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Atosiban was more efficacious than ritodrine for preterm labour, because of fewer side-effects
OB S T E TR ICS
Atosiban was more efficacious than ritodrine for preterm labour, because of fewer side-effects Moutquin JM, Sherman D, Cohen H, et al. Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol 2000; 182: 1191}1199.
OBJECTIVE To compare the efficacy and safety of atosiban and ritodrine for the treatment of preterm labour. DESIGN Multicentre, randomized, double-blind, double-dummy, controlled trial. Allocation was computergenerated, blocked, and stratified by gestational age. SETTING Thirteen centres in Canada and Israel. SUBJECTS Two hundred and forty-seven women in preterm labour with intact membranes, cervical dilatation 43 cm, and live fetus(es) of 23}33 (mean 30) weeks gestation. Previous tocolytic therapy was allowed. Mean maternal age was 27 years and 51% of women were nulliparous. 20% of subjects were enrolled at 428 weeks gestation. 13% of pregnancies were multiple gestation. An additional five randomized women did not receive treatment and were excluded from the analysis. INTERVENTION One hundred and twenty six women were randomized to receive i.v. atosiban (6.75 mg bolus, followed by infusion at 300 lg/min for 3 h, then 100 lg/min for up to 18 h) plus placebo for ritodrine, and 121 to receive i.v. ritodrine (0.10}0.35 mg/min for up to 18 h) plus placebo for atosiban. Alternate tocolytic therapy could be given in the event of progression of labour or intolerance of the study drug. Episodes of recurrent preterm labour ((34 weeks gestation) were treated with the assigned medication if the initial tocolysis had been successful. MAIN OUTCOME MEASURES Proportion of women undelivered without use of an alternative tocolytic after 48 h and 7 days, maternal side-effects, neonatal outcomes. Analysis was by intention-to-treat.
Commentary Only two clinical trials testing atosiban against other tocolytics or placebo have been conducted. A previous study by Romero et al showed that atosiban administration resulted in a significantly ^ 2001 Harcourt Publishers Ltd doi:10.1054/ebog.2001.0229, available online at http://www.idealibrary.com on
MAIN RESULTS The proportion of women undelivered was 85% in the atosiban group and 87% in the ritodrine group after 48 h (P"0.99, odds ratio [OR] 1.01, 95% CI 0.48}1.10) and 73 and 76%, respectively, after 7 days (P"0.85, OR 0.94, CI 0.49}1.79. The proportions undelivered without the need for alternative tocolysis were 71 and 67%, respectively, after 48 h (P"0.29, OR 1.35, CI 0.77}2.37) and 64 and 53%, respectively, after 7 days (P"0.03, OR 1.85, CI 1.06}3.21). The median time to delivery or use of an alternative tocolytic agent was 38 days in the atosiban group and 12 days in the ritodrine group (P"0.1). The perinatal mortality rate was 1.4% in the atosiban group and 0.7% in the ritodrine group (P"1.0*). There was no significant difference between groups in the mean gestational age at delivery (35 weeks in both groups), mean birthweight, or proportions of infants that were admitted to neonatal intensive care (39 vs 29%) or had respiratory distress syndrome (22 vs 14%) or cerebral hemorrhage (4 vs 4%). Maternal side-effects were more commonly reported in the ritodrine group than in the atosiban group, including cardiovascular adverse events (84 vs 4%), especially tachycardia (74 vs 1%), vomiting (23 vs 8%), nervousness (8 vs 0%), and tremor (15 vs 1%) (all P(0.001*). 34% of women in the ritodrine group did not complete the study treatment (88% because of adverse events), compared to 21% in the atosiban group (4% because of adverse events) (P"0.03*). CONCLUSION In the treatment of preterm labour, atosiban, compared to ritodrine, resulted in more women remaining undelivered after 7 days without the need for an alternative tocolytic agent, mainly because it was better tolerated. * Calculated from data in article.
increased number of women with preterm labour who remained undelivered and did not require alternative tocolytic therapy after 1, 2 and 7 days, compared with placebo with possibility for tocolytic rescue.1 However, the study also showed that the rate of fetal/infant death was significantly increased in women (26 Evidence-based Obstetrics and Gynecology (2001) 3, 69d70
69
weeks gestation at admission to the study in the atosiban group compared with the placebo group. This increased rate of fetal death could only be partly explained. The present study compared atosiban with ritodrine and, in concordance with Romero et al,1 it was found that atosiban displayed tocolytic effectiveness, assessed in terms of the numbers of women who had not been delivered after 2 and 7 days; the figures were similar to those of the alternative drug (ritodrine). However, because of many withdrawals from the study due to side-effects in the ritodrine group, the proportion undelivered without the need for alternative tocolysis was significantly higher in the atosiban group than in the ritodrine group. The proportion of infants with birth weight (1500 g was significantly higher in the atosiban group than in the ritodrine group and almost all signs of neonatal morbidity among infants from multiple births were increased in the atosiban group. The methodological quality of the study was generally good, but with a few weak points. Optimal blinding was attempted by giving dummy infusions together with the assigned drug in each allocation group, although the typical side-effects of ritodrine might have, in many cases, disclosed the allocation group to the clinical care staff. The composite end-point comprised two elements: tocolytic efficacy and tolerability. The latter was very relevant in the present study, because of the many maternal side-effects of one of the treatments. The follow-up rate was excellent. The inclusion and, especially, exclusion criteria were quite extensive and restrict the generalizability of the study’s findings. It would have been interesting if the authors had given some data about the number of women admitted with preterm labour who did not meet the eligibility criteria, because such information would clarify to what extent the results could be generalized. Some exclusion criteria need more specification, e.g., how did the authors define intrauterine growth restriction, hydramnios, and suspected chorioamnionitis? The logistic
70
Evidence-based Obstetrics and Gynecology (2001) 3, 69d70 doi:10.1054/ebog.2001.0229, available online at http://www.idealibrary.com on
regression analysis may weaken the suspicion that atosiban increases neonatal morbidity in twins from atosiban treated pregnancies (explained by the authors by an imbalance in the multiple pregnancy populations treated with either study drug), although it seems strange that the number of twins with birth weight (1500 g was so much higher in the atosiban group. The results of the present study document that atosiban is as effective as ritodrine in the treatment of preterm labour, but is much better tolerated by the mother. These results are supported by the data from the study by Romero et al. In conclusion, administration of atosiban should be the first choice of tocolysis in women with preterm labour, who meet the inclusion and exclusion criteria used in this study. However, due to the increased neonatal morbidity among very preterm infants from atosiban-treated twin pregnancies (in this study) and the increased fetal/infant death rate in atosiban-treated pregnancies (26 weeks at admission,1 further controlled trials of atosiban in pregnancies (26th gestational week should be conducted, before the treatment can be routinely administrated in this subgroup of patients. Subclinical intrauterine infections may be a dominant cause of preterm labour before the 26th gestational week; therefore, increasing the efficacy of the tocolysis in women with early preterm labour might turn out to be a disadvantage for an infected fetus. Ole B. Christiansen, MD, DMSc Copenhagen University Hospital, Copenhagen, Denmark Literature cited 1. Romero R, Sibai BM, Sanchez-Ramos L et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000; 182: 1173}1183.
^ 2001 Harcourt Publishers Ltd
Atosiban was more efficacious than ritodrine for preterm labour, because of fewer side-effects Moutquin JM, Sherman D, Cohen H, et al. Double-blind, randomized, controlled trial of atosiban and ritodrine in the treatment of preterm labor: a multicenter effectiveness and safety study. Am J Obstet Gynecol 2000; 182: 1191}1199.
OBJECTIVE To compare the efficacy and safety of atosiban and ritodrine for the treatment of preterm labour. DESIGN Multicentre, randomized, double-blind, double-dummy, controlled trial. Allocation was computergenerated, blocked, and stratified by gestational age. SETTING Thirteen centres in Canada and Israel. SUBJECTS Two hundred and forty-seven women in preterm labour with intact membranes, cervical dilatation 43 cm, and live fetus(es) of 23}33 (mean 30) weeks gestation. Previous tocolytic therapy was allowed. Mean maternal age was 27 years and 51% of women were nulliparous. 20% of subjects were enrolled at 428 weeks gestation. 13% of pregnancies were multiple gestation. An additional five randomized women did not receive treatment and were excluded from the analysis. INTERVENTION One hundred and twenty six women were randomized to receive i.v. atosiban (6.75 mg bolus, followed by infusion at 300 lg/min for 3 h, then 100 lg/min for up to 18 h) plus placebo for ritodrine, and 121 to receive i.v. ritodrine (0.10}0.35 mg/min for up to 18 h) plus placebo for atosiban. Alternate tocolytic therapy could be given in the event of progression of labour or intolerance of the study drug. Episodes of recurrent preterm labour ((34 weeks gestation) were treated with the assigned medication if the initial tocolysis had been successful. MAIN OUTCOME MEASURES Proportion of women undelivered without use of an alternative tocolytic after 48 h and 7 days, maternal side-effects, neonatal outcomes. Analysis was by intention-to-treat.
