TRAAP2: Tranexamic Acid for the Prevention of Blood Loss after Cesarean Delivery

Sentilhes L. New Eng J Med 2021; 384:1623-1634. doi:0.1056/NEJMoa2028788

Clinical Question

• In patients undergoing cesarean section (CS) does the administration of tranexamic acid (TXA) when compared to a placebo result in a lower incidence of calculated estimated blood loss or red blood cell transfusion by day 2?

Background

• The use of TXA has been widely studied in post partum haemorrhage (PPH)
• The WOMAN trial showed that TXA may be beneficial in reducing the risk of death due to PPH
  • This has been lauded as a landmark trial but there are some controversies that are excellently summarised here
• The evidence surrounding the use of TXA post CS is limited and consists mainly low quality evidence and there is no strong evidence to support its use in a prophylactic manner

Design

• Multi-centre, randomised, placebo controlled, double blind trial
• Randomised to receive uterotonic agent plus either TXA or placebo
• Randomised in 1:1 ratio
  • Computer based, in blocks of 4
  • Stratified by site and whether CS done pre or during labour
• TXA and placebo in identically labelled packaging and vials
• Appropriate consent process – written informed consent obtained by treating teams if CS considered likely
• Blood loss estimated using following equation:
  • Estimated blood volume x [(pre-op haematocrit-post-op haematocrit) / post-op haematocrit]
  • Pre-op haematocrit was most recent in 8 days prior to caesarean
  • Post-op was closest to day 2 post delivery
• Physician responsible for the delivery prospectively recorded the procedures used during the third stage of labor and clinical outcomes identified in the immediate postpartum period
• Adverse events were assessed until hospital discharge and a telephone interview was conducted at 3 months post delivery
• 4525 patients required
  • 4072 patients estimated (80% power to detect a 20% relative difference in incidence of primary outcome, with 5% type 1 error rate)
  • Allowed for up to 10% to be lost to follow, deliver vaginally or not have blood tests taken on day 2
  • Predominantly based on data from ECSSIT trial
• Performed with modified intention to treat population
  • Those who withdrew consent, delivered vaginally, or deemed ineligible after randomisation were excluded
• There were two pre-specified pre-protocol populations: those who received TXA within 3 minutes and those who received TXA within 10 minutes
• Registered with clinicaltrials.gov NCT3431805

Setting

• 27 centres in France
• March 2018 – January 2020

Population

• Inclusion:
  • > 18 yo
  • >/= 34 weeks gestation
  • expected to undergo Caesarean before or during labour
• Exclusion:
  • Known or suspected increased risk of VTE / arterial embolism
  • Increased risk of bleeding (including administration of LMWH or anti-platelet in week prior)
  • History of seizures or epilepsy
  • Eclampsia
  • Autoimmune disease
  • Failed operative vaginal delivery
  • Sensitivity to trial drugs
  • Hb < 9g/dL in the week prior
  • Poor comprehension of spoken French
• 4551 randomised
  • 2276 – TXA
  • 2275 – placebo
• Baseline demographics similar
  • Age: 33.3 (TXA) vs 33.5 (Placebo)
  • BMI: 26.3 vs. 26.1
  • Primip: 37.2% vs. 36.6%
  • Prior CS: 51.8% vs. 52.4%
  • History of PPH: 5.1% vs. 4.5%
  • Multiple pregnancies: 7.2% vs. 7.2%
  • Timing of CS – during labour: 28.9% vs. 29.2%
  • GA: 3.0% vs. 3.8%
  • Prophylactic uterotonic: 98.9% vs. 99.0%
  • Anticoagulant prophylaxis post delivery: 58.8% vs. 59.1%
  • Median duration of interval from birth to TXA: 2 mins vs. 2 mins

Intervention

• 1g TXA
  • 10ml vial

Control

• Normal saline
  • Identically labeled vial

Management common to both groups

• Either TXA or placebo given over 30-60 seconds in the first three minutes after birth
• This was given after bolus prophylactic uterotonics given (5-10u oxytocin or or 100 μg of carbetocin)
  • Subsequent oxytocin infusion at discretion of treating unit
• All spent at least 2 hours in PACU / Recovery until bleeding diminished to expected amount

