It’s Time for Tranexamic Acid (TXA) in Massive Hemorrhage

Background: Bleeding from massive hemorrhage in trauma and post-partum are a major cause of death worldwide. There have been two large randomized controlled trials, in trauma and post-partum hemorrhage that have shown administration of TXA within 3 hrs of bleeding onset reduces death due to bleeding. The current meta-analysis that we are going to best panerai replica review sought to quantify the effect of treatment delay in acute severe bleeding by analyzing individual patient-level data from the two randomized clinical trials mentioned above.

What They Did:

• Individual patient-level data meta-analysis of 2 randomized trials done with more than 1000 patients each, that assessed the effects of antifibrinolytics in acute severe bleeding.

Outcomes:

• Primary: Absence of Death from Bleeding
• Secondary: Vascular occlusive fatal and non-fatal events (MI, stroke, PE, and DVT)

Inclusion:

• Randomized placebo-controlled trials done with more than 1000 patients that assessed the effects of antifibrinolytics in acute severe bleeding

Exclusion:

• Ongoing trials without complete data
• Not a randomized placebo-controlled trial with >1000 patients

Results:

• 40,138 patients from two randomized trials of tranexamic acid in acute severe bleeding (traumatic and post-partum hemorrhage)
  • CRASH-2 (Trauma Study): 20,127 patients
  • WOMAN (Post-Partum Hemorrhage Study): 20,011 patients
  • 3,558 total deaths
    • 1,408 (40%) of deaths from bleeding
    • 884 (63%) of the bleeding deaths occurred within 12 hours of onset

• TXA Increased Overall Survival from Bleeding:
  • TXA Group: 96.6%
  • Placebo Group: 96.0%
  • ARR = 0.6%
  • NNT = 167
  • OR 1.20; 95% CI 1.08 – 1.33; p = 0.001
• No Increase in Vascular Occlusive Events with TXA
  • TXA Group: 0.2%
  • Placebo Group: 0.3%
  • OR 0.73; 95% CI 0.49 – 1.09
• Effect of Treatment Delay on Survival:

• Survival Benefit Decreased by 10% for Every 15 min of Treatment Delay Until 3hr, After Which There was no Benefit

Strengths:

• Trials that were RCT and had over 1000 patients were selected to reduce selection bias.
• Primary outcome was death due to bleeding and not all-cause mortality, as antifibrinolytics would not affect other causes of death
• Quality of included trials assessed by evaluating sequence generation, allocation concealment, blinding, data completeness, and risk of selective reporting, all of which are important to minimize bias in studies
• All analyses were done according to the intention-to-treat principle
• The funders of the CRASH-2 and WOMAN trials had no role in this study design, data collection, data analysis, data interpretation, or writing of this meta-analysis
• Assessed the effect of treatment delay on treatment effectiveness

Limitations:

• In trauma patients, the exact time of bleeding onset is often unknown, making some measurement error a possibility and potentially underestimating the effectiveness of TXA
• In post-partum hemorrhage the time of bleeding onset was the time of birth, making some measurement error a possibility and potentially overestimating the effectiveness of TXA
• It is possible that deaths due to bleeding and deaths from vascular occlusive events could have been misclassified (i.e. DIC)
• More randomized clinical trials could have been included in this meta-analysis, but smaller trials are underpowered to assess effects on death

Discussion:

• The authors of the paper also evaluated the relative treatment benefit observed by 60 minute intervals of treatment delay from time of onset of bleeding. There appears to be no additional benefit when TXA was given in the first hour, but it is also important to mention that a higher proportion of penetrating injuries are seen and treated in this time period, and many of them may have been unsurvivable injuries, therefore making the effect seem non-beneficial during this hour

Author Conclusion: “Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration.  Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid.”

Clinical Take Home Point: In patients with massive bleeding from trauma or post-partum hemorrhage, giving TXA as soon as bleeding is suspected, reduces mortality from bleeding.

• Most deaths, in trauma and postpartum from hemorrhage, occur within hours of bleeding onset
• The mortality benefit of TXA appears to diminish over time and is lost at 3 hours after major hemorrhage begins
• In this trial, there was no evidence of adverse effects (vascular occlusive events) associated with TXA treatment

References:

1. Gayet-Ageron A et al. Effect of Treatment Delay on the Effectiveness and Safety of Antifibrinolytics in Acute Severe Haemorrhage: A Meta-Analysis of Individual Patient-Level Data From 40138 Bleeding Patients. Lancet 2017. PMID: 29126600
2. Effects of Tranexamic Acid on Death, Vascular Occlusive Events, And Blood Transfusion in Trauma Patients With Significant Haemorrhage (CRASH-2): A Randomised, Placebo-Controlled Trial. Lancet 2010. PMID: 20554319
3. 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. Lancet 2017. PMID: 28456509

For More Thoughts on This Topic Checkout:

• Janos Baombe at St. Emlyn’s Blog: JC – Does Earlier TXA Save Lives?
• The Resus Room: Tranexamic Acid Time to Treatment

Post Peer Reviewed By: Scott Wieters (Twitter: @EMedCoach)