Commentary Only two clinical trials testing atosiban against other tocolytics or placebo have been conducted. A previous study by Romero et al showed that atosiban administration resulted in a significantly ^ 2001 Harcourt Publishers Ltd doi:10.1054/ebog.2001.0229, available online at http://www.idealibrary.com on
MAIN RESULTS The proportion of women undelivered was 85% in the atosiban group and 87% in the ritodrine group after 48 h (P"0.99, odds ratio [OR] 1.01, 95% CI 0.48}1.10) and 73 and 76%, respectively, after 7 days (P"0.85, OR 0.94, CI 0.49}1.79. The proportions undelivered without the need for alternative tocolysis were 71 and 67%, respectively, after 48 h (P"0.29, OR 1.35, CI 0.77}2.37) and 64 and 53%, respectively, after 7 days (P"0.03, OR 1.85, CI 1.06}3.21). The median time to delivery or use of an alternative tocolytic agent was 38 days in the atosiban group and 12 days in the ritodrine group (P"0.1). The perinatal mortality rate was 1.4% in the atosiban group and 0.7% in the ritodrine group (P"1.0*). There was no significant difference between groups in the mean gestational age at delivery (35 weeks in both groups), mean birthweight, or proportions of infants that were admitted to neonatal intensive care (39 vs 29%) or had respiratory distress syndrome (22 vs 14%) or cerebral hemorrhage (4 vs 4%). Maternal side-effects were more commonly reported in the ritodrine group than in the atosiban group, including cardiovascular adverse events (84 vs 4%), especially tachycardia (74 vs 1%), vomiting (23 vs 8%), nervousness (8 vs 0%), and tremor (15 vs 1%) (all P(0.001*). 34% of women in the ritodrine group did not complete the study treatment (88% because of adverse events), compared to 21% in the atosiban group (4% because of adverse events) (P"0.03*). CONCLUSION In the treatment of preterm labour, atosiban, compared to ritodrine, resulted in more women remaining undelivered after 7 days without the need for an alternative tocolytic agent, mainly because it was better tolerated. * Calculated from data in article.
increased number of women with preterm labour who remained undelivered and did not require alternative tocolytic therapy after 1, 2 and 7 days, compared with placebo with possibility for tocolytic rescue.1 However, the study also showed that the rate of fetal/infant death was significantly increased in women (26 Evidence-based Obstetrics and Gynecology (2001) 3, 69d70
69
weeks gestation at admission to the study in the atosiban group compared with the placebo group. This increased rate of fetal death could only be partly explained. The present study compared atosiban with ritodrine and, in concordance with Romero et al,1 it was found that atosiban displayed tocolytic effectiveness, assessed in terms of the numbers of women who had not been delivered after 2 and 7 days; the figures were similar to those of the alternative drug (ritodrine). However, because of many withdrawals from the study due to side-effects in the ritodrine group, the proportion undelivered without the need for alternative tocolysis was significantly higher in the atosiban group than in the ritodrine group. The proportion of infants with birth weight (1500 g was significantly higher in the atosiban group than in the ritodrine group and almost all signs of neonatal morbidity among infants from multiple births were increased in the atosiban group. The methodological quality of the study was generally good, but with a few weak points. Optimal blinding was attempted by giving dummy infusions together with the assigned drug in each allocation group, although the typical side-effects of ritodrine might have, in many cases, disclosed the allocation group to the clinical care staff. The composite end-point comprised two elements: tocolytic efficacy and tolerability. The latter was very relevant in the present study, because of the many maternal side-effects of one of the treatments. The follow-up rate was excellent. The inclusion and, especially, exclusion criteria were quite extensive and restrict the generalizability of the study’s findings. It would have been interesting if the authors had given some data about the number of women admitted with preterm labour who did not meet the eligibility criteria, because such information would clarify to what extent the results could be generalized. Some exclusion criteria need more specification, e.g., how did the authors define intrauterine growth restriction, hydramnios, and suspected chorioamnionitis? The logistic
70
Evidence-based Obstetrics and Gynecology (2001) 3, 69d70 doi:10.1054/ebog.2001.0229, available online at http://www.idealibrary.com on
regression analysis may weaken the suspicion that atosiban increases neonatal morbidity in twins from atosiban treated pregnancies (explained by the authors by an imbalance in the multiple pregnancy populations treated with either study drug), although it seems strange that the number of twins with birth weight (1500 g was so much higher in the atosiban group. The results of the present study document that atosiban is as effective as ritodrine in the treatment of preterm labour, but is much better tolerated by the mother. These results are supported by the data from the study by Romero et al. In conclusion, administration of atosiban should be the first choice of tocolysis in women with preterm labour, who meet the inclusion and exclusion criteria used in this study. However, due to the increased neonatal morbidity among very preterm infants from atosiban-treated twin pregnancies (in this study) and the increased fetal/infant death rate in atosiban-treated pregnancies (26 weeks at admission,1 further controlled trials of atosiban in pregnancies (26th gestational week should be conducted, before the treatment can be routinely administrated in this subgroup of patients. Subclinical intrauterine infections may be a dominant cause of preterm labour before the 26th gestational week; therefore, increasing the efficacy of the tocolysis in women with early preterm labour might turn out to be a disadvantage for an infected fetus. Ole B. Christiansen, MD, DMSc Copenhagen University Hospital, Copenhagen, Denmark Literature cited 1. Romero R, Sibai BM, Sanchez-Ramos L et al. An oxytocin receptor antagonist (atosiban) in the treatment of preterm labor: a randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000; 182: 1173}1183.
^ 2001 Harcourt Publishers Ltd