Alternative routes for tranexamic acid treatment in obstetric bleeding (WOMAN-PharmacoTXA trial): a randomised trial and pharmacological study in caesarean section births.

OBJECTIVE: To examine the safety, efficacy and pharmacology of intravenous (IV), intramuscular (IM) and oral tranexamic acid (TXA) use in pregnant women. DESIGN: Randomised, open-label trial. SETTING: Hospitals in Pakistan and Zambia. POPULATION: Women giving birth by caesarean section. METHODS: Women were randomised to receive 1 g IV, 1 g IM, 4 g oral TXA or no TXA. Adverse events in women and neonates were recorded. TXA concentration in whole blood was measured and the concentrations over time were examined with population pharmacokinetics. The relationship between drug exposure and D-dimer was explored. The trial registration is NCT04274335. MAIN OUTCOME MEASURES: Concentration of TXA in maternal blood. RESULTS: Of the 120 women included in the randomised safety study, there were no serious maternal or neonatal adverse events. TXA concentrations in 755 maternal blood and 87 cord blood samples were described by a two-compartment model with one effect compartment linked by rate transfer constants. Maximum maternal concentrations were 46.9, 21.6 and 18.1 mg/L for IV, IM and oral administration, respectively, and 9.5, 7.9 and 9.1 mg/L in the neonates. The TXA response was modelled as an inhibitory effect on the D-dimer production rate. The half-maximal inhibitory concentration (IC50 ) was 7.5 mg/L and was achieved after 2.6, 6.4 and 47 minutes with IV, IM and oral administration of TXA, respectively. CONCLUSIONS: Both IM and oral TXA are well tolerated. Oral TXA took about 1 hour to reach minimum therapeutic concentrations and would not be suitable for emergency treatment. Intramuscular TXA inhibits fibrinolysis within 10 minutes and may be a suitable alternative to IV.

Tranexamic acid by the intramuscular or intravenous route for the prevention of postpartum haemorrhage in women at increased risk: a randomised placebo-controlled trial (I'M WOMAN).

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.

Postpartum haemorrhage in anaemic women: assessing outcome measures for clinical trials.

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.

Acceptability and feasibility of screening pregnant women for sexually transmitted infections in Rawalpindi, Pakistan.

Objectives: To understand the acceptability and feasibility of sexually transmitted infection (STI) testing during antenatal care, along with the prevalence of STIs, in Rawalpindi, Pakistan. Methods: We enrolled pregnant women seeking antenatal care and performed STI testing using Cepheid GeneXpert® CT/NG and TV kits and Alere Determine™ HIV and syphilis tests. We used interviewer-administered surveys to collect medical, social, and sexual histories. Participants testing positive for STIs and their partners were treated. Results: We enrolled 1001 women from September to December 2019. Nearly all women offered to participate in this study enrolled. Most women understood the effects an STI can have on their pregnancy (99.6%) and valued STI screening during pregnancy (98.1%). 11 women tested positive for any STI: (Chlamydia trachomatis = 4, Neisseria gonorrhoeae = 1, and Trichomonas vaginalis = 6). Of those, six presented for a test-of-cure, and two were positive for Trichomonas vaginalis. None tested positive for HIV infection or syphilis (n = 503). Conclusions: STI testing during antenatal care in Rawalpindi was acceptable, valued, understood, and feasible. The prevalence of STIs in pregnant women was low. Continued prevalence monitoring is warranted.

WOMAN-PharmacoTXA trial: Study protocol for a randomised controlled trial to assess the pharmacokinetics and pharmacodynamics of intramuscular, intravenous and oral administration of tranexamic acid in women giving birth by caesarean section.

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).

A high-dose 24-hour tranexamic acid infusion for the treatment of significant gastrointestinal bleeding: HALT-IT RCT.

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.

Acute gastrointestinal bleeding (bleeding from the gut) is a common emergency and an important cause of death and illness worldwide. In the UK, more than 65,000 people each year are admitted to hospital because of acute gastrointestinal bleeding; approximately 10% of them die within 30 days. Gastrointestinal bleeding is also common in low- and middle-income countries. The care of patients with gastrointestinal bleeding has improved in recent decades, but death rates remain high. Gastrointestinal bleeding is often caused by stomach ulcers, but also by liver damage owing to alcohol or hepatitis C infection. An effective and affordable treatment for gastrointestinal bleeding could save many lives and may reduce the need for blood transfusions, which is important because blood is a scarce resource in some health-care settings. Tranexamic acid, also known as TXA, is a cheap drug that reduces bleeding in other conditions. It helps blood to clot, thereby decreasing bleeding. A trial in bleeding accident victims found that tranexamic acid reduced the chances of bleeding to death, without any increase in side effects. We wanted to find out if tranexamic acid safely improves outcomes in patients with gastrointestinal bleeding, particularly to prevent deaths. To investigate this, the HALT-IT (Haemorrhage ALleviation with Tranexamic acid ­ Intestinal system) trial studied 12,009 patients with significant gastrointestinal bleeding in 164 hospitals across 15 countries. Half of the patients received tranexamic acid and the other half received a dummy drug, called a placebo. The treatments were assigned randomly and given in addition to all other treatments needed. Neither the patient nor the doctor knew which treatment a patient received. The trial showed that tranexamic acid did not reduce deaths from gastrointestinal bleeding. Instead, tranexamic acid was linked to an increased risk of complications, including unwanted blood clots (such as deep-vein thrombosis) and seizures. The economic analysis indicated that giving tranexamic acid to patients with gastrointestinal bleeding does not represent value for money for the NHS.

Learning Active Implementation Frameworks: the role of implementation teams in a case study from Pakistan.

In Pakistan, although coverage of Maternal, Newborn, and Child Health (MNCH) services has increased, the attributable disease burden remains high, indicating quality of these services remains suboptimal. To address this quality gap, challenges associated with the implementation of MNCH services will need to be addressed and effective use of the various MNCH guidelines will need to be supported, evaluated, and continuously improved. Even though the application of the field of implementation science and practice in the low- and middle-income settings has been limited, it is our belief, based on the experience described in this article that these competencies could enhance health professionals' ability to, not only successfully integrate MNCH guidelines into health systems, but to also support their effective and sustainable use. To address this capacity gap in Pakistan, the Health Services Academy, as a member of the World Health Organization's Human Reproduction Program (HRP) Alliance for Research Capacity Strengthening (RCS), has engaged, over the course of 16 months, in the 'Implementation for the Professional Learner Program' in 2019. This innovative implementation science and practice capacity-building program is developed and conducted by The World Health Organization (WHO) Collaborating Centre for Research Evidence for Sexual and Reproductive Health at the University of North Carolina at Chapel Hill (UNC). The initial cohort of this Program also included Palestine's West Bank, and Egypt. The objectives of this Program were to cultivate implementation science and practice competencies, and to support the development of national, community-based or institution-based implementation teams. The expected outcomes of this program included, further enhancement of the capacity of local health professionals in implementation science, systemic change and the effective use of innovations in practice at sub-national/regional levels.

Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial.

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.

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

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