1. 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

2. Key conclusions
‘…atosiban [TRACTOCILE] was found to have similar tocolytic efficacy to … placebo’
‘...atosiban was associated with more infant deaths [than placebo]…’
‘…atosiban was found to have similar tocolytic efficacy to -agonists…’
‘…compared with placebo, atosiban resulted in lower birthweight…’
‘More atosiban-exposed infants had birthweights < 1500g than infants exposed to -agonists’
‘A direct comparison between atosiban and calcium channel blockers is long overdue…’

3. 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

4. 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

5. Atosiban: tocolytic efficacy and tolerability vs placebo
WOMEN REMAINING UNDELIVERED AND NOT REQUIRING AN ALTERNATIVE TOCOLYTIC WITHIN 48 HOURS (%)
100
Atosiban
P = 0.008
Placebo 80 60
67.1%
55.7% 40 20
2. Romero et al 2000

6. 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

7. 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

8. 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

9. 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

10. Atosiban: tocolytic efficacy and tolerability vs -agonists
WOMEN REMAINING UNDELIVERED AND NOT REQUIRING AN ALTERNATIVE TOCOLYTIC (%)
P = 0.08
Atosiban 80
-agonists
P =
74.4%
70.1% 60
59.7% 40
47.4% 20
at 48 hours
at 7 days
4. Moutquin et al 2001

11. 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

12. 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

13. Two studies have recently been published11,12
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.

14. 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

15. Summary of trials included to assess key outcomes in the Cochrane Systematic Review

16. The atosiban evidence base
1Goodwin 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
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 et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
6Goodwin 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)
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
Placebo-controlled
versus -agonists

17. Trials used to assess efficacy versus placebo
1Goodwin 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
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 et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
6Goodwin 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)
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

18. Trials used to assess efficacy versus -agonists
1Goodwin 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
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 et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
6Goodwin 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)
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

19. Trials used to assess infant death versus placebo
1Goodwin 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
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 et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
6Goodwin 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)
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

20. The atosiban evidence base
Efficacy versus placebo
The atosiban evidence base
1Goodwin 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
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 et al 2000 – Phase III maintenance placebo-controlled trial (PTL-098; 513 patients)
6Goodwin 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)
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 -agonists
Infant death versus placebo

21. 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.

22. Tractocile® key messages
TRACTOCILE offers proven safety and efficacy for mother and baby, as documented in large, well-designed, 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.

23. References cited in slide kit
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.