Effect of tranexamic acid in traumatic brain injury: a nested randomised, placebo controlled trial (CRASH-2 Intracranial Bleeding Study).

OBJECTIVE: To assess the effect of tranexamic acid (which reduces bleeding in surgical patients and reduces mortality due to bleeding in trauma patients) on intracranial haemorrhage in patients with traumatic brain injury. METHODS: A nested, randomised, placebo controlled trial. All investigators were masked to treatment allocation. All analyses were by intention to treat. Patients 270 adult trauma patients with, or at risk of, significant extracranial bleeding within 8 hours of injury, who also had traumatic brain injury. INTERVENTIONS: Patients randomly allocated to tranexamic acid (loading dose 1 g over 10 minutes, then infusion of 1 g over 8 hours) or matching placebo. MAIN OUTCOME MEASURES: Intracranial haemorrhage growth (measured by computed tomography) between hospital admission and then 24-48 hours later, with adjustment for Glasgow coma score, age, time from injury to the scans, and initial haemorrhage volume. RESULTS: Of the 133 patients allocated to tranexamic acid and 137 allocated to placebo, 123 (92%) and 126 (92%) respectively provided information on the primary outcome. All patients provided information on clinical outcomes. The mean total haemorrhage growth was 5.9 ml (SD 26.8) and 8.1 mL (SD 29.2) in the tranexamic acid and placebo groups respectively (adjusted difference -3.8 mL (95% confidence interval -11.5 to 3.9)). New focal cerebral ischaemic lesions occurred in 6 (5%) patients in the tranexamic acid group versus 12 (9%) in the placebo group (adjusted odds ratio 0.51 (95% confidence interval 0.18 to 1.44)). There were 14 (11%) deaths in the tranexamic acid group and 24 (18%) in the placebo group (adjusted odds ratio 0.47 (0.21 to 1.04)). CONCLUSIONS: This trial shows that neither moderate benefits nor moderate harmful effects of tranexamic acid in patients with traumatic brain injury can be excluded. However, the analysis provides grounds for further clinical trials evaluating the effect of tranexamic acid in this population. Trial registration ISRCTN86750102

CRASH-2 - Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage

A large randomised placebo controlled trial among trauma patients with or at risk of significant haemorrhage, of the effects of antifibrinolytic treatment on death and transfusion requirement. CRASH-2 is a randomised, controlled, double-blind trial undertaken in 274 hospitals in 40 countries. A total of 20211 adult trauma patients, with, or at risk of, significant bleeding (haemorrhage) were randomly assigned within 8 hours of injury to either tranexamic acid (TXA) or matching placebo. The primary outcome was death in hospital within four weeks of injury and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury, and other. This dataset is available at https://freebird.lshtm.ac.uk/index.php/data-sharing/downloads/crash2

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

El ácido tranexámico puede reducir la sangría en pacientes sometidos a cirugía electiva. En el presente estudio se evaluaron los efectos de la administración temprana de ácido tranexámico en eventos oclusivos vasculares, en recepción de transfusión de sangre y en muerte, en pacientes de trauma. Se realizó un ensayo controlado aleatorio que incluyó a 20211 pacientes adultos con trauma y sangrado significativo o riesgo de él, de 274 hospitales de 40 países. Los pacientes fueron asignados aleatoriamente dentro de las 8 horas de la lesión. La aleatorización fue equilibrada por centro, con una secuencia de asignación basada en un tamaño de bloque de ocho, generado con un número aleatorio de computadora generador. Tanto los participantes como el personal del estudio (investigadores del sitio y personal del centro de coordinación de ensayos) fueron enmascarados para asignación de tratamiento de ácido tranexámico (dosis de carga de 1 g en 10 min, luego infusión de 1 g en 8 h) o placebo compatible. Como resultado del estudio, los autores indican que el ácido tranexámico reduce el riesgo de muerte, de manera segura, en los pacientes de trauma con sagrado

Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women. METHODS/DESIGN: The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1 g of TXA or matching placebo by intravenous injection immediately (within 15 min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia. DISCUSSION: The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia. TRIAL REGISTRATION: ISRCTN, ISRCTN62396133 . Registered on 7 December 2017; ClincalTrials.gov, ID: NCT03475342 . Registered on 23 March 2018

Blood transfusion and the anaesthetist: management of massive haemorrhage

Hospitals must have a major haemorrhage protocol in place and this should include clinical, laboratory and logistic responses.Immediate control of obvious bleeding is of paramount importance (pressure, tourniquet, haemostatic dressings).The major haemorrhage protocol must be mobilised immediately when a massive haemorrhage situation is declared.A fibrinogen < 1 g.l−1 or a prothrombin time (PT) and activated partial thromboplastin time (aPTT) of > 1.5 times normal represents established haemostatic failure and is predictive of microvascular bleeding. Early infusion of fresh frozen plasma (FFP; 15 ml.kg−1) should be used to prevent this occurring if a senior clinician anticipates a massive haemorrhage.Established coagulopathy will require more than 15 ml.kg−1 of FFP to correct. The most effective way to achieve fibrinogen replacement rapidly is by giving fibrinogen concentrate or cryoprecipitate if fibrinogen is unavailable.1:1:1 red cell:FFP:platelet regimens, as used by the military, are reserved for the most severely traumatised patients.A minimum target platelet count of 75 × 109.l−1 is appropriate in this clinical situation.Group-specific blood can be issued without performing an antibody screen because patients will have minimal circulating antibodies. O negative blood should only be used if blood is needed immediately.In hospitals where the need to treat massive haemorrhage is frequent, the use of locally developed shock packs may be helpful.Standard venous thromboprophylaxis should be commenced as soon as possible after haemostasis has been secured as patients develop a prothrombotic state following massive haemorrhage

Prevention of haematoma progression by tranexamic acid in intracerebral haemorrhage patients with and without spot sign on admission scan: a statistical analysis plan of a pre-specified sub-study of the TICH-2 trial

Objective We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants’ spot sign status. Results Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients