2022
Collaborators, The CRASH-4
Intramuscular tranexamic acid for symptomatic mild traumatic brain injury in older adults: a pilot randomised, placebo-controlled trial (The CRASH-4 trial pilot phase). Journal Article Forthcoming
In: Forthcoming.
Abstract | Links | BibTeX | Tags:
@article{nokey,
title = {Intramuscular tranexamic acid for symptomatic mild traumatic brain injury in older adults: a pilot randomised, placebo-controlled trial (The CRASH-4 trial pilot phase).},
author = {The CRASH-4 Collaborators},
url = {https://crash4.lshtm.ac.uk/wp-content/uploads/2022/09/CRASH-4-Pilot-phase-paper.pdf},
year = {2022},
date = {2022-09-01},
urldate = {2022-09-01},
abstract = {Background
Mild traumatic brain injury (TBI) can cause death, disability and dementia in older adults. Timely tranexamic acid (TXA) treatment, by preventing or limiting intracranial bleeding, could reduce these risks. The CRASH-4 trial will assess the effects of early intramuscular TXA in older adults with mild TBI. To test the trial procedures and the acceptability of the intervention, we conducted a pilot phase.
Methods
We recruited patients aged 50 years or older if they had a history or signs (laceration, bruise, swelling or pain in head or face) of a head injury; a GCS ≥ 13; any impairment of consciousness and were within 3 hours of the injury. We enrolled patients at the scene of the injury or in the ambulance. We also enrolled patients who presented directly to the emergency department. We randomly allocated patients to receive an intramuscular injection of 500 mg tranexamic acid or matching placebo. We gave one 5mL injection (100mg/ml TXA or placebo) or two 2.5mL injections depending on muscle mass. The objectives of the pilot were (1) to test all trial procedures, including the willingness of paramedics and emergency physicians to recruit patients and the willingness of patients to be enrolled, (2) to determine the rate of recruitment (number of patients per site per month), (3) to assess the acceptability of the intramuscular injection and (4) to determine event rates and rates of follow up.
Results
We recruited 493 patients between April 2021 and July 2022. Their mean age was 73 years (SD=12 years) and 246 (50%) of patients were female. The mean time from injury to randomization was 2.4 hours (SD=0.7 hours). The average recruitment rate was 1.7 patients per site per month. A single 5mL injection was received by 62% of patients and 38% of patients received two 2.5mL injections. An injection site reaction was reported in 4 patients, all of whom had bruising at the injection site (0.8%). There were 27 serious adverse events reported but none were suspected to be related to the trial treatment. Of the 483 randomised participants with outcome data, 54% were discharged from the emergency department within 24 h of their injury (n=261). Of the 220 patients that were admitted to hospital, 41% were admitted due to their head injury, 45% were admitted for another injury or medical condition, 4% were admitted while awaiting transfer to the community and 10% were admitted for other reasons. The average duration of hospital admission was 0.4 days (IQR=0.2-2.2). The average duration of admission was 4.6 days (IQR=2.1-10.7) for patients with intracranial haemorrhage compared to 0.4 days (IQR=0.2-1.8) for patients who did not. 43 patients had intracranial bleeding (9%), 3 had neurosurgery (0.6%) and 7 patients died (1.5%).
Discussion
The intramuscular injection (TXA or placebo) was well tolerated by older adults with mild TBI. Based on the observed recruitment and outcome event rates, a large trial of the efficacy and safety of early intramuscular tranexamic acid for older adults with mild traumatic brain injury appears feasible.
Trial registration: The trial is registered at ClinicalTrials.gov: NCT04521881 and EudraCT number: 2020-003391-40.
Keywords: Antifibrinolytic; clinical trial; tranexamic acid; traumatic brain injury; intracranial bleeding.
},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
Background
Mild traumatic brain injury (TBI) can cause death, disability and dementia in older adults. Timely tranexamic acid (TXA) treatment, by preventing or limiting intracranial bleeding, could reduce these risks. The CRASH-4 trial will assess the effects of early intramuscular TXA in older adults with mild TBI. To test the trial procedures and the acceptability of the intervention, we conducted a pilot phase.
