Tranexamic acid is popular for the treatment of freckles and nosebleeds – oh, and major bleeding in the setting of trauma. But, originally, the drug was developed for use in controlling hemorrhage in obstetrics and gynecology. Finally, then, we have a trial examining its use for its intended purpose.
Comprising 20,060 patients with clinically significant post-partum hemorrhage across 193 hospitals in 21 countries, the WOMAN trial is – inconveniently – negative as originally designed. The initial study design called for 15,000 patients and a composite endpoint of hysterectomy or death within six weeks of childbirth. However, as the study progressed, it was clear the standard practice in the settings involved indicated the intervention was going to have no effect on hysterectomy rates, and the trial was then expanded to examine the effect on mortality.
Mortality within 6 weeks was 2.3% in the TXA cohort and 2.6% with placebo a relative risk of 0.88 (0.74-1.05).
There is, however, some layered complexity in these outcomes. Broken down by cause of death, deaths due to bleeding were 1.5% in the TXA cohort compared with 1.9% with placebo, reaching “statistical significance” with a p-value of 0.045. Then, if you further unpack these results, it seems even within the TXA cohort there is probably a time-to-treatment effect similar to CRASH-2. Mortality was 1.2% in those receiving their TXA within 3 hours compared with 1.7% treated with placebo. In those treated beyond 3 hours, there was no difference in outcomes – and much higher mortality, regardless (2.6% vs. 2.5%).
So, what should we take away from these data? Is TXA more than just a treatment for freckles, or are these authors and the lay media exaggerating secondary outcomes in the setting of an overall negative trial? As usual, the answer is a little bit of both. The magnitude of the treatment effect, considering the size of this trial, is very, very small. That said, death is a quite meaningful clinical outcome, TXA is fairly inexpensive, and no specific harms were detected in this trial. Therefore, in the settings in which this trial was conducted – Nigeria, Pakistan, Sudan, Albania, etc. – this is likely an important treatment for post-partum hemorrhage.
In more robust clinical settings where additional resources are typically available to support the resuscitation of women suffering bleeding complications from childbirth, the effect size on mortality is likely even much smaller. There may be clinically important effects regarding hysterectomy, hemostasis, and reduction in transfusion utilization, but I again suspect they will be very small and difficult to quantify without a similarly large trial. Then, as the NNT increases for clinically important outcomes, even the very rare harms of a treatment become relevant – and failure of this trial to detect harms may simply be a limit of its statistical power.
Ultimately, as the mortality benefit decreases, the range of acceptable practice variation for protocols incorporating TXA increases. This is an important trial – but, as typically, not quite as breathlessly so.
“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”