Search

Abstract Explaining predictions for drug repositioning with biological knowledge graphs is a challenging problem. Graph completion methods using symbolic reasoning predict drug treatments and associated rules to generate evidence representing the therapeutic basis of the drug. Yet the vast amounts of generated paths that are biologically irrelevant or not mechanistically meaningful within the context of disease biology can limit utility. We use a reinforcement learning based knowledge graph completion model combined with an automatic filtering approach that produces the most relevant rules and biological paths explaining the predicted drug’s therapeutic connection to the disease. In this work we validate the approach against preclinical experimental data for Fragile X syndrome demonstrating strong correlation between automatically extracted paths and experimentally derived transcriptional changes of selected genes and pathways of drug predictions Sulindac and Ibudilast. Additionally, we show it reduces the number of generated paths in two case studies, 85% for Cystic fibrosis and 95% for Parkinson’s disease.

The Romance Inter-Views are short, multiple Q&A pairs that address key issues, definitions and ideas regarding Romance linguistics or general linguistics from a Romance viewpoint. Prominent exponents of different approaches to the study of Romance linguistics are asked to answer some general questions. The answers are then assembled so that readers can get a comparative picture of what’s going on in the field. This is the third Inter-view. The first Inter-view, on Syntax, can be found here. The second Inter-view, on Cartography, can be found here.

Abstract Background Postpartum haemorrhage (PPH) causes about 70,000 maternal deaths every year. Tranexamic acid (TXA) is a life-saving treatment for women with PPH. Intravenous (IV) TXA reduces deaths due to PPH by one-third when given within 3 h of childbirth. Because TXA is more effective when given early and PPH usually occurs soon after childbirth, giving TXA just before childbirth might prevent PPH. Although several randomised trials have examined TXA for PPH prevention, the results are inconclusive. Because PPH only affects a small proportion of births, we need good evidence on the balance of benefits and harms before using TXA to prevent PPH. TXA is usually given by slow IV injection. However, recent research shows that TXA is well tolerated and rapidly absorbed after intramuscular (IM) injection, achieving therapeutic blood levels within minutes of injection. Methods The I’M WOMAN trial is an international, multicentre, three-arm, randomised, double-blind, placebo-controlled trial to assess the effects of IM and IV TXA for the prevention of PPH in women with one or more risk factors for PPH giving birth vaginally or by caesarean section. Discussion The trial will provide evidence of the benefits and harms of TXA for PPH prevention and the effects of the IM and IV routes of administration. The IM route should be as effective as the IV route for preventing bleeding. There may be fewer side effects with IM TXA because peak blood concentrations are lower than with the IV route. IM TXA also has practical advantages as it is quicker and simpler to administer. By avoiding the need for IV line insertion and a slow IV injection, IM administration would free up overstretched midwives and doctors to focus on looking after the mother and baby and expand access to timely TXA treatment. Trial registration ClinicalTrials.gov NCT05562609. Registered on 3 October 2022. ISRCTN Registry ISRCTN12590098. Registered on 20 January 2023. Pan African Clinical Trial Registry PACTR202305473136570. Registered on 18 May 2023.

Efforts to develop empathetic agents, or systems capable of responding appropriately to emotional content, have increased as the deployment of such systems in socially complex scenarios becomes more commonplace. In the context of human-machine communication (HMC), the ability to create the perception of empathy is achieved in large part through linguistic behavior. However, studies of how language is used to display and respond to emotion in ways deemed empathetic are limited. This article aims to address this gap, demonstrating how an interactional linguistics informed methodological approach can be applied to the study of empathy in HMC. We present an analysis of empathetic response strategies in HMC and examine how these diverge from the practices employed in human-human dialogue. The specific challenges encountered by current systems are reviewed and their implications for future work on HMC considered.

Abstract The public enquiry into the mass casualty incident at the Manchester Arena in the UK in which 23 people died and over 1000 were injured, identified the need for timely intramuscular administration of tranexamic acid to trauma patients. Since then, a number of studies and trials have been carried out and UK paramedics are now authorized to give intramuscular tranexamic acid in the pre-hospital setting. In Japan, pre-hospital administration by emergency life-saving technicians is not yet authorized, despite the fact that tranexamic acid was invented by Japanese scientists. In Japan, the need for the pre-hospital administration of tranexamic acid has been raised on several occasions, where a patient died from traumatic bleeding prior to hospital admission. This paper summarizes the evidence on the use of tranexamic acid in patients with traumatic bleeding, including new evidence on the intramuscular route.

This paper is a rebuttal to Gärtner (2023, https://doi.org/10.5964/bioling.11715).

Background: Postpartum haemorrhage (PPH) is responsible for over 50,000 maternal deaths every year. Most of these deaths are in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases surgical bleeding and reduces deaths from bleeding after traumatic injury. When given within three hours of birth, TXA reduces deaths from bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. World-wide, over one-third of pregnant women are anaemic and many are severely anaemic. These women have an increased risk of PPH and are more likely to die if PPH occurs. There is an urgent need to identify ways to prevent severe postpartum bleeding in anaemic women. The WOMAN-2 trial will quantify the effects of TXA on postpartum bleeding in women with anaemia. Results: This statistical analysis plan (version 1.0; dated 22 February 2023) has been written based on information in the WOMAN-2 Trial protocol version 2.0, dated 30 June 2022. The primary outcome of the WOMAN-2 trial is the proportion of women with a clinical diagnosis of primary PPH. Secondary outcomes are maternal blood loss and its consequences (estimated blood loss, haemoglobin, haemodynamic instability, blood transfusion, signs of shock, use of interventions to control bleeding); maternal health and wellbeing (fatigue, headache, dizziness, palpitations, breathlessness, exercise tolerance, ability to care for her baby, health related quality of life, breastfeeding); and other health outcomes (deaths, vascular occlusive events, organ dysfunction, sepsis, side effects, time spent in higher level facility, length of hospital stay, and status of the baby). Conclusions: WOMAN-2 will provide reliable evidence about the effects of TXA in women with anaemia. Registration: WOMAN-2 was prospectively registered at the International Standard Randomised Controlled Trials registry (ISRCTN62396133) on 07/12/2017 and ClinicalTrials.gov on 23/03/2018 (NCT03475342).

Pathogens have developed intricate strategies to overcome the host’s innate immune responses. In this paper we use live-cell microscopy with a single bacterium resolution to follow in real time interactions between the food-borne pathogen L. monocytogenes and host macrophages, a key event controlling the infection in vivo. We demonstrate that infection results in heterogeneous outcomes, with only a subset of bacteria able to establish a replicative invasion of macrophages. The fate of individual bacteria in the same host cell was independent from the host cell and non-cooperative, being independent from co-infecting bacteria. A higher multiplicity of infection resulted in a reduced probability of replication of the overall bacterial population. By use of internalisation assays and conditional probabilities to mathematically describe the two-stage invasion process, we demonstrate that the higher MOI compromises the ability of macrophages to phagocytose bacteria. We found that the rate of phagocytosis is mediated via the secreted Listeriolysin toxin (LLO), while the probability of replication of intracellular bacteria remained constant. Using strains expressing fluorescent reporters to follow transcription of either the LLO-encoding hly or actA genes, we show that replicative bacteria exhibited higher PrfA regulon expression in comparison to those bacteria that did not replicate, however elevated PrfA expression per se was not sufficient to increase the probability of replication. Overall, this demonstrates a new role for the population-level, but not single cell, PrfA-mediated activity to regulate outcomes of host pathogen interactions.

Abstract Background Early identification of bleeding at the scene of an injury is important for triage and timely treatment of injured patients and transport to an appropriate facility. The aim of the study is to compare the performance of different bleeding scores. Methods We examined data from the Swiss Trauma Registry for the years 2015–2019. The Swiss Trauma Registry includes patients with major trauma (injury severity score (ISS) ≥ 16 and/or abbreviated injury scale (AIS) head ≥ 3) admitted to any level-one trauma centre in Switzerland. We evaluated ABC, TASH and Shock index (SI) scores, used to predict massive transfusion (MT) and the BATT score and used to predict death from bleeding. We evaluated the scores when used prehospital and in-hospital in terms of discrimination (C-Statistic) and calibration (calibration slope). The outcomes were early death within 24 h and the receipt of massive transfusion (≥ 10 Red Blood cells (RBC) units in the first 24 h or ≥ 3 RBC units in the first hour). Results We examined data from 13,222 major trauma patients. There were 1,533 (12%) deaths from any cause, 530 (4%) early deaths within 24 h, and 523 (4%) patients who received a MT (≥ 3 RBC within the first hour). In the prehospital setting, the BATT score had the highest discrimination for early death (C-statistic: 0.86, 95% CI 0.84–0.87) compared to the ABC score (0.63, 95% CI 0.60–0.65) and SI (0.53, 95% CI 0.50–0.56), P

Background: Tranexamic acid (TXA) reduces the risk of death and is recommended as a treatment for women with severe postpartum bleeding. There is hope that giving TXA shortly before or immediately after birth could prevent postpartum bleeding. Extending the use of TXA to prevent harmful postpartum bleeding could improve outcomes for millions of women; however we must carefully consider the balance of benefits and potential harms. This article describes the protocol for a systematic review and individual patient data (IPD) meta-analysis to assess the effectiveness and safety of TXA for preventing postpartum bleeding in all women giving birth, and to explore how the effects vary by underlying risk and other patient characteristics. Methods: We will search for prospectively registered, randomised controlled trials involving 500 patients or more assessing the effects of TXA in women giving birth. Two authors will extract data and assess risk of bias. IPD data will be sought from eligible trials. Primary outcomes will be life-threatening bleeding and thromboembolic events. We will use a one-stage model to analyse the data. Subgroup analyses will be conducted to explore whether the effectiveness and safety of TXA varies by underlying risk, type birth, maternal haemoglobin (Hb), and timing of TXA. This protocol is registered on PROSPERO (CRD42022345775). Conclusions: This systematic review and IPD meta-analysis will address important clinical questions about the effectiveness and safety of the use of TXA for the prevention of postpartum bleeding that cannot be answered reliably using aggregate data and will inform the decision of who to treat. PROSPERO registration: CRD42022345775 Keywords Anti-fibrinolytics; Tranexamic acid; childbirth; postpartum haemorrhage; meta-analysis

Abstract Background Tranexamic acid reduces head injury deaths in patients with CT scan evidence of intracranial bleeding after mild traumatic brain injury (TBI). However, the cost-effectiveness of tranexamic acid for people with mild TBI in the pre-hospital setting, prior to CT scanning, is uncertain. A large randomised controlled trial (CRASH-4) is planned to address this issue, but the economic justification for it has not been established. The aim of the analysis was to estimate the likelihood of tranexamic acid being cost-effective given current evidence, the treatment effects required for cost-effectiveness, and the expected value of performing further research. Methods An early economic decision model compared usual care for mild TBI with and without tranexamic acid, for adults aged 70 and above. The evaluation was performed from a UK healthcare perspective over a lifetime time horizon, with costs reported in 2020 pounds (GBP) and outcomes reported as quality-adjusted life years (QALYs). All analyses used a £20,000 per QALY cost-effectiveness threshold. Results In the base case analysis, tranexamic acid was associated with an incremental cost-effectiveness ratio of £4885 per QALY gained, but the likelihood of it being cost-effective was highly dependent on the all-cause mortality treatment effect. The value of perfect information was £22.4 million, and the value of perfect information for parameters that could be collected in a trial was £21.9 million. The all-cause mortality risk ratio for tranexamic acid and the functional outcomes following TBI had the most impact on cost-effectiveness. Conclusions There is a high degree of uncertainty in the cost-effectiveness of tranexamic acid for older adults experiencing mild TBI, meaning there is a high value of performing future research in the UK. The value in a global context is likely to be far higher.

Objectives HALT-IT was an international, randomised trial which assessed the effects of tranexamic acid (TXA) in 12 009 patients with gastrointestinal (GI) bleeding. The results found no evidence that TXA reduces death. It is widely accepted that results of trials should be interpreted in the context of other relevant evidence. We conducted a systematic review and individual patient data (IPD) meta-analysis to assess if the results of HALT-IT are compatible with evidence for TXA in other bleeding conditions.Design Systematic review and IPD meta-analysis of randomised trials involving ≥5000 patients assessing TXA for bleeding. We searched our Antifibrinolytics Trials Register on 1 November 2022. Two authors extracted data and assessed risk of bias.Data synthesis We used a one-stage model to analyse IPD in a regression model stratified by trial. We assessed heterogeneity of the effect of TXA on death within 24 hours and vascular occlusive events (VOEs).Results We included IPD for 64 724 patients from four trials involving patients with traumatic, obstetric and GI bleeding. Risk of bias was low. There was no evidence for heterogeneity between trials for the effect of TXA on death or for the effect of TXA on VOEs. TXA reduced the odds of death by 16% (OR=0.84, 95% CI: 0.78 to 0.91, p

Background Tranexamic acid reduced haematoma expansion and early death, but did not improve functional outcome in the tranexamic acid for hyperacute spontaneous intracerebral haemorrhage-2 (TICH-2) trial. In a predefined subgroup, there was a statistically significant interaction between prerandomisation baseline systolic blood pressure (SBP) and the effect of tranexamic acid on functional outcome (p=0.019).Methods TICH-2 was an international prospective double-blind placebo-controlled randomised trial evaluating intravenous tranexamic acid in patients with acute spontaneous intracerebral haemorrhage (ICH). Prerandomisation baseline SBP was split into predefined ≤170 and >170 mm Hg groups. The primary outcome at day 90 was the modified Rankin Scale (mRS), a measure of dependency, analysed using ordinal logistic regression. Haematoma expansion was defined as an increase in haematoma volume of >33% or >6 mL from baseline to 24 hours. Data are OR or common OR (cOR) with 95% CIs, with significance at p170 mm Hg. Tranexamic acid was associated with a favourable shift in mRS at day 90 in those with baseline SBP≤170 mm Hg (cOR 0.73, 95% CI 0.59 to 0.91, p=0.005), but not in those with baseline SBP>170 mm Hg (cOR 1.05, 95% CI 0.85 to 1.30, p=0.63). In those with baseline SBP≤170 mm Hg, tranexamic acid reduced haematoma expansion (OR 0.62, 95% CI 0.47 to 0.82, p=0.001), but not in those with baseline SBP>170 mm Hg (OR 1.02, 95% CI 0.77 to 1.35, p=0.90).Conclusions Tranexamic acid was associated with improved clinical and radiological outcomes in ICH patients with baseline SBP≤170 mm Hg. Further research is needed to establish whether certain subgroups may benefit from tranexamic acid in acute ICH.Trial registration number ISRCTN93732214.

Background: The prevalence of genital chlamydia and gonorrhoea is higher in the 16–24 years age group than those in other age group. With users, we developed the theory-based safetxt intervention to reduce sexually transmitted infections. Objectives: To establish the effect of the safetxt intervention on the incidence of chlamydia/gonorrhoea infection at 1 year. Design: A parallel-group, individual-level, randomised superiority trial in which care providers and outcome assessors were blinded to allocation. Setting: Recruitment was from 92 UK sexual health clinics. Participants: Inclusion criteria were a positive chlamydia or gonorrhoea test result, diagnosis of non-specific urethritis or treatment started for chlamydia/gonorrhoea/non-specific urethritis in the last 2 weeks; owning a personal mobile phone; and being aged 16–24 years. Allocation: Remote computer-based randomisation with an automated link to the messaging system delivering intervention or control group messages. Intervention: The safetxt intervention was designed to reduce sexually transmitted infection by increasing partner notification, condom use and sexually transmitted infection testing before sex with new partners. It employed educational, enabling and incentivising content delivered by 42–79 text messages over 1 year, tailored according to type of infection, gender and sexuality. Comparator: A monthly message regarding trial participation. Main outcomes: The primary outcome was the incidence of chlamydia and gonorrhoea infection at 12 months, assessed using nucleic acid amplification tests. Secondary outcomes at 1 and 12 months included self-reported partner notification, condom use and sexually transmitted infection testing prior to sex with new partner(s). Results: Between 1 April 2016 and 23 November 2018, we assessed 20,476 people for eligibility and consented and randomised 6248 participants, allocating 3123 to the safetxt intervention and 3125 to the control. Primary outcome data were available for 4675 (74.8%) participants. The incidence of chlamydia/gonorrhoea infection was 22.2% (693/3123) in the intervention group and 20.3% (633/3125) in the control group (odds ratio 1.13, 95% confidence interval 0.98 to 1.31). There was no evidence of heterogeneity in any of the prespecified subgroups. Partner notification was 85.6% in the intervention group and 84.0% in the control group (odds ratio 1.14, 95% confidence interval 0.99 to 1.33). At 12 months, condom use at last sex was 33.8% in the intervention group and 31.2% in the control group (odds ratio 1.14, 95% confidence interval 1.01 to 1.28) and condom use at first sex with most recent new partner was 54.4% in the intervention group and 48.7% in the control group (odds ratio 1.27, 95% confidence interval 1.11 to 1.45). Testing before sex with a new partner was 39.5% in the intervention group and 40.9% in the control group (odds ratio 0.95, 95% confidence interval 0.82 to 1.10). Having two or more partners since joining the trial was 56.9% in the intervention group and 54.8% in the control group (odds ratio 1.11, 95% confidence interval 1.00 to 1.24) and having sex with someone new since joining the trial was 69.7% in the intervention group and 67.4% in the control group (odds ratio 1.13, 95% confidence interval 1.00 to 1.28). There were no differences in safety outcomes. Additional sensitivity and per-protocol analyses showed similar results. Limitations: Our understanding of the mechanism of action for the unanticipated effects is limited. Conclusions: The safetxt intervention did not reduce chlamydia and gonorrhoea infections, with slightly more infections in the intervention group. The intervention increased condom use but also increased the number of partners and new partners. Randomised controlled trials are essential for evaluating health communication interventions, which can have unanticipated effects. Future work: Randomised controlled trials evaluating novel interventions in this complex area are needed. Trial registration: This trial is registered as ISRCTN64390461. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 11, No. 1. See the NIHR Journals Library website for further project information.

Abstract Background Postpartum haemorrhage (PPH) is a leading cause of maternal mortality worldwide. Maternal anaemia greatly increases the risk of PPH, and over a third of all pregnant women are anaemic. Because anaemia reduces the oxygen-carrying capacity of the blood, anaemic women cannot tolerate the same volume of blood loss as healthy women. Yet the same blood loss threshold is used to define PPH in all women. The lack of an established PPH definition in anaemic women means the most appropriate outcome measures for use in clinical trials are open to question. We used data from the WOMAN-2 trial to examine different definitions of PPH in anaemic women and consider their appropriateness as clinical trial outcome measures. Main body The WOMAN-2 trial is assessing tranexamic acid (TXA) for PPH prevention in women with moderate or severe anaemia at baseline. To obtain an accurate, precise estimate of the treatment effect, outcome measures should be highly specific and reasonably sensitive. Some outcome misclassification is inevitable. Low sensitivity reduces precision, but low specificity biases the effect estimate towards the null. Outcomes should also be related to how patients feel, function, or survive. The primary outcome in the WOMAN-2 trial, a ‘clinical diagnosis of PPH’, is defined as estimated blood loss > 500 ml or any blood loss within 24 h sufficient to compromise haemodynamic stability. To explore the utility of several PPH outcome measures, we analysed blinded data from 4521 participants. For each outcome, we assessed its: (1) frequency, (2) specificity for significant bleeding defined as shock index ≥1.0 and (3) association with fatigue (modified fatigue symptom inventory [MFSI]), physical endurance (six-minute walk test) and breathlessness. A clinical diagnosis of PPH was sufficiently frequent (7%), highly specific for clinical signs of early shock (95% specificity for shock index ≥1) and associated with worse maternal functioning after childbirth. Conclusion Outcome measures in clinical trials of interventions for PPH prevention should facilitate valid and precise estimation of the treatment effect and be important to women. A clinical diagnosis of PPH appears to meet these criteria, making it an appropriate primary outcome for the WOMAN-2 trial. Trial registration ClinicalTrials.gov NCT03475342, registered on 23 March 2018; ISRCTN62396133, registered on 7 December 2017; Pan African Clinical Trial Registry PACTR201909735842379, registered on 18 September 2019.

Abstract Background Tranexamic acid (TXA) reduces surgical bleeding and reduces death from bleeding after trauma and childbirth. However, its effects on thrombotic events and seizures are less clear. We conducted a systematic review and meta-analysis to examine the safety of TXA in bleeding patients. Methods For this systematic review and meta-analysis, we searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials from inception until June 1, 2020. We included randomized trials comparing intravenous tranexamic acid and placebo or no intervention in bleeding patients. The primary outcomes were thrombotic events, venous thromboembolism, acute coronary syndrome, stroke and seizures. A meta-analysis was performed using a random effects model and meta-regression analysis was performed to evaluate how effects vary by dose. We assessed the certainty of evidence using the grading of recommendations, assessment, development and evaluations (GRADE) approach. Results A total of 234 studies with 102,681 patients were included in the meta-analysis. In bleeding patients, there was no evidence that TXA increased the risk of thrombotic events (RR = 1.00 [95% CI 0.93–1.08]), seizures (1.18 [0.91–1.53]), venous thromboembolism (1.04 [0.92–1.17]), acute coronary syndrome (0.88 [0.78–1.00]) or stroke (1.12 [0.98–1.27]). In a dose-by-dose sensitivity analysis, seizures were increased in patients receiving more than 2 g/day of TXA (3.05 [1.01–9.20]). Meta-regression showed an increased risk of seizures with increased dose of TXA (p = 0.011). Conclusion Tranexamic acid did not appear to increase the risk of thrombotic events in bleeding patients. However, because there may be dose-dependent increase in the risk of seizures, very high doses should be avoided.

Objective To perform an economic evaluation of tranexamic acid (TXA) versus no-TXA, in addition to current clinical practice, for acute gastrointestinal bleeding, using the results of the HALT-IT trial (NCT01658124), a large randomised controlled trial which included 11 937 patients.Design A cost-effectiveness modelling analysis, performed over a lifetime time horizon.Setting The analysis was performed from a UK health service perspective.Participants The model includes adults with acute gastrointestinal bleeding.Outcomes measures The model reports costs in Great British pounds in 2021 and outcomes as life years (LYs) and quality-adjusted life years (QALYs). Cost-effectiveness was evaluated using incremental cost-effectiveness ratios (ICERs), reported as the cost per QALY gained.Methods A Markov model was developed to calculate the overall costs and health outcomes of TXA administration versus no-TXA. The model used data of the treatment effectiveness from the HALT-IT trial, which showed that TXA administration for acute gastrointestinal bleeding did not reduce all-cause mortality (risk ratio 1.03, 95% CI 0.92 to 1.16) compared with no-TXA. Data on health-related quality of life, costs and long-term mortality risks were derived from the literature. Costs and effects are discounted at 3.5% per annum.Results TXA was associated with marginally fewer LYs and QALYs, and lower costs, than treatment without TXA. The ICER associated with no-TXA was £1576 per LY gained and £2209 per QALY gained. No-TXA was 64% likely to be cost-effective at a £20 000 willingness-to-pay threshold, while TXA was 36% likely to be cost-effective.Conclusion Though inexpensive, TXA administration for patients with acute gastrointestinal bleeding is unlikely to be cost-effective.

Abstract Background In large multicentre trials in diverse settings, there is uncertainty about the need to adjust for centre variation in design and analysis. A key distinction is the difference between variation in outcome (independent of treatment) and variation in treatment effect. Through re-analysis of the CRASH-2 trial (2010), this study clarifies when and how to use multi-level models for multicentre studies with binary outcomes. Methods CRASH-2 randomised 20,127 trauma patients across 271 centres and 40 countries to either single-dose tranexamic acid or identical placebo, with all-cause death at 4 weeks the primary outcome. The trial data had a hierarchical structure, with patients nested in hospitals which in turn are nested within countries. Reanalysis of CRASH-2 trial data assessed treatment effect and both patient and centre level baseline covariates as fixed effects in logistic regression models. Random effects were included to assess where there was variation between countries, and between centres within countries, both in underlying risk of death and in treatment effect. Results In CRASH-2, there was significant variation between countries and between centres in death at 4 weeks, but absolutely no differences between countries or centres in the effect of treatment. Average treatment effect was not altered after accounting for centre and country variation in this study. Conclusions It is important to distinguish between underlying variation in outcomes and variation in treatment effects; the former is common but the latter is not. Stratifying randomisation by centre overcomes many statistical problems and including random intercepts in analysis may increase power and decrease bias in mean and standard error estimates. Trial registration Current Controlled Trials ISRCTN86750102 , ClinicalTrials.gov NCT00375258 , and South African Clinical Trial Register DOH-27-0607-1919

Abstract Background Tranexamic acid reduces surgical blood loss and reduces deaths from bleeding in trauma patients. Tranexamic acid must be given urgently, preferably by paramedics at the scene of the injury or in the ambulance. We developed a simple score (Bleeding Audit Triage Trauma score) to predict death from bleeding. Methods We conducted an external validation of the BATT score using data from the UK Trauma Audit Research Network (TARN) from 1st January 2017 to 31st December 2018. We evaluated the impact of tranexamic acid treatment thresholds in trauma patients. Results We included 104,862 trauma patients with an injury severity score of 9 or above. Tranexamic acid was administered to 9915 (9%) patients. Of these 5185 (52%) received prehospital tranexamic acid. The BATT score had good accuracy (Brier score = 6%) and good discrimination (C-statistic 0.90; 95% CI 0.89–0.91). Calibration in the large showed no substantial difference between predicted and observed death due to bleeding (1.15% versus 1.16%, P = 0.81). Pre-hospital tranexamic acid treatment of trauma patients with a BATT score of 2 or more would avoid 210 bleeding deaths by treating 61,598 patients instead of avoiding 55 deaths by treating 9915 as currently. Conclusion The BATT score identifies trauma patient at risk of significant haemorrhage. A score of 2 or more would be an appropriate threshold for pre-hospital tranexamic acid treatment.

Abstract Background The CRASH-3 trial hypothesised that timely tranexamic acid (TXA) treatment might reduce deaths from intracranial bleeding after traumatic brain injury (TBI). To explore the mechanism of action of TXA in TBI, we examined the timing of its effect on death. Methods The CRASH-3 trial randomised 9202 patients within 3 h of injury with a GCS score ≤ 12 or intracranial bleeding on CT scan and no significant extracranial bleeding to receive TXA or placebo. We conducted an exploratory analysis of the effects of TXA on all-cause mortality within 24 h of injury and within 28 days, excluding patients with a GCS score of 3 or bilateral unreactive pupils, stratified by severity and country income. We pool data from the CRASH-2 and CRASH-3 trials in a one-step fixed effects individual patient data meta-analysis. Results There were 7637 patients for analysis after excluding patients with a GCS score of 3 or bilateral unreactive pupils. Of 1112 deaths, 23.3% were within 24 h of injury (early deaths). The risk of early death was reduced with TXA (112 (2.9%) TXA group vs 147 (3.9%) placebo group; risk ratio [RR] RR 0.74, 95% CI 0.58–0.94). There was no evidence of heterogeneity by severity (p = 0.64) or country income (p = 0.68). The risk of death beyond 24 h of injury was similar in the TXA and placebo groups (432 (11.5%) TXA group vs 421 (11.7%) placebo group; RR 0.98, 95% CI 0.69–1.12). The risk of death at 28 days was 14.0% in the TXA group versus 15.1% in the placebo group (544 vs 568 events; RR 0.93, 95% CI 0.83–1.03). When the CRASH-2 and CRASH-3 trial data were pooled, TXA reduced early death (RR 0.78, 95% CI 0.70–0.87) and death within 28 days (RR 0.88, 95% CI 0.82–0.94). Conclusions Tranexamic acid reduces early deaths in non-moribund TBI patients regardless of TBI severity or country income. The effect of tranexamic acid in patients with isolated TBI is similar to that in polytrauma. Treatment is safe and even severely injured patients appear to benefit when treated soon after injury. Trial registration ISRCTN15088122 , registered on 19 July 2011; NCT01402882 , registered on 26 July 2011.

Abstract Background Early treatment with tranexamic acid may reduce deaths after traumatic brain injury (TBI). In mild and moderate TBI, there is a time to treatment interaction, with early treatment being most beneficial. Time to treatment was recorded by clinicians and is subject to error. Using monitoring data from the CRASH-3 trial, we examine the impact of errors in time to treatment on estimated treatment effects. Methods The CRASH-3 trial was a randomised trial of the effect of tranexamic acid on death and vascular occlusive events in 12,737 TBI patients. This analysis includes the 8107 patients with a Glasgow coma scale score of 9 to 15 since previous analyses showed that these patients benefit most from early treatment. Clinician-recorded time to treatment was checked against ambulance and hospital records for 1368/12,737 (11%) patients. Patients who died were preferentially selected for monitoring and we monitored 36% of head injury deaths. We describe measurement errors using Bland-Altman graphs. We model the effect of tranexamic acid on head injury death using logistic regression with a time-treatment interaction term. We use regression calibration, multiple imputation and Bayesian analysis to estimate the impact of time to treatment errors. Results Clinicians rounded times to the nearest half or full hour in 66% of cases. Monitored times were also rounded and were identical to clinician times in 63% of patients. Times were underestimated by an average of 9 min (95% CI − 85, 66). There was more variability between clinician-recorded and monitored times in low- and middle-income countries than in high-income countries. The treatment effect estimate at 1 h was greater for monitored times OR = 0.61 (95% CI 0.47, 0.81) than for clinician-recorded times OR = 0.63 (95% CI 0.48, 0.83). All three adjustment methods gave similar time to treatment interactions. For Bayesian methods, the treatment effect at 1 h was OR = 0.58 (95% CI 0.43, 0.78). Using monitored times increased the time-treatment interaction term from 1.15 (95% CI 1.03, 1.27) to 1.16 (95% CI 1.05, 1.28). Conclusions Accurate estimation of time from injury to treatment is challenging, particularly in low resource settings. Adjustment for known errors in time to treatment had minimal impact on the trial results. Trial registration ClinicalTrials.gov NCT01402882 . Registered on 25 July 2011

Abstract Background Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. Methods The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. Results Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55–3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. Conclusions Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure.

Abstract The 2019 UK general election took place against a background of rising online hostility levels toward politicians, and concerns about the impact of this on democracy, as a record number of politicians cited the abuse they had been receiving as a reason for not standing for re-election. We present a four-factor framework in understanding who receives online abuse and why. The four factors are prominence, events, online engagement and personal characteristics. We collected 4.2 million tweets sent to or from election candidates in the six week period spanning from the start of November until shortly after the December 12th election. We found abuse in 4.46% of replies received by candidates, up from 3.27% in the matching period for the 2017 UK general election. Abuse levels have also been climbing month on month throughout 2019. Abuse also escalated throughout the campaign period. Abuse focused mainly on a small number of high profile politicians, with the most prominent individuals receiving not only more abuse by volume, but also as a percentage of replies. Abuse is “spiky”, triggered by external events such as debates, or certain tweets. Some tweets may become viral targets for personal abuse. On average, men received more general and political abuse; women received more sexist abuse. Conservative candidates received more political and general abuse. We find that individuals choosing not to stand for re-election had received more abuse across the preceding year.

Abstract Background Multiple trauma scores have been developed and validated, including the Revised Trauma Score (RTS) and the Mechanism, Glasgow Coma Scale, Age, and Arterial Pressure (MGAP) score. However, these scores are complex to calculate or have low prognostic abilities for trauma mortality. Therefore, we aimed to develop and validate a trauma score that is easier to calculate and more accurate than the RTS and the MGAP score. Methods The study was a retrospective prognostic study. Data from patients registered in the Japan Trauma Databank (JTDB) were dichotomized into derivation and validation cohorts. Patients’ data from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) trial were assigned to another validation cohort. We obtained age and physiological variables at baseline, created ordinal variables from continuous variables, and defined integer weighting coefficients. Score performance to predict all-cause in-hospital death was assessed using the area under the curve in receiver operating characteristics (AUROC) analyses. Results Based on the JTDB derivation cohort (n = 99,867 with 12.5% mortality), the novel score ranged from 0 to 14 points, including 0–2 points for age, 0–6 points for the Glasgow Coma Scale, 0–4 points for systolic blood pressure, and 0–2 points for respiratory rate. The AUROC of the novel score was 0.932 for the JTDB validation cohort (n = 76,762 with 10.1% mortality) and 0.814 for the CRASH-2 cohort (n = 19,740 with 14.6% mortality), which was superior to RTS (0.907 and 0.808, respectively) and MGAP score (0.918 and 0.774, respectively) results. Conclusions We report an easy-to-use trauma score with better prognostication ability for in-hospital mortality compared to the RTS and MGAP score. Further studies to test clinical applicability of the novel score are warranted.

We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6–36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6–17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: −2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: −2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition.