Methods
We recruited patients aged 50 years or older if they had a history or signs (laceration, bruise, swelling or pain in head or face) of a head injury; a GCS ≥ 13; any impairment of consciousness and were within 3 hours of the injury. We enrolled patients at the scene of the injury or in the ambulance. We also enrolled patients who presented directly to the emergency department. We randomly allocated patients to receive an intramuscular injection of 500 mg tranexamic acid or matching placebo. We gave one 5mL injection (100mg/ml TXA or placebo) or two 2.5mL injections depending on muscle mass. The objectives of the pilot were (1) to test all trial procedures, including the willingness of paramedics and emergency physicians to recruit patients and the willingness of patients to be enrolled, (2) to determine the rate of recruitment (number of patients per site per month), (3) to assess the acceptability of the intramuscular injection and (4) to determine event rates and rates of follow up.
Results
We recruited 493 patients between April 2021 and July 2022. Their mean age was 73 years (SD=12 years) and 246 (50%) of patients were female. The mean time from injury to randomization was 2.4 hours (SD=0.7 hours). The average recruitment rate was 1.7 patients per site per month. A single 5mL injection was received by 62% of patients and 38% of patients received two 2.5mL injections. An injection site reaction was reported in 4 patients, all of whom had bruising at the injection site (0.8%). There were 27 serious adverse events reported but none were suspected to be related to the trial treatment. Of the 483 randomised participants with outcome data, 54% were discharged from the emergency department within 24 h of their injury (n=261). Of the 220 patients that were admitted to hospital, 41% were admitted due to their head injury, 45% were admitted for another injury or medical condition, 4% were admitted while awaiting transfer to the community and 10% were admitted for other reasons. The average duration of hospital admission was 0.4 days (IQR=0.2-2.2). The average duration of admission was 4.6 days (IQR=2.1-10.7) for patients with intracranial haemorrhage compared to 0.4 days (IQR=0.2-1.8) for patients who did not. 43 patients had intracranial bleeding (9%), 3 had neurosurgery (0.6%) and 7 patients died (1.5%).
Discussion
The intramuscular injection (TXA or placebo) was well tolerated by older adults with mild TBI. Based on the observed recruitment and outcome event rates, a large trial of the efficacy and safety of early intramuscular tranexamic acid for older adults with mild traumatic brain injury appears feasible.
Trial registration: The trial is registered at ClinicalTrials.gov: NCT04521881 and EudraCT number: 2020-003391-40.
Keywords: Antifibrinolytic; clinical trial; tranexamic acid; traumatic brain injury; intracranial bleeding.
Nutbeam, Tim; Roberts, Ian; Weekes, Lauren; Shakur-Still, Haleema; Brenner, Amy; Ageron, Francois-Xavier
In: British Journal of Anaesthesia, 2022.
@article{nokey,
title = {Use of tranexamic acid in major trauma: a sex-disaggragated analysis of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2 and CRASH-3) trials and UK trauma registry (Trauma and Audit Research Network) data},
author = {Tim Nutbeam and Ian Roberts and Lauren Weekes and Haleema Shakur-Still and Amy Brenner and Francois-Xavier Ageron},
doi = {https://doi.org/10.1016/j.bja.2022.03.032},
year = {2022},
date = {2022-05-18},
urldate = {2022-05-18},
journal = {British Journal of Anaesthesia},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Williams, Jack; Ker, Katharine; Roberts, Ian; Shakur-Still, Haleema; Miners, Alec
In: Trials, vol. 23, no. 370, 2022.
@article{nokey,
title = {A cost-effectiveness and value of information analysis to inform future research of tranexamic acid for older adults experiencing mild traumatic brain injury},
author = {Jack Williams and Katharine Ker and Ian Roberts and Haleema Shakur-Still and Alec Miners},
doi = {https://doi.org/10.1186/s13063-022-06244-6},
year = {2022},
date = {2022-05-03},
urldate = {2022-05-03},
journal = {Trials},
volume = {23},
number = {370},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2021
Goodwin, Laura; Nicholson, Helen; Robinson, Maria; Bedson, Adam; Black, Sarah; Kirby, Kim; Taylor, Hazel; Voss, Sarah; Benger, Jonathan
In: Emergency Medicine Journal , pp. 1-7, 2021.
