Transcript Document

Interrogating the conclusions of
the Cochrane Systematic Review
on oxytocin receptor antagonists for
inhibiting preterm labour
Papatsonis D, Flenady V, Cole S and Liley H. Cochrane
Database Syst Rev 2005; Jul 20(3): CD004452
Key conclusions
1.
‘…atosiban [TRACTOCILE] was found to have similar
tocolytic efficacy to … placebo’
2.
‘...atosiban was associated with more infant deaths
[than placebo]…’
3.
‘…atosiban was found to have similar tocolytic efficacy
to -agonists…’
4.
‘…compared with placebo, atosiban resulted in lower
birthweight…’
5.
‘More atosiban-exposed infants had birthweights
< 1500g than infants exposed to -agonists’
6.
‘A direct comparison between atosiban and calcium
channel blockers is long overdue…’
1. ‘…atosiban was found to have similar
tocolytic efficacy to … placebo’
However…
• Data are from a single trial1
• trial designed to assess preterm uterine activity
• making efficacy conclusions invalid
• sub-therapeutic doses of atosiban used
• 300 g/min for 2 hours with no bolus
1. Goodwin et al 1994
1. ‘…atosiban was found to have similar
tocolytic efficacy to … placebo’
• Birth within 48 hours is less clinically relevant
than
• Non-delivery within 48 hours and no need for
an alternative tocolytic
• this evaluates both efficacy and tolerability of the
study medication
• A larger placebo-controlled trial2 evaluated
this endpoint
• this study was excluded from the efficacy analysis
2. Romero et al 2000
Atosiban: tocolytic efficacy and
tolerability vs placebo
WOMEN REMAINING UNDELIVERED AND NOT REQUIRING AN
ALTERNATIVE TOCOLYTIC WITHIN 48 HOURS (%)
100
80
60
40
20
0
2. Romero et al 2000
P = 0.008
67.1%
55.7%
Atosiban
Placebo
2. ‘…atosiban was associated with more
infant deaths [than placebo]’
However…
• Data are from a single trial2
• widely acknowledged imbalance in groups
• more women at very low gestational ages
(< 26 weeks) and in more advanced labour were
given atosiban (p=0.008 vs placebo)
• investigators concluded that the infant deaths
were associated with extreme prematurity
• not the administered study medication
2. Romero et al 2000
Gestational ages on admission
compared with placebo
Gestational age at
admission
Number
Atosiban
Placebo
<26 weeks
24/246 (10%)
13/255 (5%)
26 to <28 weeks
19/246 (8%)
21/255 (8%)
28 to <32 weeks
107/246 (44%)
105/255 (41%)
32 weeks
96/246 (39%)
116/255 (45%)
2. Romero et al 2000
2. ‘…atosiban was associated with more
infant deaths [than placebo]’
Despite the imbalanced groups…
• most mortality parameters were comparable
with placebo
• fetal, perinatal and neonatal death all comparable
• infant mortality was only significantly higher when
data up to 12 months of age were included3
• subsequent trials4 have not demonstrated an
increase in infant deaths
• after > 70,000 treatments there is no
suggestion of increased mortality with atosiban5
3. Goodwin et al 1998; 4. Moutquin et al 2001; 5. PSUR data on file
3. ‘…atosiban was found to have similar
tocolytic efficacy to -agonists…’
However…
• atosiban is as effective as -agonists at
48 hours and more effective at 7 days4
• atosiban has a significantly superior side
effect profile4
• particularly with respect to maternal
cardiovascular events
4. Moutquin et al 2001
Atosiban: tocolytic efficacy and
tolerability vs -agonists
WOMEN REMAINING UNDELIVERED AND NOT REQUIRING AN
ALTERNATIVE TOCOLYTIC (%)
P = 0.08
80
60
74.4%
P = 0.0003
70.1%
59.7%
47.4%
40
20
0
at 48 hours
4. Moutquin et al 2001
at 7 days
Atosiban
-agonists
4. ‘…compared with placebo, atosiban
resulted in lower birthweights…’
However…
• these data are derived from two trials of very
different designs
• neither trial alone reported significant differences
in birthweight
• despite the acknowledged imbalance in treatment
groups in the largest of these trials2
2. Romero et al 2000
5. ‘More atosiban-exposed infants had
birthweights < 1500g than infants
exposed to -agonists’
However…
• this outcome is based on two trials6,7
• does not include the complete data set available
• atosiban versus salbutamol excluded8
• atosiban versus terbutaline excluded9
• the largest trials have demonstrated comparable
birth weights in infants born to mothers given
atosiban or -agonists4
• these results have been confirmed in more than 800
women in routine clinical practice10
4. Moutquin et al 2001; 6. Goodwin et al 1996; 7. Moutquin et al 2000; 8. Cabrol et al 2001; 9. Maršál et al
2001; 10. Husslein et al 2005
6. ‘A direct comparison between atosiban
and calcium channel blockers is long
overdue…’