Background: Tranexamic acid reduces blood loss in surgery and the risk of death in trauma patients. Meta-analyses of small trials suggest that tranexamic acid decreases the number of deaths from gastrointestinal bleeding, but these meta-analyses are prone to selection bias. Objective: The trial provides reliable evidence of the effect of tranexamic acid on mortality, rebleeding and complications in significant acute gastrointestinal bleeding. Design: A multicentre, randomised, placebo-controlled trial and economic analysis. Patients were assigned by selecting one treatment pack from a box of eight, which were identical apart from the pack number. Patients, caregivers and outcome assessors were masked to allocation. The main analyses were by intention to treat. Setting: The setting was 164 hospitals in 15 countries, co-ordinated from the London School of Hygiene & Tropical Medicine. Participants: Adults with significant upper or lower gastrointestinal bleeding (n = 12,009) were eligible if the responsible clinician was substantially uncertain about whether or not to use tranexamic acid. The clinical diagnosis of significant bleeding implied a risk of bleeding to death, including hypotension, tachycardia or signs of shock, or urgent transfusion, endoscopy or surgery. Intervention: Tranexamic acid (a 1-g loading dose over 10 minutes, then a 3-g maintenance dose over 24 hours) or matching placebo. Main outcome measures: The primary outcome was death due to bleeding within 5 days of randomisation. Secondary outcomes were all-cause and cause-specific mortality; rebleeding; need for endoscopy, surgery or radiological intervention; blood product transfusion; complications; disability; and days spent in intensive care or a high-dependency unit. Results: A total of 12,009 patients were allocated to receive tranexamic acid (n = 5994, 49.9%) or the matching placebo (n = 6015, 50.1%), of whom 11,952 (99.5%) received the first dose. Death due to bleeding within 5 days of randomisation occurred in 222 (3.7%) patients in the tranexamic acid group and in 226 (3.8%) patients in the placebo group (risk ratio 0.99, 95% confidence interval 0.82 to 1.18). Thromboembolic events occurred in 86 (1.4%) patients in the tranexamic acid group and 72 (1.2%) patients in the placebo group (risk ratio 1.20, 95% confidence interval 0.88 to 1.64). The risk of arterial thromboembolic events (myocardial infarction or stroke) was similar in both groups (0.7% in the tranexamic acid group vs. 0.8% in the placebo group; risk ratio 0.92, 95% confidence interval 0.60 to 1.39), but the risk of venous thromboembolic events (deep-vein thrombosis or pulmonary embolism) was higher in tranexamic acid-treated patients than in placebo-treated patients (0.8% vs. 0.4%; risk ratio 1.85, 95% confidence interval 1.15 to 2.98). Seizures occurred in 38 patients who received tranexamic acid and in 22 patients who received placebo (0.6% vs. 0.4%, respectively; risk ratio 1.73, 95% confidence interval 1.03 to 2.93). In the base-case economic analysis, tranexamic acid was not cost-effective and resulted in slightly poorer health outcomes than no tranexamic acid. Conclusions: Tranexamic acid did not reduce death from gastrointestinal bleeding and, although inexpensive, it is not cost-effective in adults with acute gastrointestinal bleeding. Future work: These results caution against a uniform approach to the management of patients with major haemorrhage and highlight the need for randomised trials targeted at specific pathophysiological processes. Limitations: Although this is one of the largest randomised trials in gastrointestinal bleeding, we cannot rule out a modest increase or decrease in death due to bleeding with tranexamic acid. Trial registration: Current Controlled Trials ISRCTN11225767, ClinicalTrials.gov NCT01658124 and EudraCT 2012-003192-19. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 58. See the NIHR Journals Library website for further project information.

Background: Intravenous tranexamic acid (TXA) within 3 hours of birth significantly reduces death due to bleeding in women with postpartum haemorrhage (PPH). Most PPH deaths occur in the first hours after giving birth and treatment delay decreases survival. One barrier to rapid TXA treatment is the need for intravenous injection. Intramuscular injection and oral solution of TXA would be easier and faster to administer and would require less training. However, the pharmacokinetics (PK), pharmacodynamics and safety of TXA administered by different routes in pregnant women have not been established. The main aim of this study is to ascertain whether IM and oral solution of TXA will be absorbed at levels sufficient to inhibit fibrinolysis in pregnant women. Methods: WOMAN-PharmacoTXA is a prospective, randomised, open label trial to be conducted in Zambia and Pakistan. Adult women undergoing caesarean section with at least one risk factor for PPH will be included. Women will be randomised to receive one of the following about 1 hour prior to caesarean section: 1-gram TXA IV, 1-gram TXA IM, 4-grams TXA oral solution or no TXA. Randomisation will continue until 120 participants with at least six post randomisation PK samples are included. TXA concentration in maternal blood samples will be measured at baseline and at different time points during 24 hours after receipt of intervention. Blood TXA concentration will be measured from the umbilical cord and neonate. The primary endpoint is maternal blood TXA concentrations over time. Secondary outcomes include umbilical cord and neonate TXA concentration D-dimer concentration, blood loss and clinical diagnosis of PPH, injection site reactions and maternal and neonate adverse events. Discussion: The WOMAN-PharmacoTXA trial will provide important data on pharmacokinetics, pharmacodynamics and safety of TXA after IV, intramuscular and oral administration in women giving birth by caesarean section. Trial registration: ClincalTrials.gov, NCT04274335 (18/02/2020).

Rationale Clinical trials are the gold standard for testing interventions. COVID-19 has further raised their public profile and emphasised the need to deliver better, faster, more efficient trials for patient benefit. Considerable overlap exists between data required for trials and data already collected routinely in electronic healthcare records (EHRs). Opportunities exist to use these in innovative ways to decrease duplication of effort and speed trial recruitment, conduct and follow-up.Approach The National Institute of Health Research (NIHR), Health Data Research UK and Clinical Practice Research Datalink co-organised a national workshop to accelerate the agenda for ‘data-enabled clinical trials’. Showcasing successful examples and imagining future possibilities, the plenary talks, panel discussions, group discussions and case studies covered: design/feasibility; recruitment; conduct/follow-up; collecting benefits/harms; and analysis/interpretation.Reflection Some notable studies have successfully accessed and used EHR to identify potential recruits, support randomised trials, deliver interventions and supplement/replace trial-specific follow-up. Some outcome measures are already reliably collected; others, like safety, need detailed work to meet regulatory reporting requirements. There is a clear need for system interoperability and a ‘route map’ to identify and access the necessary datasets. Researchers running regulatory-facing trials must carefully consider how data quality and integrity would be assessed. An experience-sharing forum could stimulate wider adoption of EHR-based methods in trial design and execution.Discussion EHR offer opportunities to better plan clinical trials, assess patients and capture data more efficiently, reducing research waste and increasing focus on each trial’s specific challenges. The short-term emphasis should be on facilitating patient recruitment and for postmarketing authorisation trials where research-relevant outcome measures are readily collectable. Sharing of case studies is encouraged. The workshop directly informed NIHR’s funding call for ambitious data-enabled trials at scale. There is the opportunity for the UK to build upon existing data science capabilities to identify, recruit and monitor patients in trials at scale.

Background: Tranexamic acid safely reduces mortality in traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury and can cause brain herniation and death. We assessed the effects of tranexamic acid in traumatic brain injury patients. Objective: To assess the effects of tranexamic acid on death, disability and vascular occlusive events in traumatic brain injury patients. We also assessed cost-effectiveness. Design: Randomised trial and economic evaluation. 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. All analyses were by intention to treat. We assessed the cost-effectiveness of tranexamic acid versus no treatment from a UK NHS perspective using the trial results and a Markov model. Setting: 175 hospitals in 29 countries. Participants: Adults with traumatic brain injury within 3 hours of injury with a Glasgow Coma Scale score of ≤ 12 or any intracranial bleeding on computerised tomography scan, and no major extracranial bleeding, were eligible. Intervention: Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo. Main outcome measures: Head injury death in hospital within 28 days of injury in patients treated within 3 hours of injury. Secondary outcomes were early head injury deaths, all-cause and cause-specific mortality, disability, vascular occlusive events, seizures, complications and adverse events. Results: Among patients treated within 3 hours of injury (n = 9127), the risk of head injury death was 18.5% in the tranexamic acid group versus 19.8% in the placebo group (855/4613 vs. 892/4514; risk ratio 0.94, 95% confidence interval 0.86 to 1.02). In a prespecified analysis excluding patients with a Glasgow Coma Scale score of 3 or bilateral unreactive pupils at baseline, the results were 12.5% in the tranexamic acid group versus 14.0% in the placebo group (485/3880 vs. 525/3757; risk ratio 0.89, 95% confidence interval 0.80 to 1.00). There was a reduction in the risk of head injury death with tranexamic acid in those with mild to moderate head injury (166/2846 vs. 207/2769; risk ratio 0.78, 95% confidence interval 0.64 to 0.95), but in those with severe head injury (689/1739 vs. 685/1710; risk ratio 0.99, 95% confidence interval 0.91 to 1.07) there was no apparent reduction (p-value for heterogeneity = 0.030). Early treatment was more effective in mild and moderate head injury (p = 0.005), but there was no obvious impact of time to treatment in cases of severe head injury (p = 0.73). The risk of disability, vascular occlusive events and seizures was similar in both groups. Tranexamic acid is highly cost-effective for mild and moderate traumatic brain injury (base case of £4288 per quality-adjusted life-year gained). Conclusion: Early tranexamic acid treatment reduces head injury deaths. Treatment is cost-effective for patients with mild or moderate traumatic brain injury, or those with both pupils reactive. Future work: Further trials should examine early tranexamic acid treatment in mild head injury. Research on alternative routes of administration is needed. Limitations: Time to treatment may have been underestimated. Trial registration: Current Controlled Trials ISRCTN15088122, ClinicalTrials.gov NCT01402882, EudraCT 2011-003669-14, Pan African Clinical Trial Registry PACTR20121000441277. Funding: The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 26. See the NIHR Journals Library website for further project information. In addition, funding was provided by JP Moulton Charitable Trust, Joint Global Health Trials (Medical Research Council, Department for International Development and the Wellcome Trust). This project was funded by the NIHR Global Health Trials programme.

