Why is this a landmark trial?

Three reasons:

1. Clinical significance of the findings: reducing maternal mortality.
2. Relevance to much of world's population, in particular to low resource settings where post-partum haemorrhage (PPH) is disproportionately burdensome.
3. Quality – a massive, double-blinded randomised controlled trial.

So, what did they do?

They randomised 20,060 women with PPH to receive either 1g of tranexamic acid (100mg/min slow IV) or placebo, across 21 countries and 193 hospitals. Although only 569 (2.8%) patients were from a high resource country (UK).

What did they find?

Mortality due to haemorrhage was reduced by almost 20% (RR 0.81, NNT 267) after receiving tranexamic acid (TXA), and by 30% (RR 0.69) when given within 3 hours of birth.

Hysterectomies were not reduced by TXA use. There was no increased risk of thromboembolic events.

Be smart

While on the surface this suggests we should move to routine use of TXA in managing all PPH, the risk of PPH-death in most high resource countries is relatively low. 99% of all PPH deaths are in low resource countries.

In the WOMAN trial the risk of death in the placebo group was 1.9%. In contrast the latest maternal mortality data from MBRACE-UK (2014-16) reports 0.78 haemorrhage-deaths per 100,000 maternities, which using a conservative 5% PPH incidence (depending on definition), yields a PPH-mortality risk of 0.016% – 100x less than the study population.

Thus in a high resource setting the TXA NNT to avoiding one maternal death is generously at least 20,000 PPH cases.

In high resource settings, TXA use should be considered second-line therapy in managing severe PPH when other measures are inadequate. In low resource settings where maternal PPH mortality Is high, TXA reduces maternal mortality and should be routinely used.

Context is everything.

summary

• WOMAN Trial Collaborators.
• Lancet. 2017 May 27; 389 (10084): 2105-2116.

BackgroundPost-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 placebo group.InterpretationTranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.FundingLondon School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

This article appears in the collections: Inadvertent spinal tranexamic acid: a devastating error and Landmark articles in Anesthesia.

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