@article{nokey,
title = { Barriers and facilitators to the administration of prehospital tranexamic acid: a paramedic interview study using the theoretical domains framework},
author = {Laura Goodwin and Helen Nicholson and Maria Robinson and Adam Bedson and Sarah Black and Kim Kirby and Hazel Taylor and Sarah Voss and Jonathan Benger},
doi = {10.1136/ emermed-2020-210622},
year = {2021},
date = {2021-10-25},
urldate = {2021-10-25},
journal = {Emergency Medicine Journal },
pages = {1-7},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
Grassin-Delyle, Stanislas; Shakur-Still, Haleema; Picetti, Roberto; Frimley, Lauren; Jarman, Heather; Davenport, Ross; McGuinness, William; Moss, Phil; Pott, Jason; Tai, Nigel; Lamy, Elodie; Urien, Saïk; Prowse, Danielle; Thayne, Andrew; Gilliam, Catherine; Pynn, Harvey; Roberts, Ian
Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial. Journal Article
In: British journal of anaesthesia, vol. 126, no. 1, pp. 201–209, 2020.
Abstract | Links | BibTeX | Tags:
@article{lshtm4658851,
title = {Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial.},
author = {Stanislas Grassin-Delyle and Haleema Shakur-Still and Roberto Picetti and Lauren Frimley and Heather Jarman and Ross Davenport and William McGuinness and Phil Moss and Jason Pott and Nigel Tai and Elodie Lamy and Saïk Urien and Danielle Prowse and Andrew Thayne and Catherine Gilliam and Harvey Pynn and Ian Roberts},
url = {https://crash4.lshtm.ac.uk/wp-content/uploads/2021/05/Grassin-Delyle-et-al-2020.pdf, Click Here to Download Article},
year = {2020},
date = {2020-09-01},
journal = {British journal of anaesthesia},
volume = {126},
number = {1},
pages = {201--209},
publisher = {Elsevier BV},
abstract = {BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0.5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0.5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).2019
CRASH-3, Trial Collaborators
In: LANCET, vol. 394, no. 10210, pp. 1713–1723, 2019.
Abstract | Links | BibTeX | Tags:
@article{lshtm4655598,
title = {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 trial.},
author = {Trial Collaborators CRASH-3},
url = {https://crash4.lshtm.ac.uk/wp-content/uploads/2021/05/CRASH-3-Trial-Collaborators-2019.pdf, Click Here to Download Article},
year = {2019},
date = {2019-11-01},
journal = {LANCET},
volume = {394},
number = {10210},
pages = {1713--1723},
publisher = {ELSEVIER SCIENCE INC},
abstract = {BACKGROUND: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. METHODS: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). RESULTS: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among 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]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). INTERPRETATION: Our 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. FUNDING: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). TRANSLATIONS: For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. METHODS: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). RESULTS: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among 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]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). INTERPRETATION: Our 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. FUNDING: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). TRANSLATIONS: For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.
2022
Collaborators, The CRASH-4
Intramuscular tranexamic acid for symptomatic mild traumatic brain injury in older adults: a pilot randomised, placebo-controlled trial (The CRASH-4 trial pilot phase). Journal Article Forthcoming
In: Forthcoming.
Abstract | Links | BibTeX | Tags:
@article{nokey,
title = {Intramuscular tranexamic acid for symptomatic mild traumatic brain injury in older adults: a pilot randomised, placebo-controlled trial (The CRASH-4 trial pilot phase).},
author = {The CRASH-4 Collaborators},
url = {https://crash4.lshtm.ac.uk/wp-content/uploads/2022/09/CRASH-4-Pilot-phase-paper.pdf},
year = {2022},
date = {2022-09-01},
urldate = {2022-09-01},
abstract = {Background
Mild traumatic brain injury (TBI) can cause death, disability and dementia in older adults. Timely tranexamic acid (TXA) treatment, by preventing or limiting intracranial bleeding, could reduce these risks. The CRASH-4 trial will assess the effects of early intramuscular TXA in older adults with mild TBI. To test the trial procedures and the acceptability of the intervention, we conducted a pilot phase.
