A nested mechanistic sub-study into the effect of tranexamic acid versus placebo on intracranial haemorrhage and cerebral ischaemia in isolated traumatic brain injury: study protocol for a randomised controlled trial (CRASH-3 Trial Intracranial Bleeding Mechanistic Sub-Study [CRASH-3 IBMS])

Mahmood, Abda; Roberts, Ian; Shakur, Haleema

doi:10.1186/s13063-017-2073-6

Cited by 21 publications

(29 citation statements)

References 71 publications

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“…30 A nested randomized controlled trial (RCT) within the CRASH-3 trial (CRASH-3 IBMS) is the mechanistic substudy to evaluate the effect of TxA on intracranial hemorrhage and cerebral ischemia in isolated TBI. 31 The other trial is investigating the application of TxA in a prehospital setting in TBI patients within 2 hours of injury (NCT02645552, NCT01990768). 32…”

Section: Ongoing Researchmentioning

confidence: 99%

Tranexamic Acid in Neuroanesthesia and Neurocritical Care: Time for Its Critical Appraisal

Hooda

Radhakrishnan

2019

Journal of Neuroanaesthesiology and Critical Care

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There is a renewed interest in the use of antifibrinolytics, especially tranexamic acid (TxA), in varied clinical settings such as trauma, perioperative bleeding, cardiac surgery, and multilevel spine instrumentation procedures. Because of its prothrombotic potential, the use of TxA in neurosurgical disorders has not gained popularity since this subset of the population is more prone to developing thromboembolic complications. However, recent studies have shown that TxA reduces blood loss, reduces the need for allogeneic blood transfusion, and is associated with minimal side effects. In this narrative review, Google Scholar, PubMed, and EMBASE databases were searched to identify publications relevant to the current use of TxA in varied neurosurgical and critical care settings. These publications were analyzed, and a summary of the findings and the role of future research on this drug are presented in this review.

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Section: Ongoing Researchmentioning

confidence: 99%

Tranexamic Acid in Neuroanesthesia and Neurocritical Care: Time for Its Critical Appraisal

Hooda

Radhakrishnan

2019

Journal of Neuroanaesthesiology and Critical Care

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“…In line with ICH-GCP guidelines, an AE is considered as serious if it results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or in a congenital anomaly/birth defect 16 . If there is a possibility that an AE is due to the trial drug, it is an adverse reaction.…”

Section: Statistical Analysis Planmentioning

confidence: 99%

“…This sub-study aims to examine the mechanism of action of tranexamic acid by evaluating brain images acquired before and after randomisation 16 . Brain images are primarily examined for evidence of intracranial haemorrhage and cerebral infarction.…”

Section: Other Analyses: To Be Reported In Separate Publicationsmentioning

confidence: 99%

Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

Roberts¹,

Belli²,

Brenner³

et al. 2018

Wellcome Open Res

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Background: Worldwide, traumatic brain injury (TBI) kills or hospitalises over 10 million people each year. Early intracranial bleeding is common after TBI, increasing the risk of death and disability. Tranexamic acid reduces blood loss in surgery and death due to bleeding in trauma patients with extra-cranial injury. Early administration of tranexamic acid in TBI patients might limit intracranial bleeding, reducing death and disability. The CRASH-3 trial aims to provide reliable evidence on the effect of tranexamic acid on death and disability in TBI patients. We will randomly allocate about 13,000 TBI patients to an intravenous infusion of tranexamic acid or matching placebo in addition to usual care. This paper presents a protocol update (version 2.1) and statistical analysis plan for the CRASH-3 trial. Results: The primary outcome is head injury death in hospital within 28 days of injury for patients treated within 3 hours of injury (deaths in patients treated after 3 hours will also be reported). Because there are strong scientific reasons to expect that tranexamic acid will be most effective in patients treated immediately after injury and less effective with increasing delay, the effect in patients treated within one hour of injury is of particular interest. Secondary outcomes are all-cause and cause-specific mortality, vascular occlusive events (myocardial infarction, pulmonary embolism, deep vein thrombosis, stroke), disability based on the Disability Rating Scale and measures suggested by patient representatives, seizures, neurosurgical intervention, neurosurgical blood loss, days in intensive care and adverse events. Sub-group analyses will examine the effect of tranexamic acid on head injury death stratified by time to treatment, severity of TBI and baseline risk. Conclusion: The CRASH-3 trial will provide reliable evidence of the effectiveness and safety of tranexamic acid in patients with acute TBI. Registration: International Standard Randomised Controlled Trials registry ( ISRCTN15088122) 19/07/2011, and ClinicalTrials.gov ( NCT01402882) 25/07/2011.

