Background

This post is cross-posted on REBEL EM.

Post-partum hemorrhage (PPH) is the leading cause of maternal death worldwide. It is typically defined as > 500 ml of blood loss within 24 hours of giving birth. However, PPH encompasses a broad spectrum of disease from mild oozing over hours to rapid exsanguination and death. The burden of mortality from PPH is shouldered mainly by developing countries thus requiring cost-effective treatment modalities. Tranexamic acid (TXA) is one such possibly modality. TXA works by inhibiting the breakdown of fibrinogen and fibrin by plasmin. In essence, it stabilizes clot that the body naturally forms. TXA has a well established role in reducing death in trauma patients as demonstrated in the CRASH-2 trial (CRASH-2 2010) and is already used by many performing resuscitations in resource strapped locations due to its availability and low cost. Whether TXA reduces mortality while avoiding significant clotting complications (DVT, PE, ACS, CVA) is unknown.

Clinical Question

Does early administration of TXA reduce death and hysterectomy rate in patients with PPH when compared to placebo.

Population

Women > 16 years of age diagnosed with PPH after a vaginal or caesarean section in 193 hospitals in 21 countries. Clinicians enrolling patients had to be uncertain about whether TXA should be used in a particular case or not.

Intervention

TXA 1 gm slow IV injection (1 ml/min of 10 mg/ml solution). A second dose could be administered if bleeding continued after 30 minutes or stopped and restarted anytime within the 1st 24 hours

Control

Placebo with identical packaging, volume and instructions

Outcomes

Original Primary Outcome: All-cause mortality or hysterectomy within 42 days of giving birth
Final Primary Outcome: Death from post-partum hemorrhage

Design

Multicenter, multinational, Randomized, double-blind, placebo-controlled trial

Excluded

Clinician was certain that TXA would either clearly be beneficial or clearly would not be appropriate

Primary Results

  • Initial Plan
    • Enroll 15,000 patients
    • Primary endpoint: all-cause mortality or hysterectomy
    • 90% power to detect a 25% relative reduction
  • Revised Plan
    • Enroll 20,000 patients
    • Primary endpoint: death from PPH
    • 90% power to detect a 25% relative reduction
  • Ultimately, enrolled 20,060 women and randomized to TXA or placebo
    • TXA group: 10,036/10,051 patients included for analysis
    • Placebo group: 9,985/10,009 patients included for analysis

Critical Results:

  • Death from all causes or hysterectomy (original primary endpoint)
    • No statistically significant difference
    • TXA 5.3% vs. Placebo 5.5%
    • RR = 0.97 (CI 0.87 – 1.09, p = 0.65)
  • Death due to PPH (revised primary outcome)
    • Statistically significant benefit to TXA
    • TXA 1.5% (155/10,036) vs Placebo 1.9% (191/9,985)
    • Risk Ratio (RR): 0.81 (CI 0.65 – 1.00, p = 0.045)
    • Absolute risk reduction = 0.4%
    • NNT = 267 (Fragility Index = 0)
  • No difference in adverse events including thromboembolic events
  • Secondary Outcomes
    • Death due to PPH (TXA given < 3 hours)
      • TXA 1.2% vs. Placebo 1.7%
      • RR = 0.69 (CI 0.62 – 0.91, p = 0.008)
    • Death due to PPH (TXA given > 3 hours)
      • TXA 2.6% vs. Placebo 2.5%
      • RR = 1.07 (CI 0.76 – 1.51 , p = 0.70)
    • Hysterectomy rate
      • TXA 3.6% vs. Placebo 3.5%
      • RR = 1.02 (CI 0.88 – 1.07, p = 0.84)

Strengths

  • Study asks a clinically important, patient centered question
  • Large, multicenter, multinational trial
  • Randomization and blinding was appropriately performed to minimize the risk of bias
  • Follow up was excellent (99.74%)
  • Pharma (Pfizer) did help fund the study but had no role in study design, data collection, data analysis, data interpretation or writing of the report

Limitations

  • Patients were only enrolled in the study if clinicians were uncertain if they would benefit from TXA or not. This may act to underestimate the benefit of TXA in PPH
  • The primary endpoint was altered after initiation of the trial (see details below)
  • Diagnosis of PPH made clinically and no assessment of inter-rater reliability in making this determination

Discussion

  • Primary endpoint was changed during study. Investigators learned that the decision to perform hysterectomy was most commonly made at the time of randomization and, thus, could not be affected by the intervention
  • The change in the primary endpoint was performed prior to any data analysis or unmasking of data
  • As with the CRASH-2 study, the data show a consistent association of delayed administration of TXA with harm

Author's Conclusions

“Tranexamic 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.”

Our Conclusions

TXA may be a beneficial intervention in preventing death from bleeding in patients with post-partum hemorrhage without increasing the risk of VTE. Unfortunately, we cannot offer a definitive bottom line due to methodology issues mainly revolving around alteration of the primary outcome. Even after forgiving the methodological issues, the NNT was large (267) with a fragility index of 0.

Potential Impact To Current Practice

PPH is a complicated disease and it was unlikely that a single medication was going to significantly change outcomes. Although the benefit of TXA in PPH was modest at best, the absence of increased VTE or other complications is reassuring for proponents of it’s use and may empower others to employ the drug.

Bottom Line

The WOMAN study demonstrated that TXA confers a small but significant decrease in death from bleeding in patients with PPH without an increase in thromboembolic events. It is reasonable to consider using TXA, an inexpensive medication, in the treatment of this life-threatening disorder.

Read More

Broome Docs: Thoughts on the WOMAN Trial

EM Lit of Note: Tranexamic Acid & the WOMAN Trial

The Bottom line: WOMAN Trial

References

CRASH-2 trial collaborators. Effects of tanexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a ransomised placebo-controlled trial. Lancet 2010; 376: 23-32. PMID: 20554319