Methods
We recruited patients aged 50 years or older if they had a history or signs (laceration, bruise, swelling or pain in head or face) of a head injury; a GCS ≥ 13; any impairment of consciousness and were within 3 hours of the injury. We enrolled patients at the scene of the injury or in the ambulance. We also enrolled patients who presented directly to the emergency department. We randomly allocated patients to receive an intramuscular injection of 500 mg tranexamic acid or matching placebo. We gave one 5mL injection (100mg/ml TXA or placebo) or two 2.5mL injections depending on muscle mass. The objectives of the pilot were (1) to test all trial procedures, including the willingness of paramedics and emergency physicians to recruit patients and the willingness of patients to be enrolled, (2) to determine the rate of recruitment (number of patients per site per month), (3) to assess the acceptability of the intramuscular injection and (4) to determine event rates and rates of follow up.
Results
We recruited 493 patients between April 2021 and July 2022. Their mean age was 73 years (SD=12 years) and 246 (50%) of patients were female. The mean time from injury to randomization was 2.4 hours (SD=0.7 hours). The average recruitment rate was 1.7 patients per site per month. A single 5mL injection was received by 62% of patients and 38% of patients received two 2.5mL injections. An injection site reaction was reported in 4 patients, all of whom had bruising at the injection site (0.8%). There were 27 serious adverse events reported but none were suspected to be related to the trial treatment. Of the 483 randomised participants with outcome data, 54% were discharged from the emergency department within 24 h of their injury (n=261). Of the 220 patients that were admitted to hospital, 41% were admitted due to their head injury, 45% were admitted for another injury or medical condition, 4% were admitted while awaiting transfer to the community and 10% were admitted for other reasons. The average duration of hospital admission was 0.4 days (IQR=0.2-2.2). The average duration of admission was 4.6 days (IQR=2.1-10.7) for patients with intracranial haemorrhage compared to 0.4 days (IQR=0.2-1.8) for patients who did not. 43 patients had intracranial bleeding (9%), 3 had neurosurgery (0.6%) and 7 patients died (1.5%).
Discussion
The intramuscular injection (TXA or placebo) was well tolerated by older adults with mild TBI. Based on the observed recruitment and outcome event rates, a large trial of the efficacy and safety of early intramuscular tranexamic acid for older adults with mild traumatic brain injury appears feasible.
Trial registration: The trial is registered at ClinicalTrials.gov: NCT04521881 and EudraCT number: 2020-003391-40.
Keywords: Antifibrinolytic; clinical trial; tranexamic acid; traumatic brain injury; intracranial bleeding.
},
keywords = {},
pubstate = {forthcoming},
tppubtype = {article}
}
Background
Mild traumatic brain injury (TBI) can cause death, disability and dementia in older adults. Timely tranexamic acid (TXA) treatment, by preventing or limiting intracranial bleeding, could reduce these risks. The CRASH-4 trial will assess the effects of early intramuscular TXA in older adults with mild TBI. To test the trial procedures and the acceptability of the intervention, we conducted a pilot phase.
Methods
We recruited patients aged 50 years or older if they had a history or signs (laceration, bruise, swelling or pain in head or face) of a head injury; a GCS ≥ 13; any impairment of consciousness and were within 3 hours of the injury. We enrolled patients at the scene of the injury or in the ambulance. We also enrolled patients who presented directly to the emergency department. We randomly allocated patients to receive an intramuscular injection of 500 mg tranexamic acid or matching placebo. We gave one 5mL injection (100mg/ml TXA or placebo) or two 2.5mL injections depending on muscle mass. The objectives of the pilot were (1) to test all trial procedures, including the willingness of paramedics and emergency physicians to recruit patients and the willingness of patients to be enrolled, (2) to determine the rate of recruitment (number of patients per site per month), (3) to assess the acceptability of the intramuscular injection and (4) to determine event rates and rates of follow up.
Results
We recruited 493 patients between April 2021 and July 2022. Their mean age was 73 years (SD=12 years) and 246 (50%) of patients were female. The mean time from injury to randomization was 2.4 hours (SD=0.7 hours). The average recruitment rate was 1.7 patients per site per month. A single 5mL injection was received by 62% of patients and 38% of patients received two 2.5mL injections. An injection site reaction was reported in 4 patients, all of whom had bruising at the injection site (0.8%). There were 27 serious adverse events reported but none were suspected to be related to the trial treatment. Of the 483 randomised participants with outcome data, 54% were discharged from the emergency department within 24 h of their injury (n=261). Of the 220 patients that were admitted to hospital, 41% were admitted due to their head injury, 45% were admitted for another injury or medical condition, 4% were admitted while awaiting transfer to the community and 10% were admitted for other reasons. The average duration of hospital admission was 0.4 days (IQR=0.2-2.2). The average duration of admission was 4.6 days (IQR=2.1-10.7) for patients with intracranial haemorrhage compared to 0.4 days (IQR=0.2-1.8) for patients who did not. 43 patients had intracranial bleeding (9%), 3 had neurosurgery (0.6%) and 7 patients died (1.5%).
