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 ‘…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…’

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 Atosiban P = 0.008 Placebo 80 60 67.1% 55.7% 40 20 2. Romero et al 2000

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 Atosiban 80 -agonists P = 0.0003 74.4% 70.1% 60 59.7% 40 47.4% 20 at 48 hours at 7 days 4. Moutquin et al 2001

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

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.

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 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

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

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

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

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

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, 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.

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.