because you had better methods to detect these adverse events using your EMR or is it some other reason?

4) Comparison Group: There were 31/321 (10%) of patients who did not receive TXA. Do you have any more information on why they did not receive TXA and who they did clinically?

5) Next Steps: What are the unanswered questions you have about TXA use in adult trauma patients?

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: The evidence supports the use of TXA in the treatment of adult patients with blunt trauma, but the increased risk of thromboembolism is concerning.

Case Resolution: The patient is intubated; his pelvis is placed in a binder and you start your hospital’s massive transfusion protocol. A FAST exam is positive, and the surgeons start debating whether to get more advanced imaging or take the patient directly to operating room for an exploratory laparotomy. You step out of the room and make a mental note to look up the patient tomorrow on your next shift.

Dr. Corey Heitz

Clinical Application: TXA has an absolute mortality benefit of 1.5% in CRASH-2. This new retrospective study will not change my practice but does increase our concern about thromboembolic events.

What Do I Tell My Patient? It looks like you have internal bleeding. We are going to give you blood products as well as a medicine called TXA. This can help stop the bleeding and improve your chance of survival. There is a low risk of increasing blood clotting. The surgeons will take to more about taking you to the operating room.

Keener Kontest: Last weeks’ winner was Dr. Kirby Black an EM physician from Oneida, New York. He know Hippocrates first described strokes over 2,400 years ago.

Listen to the SGEM podcast to hear this weeks’ question. Send your answer to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Now it is your turn SGEMers. What do you think about using TXA in adult trauma patients? Tweet your comments using #SGEMHOP. What questions do you have for Joaquin, Daniel and their team? Ask them on the SGEM blog. The best social media feedback will be published in AEM.

Also, don’t forget those of you who are subscribers to Academic Emergency Medicine can head over to the AEM home page to get CME credit for this podcast and article. We will put the process on the SGEM blog: