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Maternal–Foetal Medicine
of adverse foetal and maternal events from calcium channel effective than the alternatives (78% atosiban versus 57% alternative;
blockers and only one from atosiban. The former include five cases p<0.001). However, this result must be interpreted with caution – the
of acute pulmonary oedema during nicardipine use in pre-term pre-determined sample size was 400 per group, but the study was
labour, albeit in patients with cardiac risk factors,
14
five reports of closed when 585 participants had been recruited because of
recruitment difficulties and because the “difference in efficacy was
larger than the predicted 9%”, despite no mention in the study
Since the latest update of the
publication of any formal interim analyses or ‘stopping’ rules. The
Cochrane reviews and the publication
use of an end-point such as “undelivered without the need for an
alternative tocolytic” is susceptible to bias in unblinded studies.
of the RCOG guidelines there have
been a number of case reports of
The rates of peri-natal death in the TREASURE study (three
atosiban-treated patients versus 11 given usual care) also favour
adverse foetal and maternal events
atosiban and are less susceptible to biased ascertainment.
from calcium channel blockers and
Unfortunately, the TREASURE authors did not report these deaths
by intention-to-treat (n=585) but by the initial treatment received
only one from atosiban.
(n=577). The trial flow diagram suggests that no participants
crossed over to the other group for this analysis, but is not
pulmonary oedema in patients without cardiac risk factors
15–19
and a absolutely explicit on this point. The sponsor’s (Ferring)
report of severe hypotension followed by foetal death following the unpublished trial report provides a detailed description of all 14
administration of nifedipine for tocolysis in a low-risk patient.
20
peri-natal deaths, and a careful reading of these suggests that they
did indeed occur in the groups as allocated. However, again, the
There had also been an earlier report of myocardial infarction in a report was not explicit on this point. Readers may wish to exercise
case where both ritodrine and nifedipine were used
20
and atrial caution in interpreting the mortality data from TREASURE until this
fibrillation with rapid ventricular response was treated with issue is resolved. For the purpose of including these data in the
cardioversion in a 38-year-old woman who was 33 weeks’ pregnant relevant Cochrane reviews, the mortality data should be provided
and experiencing pre-term labour on treatment with nifedipine.
21
by intention-to-treat and subdivided by the control drug used. The
There has also been one case report of pulmonary oedema in a company retains the trial database and hopefully will eventually be
woman (33 years of age) following the use of atosiban, able to provide the data to the Cochrane reviewers.
indomethacin and steroids for tocolysis at 32 weeks’ gestation.
22
This sort of evidence is not very reliable because it may reflect Two other recent small trials compared atosiban with nifedipine.
either the relative usage of the two drugs or differential reporting. One included 63 women and used alternate patient randomisation,
which has a high risk of entry bias. The treatments were not blinded
A recent large study of side effects in The Netherlands and Belgium and there was no clear primary end-point, pre-determined sample
is more reliable.
23
These authors audited all women given tocolytics size or analysis plan.
25
There were no major differences between
in these two countries over a period and assessed the side-effect the groups. The other included 80 women, did not report the
records without knowledge of the drugs administered. The side method of randomisation in sufficient detail to determine whether
effects after a single course (n=1,333) were as follows: for
nifedipine (543 patients) there were five severe (0.9%) and eight
mild (1.5%) adverse events; for beta-agonists (158 patients) there
For the extremely pre-term infant,
were three severe (1.9%) and four mild (2.5%) adverse events; and
for atosiban (576 patients) there were no severe (0%) and one mild say at gestation of 24–30 weeks, in
(0.2%) adverse event. Although these cases were not randomised,
whom there is evidence of labour
this supports the case report data and provides the strongest
evidence available that atosiban is associated with fewer side contractions and no evidence of
effects than either beta-mimetics or calcium channel blockers.
foetal distress, longer maintenance
Trials Not Yet Included in the therapy would also be rational.
Systematic Reviews
The Tractocile Efficacy Assessment Survey in Europe (TREASURE)
trial compared atosiban with usual care for the treatment of pre- the risk of entry bias was avoided, was open-label and did not
term labour.
24
It was an unblinded, randomised trial with report peri-natal mortality.
26
No reliable conclusions can be drawn
independent telephone randomisation and participants allocated to from either of these studies.
either atosiban or usual care. Usual care could include beta-
mimetics, calcium channel blockers, magnesium sulphate or any Lack of Evidence of Effectiveness Is Not the
other tocolytic apart from atosiban. The initial usual care tocolytic Same as Evidence of Ineffectiveness
was beta-mimetic in 65% of patients, calcium channel blocker in Here, we address the issue of whether tocolysis should be used at
15% of patients and beta-agonist with magnesium in 10% of all, rather than the choice of tocolytic. Many guidelines argue that it
patients. The study was designed to test the effect of the different should not be used on the grounds that no placebo-controlled trials
regimes on remaining undelivered without the need for an have ever shown a statistically significant reduction in any
alternative tocolytic. It appeared to confirm that atosiban was more substantive adverse foetal outcome such as brain damage or
48 EUROPEAN OBSTETRICS & GYNAECOLOGY
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