Superb trial in this week’s JAMA (click here). The Dutch Apostel-2 group tested the effect of a popular but unlicensed drug (nifedipine), used to suppress uterine contractions after the first 48 hours of treatment for suspected pre-term labour. Experts believe 48 hours treatment is effective, but after that, there is uncertainty whether drugs even prolong pregnancy, let alone reduce important adverse outcomes. The trial was registered, double-blind, hit its planned sample size, and reported its pre-specified primary endpoint. Perfect.
But the drug didn’t work. Here’s the graph of the proportions undelivered over time in each group. Hardly surprising that there was no difference in baby outcomes.
Apostel-2 has protected women from an ineffective drug.
The authors also state that all other drugs are equally ineffective because no maintenance tocolysis trial has shown a reduction in adverse fetal outcomes. But they don’t mention the only trial of maintenance tocolysis with the safest licensed drug used for this purpose, atosiban. It’s not easy to access, so here’s a copy (Valenzuela 2000). And here’s the main trial figure, upper line atosiban continued after 48 hours, lower line placebo after 48 hours. The figure is censored at 36 weeks.
Note 1 – these figures don’t show the same things. The upper (Apostel-2 trial of nifedipine) shows the proportion undelivered at each time point – no difference. The lower (Valenzuela trial of atosiban) shows the proportion undelivered and not given an alternative tocolytic – atosiban has a modest beneficial effect. Neither drug reduced adverse fetal outcomes. Nevertheless both trials were double blind and placebo controlled, so the lower graph is measuring a real effect of the drug.
In the absence of fetal compromise, ruptured membranes, infection or bleeding, maintenance tocolysis with atosiban remains a reasonable treatment for extremely pre-term labour.
Note 2 – I have received lecture fees from Ferring, the manufacturer of atosiban, and served on their advisory board. I oppose using unlicensed drugs when a licensed alternative exists, and have criticised the poor quality of many trials of nifedipine.