Critical Care Trailblazers: The CRASH-2 trial

Introduction

Back in the 1950s, in war-torn Japan, a husband-and-wife team of researchers, Shosuke and Utako Okamoto were scripting medical history. They were passionately focused on identifying an antagonist of clot breakdown that might arrest severe hemorrhage. Exsanguinating postpartum hemorrhage was a leading cause of maternal mortality in Japan during this period. They realized that the clot became “liquified”, often leading to unrelenting hemorrhage – the process we know today as fibrinolysis. Plasmin was later identified as the enzyme that led to clot breakdown. The couple spent tireless hours in their laboratory in pursuit of an agent that could inhibit plasmin and thus, prevent clot breakdown. They finally zeroed in on the amino acid lysine as a likely plasmin inhibitor. An analog of lysine, aminocaproic acid, was soon introduced as a potent inhibitor of plasmin. Aminocaproic acid was clinically effective, but relatively less potent and required large doses, often leading to side effects. The search for a more potent agent led to the discovery of tranexamic acid, 27 times as powerful as aminocaproic acid.

Shosuke and Utako Okamoto first reported tranexamic acid as a potent inhibitor of fibrinolysis in The Keio Journal of Medicine in September 1962 (1). However, their discovery was received with icy disdain by the male-dominated research community in Japan. Obstetricians too seemed largely uninterested; use was confined to reducing heavy menstrual bleeding and following tooth extraction. Utako Okamoto went on to become chair at the Kobe Gakuin University in Japan from 1966 to 1990. She died on 21 April 2016, just a year before the publication of the WOMAN trial that conclusively demonstrated improved survival with tranexamic acid in severe postpartum hemorrhage. Today, tranexamic acid features in the World Health Organization’s list of essential medicines.

Background to the CRASH-2 trial

The hemostatic system plays a key role in maintaining circulation following vascular injury due to major surgery or trauma. The coagulation cascade is activated to control bleeding. The clotting mechanism is countered by the fibrinolytic system that prevents excessive clotting. In some situations, the fibrinolytic mechanism appears to evoke a pathological response leading to uncontrolled hemorrhage (2). Antifibrinolytic agents appear to decrease blood loss following surgery, with no greater risk of complications (3).

A Cochrane review of 2007, including 53 randomized controlled trials (RCTs) had revealed a reduced requirement for blood transfusion with tranexamic acid use among patients undergoing elective surgery, although it had no impact on mortality (3). The CRASH-2 investigators searched for clinical trials of tranexamic acid in severe trauma, but none seemed to exist.

Considering the similar hemostatic response following major surgery and trauma, the authors of the CRASH-2 trial hypothesized that tranexamic acid might reduce hemorrhage-related mortality in victims of major trauma (4).

Population and design

The CRASH-2 RCT compared the effect of tranexamic acid compared with placebo among trauma patients who were bleeding or were at risk of significant hemorrhage. The study was conducted in 274 hospitals across 40 countries and commenced recruitment in May 2005. Randomization was in blocks of eight and stratified by center.

Inclusion criteria

Adult trauma victims with evidence of significant hemorrhage, defined as a systolic blood pressure of less than 90 mm Hg, or a heart rate of >110/min, or considered to be at risk of significant hemorrhage, within 8 hours of injury, were considered for enrolment. Patients were eligible for randomization if the treating clinician was unsure whether to treat with tranexamic acid.

Exclusion criteria

Patients who were considered likely to benefit from tranexamic acid according to clinician judgment received the drug anyway and were not included in the study. Patients who had a clear contraindication to tranexamic acid were also excluded.

Intervention

Tranexamic acid was administered as an initial loading dose of 1g over 10 minutes, followed by 1 g over 8 hours as an infusion. Each treatment pack contained four ampoules of tranexamic acid, 500 mg.

Control

The control group received normal saline as placebo. The treatment packs of tranexamic acid and placebo were identical and ensured blinding.