Discussion
The intramuscular injection (TXA or placebo) was well tolerated by older adults with mild TBI. Based on the observed recruitment and outcome event rates, a large trial of the efficacy and safety of early intramuscular tranexamic acid for older adults with mild traumatic brain injury appears feasible.
Trial registration: The trial is registered at ClinicalTrials.gov: NCT04521881 and EudraCT number: 2020-003391-40.
Keywords: Antifibrinolytic; clinical trial; tranexamic acid; traumatic brain injury; intracranial bleeding.
Mild traumatic brain injury (TBI) can cause death, disability and dementia in older adults. Timely tranexamic acid (TXA) treatment, by preventing or limiting intracranial bleeding, could reduce these risks. The CRASH-4 trial will assess the effects of early intramuscular TXA in older adults with mild TBI. To test the trial procedures and the acceptability of the intervention, we conducted a pilot phase.
Methods
We recruited patients aged 50 years or older if they had a history or signs (laceration, bruise, swelling or pain in head or face) of a head injury; a GCS ≥ 13; any impairment of consciousness and were within 3 hours of the injury. We enrolled patients at the scene of the injury or in the ambulance. We also enrolled patients who presented directly to the emergency department. We randomly allocated patients to receive an intramuscular injection of 500 mg tranexamic acid or matching placebo. We gave one 5mL injection (100mg/ml TXA or placebo) or two 2.5mL injections depending on muscle mass. The objectives of the pilot were (1) to test all trial procedures, including the willingness of paramedics and emergency physicians to recruit patients and the willingness of patients to be enrolled, (2) to determine the rate of recruitment (number of patients per site per month), (3) to assess the acceptability of the intramuscular injection and (4) to determine event rates and rates of follow up.
Results
We recruited 493 patients between April 2021 and July 2022. Their mean age was 73 years (SD=12 years) and 246 (50%) of patients were female. The mean time from injury to randomization was 2.4 hours (SD=0.7 hours). The average recruitment rate was 1.7 patients per site per month. A single 5mL injection was received by 62% of patients and 38% of patients received two 2.5mL injections. An injection site reaction was reported in 4 patients, all of whom had bruising at the injection site (0.8%). There were 27 serious adverse events reported but none were suspected to be related to the trial treatment. Of the 483 randomised participants with outcome data, 54% were discharged from the emergency department within 24 h of their injury (n=261). Of the 220 patients that were admitted to hospital, 41% were admitted due to their head injury, 45% were admitted for another injury or medical condition, 4% were admitted while awaiting transfer to the community and 10% were admitted for other reasons. The average duration of hospital admission was 0.4 days (IQR=0.2-2.2). The average duration of admission was 4.6 days (IQR=2.1-10.7) for patients with intracranial haemorrhage compared to 0.4 days (IQR=0.2-1.8) for patients who did not. 43 patients had intracranial bleeding (9%), 3 had neurosurgery (0.6%) and 7 patients died (1.5%).
Discussion
The intramuscular injection (TXA or placebo) was well tolerated by older adults with mild TBI. Based on the observed recruitment and outcome event rates, a large trial of the efficacy and safety of early intramuscular tranexamic acid for older adults with mild traumatic brain injury appears feasible.
Trial registration: The trial is registered at ClinicalTrials.gov: NCT04521881 and EudraCT number: 2020-003391-40.
Keywords: Antifibrinolytic; clinical trial; tranexamic acid; traumatic brain injury; intracranial bleeding.
Nutbeam, Tim; Roberts, Ian; Weekes, Lauren; Shakur-Still, Haleema; Brenner, Amy; Ageron, Francois-Xavier
In: British Journal of Anaesthesia, 2022.