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“…5 also have a direct effect on the structural and functional integrity of white matter, with postinjury compensatory sprouting in corticofugal projections occurring through the reestablished tPA activity. 58 Presently, the trial is recruiting, but hopefully it will be completed by 2020. This recommendation is based primarily on the CRASH-2 trial (Clinical Randomization of an Anti-fibrinolytic in trauma patients with Significant Hemorrhage), which showed a reduction in the risk of death from major bleeding by tranexamic acid in multiple trauma patients.…”

mentioning

confidence: 99%

“…To investigate this question, the CRASH-3 trail was initiated with a focus on tranexamic acid in TBI patients. 58 Presently, the trial is recruiting, but hopefully it will be completed by 2020.…”

mentioning

confidence: 99%

Plasminogen activator inhibitor‐1 augments damage by impairing fibrinolysis after traumatic brain injury

Griemert

Schwarzmaier

Hummel

et al. 2019

Annals of Neurology

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Objective Plasminogen activator inhibitor‐1 (PAI‐1) is the key endogenous inhibitor of fibrinolysis, and enhances clot formation after injury. In traumatic brain injury, dysregulation of fibrinolysis may lead to sustained microthrombosis and accelerated lesion expansion. In the present study, we hypothesized that PAI‐1 mediates post‐traumatic malfunction of coagulation, with inhibition or genetic depletion of PAI‐1 attenuating clot formation and lesion expansion after brain trauma. Methods We evaluated PAI‐1 as a possible new target in a mouse controlled cortical impact (CCI) model of traumatic brain injury. We performed the pharmacological inhibition of PAI‐1 with PAI‐039 and stimulation by tranexamic acid, and we confirmed our results in PAI‐1–deficient animals. Results PAI‐1 mRNA was time‐dependently upregulated, with a 305‐fold peak 12 hours after CCI, which effectively counteracted the 2‐ to 3‐fold increase in cerebral tissue‐type/urokinase plasminogen activator expression. PAI‐039 reduced brain lesion volume by 26% at 24 hours and 43% at 5 days after insult. This treatment also attenuated neuronal apoptosis and improved neurofunctional outcome. Moreover, intravital microscopy demonstrated reduced post‐traumatic thrombus formation in the pericontusional cortical microvasculature. In PAI‐1–deficient mice, the therapeutic effect of PAI‐039 was absent. These mice also displayed 13% reduced brain damage compared with wild type. In contrast, inhibition of fibrinolysis with tranexamic acid increased lesion volume by 25% compared with vehicle. Interpretation This study identifies impaired fibrinolysis as a critical process in post‐traumatic secondary brain damage and suggests that PAI‐1 may be a central endogenous inhibitor of the fibrinolytic pathway, promoting a procoagulatory state and clot formation in the cerebral microvasculature. Ann Neurol 2019;85:667–680

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A nested mechanistic sub-study into the effect of tranexamic acid versus placebo on intracranial haemorrhage and cerebral ischaemia in isolated traumatic brain injury: study protocol for a randomised controlled trial (CRASH-3 Trial Intracranial Bleeding Mechanistic Sub-Study [CRASH-3 IBMS])

Cited by 21 publications

References 71 publications

Tranexamic Acid in Neuroanesthesia and Neurocritical Care: Time for Its Critical Appraisal

Tranexamic Acid in Neuroanesthesia and Neurocritical Care: Time for Its Critical Appraisal

Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

Plasminogen activator inhibitor‐1 augments damage by impairing fibrinolysis after traumatic brain injury

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