Response to 'The drugs we deserve'
Article first published online: 20 JUL 2004
BJOG: An International Journal of Obstetrics & Gynaecology
Volume 111, Issue 9, page 1025, September 2004
How to Cite
Papatsonis, D. N. M. , Flenady, V. J., Dekker, G. A., Carbonne, B. and King, J. F. (2004), Response to 'The drugs we deserve'. BJOG: An International Journal of Obstetrics & Gynaecology, 111: 1025. doi: 10.1111/j.1471-0528.2004.00261.x
- Issue published online: 23 AUG 2004
- Article first published online: 20 JUL 2004
The editor (Br J Obstet Gynaecol 2003;110:969–70) pleads for the use of atosiban in the management of preterm labour. We disagree.
We agree that preterm labour is the single most important disease of pregnancy responsible for the majority of neonatal deaths not due to congenital anomalies, and for approximately 50% of childhood neurological disabilities. We also agree that we need better quality evidence about the effectiveness of tocolytic agents and, in particular, on long term follow up data on survivors.
However, you describe the newly developed tocolytic agent atosiban, an oxytocin antagonist as a potential ‘ray of hope’. Is it a ray of hope or a cry of despair? In the United States, atosiban was not approved by the FDA because there was no benefit for the fetus in the trials where atosiban was compared with betamimetics or placebo.1,2 In a large double-blind, placebo-controlled, randomized trial there were even more fetal–infant deaths in the atosiban group compared with the placebo group especially in the group with a gestational age under 26 weeks at entering the study.1 A possible explanation for this is that at lower gestational ages, where the potential benefit from tocolysis is greatest, there are less oxytocin receptors in the myometrial cells, rendering atosiban less effective. Furthermore, atosiban is an expensive agent and has to be administered intravenously. In contrast, nifedipine, a calcium channel blocker, is a relatively cheap and easy to administer (oral) drug, which is more effective as a tocolytic agent, compared with betamimetics with a lower incidence of neonatal morbidity, and a very low incidence of side effects. This is based on a Cochrane systematic review3 of the evidence from 12 randomised clinical trials with 1029 participants, in which the effects of calcium channel blockers, mainly nifedipine, used as a tocolytic agent were compared with those of betamimetic agents, mainly ritodrine.
We disagree with your assessment of the quality of this evidence; in accordance with the Cochrane methodology, poor quality trials were specifically excluded from the meta-analysis. Nifedipine was superior to the betamimetics with respect to tocolytic effectiveness (postponing delivery by seven or more days and a lower frequency of birth prior to 34 weeks), with a marked reduction in the frequency of maternal adverse side effects, and a reduction in the frequency of some clinically important adverse neonatal outcomes (less respiratory distress syndrome, a relative risk [RR] reduction of almost 40%; less intraventricular haemorrhage, RR reduction of 40%; less necrotizing enterocolitis, RR reduction of 80%). Admissions to the neonatal intensive care unit were also significantly lower, RR reduction of 20%. The relative decrease in the risk of severe adverse effects (requiring cessation of treatment) of 86% is very convincing. These findings of superior tocolytic effectiveness and better tolerance, combined with the ease of administration and low cost, make nifedipine a far preferable agent to betamimetics.
In many countries, betamimetics are the only agents licensed for use as tocolytics, and although nifedipine does not have official approval for such use, we hold the view that its use as a tocolytic could be strongly defended on the basis of this evidence. The fact that nifedipine is not licensed for preterm labour is because initially it was not developed as a tocolytic agent. Nifedipine is on the market for other indications (hypertension) and pharmaceutical companies have other (economic) interests.
There are no trials available in which nifedipine is compared with atosiban. In the absence of such trials, a recent study used an adjusted indirect comparison technique in an attempt to compare the two agents, which concluded that ‘when indirectly compared with atosiban, nifedipine tocolysis is more effective’.4 However, this is not a substitute for a trial, and we stress that such a trial is needed comparing nifedipine with atosiban, preferably with a placebo arm, and with two-year neonatal follow up. Meanwhile, we maintain that there is persuasive evidence supporting the safety and effectiveness of nifedipine when tocolysis is undertaken.5
- 3Calcium channel blockers for inhibiting preterm labour [Cochrane review]. In: The Cochrane Library, Issue 4. Chichester, UK: Wiley, 2003., , , , .
- 5Oxytocin receptor antagonists for inhibiting preterm labour [Protocol for a Cochrane review]. In: The Cochrane Library, Issue 4. Chichester, UK: Wiley, 2003., , , .