By John C. Hobbins, MD

Professor, Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora

Dr. Hobbins reports no financial relationships relevant to this field of study.

SYNOPSIS: A multicenter study involving patients in 193 countries has shown a decrease in maternal mortality in women with postpartum hemorrhage who were given tranexamic acid once the diagnosis was made.

SOURCE: WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with postpartum hemorrhage (WOMAN): An international, randomized, double-blind, placebo-controlled trial. Lancet 2017; Apr 26. doi: 10.1016/S0140-6736(17)30638-4.

Tranexamic acid has been used successfully to reduce blood loss after surgery and trauma by its ability to counter the conversion of plasminogen to plasmin, the active ingredient in the fibrinolysis that often accompanies excessive blood loss.1 Postpartum hemorrhage is the leading cause of maternal death, especially in undeveloped countries. This has led a consortium of investigators to undertake a multicenter, randomized, clinical trial in 21 countries to assess the efficacy of using tranexamic acid to diminish maternal mortality and morbidity in patients with postpartum hemorrhage.

Over a six-year period (2010-2016), 20,060 women with postpartum hemorrhage (defined as blood loss of > 500 mL after vaginal delivery or > 1,000 mL following a cesarean delivery) were enrolled from 193 hospitals. One group was randomized to receive a 1 g (10 mL) dose of tranexamic acid intravenously over a 10-minute therapeutic window. The control group received placebo in the same manner.

Initially, the primary outcomes were the need for hysterectomy up to 42 days after delivery and death from all causes. A total of 10,051 women received tranexamic acid vs. 10,009 who received placebo. There were 483 deaths in the study, 374 of which occurred within 24 hours of randomization and 43 within one hour of randomization. Most importantly, 346 (72%) were due to maternal hemorrhage.

The risk of death from bleeding was significantly less in the tranexamic group vs. placebo group (1.5% vs. 1.9%; relative risk [RR], 0.81; 95% confidence interval [CI], 0.65-1.00). After adjusting for baseline risk, the RR was 0.78 (95% CI, 0.62-0.98). Deaths from reasons other than hemorrhage were no different between groups.

The timing of when the drug was given appeared to be important. If administered within three hours, the RR of death was significantly reduced (1.2% vs. 1.7%; RR, 0.69; 95% CI, 0.52-0.91) compared with after three hours (2.6% vs. 2.5%). The need for hysterectomy to stem bleeding or to prevent death was no different between groups, but there was a significant reduction in the need for laparotomy to control bleeding (1.3% vs. 0.8%; RR, 0.64; 95% CI, 0.49-0.845).

COMMENTARY

This study, which was funded by the London School of Hygiene & Tropical Medicine and the Gates Foundation, represented a gargantuan undertaking. The hospitals involved were mostly in underdeveloped areas with limited resources. The authors originally powered their study on the hypothesis that the drug would decrease the need for hysterectomy, but since many of these operations occurred within one hour of randomization, the authors focused on death as a primary outcome measure and increased their enrollment from 15,000 to 20,000 patients.

The results suggested that giving tranexamic acid within three hours of the diagnosis of postpartum hemorrhage resulted in more than a 20% reduction in maternal death and a 40% decrease in the need for laparotomy. The logical conclusion of this tour de force investigation is that the relatively inexpensive drug can diminish maternal mortality in many areas of the world with limited resources. However, higher maternal mortality is not limited to underdeveloped areas. The U.S. maternal mortality rate is nothing to brag about, having risen from 7.2/100,000 in 1987 to 17.8/100,000 in 2011.2 In fact, the national media has picked up on the fact that the maternal mortality rate in the United States is two times higher than Canada and six times higher than Sweden.3 Also, it is very likely that we do far more laparotomies for postpartum hemorrhage than the countries involved in the above multicenter study. For these reasons, we should pay attention to the implicit message in the study: Tranexamic acid given within three hours of diagnosis of postpartum hemorrhage can save lives and decrease the need for laparotomies.

The WHO has recommended its use in postpartum hemorrhage if uterotonics fail or if there is evidence of trauma.4 Given that the common increase in fibrinolytic activity noted postpartum occurs within one hour of delivery and based on the results of the multicenter study, the authors suggested that waiting too long for an oxytocic to work could limit its effectiveness significantly. Therefore, since the drug has not been associated with side effects, such as thromboembolic events,5 and is relatively inexpensive (average $130 per 10 mL dose in the United States), one might consider giving this potentially life-saving drug to all patients once the objective diagnosis of postpartum hemorrhage is made.

Hopefully, the price of the drug will not follow the same historical course as the EpiPen.

REFERENCES

  1. CRASH-2 Collaborators, Roberts I, Shakur H, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: An exploratory analysis of the CRASH-2 randomized controlled trial. Lancet 2011;377:1096-1101.
  2. Osterman MJ, Kochanek KD, MacDorman MF, et al. Annual summary of vital statistics: 2012-2013. Pediatrics 2015;135:1115-1125.
  3. Ingraham C. Our maternal mortality rate is a national embarrassment. The Washington Post. Available at: http://wapo.st/2rRp1mt. Accessed May 20, 2017.
  4. WHO recommendations for prevention and treatment of postpartum haemorrhage. Geneva: World Health Organization; 2012. Available at: https://www.ncbi.nlm.nih.gov/books/NBK131942/. Accessed May 20, 2017.
  5. Crash-2 Collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): A randomized placebo-controlled trial. Lancet 2010;376:23-32.