CRASH-3: a win for patients with traumatic brain injury
Authors: Andrew P Cap
Journal: The Lancet (2019)

Traumatic brain injury (TBI) is among the most dreaded and tragic of diagnoses. At least one clinical trial has shown that despite the most advanced care available, mortality from TBI, either in isolation or with concomitant polytrauma, can exceed 50%.1Galvagno Jr, SM Fox EE Appana SN et al.Outcomes after concomitant traumatic brain injury and hemorrhagic shock: a secondary analysis from the Pragmatic, Randomized Optimal Platelets and Plasma Ratios trial.J Trauma Acute Care Surg. 2017; 83: 668-674Crossref PubMed Scopus (31) Google Scholar Every physician who has cared for patients with TBI has felt the frustration that stems from being unable to alter the fatal course of traumatic brain haemorrhage in a previously healthy person. Over the past several decades, patients with TBI, their families, and their health-care providers have hoped for improved approaches to treating this condition. Indeed, governments have devoted considerable resources to developing improved management strategies for TBI. What have we learned? Despite compelling physiological logic and promising preclinical data, attempts to treat patients with TBI with such diverse approaches as corticosteroids,2Edwards P Arango M Balica L et al.Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months.Lancet. 2005; 365: 1957-1959Summary Full Text Full Text PDF PubMed Scopus (558) Google Scholar progesterone,3Skolnick BE Maas AI Narayan RK et al.A clinical trial of progesterone for severe traumatic brain injury.N Engl J Med. 2014; 371: 2467-2476Crossref PubMed Scopus (354) Google Scholar and brain cooling4Cooper DJ Nichol AD Bailey M et al.Effect of early sustained prophylactic hypothermia on neurologic outcomes among patients with severe traumatic brain injury: the POLAR randomized clinical trial.JAMA. 2018; 320: 2211-2220Crossref PubMed Scopus (148) Google Scholar have been ineffective or worse. Interventions designed to target specific injury mechanisms such as increased permeability of the blood–brain barrier through bradykinin receptor inhibition (anatibant5Shakur H Andrews P Asser T et al.The BRAIN TRIAL: a randomised, placebo controlled trial of a bradykinin B2 receptor antagonist (anatibant) in patients with traumatic brain injury.Trials. 2009; 10: 109Crossref PubMed Scopus (43) Google Scholar) are promising but require further study.6Marcos-Contreras OA Martinez de Lizarrondo S Bardou I et al.Hyperfibrinolysis increases blood–brain barrier permeability by a plasmin- and bradykinin-dependent mechanism.Blood. 2016; 128: 2423-2434Crossref PubMed Scopus (76) Google Scholar The hard truths of TBI care learned from war and everyday TBI are quite simple and obvious: control bleeding, and avoid hypotension7Spaite DW Hu C Bobrow BJ et al.Mortality and prehospital blood pressure in patients with major traumatic brain injury: implications for the hypotension threshold.JAMA Surg. 2017; 152: 360-368Crossref PubMed Scopus (95) Google Scholar and hypoxia,8Spaite DW Hu C Bobrow BJ et al.The effect of combined out-of-hospital hypotension and hypoxia on mortality in major traumatic brain injury.Ann Emerg Med. 2017; 69: 62-72Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar or the patient will die. Bleeding can potentially be targeted to alter the clinical course of TBI. Coagulopathy is a widely acknowledged contributor to TBI mortality and is associated with TBI severity.9Cap AP Spinella PC Severity of head injury is associated with increased risk of coagulopathy in combat casualties.J Trauma. 2011; 71: S78-S81Crossref PubMed Scopus (39) Google Scholar Although many aspects of coagulation function have been studied in this context, fibrinolysis is clearly a major driver of TBI-associated coagulopathy10Zhang J Zhang F Dong JF Coagulopathy induced by traumatic brain injury: systemic manifestation of a localized injury.Blood. 2018; 131: 2001-2006Crossref PubMed Scopus (59) Google Scholar and haemorrhagic progression11Karri J Cardenas JC Matijevic N et al.Early fibrinolysis associated with hemorrhagic progression following traumatic brain injury.Shock. 2017; 48: 644-650Crossref PubMed Scopus (23) Google Scholar of injury. Clinical assessment of the antifibrinolytic drug tranexamic acid to reduce TBI-associated mortality is logical, particularly in view of the mortality reductions observed with tranexamic acid use in polytrauma patients without TBI12CRASH-2 trial collaboratorsEffects 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. 2010; 376: 23-32Summary Full Text Full Text PDF PubMed Scopus (2109) Google Scholar and in women with post-partum haemorrhage.13WOMAN Trial CollaboratorsEffect 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. 