@article{nokey,
title = {Use of tranexamic acid in major trauma: a sex-disaggragated analysis of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2 and CRASH-3) trials and UK trauma registry (Trauma and Audit Research Network) data},
author = {Tim Nutbeam and Ian Roberts and Lauren Weekes and Haleema Shakur-Still and Amy Brenner and Francois-Xavier Ageron},
doi = {https://doi.org/10.1016/j.bja.2022.03.032},
year = {2022},
date = {2022-05-18},
urldate = {2022-05-18},
journal = {British Journal of Anaesthesia},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Williams, Jack; Ker, Katharine; Roberts, Ian; Shakur-Still, Haleema; Miners, Alec
In: Trials, vol. 23, no. 370, 2022.
@article{nokey,
title = {A cost-effectiveness and value of information analysis to inform future research of tranexamic acid for older adults experiencing mild traumatic brain injury},
author = {Jack Williams and Katharine Ker and Ian Roberts and Haleema Shakur-Still and Alec Miners},
doi = {https://doi.org/10.1186/s13063-022-06244-6},
year = {2022},
date = {2022-05-03},
urldate = {2022-05-03},
journal = {Trials},
volume = {23},
number = {370},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2021
Goodwin, Laura; Nicholson, Helen; Robinson, Maria; Bedson, Adam; Black, Sarah; Kirby, Kim; Taylor, Hazel; Voss, Sarah; Benger, Jonathan
In: Emergency Medicine Journal , pp. 1-7, 2021.
@article{nokey,
title = { Barriers and facilitators to the administration of prehospital tranexamic acid: a paramedic interview study using the theoretical domains framework},
author = {Laura Goodwin and Helen Nicholson and Maria Robinson and Adam Bedson and Sarah Black and Kim Kirby and Hazel Taylor and Sarah Voss and Jonathan Benger},
doi = {10.1136/ emermed-2020-210622},
year = {2021},
date = {2021-10-25},
urldate = {2021-10-25},
journal = {Emergency Medicine Journal },
pages = {1-7},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
Grassin-Delyle, Stanislas; Shakur-Still, Haleema; Picetti, Roberto; Frimley, Lauren; Jarman, Heather; Davenport, Ross; McGuinness, William; Moss, Phil; Pott, Jason; Tai, Nigel; Lamy, Elodie; Urien, Saïk; Prowse, Danielle; Thayne, Andrew; Gilliam, Catherine; Pynn, Harvey; Roberts, Ian
Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial. Journal Article
In: British journal of anaesthesia, vol. 126, no. 1, pp. 201–209, 2020.
Abstract | Links | BibTeX | Tags:
@article{lshtm4658851,
title = {Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial.},
author = {Stanislas Grassin-Delyle and Haleema Shakur-Still and Roberto Picetti and Lauren Frimley and Heather Jarman and Ross Davenport and William McGuinness and Phil Moss and Jason Pott and Nigel Tai and Elodie Lamy and Saïk Urien and Danielle Prowse and Andrew Thayne and Catherine Gilliam and Harvey Pynn and Ian Roberts},
url = {https://crash4.lshtm.ac.uk/wp-content/uploads/2021/05/Grassin-Delyle-et-al-2020.pdf, Click Here to Download Article},
year = {2020},
date = {2020-09-01},
journal = {British journal of anaesthesia},
volume = {126},
number = {1},
pages = {201--209},
publisher = {Elsevier BV},
abstract = {BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0.5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0.5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).
2019
CRASH-3, Trial Collaborators
In: LANCET, vol. 394, no. 10210, pp. 1713–1723, 2019.
Abstract | Links | BibTeX | Tags:
@article{lshtm4655598,
title = {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 trial.},
author = {Trial Collaborators CRASH-3},
url = {https://crash4.lshtm.ac.uk/wp-content/uploads/2021/05/CRASH-3-Trial-Collaborators-2019.pdf, Click Here to Download Article},
year = {2019},
date = {2019-11-01},
journal = {LANCET},
volume = {394},
number = {10210},
pages = {1713--1723},
publisher = {ELSEVIER SCIENCE INC},
abstract = {BACKGROUND: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. METHODS: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). RESULTS: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among 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]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). INTERPRETATION: Our 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. FUNDING: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). TRANSLATIONS: For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. METHODS: This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). RESULTS: Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among 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]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). INTERPRETATION: Our 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. FUNDING: National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). TRANSLATIONS: For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.