Grand Rounds

Heat Stable Carbetocin: A Heat-Stable Alternative to Oxytocin?

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

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

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

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.”

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