Sample size

The risk of death in study patients was assumed to be around 20%. The authors considered a 2% improvement in survival among tranexamic acid-treated patients as a clinically important benefit. The sample size required to identify this difference was estimated to be 20,000 patients, allowing an 85% chance of attaining a two-sided p value of <0.01, and a 95% chance of a two-sided p value of <0.05. Analysis was on an intention-to-treat basis.

Results

A total of 20, 211 were randomized – 10,096 patients were assigned to receive tranexamic acid and 10,015 patients to receive placebo. After exclusion of patients who withdrew consent and those who were lost to follow-up, in the final analysis, 10,060 patients were included in the tranexamic acid arm, and 10,060 patients in the placebo arm.

Patients in the tranexamic acid and placebo arms were well-matched at baseline; there were more patients who suffered blunt (67.5% vs. 67.7%) compared to penetrating injury. The median time from injury to enrolment was 2.8 vs. 2.9 hours.

The primary outcome: all-cause hospital mortality at 4 weeks

The all-cause mortality was significantly lower in the tranexamic acid group; 1463/10,060 (14.5%) patients died in the tranexamic group compared with 1613/10,067 (16.0%) patients in the placebo group. The relative risk of mortality with tranexamic acid was 0.91, 95% CI: (0.85–0.97), p = 0.0035. Based on these figures, 67 patients required tranexamic acid treatment to save one life (the number needed to treat, NNT). The fragility index (the minimum number of patients who need to change from survivor to non-survivor status to make the result non-significant) was 48, larger than most contemporary landmark studies. On subgroup analysis, there was no difference in the all-cause mortality in subgroups of patients based on systolic blood pressures, the Glasgow coma score, blunt vs. penetrating injury, and those who received early compared to late treatment with tranexamic acid.

Secondary outcomes

Death due to bleeding was also lower in the tranexamic acid group (4.9% vs. 5.7%, p = 0.0077). Mortality associated with vascular occlusion (a potential complication of tranexamic acid use), including myocardial infarction, stroke, and pulmonary embolism, was similar between the two groups. Similarly, deaths due to multiorgan failure and traumatic brain injury were also similar. Transfusion of blood products and the number of surgical interventions performed were also similar between the two groups. The number of patients who were dead or dependent at discharge or at 28 days, and those who were asymptomatic at 28 days were also not significantly different between the two groups.

Strengths of the study

The CRASH-2 trial was one of the largest RCTs in critical care and was powered to detect a 2% difference in mortality. Being multicentric, involving 274 centers in 40 countries, it had robust external validity. The study was blinded, minimizing the risk of bias. The loss to follow-up was minimal. The primary outcome was mortality, an important and clinically appropriate endpoint.

Limitations

One of the criteria for study inclusion was a risk of significant bleeding as judged by the clinician; the subjectivity in decision-making could have led to selection bias. The treating clinicians could decide to use tranexamic acid if they considered it to be clinically indicated, and thus exclude the patient from the trial. The number of patients excluded by this criterion is unclear. Considering the relatively low incidence of occlusive events, definitive conclusions cannot be drawn regarding whether tranexamic acid administration may lead to such events. The fibrinolytic activity was not evaluated, casting doubts over the mechanism of action of tranexamic acid. Although the authors hypothesized that the efficacy of tranexamic acid might be due to its inhibitory effect on pathological hyperfibrinolytic activity that may occur in bleeding trauma patients, there is no substantive evidence to support this theory. The use of blood products was not different between groups. The lack of an effect on transfusions may be because decisions on blood product administration are usually made in the early phase of trauma, much earlier than the 8-hour window during which tranexamic acid was administered. Furthermore, it is quite likely that survival alone could have resulted in a greater window of opportunity to receive transfusions (competing risks). There was no stratification based on the severity of injury, hence it is unclear whether the efficacy of tranexamic acid may be confined to subgroups of patients with severe injury.

