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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. WOMAN Trial Collaborators. Lancet. 2017; 389: 2105–2116.

Study Population: 20,060 women aged 16 yrs and older with clinical diagnosis of postpartum hemorrhage after vaginal birth or cesarean section from 1 randomized control trial

Efficacy Endpoints

Death from all causes, death from bleeding, and hysterectomy

Harm Endpoints

Thromboembolic events and organ failure

Narrative

Postpartum hemorrhage (PPH) is the most common cause of maternal death worldwide. Tranexamic acid (TXA) is an antifibrinolytic agent that has shown to decrease bleeding in surgical patients and all cause death in trauma patients.1^, 2 In 2012, TXA was incorporated into the World Health Organization (WHO) guidelines for refractory or trauma-related PPH.3

The WOMAN trial4 was a single randomized, double-blind, placebo controlled, multi-center international study consisting of 20,060 women age 16 years and older with a diagnosis of PPH after vaginal birth or C-section. It investigated whether or not early administration of TXA reduced the rate of death and hysterectomy in patients with PPH when compared to placebo. One comparison was made -- TXA versus placebo. Outcomes were measured at hospital discharge or on day 42 if still in the hospital.

Benefits: Administration of tranexamic did not reduce all-cause mortality. However, TXA did show a reduction in the risk of death due to bleeding (Relative Risk [RR]: 0.81, 95% CI 0.62 to 0.98; Absolute Risk Difference [ARD]: 0.4%; NNT 267, very low quality evidence). There was no difference in hysterectomy rate between the two groups.

Harms: There was no difference between TXA and placebo in the rate of thromboembolic events (deep vein thrombosis, pulmonary embolism, myocardial infarction and stroke), organ failure (renal, cardiac, respiratory) or sepsis and use of uterotonics.

A recent systematic review and meta-analysis5 which only included postpartum hemorrhage following vaginal delivery and excluded cesarean sections (approximately 14000 patients from two RCTs, including the subset of patients from WOMAN trial who had postpartum hemorrhage after vaginal delivery) similarly showed no all-cause mortality benefit. This meta-analysis however showed reduced risk of hysterectomy (RR: 0.63, 95% CI, 0.42–0.94; ARD: 0.3%; NNT: 333, very low quality evidence) after postpartum hemorrhage resulting from vaginal delivery. This analysis also showed the tranexamic acid did not increase the risk of thromboembolic events, stroke, heart attack, or sepsis.

Caveats

One caveat is that the subjective inclusion criteria may have introduced selection bias into the study. Clinical diagnosis of PPH was based on the ability to estimate blood loss (500 mL after vaginal delivery or 1,000 mL C-section) which can vary between clinicians. Hemodynamic instability was also an inclusion criteria but objective measurements to define this were not discussed. Additionally, patients were enrolled only if clinicians were uncertain about giving TXA leaving out subgroup of patients with more severe pathology who were given TXA as standard of care. Excluding these patients, especially those with hemodynamic instability from severe hemorrhage may have lead to an underestimation of the TXA’s true efficacy.

Another caveat to consider is that the sample size was significantly increased from 15,000 to 20,000 after investigators discovered that the decision to perform hysterectomy was commonly made at the time of randomization and thus could not be impacted by intervention. This runs into the risk of overpowering which can interpret seemingly small and unremarkable differences between treatment and control arms as statistically significant.

Although we only reported individual outcomes in our review, the original study selected a composite outcome (death from all-causes or hysterectomy within 42 days of giving birth) as their primary outcome. The authors interpreted their results as positive despite the lack of statistical difference in this primary composite outcome. This was partly from shifting focus from all-cause mortality to cause-specific mortality specifically death due to bleeding. Although there was significantly less death from bleeding in the TXA group, the calculated fragility index was zero pointing to the lack of robustness of this dataset. We also do not consider disease-specific mortality a true efficacy endpoint.

In light of the results of this trial, WHO recommends administration of tranexamic acid to all patients with postpartum hemorrhage.3 This recommendation is not supported by the existing evidence with regards to all-cause mortality. Therefore we have assigned an NNT color recommendation of yellow (Unclear if Benefits). However, considering the safety and low cost of tranexamic acid ($45-$55 per vial), and the potentially devastating consequences of postpartum hemorrhage, we believe TXA should be considered as an attractive adjunctive therapy when other modalities (e.g. treating uterine atony) fail to control the hemorrhage.

The original manuscript was published in Medicine by the Numbers, American Family Physician as part of the partnership between TheNNT.com and AFP.

Author

Eric Tang, MD; Jessica Stetz, MD
Supervising Editors: Fredrik Amell, MD; Jarone Lee, MD

Published/Updated

August 1, 2019