BACKGROUND AND PURPOSE:

• Oxytocin is the first line drug for prevention of PPH but due to the necessity for cold-storage, it is not always a viable option in many parts of the world
• Heat-stable carbetocin is an oxytocin analogue
  • Maintains stability with ≥95% peptide purity over 36 months, even at 30°C and 75% relative humidity
    • 6 months at 40°C
    • 3 months at 50°C
  • Optimum pH  5.45 (5.25–5.65)
  • Not sensitive to freezing or light
• Widmer et al. (NEJM 2018) compared the efficacy of heat-stable carbetocin to oxytocin for PPH prevention

METHODS:

• Randomized, double-blind, controlled non-inferiority trial
  • 23 hospital sites in 10 countries (2015-2018)
  • Vaginal deliveries
• Patients were randomized to the following study arms
  • Heat-stable carbetocin 100 µg IM
  • Oxytocin 10 IU IM
• Postpartum blood loss calculated as follows
  • Blood collected in plastic drape
  • Blood collected for 1 hour or for 2 hours if bleeding continued
  • Drape (including the blood) was weighed (grams) converted to volume (mm) after weight of drape subtracted
• Primary outcomes
  • Composite outcome of (1) proportion of women with blood loss of at least 500 ml; (2) Use of additional uterotonic agents at 1 hr and up to 2 hrs
  • Proportion of women with blood loss of at least 1000 ml
• Secondary outcomes
  • Other measurements related to blood loss (e.g., additional medications/interventions)
  • Adverse effects

RESULTS:

• 29,645 women underwent randomization
• Primary outcome #1: The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents
  • 14.5% in the carbetocin group vs 14.4% in the oxytocin group
  • Consistent with non-inferiority of carbetocin
• Primary outcome #2: The frequency of blood loss of at least 1000 ml
  • 1.51% in the carbetocin group vs 1.45% in the oxytocin group
  • Close to showing non-inferiority of carbetocin but may have been underpowered (upper 95% confidence limit exceeded the noninferiority margin)
    • Researchers planned on 2% 1000 ml blood loss but in the study, 1000 ml blood loss was approximately 1.5%
  • The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between groups

CONCLUSION:

• Heat-stable carbetocin performed similarly to oxytocin in preventing blood loss of at least 500 ml or use of other uterotonic agents
• Noninferiority was not shown for the outcome of blood loss of at least 1000 ml (study was not sufficiently powered for this outcome)
• The authors state “These data inform care of women in parts of the world where a lack of heat stability is a barrier to the effective prevention of postpartum hemorrhage.”

Learn More – Primary Sources:

Heat-stable Carbetocin versus Oxytocin to Prevent Hemorrhage after Vaginal Birth

Development and stability of a heat‐stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle‐income countries

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