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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. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

Worldwide, traumatic injury is responsible for over 5 million deaths per year, the majority due to exsanguination and head injury. The antifibrinolytic drug tranexamic acid is the only drug proven to reduce deaths after traumatic injury. Several large randomized controlled trials have provided high-quality evidence of its effectiveness and safety in trauma patients. Early tranexamic acid reduces deaths on the day of the injury in polytrauma patients and patients with isolated traumatic brain injury by around 20%. Treatment is time critical; for patients to benefit, tranexamic acid must be given as soon as possible after injury. Intramuscular administration is well tolerated and rapidly absorbed, with the potential to reduce time to treatment. Because the proportional reduction in bleeding death with tranexamic acid does not vary by baseline risk, a wide range of trauma patients stands to benefit. There are far more low-risk trauma patients than high-risk patients, with a substantial proportion of bleeding deaths in the low-risk group. As such, treatment should not be limited to patients with severe traumatic hemorrhage. We must give paramedics and physicians the confidence to treat a far wider range of trauma patients while emphasizing the importance of early treatment. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

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 FROM AUTHOR]

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 FROM AUTHOR]

Background: Removal of adenomas reduces colorectal cancer incidence and mortality; however, the benefit of surveillance colonoscopy on colorectal cancer risk remains unclear. We examined heterogeneity in colorectal cancer incidence in intermediate-risk patients and the effect of surveillance on colorectal cancer incidence.Methods: We did this retrospective, multicentre, cohort study using routine lower gastrointestinal endoscopy and pathology data from patients who, after baseline colonoscopy and polypectomy, were diagnosed with intermediate-risk adenomas mostly (>99%) between Jan 1, 1990, and Dec 31, 2010, at 17 hospitals in the UK. These patients are currently offered surveillance colonoscopy at intervals of 3 years. Patients were followed up through to Dec 31, 2014.We assessed the effect of surveillance on colorectal cancer incidence using Cox regression with adjustment for patient, procedural, and polyp characteristics. We defined lower-risk and higher-risk subgroups on the basis of polyp and procedural characteristics identified as colorectal cancer risk factors. We estimated colorectal cancer incidence and standardised incidence ratios (SIRs) using as standard the general population of England in 2007. This trial is registered, number ISRCTN15213649.Findings: 253 798 patients who underwent colonic endoscopy were identified, of whom 11 944 with intermediate-risk adenomas were included in this analysis. After a median follow-up of 7·9 years (IQR 5·6-11·1), 210 colorectal cancers were diagnosed. 5019 (42%) patients did not attend surveillance and 6925 (58%) attended one or more surveillance visits. Compared to no surveillance, one or two surveillance visits were associated with a significant reduction in colorectal cancer incidence rate (adjusted hazard ratio 0·57, 95% CI 0·40-0·80 for one visit; 0·51, 0·31-0·84 for two visits). Without surveillance, colorectal cancer incidence in patients with a suboptimal quality colonoscopy, proximal polyps, or a high-grade or large adenoma (≥20 mm) at baseline (8865 [74%] patients) was significantly higher than in the general population (SIR 1·30, 95% CI 1·06-1·57). By contrast, in patients without these features, colorectal cancer incidence was lower than that of the general population (SIR 0·51, 95% CI 0·29-0·84).Interpretation: Colonoscopy surveillance benefits most patients with intermediate-risk adenomas. However, some patients are already at low risk after baseline colonoscopy and the value of surveillance for them is unclear.Funding: National Institute for Health Research Health Technology Assessment, Cancer Research UK. [ABSTRACT FROM AUTHOR]

Background: Women are less likely than men to receive some emergency treatments. This study examines whether the effect of tranexamic acid (TXA) on mortality in trauma patients varies by sex and whether the receipt of TXA by trauma patients varies by sex.Methods: First, we conducted a sex-disaggregated analysis of data from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 and CRASH-3 trials. We used interaction tests to determine whether the treatment effect varied by sex. Second, we examined data from the Trauma and Audit Research Network (TARN) to explore sex differences in the receipt of TXA. We used logistic regression models to estimate the odds ratio for receipt of TXA in females compared with males. Results are reported as n (%), risk ratios (RR), and odds ratios (OR) with 95% confidence intervals.Results: Overall, 20 211 polytrauma patients (CRASH-2) and 12 737 patients with traumatic brain injuries (CRASH-3) were included in our analysis. TXA reduced the risk of death in females (RR=0.69 [0.52-0.91]) and in males (RR=0.80 [0.71-0.90]) with no significant heterogeneity by sex (P=0.34). We examined TARN data for 216 364 patients aged ≥16 yr with an Injury Severity Score ≥9 with 98 879 (46%) females and 117 485 (54%) males. TXA was received by 7198 (7.3% [7.1-7.4%]) of the females and 19 697 (16.8% [16.6-17.0%]) of the males (OR=0.39 [0.38-0.40]). The sex difference in the receipt of TXA increased with increasing age.Conclusions: Administration of TXA to patients with bleeding trauma reduces mortality to a similar extent in women and men, but women are substantially less likely to be treated with TXA. [ABSTRACT FROM AUTHOR]