Large Carbetocin trial published

The results of a large Carbetocin trial have been published in the New England Journal of Medicine. This is an important trial because, until now, we haven’t had enough evidence about the effectiveness of this drug to prevent postpartum haemorrhage when used as part of an actively managed third stage of labour.

The drug is, however, increasing in popularity. The authors of a recent Cochrane network analysis, for instance, noted that:

“Carbetocin has the least side-effects (less vomiting, high blood pressure and fever) among the top three drug options [which have been found to be of use in preventing postpartum haemorrhage], but to date studies of carbetocin were small and of poor quality.” (Gallos et al 2018).

Carbetocin has an action similar to oxytocin, in that it binds to oxytocin receptors. But carbetocin has been developed to be longer-acting than oxytocin, which has made it popular in some settings, and it can be manufactured in a heat-stable form which does not need to be kept in a fridge. It is thus a better option where refrigeration is not easily available.

Well not any more. Widmer et al (2018) randomised 29,645 women across 23 sites in ten countries.

“Women who expected to give birth vaginally and who had a singleton pregnancy and cervical dilatation of 6 cm or less were eligible. Women were not eligible if they were in an advanced stage of labor (cervical dilatation >6 cm); were too distressed to provide informed consent; had known allergies to carbetocin, oxytocin homologues, or excipients; or had a serious cardiovascular disorder, serious hepatic or renal disease, or epilepsy. All the participants provided written informed consent.

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Women underwent randomization when vaginal birth was imminent. Women were randomly assigned to receive a single intramuscular injection of either heat-stable carbetocin at a dose of 100 μg or oxytocin at a dose of 10 IU. Immediately after the birth of the baby, the drug was administered and the management of the third stage of labor was conducted as recommended in the WHO guidelines.² Once the umbilical cord was clamped and cut, a plastic drape for blood collection (BRASSS-V Drape) was placed under the woman’s buttocks. Blood was collected for 1 hour or for 2 hours if the bleeding continued beyond 1 hour. The drape with the blood was then weighed by a digital scale, with the weight recorded in grams and then converted to volume (milliliters) after the weight of the drape was subtracted at the analysis stage.” (Widmer et al 2018)

This was a non-inferiority trial; a type of study carried out when the existing treatment is thought or known to be beneficial and it is deemed unethical to use a new treatment and a placebo. The idea is to see whether the new drug (in this case, carbetocin) is as good as (or non-inferior to) the existing one. The double negatives can be confusing, but it is done in the name of ethics. The authors found that, “Heat-stable carbetocin was noninferior to oxytocin for the prevention of blood loss of at least 500 ml or the use of additional uterotonic agents. Noninferiority was not shown for the outcome of blood loss of at least 1000 ml; low event rates for this outcome reduced the power of the trial.” (Widmer et al 2018)

As always, I would encourage anyone interested in this area to read the research in full, and to bear in mind that there is always both a bigger context to consider and a need to translate the results of such research into forms that are available to the individual women who need to make decisions about their care.

More information in our placental birth resources hub:

Placental birth resources

Here’s a link to the study in full, and the abstract is below.

The Research

Background: Postpartum hemorrhage is the most common cause of maternal death. Oxytocin is the standard therapy for the prevention of postpartum hemorrhage, but it requires cold storage, which is not available in many countries. In a large trial, we compared a novel formulation of heat-stable carbetocin with oxytocin.

Methods: We enrolled women across 23 sites in 10 countries in a randomized, double-blind, noninferiority trial comparing intramuscular injections of heat-stable carbetocin (at a dose of 100 μg) with oxytocin (at a dose of 10 IU) administered immediately after vaginal birth. Both drugs were kept in cold storage (2 to 8°C) to maintain double-blinding. There were two primary outcomes: the proportion of women with blood loss of at least 500 ml or the use of additional uterotonic agents, and the proportion of women with blood loss of at least 1000 ml. The noninferiority margins for the relative risks of these outcomes were 1.16 and 1.23, respectively.

Results: A total of 29,645 women underwent randomization. The frequency of blood loss of at least 500 ml or the use of additional uterotonic agents was 14.5% in the carbetocin group and 14.4% in the oxytocin group (relative risk, 1.01; 95% confidence interval [CI], 0.95 to 1.06), a finding that was consistent with noninferiority. The frequency of blood loss of at least 1000 ml was 1.51% in the carbetocin group and 1.45% in the oxytocin group (relative risk, 1.04; 95% CI, 0.87 to 1.25), with the confidence interval crossing the margin of noninferiority. The use of additional uterotonic agents, interventions to stop bleeding, and adverse effects did not differ significantly between the two groups.

Conclusions: Heat-stable carbetocin was noninferior to oxytocin for the prevention of blood loss of at least 500 ml or the use of additional uterotonic agents. Noninferiority was not shown for the outcome of blood loss of at least 1000 ml; low event rates for this outcome reduced the power of the trial. (Funded by Merck Sharpe & Dohme; CHAMPION Australian New Zealand Clinical Trials Registry number, ACTRN12614000870651; EudraCT number, 2014-004445-26; and Clinical Trials Registry–India number, CTRI/2016/05/006969.)