SGEM#80: CRASH-2 (Classic Paper)

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Date: June 12th, 2014

Guest Skeptic: Dr. Anand Swaninathan is an assistant program director at NYU/Bellevue Hospital in the Department of Emergency Medicine.

Case Scenario: You are working in a busy urban trauma center when EMS slams through the doors with a 22-year-old man who was in a major MVC. The patient has significant abdominal and pelvic trauma and is hypotensive and tachycardic. You mobilize your resources and within minutes, the patient is intubated, his pelvis is placed in a binder and blood is being infused through a peripheral intravenous line. Your trauma colleagues are waiting to take the patient to the operating room for an exploratory laparotomy based on your positive FAST exam. Before they leave, one of you bright residents asks if you should start Tranexamic acid on the patient.

Question: Does tranexamic acid (TXA) reduce mortality in patients who have sustained major trauma?

Background: Injuries are a major cause of death worldwide. Millions of people die every year from traffic injuries. In fact, they are the 9^th leading cause of death around the world. Additionally, another 1.5 million people die every year from interpersonal violence. Hemorrhage accounts for about 1/3 of all trauma deaths and as such, it should be our goal to find treatments to decrease death from hemorrhage.

Our bodies have a finely tuned system that allows blood to flow freely and not clot too easily while also allowing the body to form clots when needed. This balance is upset in trauma by loss of blood and factors, acidosis, hypothermia and the inflammatory cascade. Hyperfibrinolysis often occurs making hemostasis extremely challenging.

TXA is a synthetic derivative of lysine that inhibits fibrinolysis and thus stabilizing clots that are formed. TXA has been widely used in elective surgical cases and has shown decreased need for blood transfusion and reduction in mortality. It makes sense, then to apply TXA to the trauma patient to see if we can get similar effects.

Five Reasons for Picking CRASH-2:

Instant classic that everyone providing trauma care should know despite being published only 4 years ago.
It does not involve a fancy new expensive drug (cheap).
It also affects an important patient oriented outcomes like…saving a life.
It is very easy to give (loading dose of 1 g of infused
over 10 minutes, followed by an IV infusion of 1 g over 8 h.
It is something I can give in the small/rural hospital setting

Article: Effects of tanexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised placebo-controlled trial. Lancet 2010

Population: Adult trauma patients within 8-hours of injury with or at risk of significant bleeding, from 274 hospitals in 40 countries. N=20, 211). Significant haemorrhage was defined as systolic blood pressure < 90mm Hg or heart rate > 110 beats per minute or both.
- Exclusion: Patients for whom the responsible doctor considered that there was a clear indication for tranexamic acid were not randomly assigned. Similarly, patients for whom there was considered to be a clear contraindication to tranexamic acid treatment were not randomly assigned.
Intervention: Loading dose of 1 g of tranexamic acid infused over 10 minutes, followed by an intravenous infusion of 1 g over 8 h (n=10,060).
Control: Placebo (0.9% saline) (n=10,067).
Outcome:
- Primary Outcome: Death in hospital within four weeks of injury.
- Secondary Outcome: Receipt of a blood-products transfusion, number of units of blood products transfused, surgical intervention, occurrence of thromboembolic episodes (stroke, myocardial infarction, pulmonary embolism, clinical evidence of DVT).

Authors’ Conclusions: “TXA safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients.”

Quality Check List for Systematic Reviews:

Were these ED patients? Yes
Were the patients adequately randomized? Yes
Was the randomization process was concealed? Yes
Were the patients were analyzed in the groups to which they were randomized? Yes
Were patients recruited consecutively? Yes
Were patients in both groups were similar with respect to prognostic factors? Yes
Were participants unaware of group allocation? Yes
Were groups treated equally except for the intervention? Yes
Was follow-up was complete? No but it was excellent
Were all patient-important outcomes were considered? Yes
Was the treatment effect large enough and precise enough to be clinically significant? Yes

Key Results: All cause mortality was reduced from 16% in the placebo group to 14.5% in the TXA group (RR 0.91, 95% CI 0.85-0.97). This was an absolute risk reduction of 1.5% and was statistically significant. The calculated NNT was 68 (95% CI 0-206) to prevent one death.

Absolute reduction in mortality of 1.5% with TXA

There was no significant difference between any of the secondary outcomes:

Receipt of a blood-products transfusion
Number of units of blood products transfused
Surgical intervention
Occurrence of thromboembolic episodes (stroke, myocardial infarction, pulmonary embolism, clinical evidence of DVT)

Tranexamic acid significantly benefited the subset with systolic blood pressure <75mmHg (Fig 3, RR 0.87; 95% CI 0.76- 0.99).

This is a very pragmatic real world study which includes trauma patients from 247 hospitals in 40 countries. We do not know the breakdown of which patients were seen in various hospital settings, which may make it difficult to establish if these results can be applied to our patients. However, with such large numbers it is likely that the randomization process would help ensure generalizability.

It is refreshing to see a well conducted large clinical trial that looks at an inexpensive drug and measures meaningful outcomes rather than some manufactured combined endpoint that gives a positive result for a new expensive me too drug.

The trials of the mega expensive Factor VIIa did not work in these sick patients and had many concerning adverse effects. Although the mechanism of action of tranexamic acid in bleeding trauma patients remains unexplained, this large trial offers promise for an affordable therapeutic alternative to reduce post-traumatic bleeding and deaths.

The Bottom Line: The use of tranexamic acid in the trauma patient with significant bleeding reduces mortality by 1.5% without increasing thromboembolic events. TXA is a safe and effective treatment in patients with hemorrhagic shock from trauma in reducing mortality. It is an inexpensive therapy, which should be included in the care of these critically injured patients.

Case Resolution: Based on your knowledge of the CRASH2 study, you decide to begin TXA treatment. You give 1 gram of TXA over 10 minutes and hang an infusion of 1 gram over the next 8 hours. The patient goes for an Ex-lap where he’s found to have a grade 5 splenic laceration and a grade 3 liver laceration. The patient also has an angio of the pelvis and has embolization to some bleeding veins in the pelvis. His postoperative course is rocky but he is discharged to rehabilitation 3 weeks later.

Dr. Anand Swaminathan

Clinical Application: If it hasn’t changed what you do, it should. TXA is an inexpensive drug that is found in most hospitals that have operating rooms since it has been used in this setting for years.

This study did not find an increased rate of clinically significant clotting. TXA should be administered to patients with severe trauma. Additionally, CRASH-2 opened the doors on the use of TXA in bleeding.

We have an article showing great efficacy for epistaxis, there’s a study going on now for the use in post-partum hemorrhage. I’ve used it for intraoral bleeding in patients on agents like clopidogrel and Coumadin and in patients with massive GI bleeding. The indications for this drug continue to expand.

What Do I Tell Patients: You have had serious trauma with significant bleeding. We are going to give you a drug that should help control the bleeding and improve your chances of survival.

Keener Kontest: Last weeks winner was Benjamin Flam from Sweden. Ben knew that the deaf, dumb and blind kid sure played a mean pinball.

If you want to play the Keener Kontest this week then listen to the podcast for the question. Email me your answer at TheSGEM@gmail.com with “keener” in the subject line. The first person to correctly answer the question will receive a cool skeptical prize.