Abstract Background Acute gastrointestinal (GI) bleeding is an important cause of mortality worldwide. Bleeding can occur from the upper or lower GI tract, with upper GI bleeding accounting for most cases. The main causes include peptic ulcer/erosive mucosal disease, oesophageal varices and malignancy. The case fatality rate is around 10% for upper GI bleeding and 3% for lower GI bleeding. Rebleeding affects 5–40% of patients and is associated with a four-fold increased risk of death. Tranexamic acid (TXA) decreases bleeding and the need for blood transfusion in surgery and reduces death due to bleeding in patients with trauma and postpartum haemorrhage. It reduces bleeding by inhibiting the breakdown of fibrin clots by plasmin. Due to the methodological weaknesses and small size of the existing trials, the effectiveness and safety of TXA in GI bleeding is uncertain. The Haemorrhage ALleviation with Tranexamic acid – Intestinal system (HALT-IT) trial aims to provide reliable evidence about the effects of TXA in acute upper and lower GI bleeding. Methods The HALT-IT trial is an international, randomised, double-blind, placebo-controlled trial of tranexamic acid in 12,000 adults (increased from 8000) with acute upper or lower GI bleeding. Eligible patients are randomly allocated to receive TXA (1-g loading dose followed by 3-g maintenance dose over 24 h) or matching placebo. The main analysis will compare those randomised to TXA with those randomised to placebo on an intention-to-treat basis, presenting the results as effect estimates (relative risks) and confidence intervals. The primary outcome is death due to bleeding within 5 days of randomisation and secondary outcomes are: rebleeding; all-cause and cause-specific mortality; thromboembolic events; complications; endoscopic, radiological and surgical interventions; blood transfusion requirements; disability (defined by a measure of patient’s self-care capacity); and number of days spent in intensive care or high-dependency units. Subgroup analyses for the primary outcome will consider time to treatment, location of bleeding, cause of bleed and clinical Rockall score. Discussion We present the statistical analysis of the HALT-IT trial. This plan was published before the treatment allocation was unblinded. Trial registration Current Controlled Trials, ID: ISRCTN11225767. Registered on 3 July 2012; Clinicaltrials.gov, ID: NCT01658124. Registered on 26 July 2012.

Abstract Expert trial managers with the training and experience to overcome operational challenges are often the difference between the success and failure of a clinical trial. Considerable importance is given to the beginning and the end of the clinical trial process, with those responsible for writing a protocol, obtaining funding and analysing the data all being rewarded when the results are published. Yet, trial managers are often overlooked in terms of recognition, value and status. This article highlights some of the key barriers to achieving this and makes suggestions on how they can be addressed within clinical trials units registered with the UK Clinical Research Collaboration.

Abstract 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.

Abstract Background Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions. Main body We use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If non-bleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment. Conclusions All-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments.

Abstract Background Trauma is the leading cause of morbidity and mortality in children in the United States. The antifibrinolytic drug tranexamic acid (TXA) improves survival in adults with traumatic hemorrhage, however, the drug has not been evaluated in a clinical trial in severely injured children. We designed the Traumatic Injury Clinical Trial Evaluating Tranexamic Acid in Children (TIC-TOC) trial to evaluate the feasibility of conducting a confirmatory clinical trial that evaluates the effects of TXA in children with severe trauma and hemorrhagic injuries. Methods Children with severe trauma and evidence of hemorrhagic torso or brain injuries will be randomized to one of three arms: (1) TXA dose A (15 mg/kg bolus dose over 20 min, followed by 2 mg/kg/hr infusion over 8 h), (2) TXA dose B (30 mg/kg bolus dose over 20 min, followed by 4 mg/kg/hr infusion over 8 h), or (3) placebo. We will use permuted-block randomization by injury type: hemorrhagic brain injury, hemorrhagic torso injury, and combined hemorrhagic brain and torso injury. The trial will be conducted at four pediatric Level I trauma centers. We will collect the following outcome measures: global functioning as measured by the Pediatric Quality of Life (PedsQL) and Pediatric Glasgow Outcome Scale Extended (GOS-E Peds), working memory (digit span test), total amount of blood products transfused in the initial 48 h, intracranial hemorrhage progression at 24 h, coagulation biomarkers, and adverse events (specifically thromboembolic events and seizures). Discussion This multicenter trial will provide important preliminary data and assess the feasibility of conducting a confirmatory clinical trial that evaluates the benefits of TXA in children with severe trauma and hemorrhagic injuries to the torso and/or brain. Trial registration ClinicalTrials.gov registration number: NCT02840097. Registered on 14 July 2016.

Background: Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. Objectives: To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. Design: A series of 200 double-blinded N-of-1 trials. Setting: Participants were recruited from 50 general practices in England and Wales. Participants: Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms. Interventions: Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo. Main outcome measures: The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant’s belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant’s decision about statin treatment following the trial, and whether or not they found their own trial result helpful. Results: A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo –0.11, 95% confidence interval –0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods. Conclusions: Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial. Future work: We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications. Limitations: This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations. Trial registration: Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.

Background Antiplatelet therapy increases the risk of hematoma expansion in intracerebral hemorrhage (ICH) while the effect on functional outcome is uncertain. Methods and Results This is an exploratory analysis of the TICH‐2 (Tranexamic Acid in Intracerebral Hemorrhage‐2) double‐blind, randomized, placebo‐controlled trial, which studied the efficacy of tranexamic acid in patients with spontaneous ICH within 8 hours of onset. Multivariable logistic regression and ordinal regression were performed to explore the relationship between pre‐ICH antiplatelet therapy, and 24‐hour hematoma expansion and day 90 modified Rankin Scale score, as well as the effect of tranexamic acid. Of 2325 patients, 611 (26.3%) had pre‐ICH antiplatelet therapy. They were older (mean age, 75.7 versus 66.5 years), more likely to have ischemic heart disease (25.4% versus 2.7%), ischemic stroke (36.2% versus 6.3%), intraventricular hemorrhage (40.2% versus 27.5%), and larger baseline hematoma volume (mean, 28.1 versus 22.6 mL) than the no‐antiplatelet group. Pre‐ICH antiplatelet therapy was associated with a significantly increased risk of hematoma expansion (adjusted odds ratio [OR], 1.28; 95% CI, 1.01–1.63), a shift toward unfavorable outcome in modified Rankin Scale (adjusted common OR, 1.58; 95% CI, 1.32–1.91) and a higher risk of death at day 90 (adjusted OR, 1.63; 95% CI, 1.25–2.11). Tranexamic acid reduced the risk of hematoma expansion in the overall patients with ICH (adjusted OR, 0.76; 95% CI, 0.62–0.93) and antiplatelet subgroup (adjusted OR, 0.61; 95% CI, 0.41–0.91) with no significant interaction between pre‐ICH antiplatelet therapy and tranexamic acid (P interaction=0.248). Conclusions Antiplatelet therapy is independently associated with hematoma expansion and unfavorable functional outcome. Tranexamic acid reduced hematoma expansion regardless of prior antiplatelet therapy use. Registration URL: https://www.isrctn.com; Unique identifier: ISRCTN93732214.