Two studies have recently been
published11,12
• both compared nifedipine with atosiban
• both reported the same findings
• atosiban and nifedipine have similar efficacies
• atosiban is associated with significantly fewer
adverse events
• particularly with respect to cardiovascular events12
11. Al-Omari et al 2004; 12. Kashanian et al 2005.
Partiality of the authors
• Balanced opinion among authors of all reviews is critical
• to maintain the impartiality and independence of Cochrane
• Impartiality among the authors of this review may be
debatable
• the authors of this review are self appointed
• Drs Papatsonis and Flenady have published prolifically on
calcium channel blockers
• including the recent Cochrane systematic review on their use in
preterm labour
• both have advocated the use of nifedipine
• Nifedipine is discussed in this review but atosiban is not
discussed in the calcium channel blocker review
• some might argue that this is reflective of the authors’ own clinical
preferences
Summary of trials included to assess
key outcomes in the
Cochrane Systematic Review
The atosiban evidence base
et al 1994 – Phase II study – 120 patients
assessed effect of atosiban on preterm uterine activity (not efficacy)
atosiban administered at sub-therapeutic dose
women unlikely to be in true preterm labour
1Goodwin
2Romero
et al 2000 – Phase III placebo-controlled trial (PTL-096; 501 patients)
Placebo-controlled
imbalance of groups at randomisation; women receiving atosiban were at lower gestational ages
(P = 0.008) and in more advanced labour
13Valenzuela
et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
et al 1996 – Phase II dose-ranging study versus ritodrine – 302 patients
four atosiban dosing arms pooled (6.5 mg bolus + 300 g/min; placebo bolus + 300 g/min; 2 mg
bolus + 100 g/min; 0.6 mg bolus + 30 g/min)
6Goodwin
7Moutquin
et al 2000 – Phase III trial – CAP-001; atosiban vs ritodrine – 247 patients
8Cabrol
et al 2001 – Phase III trial – CAP-001; atosiban vs salbutamol – 241 patients
9Maršál
et al 2001 – Phase III trial – CAP-001; atosiban vs terbutaline – 249 patients
3Moutquin
et al 2001 – Phase III trial – CAP-001; atosiban vs -agonists – 742 patients (pooled)
10Husslein
et al 2005 – TREASURE; atosiban vs usual care – 811 patients
versus -agonists
Trials used to assess efficacy
versus placebo
et al 1994 – Phase II study – 120 patients
assessed effect of atosiban on preterm uterine activity (not efficacy)
atosiban administered at sub-therapeutic dose
women unlikely to be in true preterm labour
1Goodwin
et al 2000 – Phase III placebo-controlled trial (PTL-096; 501 patients)
imbalance of groups at randomisation; women receiving atosiban were at lower gestational ages
(P = 0.008) and in more advanced labour
2Romero
13Valenzuela
et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
et al 1996 – Phase II dose-ranging study versus ritodrine – 302 patients
four atosiban dosing arms pooled (6.5 mg bolus + 300 g/min; placebo bolus + 300 g/min; 2 mg
bolus + 100 g/min; 0.6 mg bolus + 30 g/min)
6Goodwin
7Moutquin
et al 2000 – Phase III trial – CAP-001; atosiban vs ritodrine – 247 patients
8Cabrol
et al 2001 – Phase III trial – CAP-001; atosiban vs salbutamol – 241 patients
9Maršál
et al 2001 – Phase III trial – CAP-001; atosiban vs terbutaline – 249 patients
3Moutquin
et al 2001 – Phase III trial – CAP-001; atosiban vs -agonists – 742 patients (pooled)
10Husslein
et al 2005 – TREASURE; atosiban vs usual care – 811 patients
Trials used to assess efficacy
versus -agonists
et al 1994 – Phase II study – 120 patients
assessed effect of atosiban on preterm uterine activity (not efficacy)
atosiban administered at sub-therapeutic dose
women unlikely to be in true preterm labour
1Goodwin
et al 2000 – Phase III placebo-controlled trial (PTL-096; 501 patients)
imbalance of groups at randomisation; women receiving atosiban were at lower gestational ages
(P = 0.008) and in more advanced labour
2Romero
13Valenzuela
et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
et al 1996 – Phase II dose-ranging study versus ritodrine – 302 patients
four atosiban dosing arms pooled (6.5 mg bolus + 300 g/min; placebo bolus + 300 g/min; 2 mg
bolus + 100 g/min; 0.6 mg bolus + 30 g/min)
6Goodwin
7Moutquin
et al 2000 – Phase III trial – CAP-001; atosiban vs ritodrine – 247 patients
8Cabrol
et al 2001 – Phase III trial – CAP-001; atosiban vs salbutamol – 241 patients
9Maršál
et al 2001 – Phase III trial – CAP-001; atosiban vs terbutaline – 249 patients
3Moutquin
et al 2001 – Phase III trial – CAP-001; atosiban vs -agonists – 742 patients (pooled)