Subsequent evidence

Exploratory analysis

In an exploratory analysis published a year later, the investigators evaluated the effect of the timing of tranexamic acid administration on outcomes (5). Overall, 1063 deaths (35%) occurred due to bleeding. Early treatment saved more lives. Death due to bleeding among patients who were administered tranexamic acid within the first hour of injury was significantly lower compared with placebo (5.3% vs. 7.7%; RR: 0.68, 95% CI 0·57–0·82). Administration between 1–3 hours also led to reduced bleeding-related mortality (4·8% vs. 6·1%; RR 0·79, 95% CI 0·64–0·97). In contrast, tranexamic acid administration after 3 hours of injury appeared to increase mortality. This exploratory analysis strongly suggested that early treatment, within the first 3 hours saves lives; later treatment may in fact, lead to harm. The systolic blood pressure, Glasgow coma score, or type of injury had no impact on the effect of tranexamic acid on death due to bleeding.

The MATTERS study

The Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERS) study evaluated the use of tranexamic acid in the combat setting, to assess the impact on coagulopathy and survival following battlefield injury. This retrospective observational study compared tranexamic administration to a control group that received standard care alone; patients included in the study had received at least one unit of packed red cells. The study was conducted at a single surgical center at Camp Bastion, in Southern Afghanistan. Patients who received tranexamic acid revealed lower mortality compared to the control group (17.4% vs 23.9%; p = 0.03). Improved survival was particularly evident among the most severely injured, in penetrating trauma, and those requiring more than 10 units of red cell transfusion (14.4% vs 28.1%; p = 0.004). The authors concluded that tranexamic acid administration combined with resuscitation based on blood products leads to improved survival and alleviation of coagulopathy. The most profound benefit was observed among patients who underwent massive transfusion. They went on to recommend tranexamic acid as part of the resuscitation strategy in severe wartime injury and hemorrhage (6). A later study by the same group found that cryoprecipitate in combination with tranexamic acid may enhance survival benefit among victims of combat injuries who required red cell transfusion (7).

The impact of the study

The CRASH-2 trial, despite limitations, generated a cascading impact in clinical practice leading to widespread acceptance and adoption by the British and American armies. The British army introduced its use in the battlefields of Afghanistan; the WHO added tranexamic acid to its list of essential medicines. However, ambivalence and inertia with the routine use of tranexamic acid in severe trauma was evident in some healthcare settings, perhaps due to the indifference of pharmaceutical companies in promoting a cheap, generic drug. As Ian Roberts, one of the CRASH-2 collaborators surmised, “if pharma is not interested, it’s not done.” The CRASH-2 trial also stimulated research on tranexamic administration in other types of bleeding. The WOMAN trial, published in 2017, including more than 20,000 patients, revealed that it is highly effective in postpartum hemorrhage; tranexamic acid significantly reduced death due to bleeding with no apparent adverse effects (8).

Summary

Exsanguinating hemorrhage from severe trauma is a monumental health problem across the globe. The CRASH-2 trial revealed that an inexpensive, widely available, and easily administered drug could save lives in patients at risk of bleeding following severe trauma. It was a large, pragmatic, real-world study conducted across several continents, thus establishing the generalizability of the results. Although the mechanism of action is unsubstantiated, tranexamic acid represents an affordable method of improving survival in trauma-related hemorrhage, with no apparent increase in thrombosis-related complications. Pre-hospital administration of tranexamic acid to all trauma victims as a single bolus appears pragmatic and easy to apply in clinical practice. The CRASH-2 trial turned out to be a truly pivotal study with the potential to save lives through a simple intervention.

References

1. Okamoto S, Okamoto U. Amino-Methyl-Cyclohexane-Carboxylic Acid: Amcha. Keio J Med. 1962;11(3):105–15.

2. Lawson JH, Murphy MP. Challenges for providing effective hemostasis in surgery and trauma. Semin Hematol. 2004 Jan;41(1 Suppl 1):55–64.

3. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, McClelland B, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD001886.

4. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet Lond Engl. 2010 Jul 3;376(9734):23–32.

5. CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet Lond Engl. 2011 Mar 26;377(9771):1096–101, 1101.e1-2.

6. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg Chic Ill 1960. 2012 Feb;147(2):113–9.

7. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg. 2013 Mar;148(3):218–25.

8. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet Lond Engl. 2017 May 27;389(10084):2105–16.