Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

Abstract

SummaryBackgroundPost-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.MethodsIn this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283.FindingsBetween March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus ...

Protocol for a pilot, randomised, double-blinded, placebo-controlled trial of prophylactic use of tranexamic acid for preventing postpartum haemorrhage (TAPPH-1)

“…24 WOMAN trial, as discussed above, did not show that the use of TXA had any effect on the incidence of thromboembolic events, organ failure, sepsis or seizure in the more than 20 000 patients studied. 29 It should be noted that TXA crosses the placenta. However, after an intravenous injection of 10 mg/kg in the mother, the concentration only rises to a maximum of 31 μg/mL of foetal serum.…”

Systematic review to identify proxy indicators to quantify the impact of eHealth tools on maternal and neonatal health outcomes in low-income and middle-income countries including Delphi consensus

“…However, recently, a new randomised, double-blind, placebo-controlled trial was published, concluding that tranexamic acid reduces PPH death of clinically diagnosed women and that early treatment seems to optimise benefits. 109 limitations The proxy indicators are probably more suitable to evaluate maternal and neonatal eHealth programmes or components of a programme. For specific maternal/ neonatal eHealth programmes or projects (eg, targeted at HIV infected mothers), additional indicators might be identifiable (eg, vertical transmission of HIV/AIDS).…”

Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

“…However, whilst the trial was underway, new research suggested a shorter therapeutic window than 8 hours 12, 13 . The new data showed that tranexamic acid is most likely to improve outcome if given soon after injury and would be unlikely to improve outcome if given beyond three hours of injury.…”

“…In 2011, the CRASH-2 trial showed that administration of tranexamic acid to poly-trauma patients within three hours of injury reduces deaths due to bleeding by about one third 11, 12 . In 2017, the WOMAN trial showed that administration of tranexamic acid to women with post-partum haemorrhage within three hours of delivery reduces deaths due to bleeding by about one third 13 . Later in 2017, results from an individual patient-level data meta-analysis of randomised trials of tranexamic acid in acute severe bleeding showed that whilst immediate treatment substantially improves survival, the survival benefit decreases by around 10% for every 15 min of treatment delay until 3 h, after which there was no benefit 14 .…”