(1) Background: Visual impairment of people with diabetic retinopathy (DR) and its high impact on different dimensions of their lives can cause a significant deterioration in the quality of life. The aim of this study was to examine the association and relationship between quality of life related to vision and the relevant clinical and sociodemographic variables in a group of patients with DR in Spain. (2) Methods: A descriptive cross-sectional study was conducted in all patients with DR over 18 years under follow-up in the Retina Service of the University Hospital of Burgos (HUBU), recruited during the months of January and February 2020. The main study variable was quality of life related to health and vision, obtained using the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25). (3) Results: In total 87 participants made up the sample, and significant differences were found in the NEI-VFQ-25 according to gender, type of diabetes, episodes of decompensated diabetes and high blood pressure (HBP) (p < 0.05). Best-corrected visual acuity (BCVA) was also correlated with the NEI-VFQ-25 (p < 0.05). (4) Conclusions: These data could facilitate the design of action protocols focused on the well-being of the patient, in addition to considering the clinical characteristics. Further studies are needed to help understand the causal relationship between variables and that includes a wider variety of factors.

Introduction An estimated 69 million traumatic brain injuries (TBI) occur each year worldwide, with most in low-income and middle-income countries. The CRASH-3 randomised trial found that intravenous administration of tranexamic acid within 3 hours of injury reduces head injury deaths in patients sustaining a mild or moderate TBI. We examined the cost-effectiveness of tranexamic acid treatment for TBI.Methods A Markov decision model was developed to assess the cost-effectiveness of treatment with and without tranexamic acid, in addition to current practice. We modelled the decision in the UK and Pakistan from a health service perspective, over a lifetime time horizon. We used data from the CRASH-3 trial for the risk of death during the trial period (28 days) and patient quality of life, and data from the literature to estimate costs and long-term outcomes post-TBI. We present outcomes as quality-adjusted life years (QALYs) and 2018 costs in pounds for the UK, and US dollars for Pakistan. Incremental cost-effectiveness ratios (ICER) per QALY gained were estimated, and compared with country specific cost-effective thresholds. Deterministic and probabilistic sensitivity analyses were also performed.Results Tranexamic acid was highly cost-effective for patients with mild TBI and intracranial bleeding or patients with moderate TBI, at £4288 per QALY in the UK, and US$24 per QALY in Pakistan. Tranexamic acid was 99% and 98% cost-effective at the cost-effectiveness thresholds for the UK and Pakistan, respectively, and remained cost-effective across all deterministic sensitivity analyses. Tranexamic acid was even more cost-effective with earlier treatment administration. The cost-effectiveness for those with severe TBI was uncertain.Conclusion Early administration of tranexamic acid is highly cost-effective for patients with mild or moderate TBI in the UK and Pakistan, relative to the cost-effectiveness thresholds used. The estimated ICERs suggest treatment is likely to be cost-effective across all income settings globally.

IntroductionYoung people aged 16 to 24 have the highest prevalence of genital chlamydia and gonorrhoea compared with other age groups and re-infection rates following treatment are high. Long-term adverse health effects include subfertility and ectopic pregnancy, particularly among those with repeated infections. We developed the safetxt intervention delivered by text message to reduce sexually transmitted infection (STI) by increasing partner notification, condom use and (STI) testing among young people in the UK.Methods and analysisA single-blind randomised trial to reliably establish the effect of the safetxt intervention on chlamydia and gonorrhoea infection at 1 year. We will recruit 6250 people aged 16 to 24 years who have recently been diagnosed with chlamydia, gonorrhoea or non-specific urethritis from health services in the UK. Participants will be allocated to receive the safetxt intervention (text messages designed to promote safer sexual health behaviours) or to receive the control text messages (monthly messages asking participants about changes in contact details) by an automated remote online randomisation system. The primary outcome will be the cumulative incidence of chlamydia and gonorrhoea infection at 1 year assessed by nucleic acid amplification tests. Secondary outcomes include partner notification, correct treatment of infection, condom use and STI testing prior to sex with new partners.Ethics and disseminationEthics approval was obtained from NHS Health Research Authority - London – Riverside Research Ethics Committee (REC reference: 15/LO/1665) and the London School of Hygiene & Tropical Medicine. We will submit the results of the trial for publication in peer-reviewed journals.Trial registration numberInternational Standard Randomised Controlled Trials Number: ISRCTN64390461. Registered on 17th March 2016. WHO trial registration data set available at: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN64390461.Trial protocol version12, 19th July 2018.

BACKGROUND:Hemorrhage is a leading cause of death after trauma and childbirth. In response to severe hemorrhage, bleeding patients often receive transfusions of red blood cells, plasma, platelets, or other blood components. We examined risk factors for transfusion in acute severe bleeding in two trials of over 20,000 patients to better understand factors associated with transfusion likelihood. STUDY DESIGN AND METHODS:We conducted a cohort analysis of data from the CRASH-2 and WOMAN trials, two multinational trials that recruited patients with traumatic and postpartum hemorrhage, respectively. For each trial, we examined the effect of 10 factors on blood transfusion likelihood. Univariate and multivariate Poisson regressions were used to analyze the relationship between risk factors and blood transfusion. RESULTS:Of the 20,207 traumatic hemorrhage patients, 10,232 (51%) received blood components. Of the 20,060 women with postpartum hemorrhage, 10,958 (55%) received blood components. For patients who suffered from traumatic hemorrhage, those greater than three hours from injury to hospitalization were more likely to be transfused (ARR 1.37; 95% CI, 1.20-1.56). Postpartum hemorrhage patients had an increased likelihood of transfusion if they gave birth outside the hospital (ARR 1.30; 95% CI 1.22-1.39), gave birth more than three hours before hospitalization (ARR 1.09; 95% CI 1.01-1.17), had a Caesarean section (ARR 1.16; 95% CI 1.08-1.25), and if they had any identifiable causes of hemorrhage other than uterine atony. CONCLUSION:Several risk factors are associated with an increased likelihood of transfusion in traumatic and postpartum hemorrhage patients. Altering modifiable factors, by reducing time from injury or childbirth to hospitalization, for example, might be able to reduce transfusions and their complications. TRIAL REGISTRATION:CRASH-2 is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258 and South African Clinical Trial Register DOH-27-0607-1919. WOMAN is registered as ISRCTN76912190, ClinicalTrials.gov NCT00872469, PACTR201007000192283, and EudraCT number 2008-008441-38.

Background: The CRASH-3 trial is a randomised trial on the effect of tranexamic acid (TXA) versus placebo on death and disability in traumatic brain injury (TBI). The CRASH-3 intracranial bleeding mechanistic study (IBMS) is a randomised trial nested within the CRASH-3 trial to examine the effect of TXA versus placebo on intracranial bleeding and infarction. Methods: Patients eligible for the CRASH-3 trial, with a GCS of 12 or less or intracranial bleeding on a pre-randomisation CT scan are eligible for the IBMS. The occurrence of intracranial bleeding, infarction, haemorrhagic oedematous lesions, mass effect and haemorrhage evacuation is examined within 28 days of randomisation using routinely collected brain scans. The primary outcome is the volume of intra-parenchymal bleeding in patients randomised within three hours of injury (adjusted for prognostic covariates). Secondary outcomes include a composite “poor” outcome, progressive and new intracranial bleeding, intracranial bleeding after neurosurgery and cerebral infarcts seen up to 28 days post-randomisation. All outcomes will be compared between treatment groups. Statistical analyses: The primary outcome will be analysed using a covariate adjusted linear mixed model. The same analysis will be done separately for patients who undergo haemorrhage evacuation post-randomisation. We will express the effect of TXA on the composite outcome, new and progressive bleeding using relative risks and 95% CIs, and on cerebral infarcts using hazard ratios and 95% CIs. We will conduct sensitivity analyses assuming missing data are MCAR or MNAR. Conclusion: The IBMS will provide information on the mechanism of action of TXA in TBI. This pre-specified statistical analysis plan is a technical extension of the published protocol. Trial registration: The CRASH-3 trial was prospectively registered at the International Standard Randomised Controlled Trials registry (19 July 2011) and ClinicalTrials.gov (25 July 2011). The registries were updated with details for the IBMS on 20 December 2016.