2017; 389: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (720) Google Scholar In The Lancet, the CRASH-3 trial collaborators14The CRASH-3 trial collaboratorsEffects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial.Lancet. 2019; (published online Oct 14)https://doi.org/10.1016/S0140-6736(19)32233-0Google Scholar report the results of a randomised, placebo-controlled trial of 12 737 adults with TBI (mean age 41·7 years [SD 19·0]; 80% men, 20% women). In patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86–1·02]). There was a significant reduction in risk of head injury-related mortality when tranexamic acid was administered within 3 h of injury to patients with mild-to-moderate TBI (RR 0·78 [95% CI 0·64–0·95]), but not in patients with severe head injury (0·99 [0·91–1·07]). This study represents an enormous effort in studying a difficult clinical problem. Considering the results of CRASH-3 with those of CRASH-212CRASH-2 trial collaboratorsEffects 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. 2010; 376: 23-32Summary Full Text Full Text PDF PubMed Scopus (2109) Google Scholar (20 211 patients with trauma) and WOMAN13WOMAN Trial CollaboratorsEffect 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. 2017; 389: 2105-2116Summary Full Text Full Text PDF PubMed Scopus (720) Google Scholar (20 060 patients with peripartum haemorrhage), more than 53 000 patients have been randomly assigned in the study of tranexamic acid and the drug's effects on patients with bleeding. The results of each study independently and together are clear: tranexamic acid reduces risk of death due to bleeding, regardless of the cause. Furthermore, tranexamic acid must be given early—within 3 h of bleeding onset—to be effective. These data suggest a fundamental truth regarding the pathophysiology of life-threatening haemorrhage—namely, that early activation of the fibrinolytic protease cascade is intimately linked to poor outcomes in patients with bleeding, perhaps because of various mechanisms,15Cap AP Plasmin: a driver of hemovascular dysfunction.Blood. 2016; 128: 2375-2376Crossref PubMed Scopus (8) Google Scholar including worsened bleeding due to clot breakdown, activation of inflammatory pathways, and increased endothelial permeability leading to tissue, especially brain, oedema. Tranexamic acid offers a means to mitigate this maladaptive response to injury. CRASH-3 is the first trial of a pharmacological intervention applied in the acute setting to show improved outcomes in patients with TBI. The use of 28-day head injury-related mortality as the primary endpoint probably biased the treatment effect towards the null because tranexamic acid is most likely to benefit patients with TBI with intracranial bleeding at risk of early mortality, whereas late deaths are unlikely to be affected by tranexamic acid. Indeed, the authors report that the greatest reduction in head injury-related deaths occurred in the first 24 h after injury in a manner consistent with that observed in CRASH-2. Future studies of tranexamic acid or other haemostatic interventions should reflect what is physiologically plausible and focus on endpoints of early bleeding-related death that clearly link intervention to outcome. In the CRASH-3 trial, tranexamic acid appears to be safe in patients with TBI, but as acknowledged by the authors, a clot-stabilising intervention such as tranexamic acid might cause an increase in risk of venous thromboembolism that was not captured in the study. An additional important limitation of the CRASH-2, CRASH-3, and WOMAN trials is that tranexamic acid dosing regimens were very similar. Future study might be warranted to explore the effects of increased tranexamic acid doses in bleeding patients, or possibly alternative routes of administration such as intramuscular administration that might facilitate earlier intervention. Future studies of TBI could consider combining the antifibrinolytic effects of tranexamic acid on bleeding with blockade of bradykinin receptors, which could reduce brain oedema and potentially yield greater reductions in mortality. Despite its limitations, CRASH-3 is a remarkable study that will change practice, and tranexamic acid will benefit future patients with TBI who might reasonably have a chance of recovery from their injuries. I declare no competing interests. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting the views of the US Department of the Army or the US Department of Defense. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trialOur results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. Full-Text PDF Open Access