Early tranexamic acid 1 gram IV infusion in addition to usual care reduces death due to bleeding in women with postpartum hemorrhage

EBM Focus - Volume 12, Issue 20

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Reference - WOMAN trial (Lancet 2017 Apr 26 early online) (level 1 [likely reliable] evidence)

  • Tranexamic acid (TXA) reduces bleeding and related morbidity following trauma and surgery, but evidence for treating postpartum hemorrhage (PPH) is limited.
  • In the WOMAN trial, 20,060 women in 21 countries with PPH were randomized to TXA vs. saline IV infusion in addition to usual care including uterotonic prophylaxis.
  • Death due to bleeding occurred in 1.2% with TXA vs. 1.7% with saline (risk ratio 0.69, 95% CI 0.52-0.91, NNT 200) in the pre-specified subgroup of women who had TXA within 3 hours of delivery. The difference in rates in women who had TXA > 3 hours after delivery (2.6% vs. 2.5%) was not significant.

Postpartum hemorrhage (PPH) has a prevalence of 7%-26% (depending on the region) and is a major cause of maternal death (PLoS One 2012;7(7):e41114, BJOG. 2017 Apr;124(5):e106, WHO 2012). Treatment options include oxytocin, other medications, surgical repair, and hysterectomy if there is massive bleeding unresponsive to other treatments. Tranexamic acid (TXA), which impairs plasmin-mediated fibrin clot breakdown, has been used to reduce bleeding following trauma, during surgery, and for menorrhagia (Curr Opin Anaesthesiol 2015 Apr;28(2):191, Anaesthesiol Intensive Ther 2015;47(4):339, Lancet 2010 Jul 3;376(9734):23). There is low-to-moderate quality evidence that prophylactic TXA may reduce the risk of PPH in some women (Cochrane Database Syst Rev 2015 Jun 16;(6):CD007872), but evidence for treating PPH is limited. To evaluate TXA for treating PPH, the recent WOMAN trial, conducted in 21 countries, randomized 20,060 women ≥ 16 years old with PPH to TXA vs. saline IV infusion in addition to usual care (including uterotonic prophylaxis in 96%). PPH was defined as estimated blood loss > 500 mL after vaginal birth, blood loss > 1,000 mL after cesarean section, or any blood loss leading to hemodynamic instability. The specific TXA used was cyklokapron 1 gram (10 mg/mL) administered at 1 mL/minute. Patients had a second dose of the study drug if bleeding continued after 30 minutes or restarted within 24 hours. Cesarean section was performed in 29% of women, and uterine atony was the primary cause of PPH in 64%.

TXA significantly reduced the risk of death due to bleeding, which occurred in 1.5% with TXA vs. 1.9% with saline (risk ratio 0.81, 95% CI 0.65-1, NNT 250). The difference was greater among the pre-specified subgroup of 14,928 women who had the study drug within 3 hours of delivery (1.2% vs. 1.7%, risk ratio 0.69, 95% CI 0.52-0.91, NNT 200) and was not significant among the subgroup of women who had the drug > 3 hours after delivery (in 2.6% vs. 2.5%). TXA did not significantly reduce the risk of hysterectomy (in 3.6% vs. 3.5%), all-cause mortality (in 2.3% vs. 2.6%), or death due to pulmonary embolism, organ failure, sepsis, or eclampsia (each in

< 0.3% of the cohort). There were also no significant differences between groups in rates of thromboembolic events (in 0.3% in both groups) or other complications.

This trial demonstrates that IV tranexamic acid (TXA) administered within 3 hours of delivery reduces the risk of death due to bleeding in women with postpartum hemorrhage (PPH). The absolute risk reduction is small, but the relative risk reduction is moderate-to-large. The analyses based on time of TXA administration should be taken as evidence that the benefit of TXA may decrease with longer delays from delivery, rather than evidence that TXA is ineffective if administered >

3 hours after delivery specifically. TXA did not reduce hysterectomy rates. This may be partially explained by the observation that the decision to perform a hysterectomy was often made when the patient was enrolled, reducing the potential influence of TXA on hysterectomy rates (the precise number of these cases was not reported). Also, TXA did not significantly reduce all-cause mortality. However, the direction and magnitude of risk difference in all-cause mortality is consistent with that of death due to bleeding; the non-significant differences in death due to other causes may have diluted the beneficial effects of TXA on all-cause mortality. Despite the caveats, this large multinational randomized trial provides the first high-quality evidence that early IV administration of TXA in addition to usual care reduces death due to bleeding following PPH.

For more information, see the Postpartum hemorrhage topic in DynaMed Plus. DynaMed users click here.