Outcome

• Primary outcome:
  • Postpartum hemorrhage (defined as a calculated estimated blood loss greater than 1000 ml or red-cell transfusion by day 2): – significantly reduced in tranexamic acid group
  • 556/2086 (26.7%) TXA vs. 653/2067 (31.6%) Placebo
    • Adjusted RR 0.84 (95% CI – 0.75 – 0.93, p = 0.003)
    • No difference between pre-specified subgroups (PPH risk and timing of CS)
• Secondary outcomes:
  • No significant differences in:
    • Gravimetrically estimated blood loss: 689ml vs. 719ml
      • Estimated by suction volume and swab weight
    • Clinically significant blood loss: 13.6% (TXA) vs. 14.8% (Placebo)
    • Additional uterotonic agents for excessive bleeding: 5.9% vs. 7.2%
    • Blood transfusion: 1.9% vs. 1.8%
    • Number of units transfused: 3.1 vs. 3.2
  • Significant difference in pre and post-operative Hb:
    • Peripartum change -1.2 g/L vs. -1.4g/L (p < 0.001)
• Adverse Events:
  • In PACU or OR:
    • Higher rates of nausea and vomiting
      • 43.0% vs. 36.3% (p < 0.001)
  • D2 after delivery:
    • No significant differences between groups for urea, creatinine, AST, ALT
  • Up to 3 months after delivery:
    • No significant difference for:
      • Seizure: <0.1% vs. <0.1% (1 in each arm)
      • DVT/PE: 0.4% vs. 0.1% (8 cases in TXA arm, 2 in placebo)

Authors’ Conclusions

• The use of TXA in this setting reduced the incidence of PPH (as defined by calculated estimated blood loss > 1000ml or red cell transfusion by day 2).
• However there was no reduction in clinical secondary outcomes

Strengths

• Large, multi-centre trial
• Well balanced balanced baseline characteristics
  • High proportions of risk factors for PPH (previous caesarean, prior PPH, obesity, multiple pregnancy, emergency caesarean) present in baseline characteristics
  • This is important to ensure that two low risk cohorts not being analysed
  • Sensible pre-specified subgroup looking at the use of TXA in those at high risk of PPH vs. low risk
    • Defined as presence of a one or more risk factor with an OR > 3
• Good randomisation and blinding strategy results in strong internal validity
• Pragmatic statistical analysis plan
  • Although large numbers of women were randomized but not assessed for the primary outcome in the modified intention to treat analysis, the statistical analysis plan allowed for up to 10% drop out following randomisation
• Sensible use of a standardised method of estimating blood loss given clinicians’ estimations are often incorrect
  • The values of estimated blood loss obtained by the gravimetrical method (suction volume, and weighing swabs) and the standardised equation similar
• Minimal cross-over / protocol violations
  • Only 1.4% in each group received no treatment
  • Only 0.1% in each group received the opposite treatment
• Good follow up at three months – important for reporting adverse events
  • 93.5% (TXA) vs. 94.4% (Placebo) completed follow up interviews at three months

Weaknesses

• The primary outcome is not patient orientated
  • Although the trial is not adequately powered for clinically relevant secondary outcomes there is no suggestion that TXA reduces the rate of these
    • The authors rightly acknowledge this in the conclusion
• As discussed, the statistical plan allowed for up to 10% drop out from those who are randomised to receive a treatment, however:
  • The rates were slightly higher than 10% in each arm:
    • TXA – 10.5%
    • Placebo – 11.8%
      • This may introduce an attrition bias
  • 210 (4.6%) patients excluded for unknown reasons or meeting exclusion criteria following randomisation
    • This may introduce a selection bias
  • 278 (6.1%) had missing data for the primary outcome
    • The appendix has a comparison of where only complete cases are analysed (the data presented above) against the imputation of missing values as failures (i.e. they were assumed to have PPH)
      • If the missing values are treated as failures then the p value > 0.005
        • TXA 31.1% vs Placebo 36.0% p = 0.006
• PPH is a heterogenous process
  • The 4Ts is a common acronym for PPH reasons: uterine tone, retained tissue, trauma, thrombin
    • TXA does not have a plausible biological mechanism of action in the treatment of PPH for anything other than trauma
    • No documentation of suspected reasons for PPH is recorded
    • The protocol allowed for the use of a oxytocin infusion as per local hospital policy following the uterotonic bolus
      • No mention is made of how many had an oxytocin infusion after
        • This could be an important confounder
• The study excluded those who are increased risk of bleeding – would these patients potentially benefit more?
• The BNF suggests that TXA should be given as a slow IV injection (at a rate not exceeding 100mg/minute)
  •  The protocol states it should be given over 30 to 60 seconds (20x as fast)
    • This may be a reason for the increased rate of vomiting and nausea
• Approximately 25% did not receive TXA within three minutes in each arm
  • This is understandable as it is an already frenetic time ensuring that uterotonics are given, and that the baby and parents are well!
  • This delay did not seem to have an effect though as in the protocol analysis which included those who received TXA/placebo within 10 minutes still showed a significant reduction in the primary outcome

The Bottom Line

• The use of prophylactic TXA for caesarean delivery reduces the rates of PPH as defined by an estimated blood loss of > 1000ml or red cell transfusion by day 2
• I will not use TXA in a routine prophylactic manner given this did not seem to show any trend to a reduction in meaningful clinical outcomes, and an increased risk of nausea and vomiting

External Links

• Management of PPH: RANZCOG Guideline
• TXA Product Information Sheet

Metadata

Summary author: George Walker
Summary date: 9th May 2021
Peer-review editor: David Slessor

Image by: iStock