Abstract Background In severe post-partum haemorrhage, death can occur within hours of bleeding onset so interventions to control the bleeding must be given immediately. In clinical trials of treatments for life-threatening bleeding, established treatments are given priority and the trial treatment is usually given last. However, enrolling patients in whom severe maternal morbidity or death is imminent or inevitable at the time of randomisation may dilute the effects of a trial treatment. Methods We conducted an exploratory analysis of data from the WOMAN trial, an international, randomised placebo-controlled trial of the effects of tranexamic acid on death and surgical intervention in 20,060 women with post-partum haemorrhage. We assessed the impact of early maternal death or hysterectomy due to exsanguination on the effect of tranexamic acid on each of these respective outcomes. We conducted repeated analyses excluding patients with these outcomes at increasing intervals from the time of randomisation. We quantified treatment effects using risk ratios (RR) and 99% confidence intervals (CI) and prepared cumulative failure plots. Results Among 14,923 women randomised within 3 h of delivery (7518 tranexamic acid and 7405 placebo), there were 216 bleeding deaths (1.5%) and 383 hysterectomies due to bleeding (2.8%). After excluding deaths from exsanguination at increasing time intervals following randomization, there was a significant reduction in the risk of death due to bleeding with tranexamic acid (RR = 0.41; 99% CI 0.19–0.89). However, after excluding hysterectomies at increasing time intervals post-randomization, there was no reduction in the risk of hysterectomy due to bleeding with tranexamic acid (RR = 0.79; 99% CI 0.33–1.86). Conclusions Findings from this analysis provide further evidence that tranexamic acid reduces the risk of death from exsanguination in women who experience postpartum haemorrhage. It is uncertain whether tranexamic acid reduces the risk of hysterectomy for bleeding after excluding early hysterectomies. Trial registration ISRCTN trial registration number ISRCTN76912190, 8 Dec 2008; ClinicalTrials.gov number NCT00872469, 30 March 2009; PACTR number PACTR201007000192283, 9 Feb 2010; EudraCT number 2008–008441-38, 8 Dec 2010 (retrospectively registered).

Abstract Background Peripartum hysterectomy can cause significant morbidity and mortality. Most studies of peripartum hysterectomy are from high income countries. This cohort study examined risk factors for peripartum hysterectomy using data from Africa, Asia, Europe and the Americas. Methods We used data from the World Maternal Antifibrinolytic (WOMAN) trial carried out in 193 hospitals in 21 countries. Peripartum hysterectomy was defined as hysterectomy within 6 weeks of delivery as a complication of postpartum haemorrhage. Univariable and multivariable random effects logistic regression models were used to analyse risk factors. A hierarchical conceptual framework guided our multivariable analysis. Results Five percent of women had a hysterectomy (1020/20,017). Haemorrhage from placenta praevia/accreta carried a higher risk of hysterectomy (17%) than surgical trauma/tears (5%) and uterine atony (3%). The adjusted odds ratio (AOR) for hysterectomy in women with placenta praevia/accreta was 3.2 (95% CI: 2.7–3.8), compared to uterine atony. The risk of hysterectomy increased with maternal age. Caesarean section was associated with fourfold higher odds of hysterectomy than vaginal delivery (AOR 4.3, 95% CI: 3.6–5.0). Mothers in Asia had a higher hysterectomy incidence (7%) than mothers in Africa (5%) (AOR: 1.2, 95% CI: 0.9–1.7). Conclusions Placenta praevia/accreta is associated with a higher risk of peripartum hysterectomy. Other risk factors for hysterectomy are advanced maternal age, caesarean section and giving birth in Asia.

Abstract Background Early treatment with tranexamic acid reduces deaths due to bleeding after post-partum haemorrhage. We report the prevalence of haematological, coagulation and fibrinolytic abnormalities in Nigerian women with postpartum haemorrhage. Methods We performed a secondary analysis of the WOMAN trial to assess laboratory data and rotational thromboelastometry (ROTEM) parameters in 167 women with postpartum haemorrhage treated at University College Hospital, Ibadan, Nigeria. We defined hyper-fibrinolysis as EXTEM maximum lysis (ML) > 15% on ROTEM. We defined coagulopathy as EXTEM clot amplitude at 5 min (A5) 1.5. Results Among the study cohort, 53 (40%) women had severe anaemia (haemoglobin

Abstract Background Tranexamic acid prevents blood clots from breaking down and reduces bleeding. However, it is uncertain whether tranexamic acid is effective in traumatic brain injury. The CRASH-3 trial is a randomised controlled trial that will examine the effect of tranexamic acid (versus placebo) on death and disability in 13,000 patients with traumatic brain injury. The CRASH-3 trial hypothesizes that tranexamic acid will reduce intracranial haemorrhage, which will reduce the risk of death. Although it is possible that tranexamic acid will reduce intracranial bleeding, there is also a potential for harm. In particular, tranexamic acid may increase the risk of cerebral thrombosis and ischaemia. The protocol detailed here is for a mechanistic sub-study nested within the CRASH-3 trial. This mechanistic sub-study aims to examine the effect of tranexamic acid (versus placebo) on intracranial bleeding and cerebral ischaemia. Methods The CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) is nested within a prospective, double-blind, multi-centre, parallel-arm randomised trial called the CRASH-3 trial. The CRASH-3 IBMS will be conducted in a cohort of approximately 1000 isolated traumatic brain injury patients enrolled in the CRASH-3 trial. In the CRASH-3 IBMS, brain scans acquired before and after randomisation are examined, using validated methods, for evidence of intracranial bleeding and cerebral ischaemia. The primary outcome is the total volume of intracranial bleeding measured on computed tomography after randomisation, adjusting for baseline bleeding volume. Secondary outcomes include progression of intracranial haemorrhage (from pre- to post-randomisation scans), new intracranial haemorrhage (seen on post- but not pre-randomisation scans), intracranial haemorrhage following neurosurgery, and new focal ischaemic lesions (seen on post-but not pre-randomisation scans). A linear regression model will examine whether receipt of the trial treatment can predict haemorrhage volume. Bleeding volumes and new ischaemic lesions will be compared across treatment groups using relative risks and 95% confidence intervals. Discussion The CRASH-3 IBMS will provide an insight into the mechanism of action of tranexamic acid in traumatic brain injury, as well as information about the risks and benefits. Evidence from this trial could inform the management of patients with traumatic brain injury. Trial registration The CRASH-3 trial was prospectively registered and the CRASH-3 IBMS is an addition to the original protocol registered at the International Standard Randomised Controlled Trials registry ( ISRCTN15088122 ) 19 July 2011, and ClinicalTrials.gov on 25 July 2011 (NCT01402882).

Background: Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. Objective: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). Design: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. Setting: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). Participants: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset. Exclusion criteria: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. Conclusions: Tranexamic acid did not affect a patient’s functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. Future work: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed. Trial registration: Current Controlled Trials ISRCTN93732214. Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.

Abstract Introduction: The Anti-fibrinolytics Trialists Collaboration aims to increase knowledge about the effectiveness and safety of anti-fibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of anti-fibrinolytics for acute intracranial haemorrhage. Methods: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42019128260). We will conduct an individual patient data meta-analysis of randomised controlled trials with 500 patients or more assessing the effects of anti-fibrinolytics in acute intracranial haemorrhage. The primary outcomes will be 1) death from stroke or head injury within 30 days of randomisation, and 2) death from stroke or head injury, or dependency within 90 days of randomisation. The primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of anti-fibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of anti-fibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. Conclusions: This IPD meta-analysis will examine important clinical questions about the effects of anti-fibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.

Background: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. To determine whether TXA has pro-thrombotic effects in women with PPH, we measured endogenous thrombin potential (ETP), coagulation factors V, VIII, von Willebrand (vW), fibrinogen, D-Dimers and platelet function. Methods: We conducted a sub-study within the WOMAN trial, an international randomized, parallel-group, double blind, placebo-controlled trial. Women with primary PPH were randomly allocated to receive 1 gram of tranexamic acid or matching placebo. Baseline blood samples were collected just prior to the first dose and a follow up sample was collected 30±15 minutes afterwards. We compared before and after changes in coagulation parameters between treatment groups using repeated measurement ANOVA. Change in ETP was the primary outcome. We did an intention-to-treat analysis using ANCOVA with adjustment for baseline and the time interval between the blood samples. Findings: A total of 187 patients were randomized to receive TXA (n=93) or matching placebo (n=94). Six patients were excluded due to incomplete data. The reduction in ETP from baseline to follow up was 43.2 nM*min (95%CI, -16.6 to 103.1) in the TXA group and 4.6 nM*min (95%CI, -51.4 to 60.6) in the placebo group. The difference was not statistically significant (95%CI, -42.9 to 120). There were no significant effects of TXA treatment on any other parameters (ADPtest, TRAPtest, coagulation factors activity, fibrinogen levels, D-Dimer level). Conclusion: We found no evidence that tranexamic acid treatment for PPH has substantial pro-coagulant effects. However, larger studies are needed to confirm or refute more modest effects. Trial registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAPlat included on 28/10/2013) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAPlat included on 28/10/2013).