10Husslein
et al 2005 – TREASURE; atosiban vs usual care – 811 patients
Trials used to assess infant death
versus placebo
et al 1994 – Phase II study – 120 patients
assessed effect of atosiban on preterm uterine activity (not efficacy)
atosiban administered at sub-therapeutic dose
women unlikely to be in true preterm labour
1Goodwin
et al 2000 – Phase III placebo-controlled trial (PTL-096; 501 patients)
imbalance of groups at randomisation; women receiving atosiban were at lower gestational ages
(P = 0.008) and in more advanced labour
2Romero
13Valenzuela
et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
et al 1996 – Phase II dose-ranging study versus ritodrine – 302 patients
four atosiban dosing arms pooled (6.5 mg bolus + 300 g/min; placebo bolus + 300 g/min; 2 mg
bolus + 100 g/min; 0.6 mg bolus + 30 g/min)
6Goodwin
7Moutquin
et al 2000 – Phase III trial – CAP-001; atosiban vs ritodrine – 247 patients
8Cabrol
et al 2001 – Phase III trial – CAP-001; atosiban vs salbutamol – 241 patients
9Maršál
et al 2001 – Phase III trial – CAP-001; atosiban vs terbutaline – 249 patients
3Moutquin
et al 2001 – Phase III trial – CAP-001; atosiban vs -agonists – 742 patients (pooled)
10Husslein
et al 2005 – TREASURE; atosiban vs usual care – 811 patients
Efficacy versus placebo
The atosiban evidence base
et al 1994 – Phase II study – 120 patients
assessed effect of atosiban on preterm uterine activity (not efficacy)
atosiban administered at sub-therapeutic dose
women unlikely to be in true preterm labour
1Goodwin
2Romero
et al 2000 – Phase III placebo-controlled trial (PTL-096; 501 patients)
imbalance of groups at randomisation; women receiving atosiban were at lower gestational ages
(P = 0.008) and in more advanced labour
13Valenzuela
Efficacy versus -agonists
et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
et al 1996 – Phase II dose-ranging study versus ritodrine – 302 patients
four atosiban dosing arms pooled (6.5 mg bolus + 300 g/min; placebo bolus + 300 g/min; 2 mg
bolus + 100 g/min; 0.6 mg bolus + 30 g/min)
6Goodwin
7Moutquin
et al 2000 – Phase III trial – CAP-001; atosiban vs ritodrine – 247 patients
8Cabrol
et al 2001 – Phase III trial – CAP-001; atosiban vs salbutamol – 241 patients
9Maršál
et al 2001 – Phase III trial – CAP-001; atosiban vs terbutaline – 249 patients
3Moutquin
et al 2001 – Phase III trial – CAP-001; atosiban vs -agonists – 742 patients (pooled)
10Husslein
et al 2005 – TREASURE; atosiban vs usual care – 811 patients
Infant death versus placebo
An independent expert’s*
opinion…
• ‘…the [placebo-controlled] trials were not
similar enough in their clinical characteristics to
be combined in a meta-analysis…’
• ‘…the very small event rates associated with
most of these results mean that there is a lot of
uncertainty around the overall result…’
• ‘…[the findings] do not justify any change to
clinical practice recommendations…’
*Douglas Badenoch, Minervation, Oxford, UK.
Tractocile® key messages
• TRACTOCILE offers proven safety and efficacy for
mother and baby, as documented in large, welldesigned, randomised controlled trials7–9
• The use of TRACTOCILE is supported by long-term
infant safety data, with no long-term safety or
developmental concerns at 2 years3
• TRACTOCILE is associated with a placebo-level risk
of cardiovascular events2
2. Romero et al 2000; 3. Goodwin et al 1998; 7. Moutquin et al 2000; 8. Cabrol et al 2001; 9. Maršál et al 2001.
References cited in slide kit
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2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Goodwin TM et al. The effect of the oxytocin antagonist atosiban on preterm uterine
activity in the human. Am J Obstet Gynecol 1994; 170(2): 474–478.
Romero R et al. Am J Obstet Gynecol 2000; 182(5): 1173–1183.
Goodwin TM et al. [poster]. 46th ACOG Annual Meeting; 1998 May 9–13; New Orleans,
Louisiana.
Moutquin J-M and the Worldwide Atosiban versus Beta-agonists Study Group. BJOG
2001; 108(2): 133–142.
PSUR data on file, Ferring Pharmaceuticals.
Goodwin TM et al. Obstet Gynecol 1996; 88(3): 331–336.
Moutquin J-M et al. Am J Obstet Gynecol 2000; 182(5): 1191–1199.
Cabrol D et al. Eur J Obstet Gynecol Reprod Biol 2001; 98(2): 177–185.
Maršál K et al. Acta Obstet Gynecol Scand 2001; 80(5): 413–422.
Husslein P et al. Poster presented at COGI, Athens, Greece, 2005.
Al-Omari WR. [abstract]. XVIII European Congress of Obstetrics and Gynaecology;
2004 May 12–15; Athens, Greece, 2004: 103.
Kashanian M et al. Int J Gynaecol Obstet 2005; [epub ahead of print].
Valenzuela GJ et al. Am J Obstet Gynecol 2000; 182(5): 1184–1190.