Developments in the pharmacotherapeutic ... - Porodnice.cz

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Developments in the pharmacotherapeutic ... - Porodnice.cz

Developments in the pharmacotherapeutic management of spontaneous preterm laboriii) prevention of oxytocin-mediated stimulation of PGsecretion in the decidua and fetal membranes, furtherenhancing the negative effects in i) and ii) [88] .4.2.2 EfficacyThe first pilot study of atosiban was carried out on13 patients in whom atosiban caused marked (in some casestotal) inhibition of their uterine contractions, without anyfetomaternal side effects [89] . This was followed by anotherpilot study that found inhibition of uterine contractions innine out of 12 women treated with atosiban without anyapparent side effects [90] . Goodwin et al. [91] published atriad of papers in which atosiban appeared to be effectivein reducing myometrial contractility, with similar efficacyto ritodrine [92] , while it was well tolerated by trialparticipants [93] and lacked the side effects of ritodrine [92] .The RCT by Romero et al. [94] was a Phase IIIplacebo-controlled study of atosiban that allowed alternativetocolytic rescue if labor continued despite initial tocolytictherapy. Their primary outcome measure was the time fromadministration of atosiban or placebo to delivery ortherapeutic failure. There was no significant difference in thisend-point between the treatment and placebo arms of thetrial, but the percentage of women remaining undeliveredand not requiring tocolytic rescue with another tocolyticagent was significantly lower with atosiban at all three timesof assessment (24 h, 48 h and 7 days). The effects of atosibanwere more favorable in women who presented beyond28 weeks of gestation.The largest RCT of tocolytic therapy ever conductedinvolved atosiban [95] . This was a pooled analysis of threeprespecified subgroup reports produced by collaborativegroups from eight different countries [96-98] . This trialcompared the effectiveness and safety of atosiban with thatof three β -agonists (ritodrine, salbutamol and terbutaline).The primary end-point was the number of women remainingundelivered at 48 h and at 7 days. Using an intention-to-treatanalysis, no significant difference in effectiveness was foundbetween atosiban and β -agonist therapy. This analysisincluded women who did not receive study drug, those whowere protocol violations, those who failed and had alternativetocolytic therapy and those in whom tocolytics were successfulbut who contracted again and had repeat courses. With thisamalgam it is not surprising it was difficult to show a differencein effectiveness. When only those who received study drugas planned were compared, atosiban was found to havesuperior efficacy (a composite outcome of safety andtolerability) than β -agonists [95] .A double-blind RCT by Valenzuela et al. [99] comparedthe efficacy of atosiban maintenance therapy to placebo inwomen with SPTL who had achieved uterine quiescencewith intravenous atosiban. Subcutaneous infusion of atosibansignificantly prolonged uterine quiescence (median of32.6 days with atosiban versus 27.6 days with placebo) andtreatment was well tolerated.A controversial Cochrane systematic review was publishedin 2005 assessing the tocolytic effects of atosiban versusplacebo or any other tocolytic agent [100] . This reviewincluded six trials involving a total of 1695 women and foundno reduction in preterm birth with atosiban compared toplacebo or β -agonists. Papatsonis et al. [100] also reported adecrease in infant birth-weight with atosiban treatment, aswell as a higher frequency of maternal adverse drug reactions.However, the review has been criticized by a number ofopinion leaders who have expressed concerns that there mayhave been unintentional bias in favor of CCBs and that thereview’s methodology did not enable the outcomes to beevaluated. Others felt that there was no rationale behindthe selection of the trials and that the review exemplified thedrawbacks of meta-analyses with respect to selection bias andabsence of quality weighting. One opinion leader, much ofwhose published research occupied the review, expressed hisconcerns that acknowledgement of his assistance impliedthat he concurred with their conclusion. He felt that theanalysis was ‘flawed’ and ‘not up to the high standards ofCochrane Reviews’ [101] . Others recorded that the reviewcontained a worrying degree of ‘subjectivism’ with respect tostudy inclusion and interpretation, which focused on datataken out of original context and without reference tosubject profiles. A detailed critique of the shortcomings ofthe review and comments of opinion leaders is contained ina separate review [53] .4.2.3 Safety4.2.3.1 Maternal effectsAtosiban has placebo-level fetomaternal and neonatalside effects or minor effects such as erythema aroundinjection sites [99] . Atosiban was associated with onlyone-tenth of the cardiovascular side effects of β -agonists(81 versus 8%) and β -agonists resulted in a 15-fold increasedrisk (15 versus 1%) in the need to discontinue therapydue to unacceptable side effects [95] .Atosiban has affinity for vasopressin receptors (V 1a , V 1band V 2 ) as well as oxytocin receptors but no dangerousmaternal complications pertaining to this have beenreported to date, with no significant renal, cardiovascular orneurological complications. Theoretically, oxytocin antagonismin tissues that express oxytocin receptors may inhibit milkrelease or postpartum uterine contraction but the shortduration and readily reversible effect of atosiban makesthese risks negligible [102] .4.2.3.2 Fetal effectsOver the long history of atosiban use since the first pilottrials and during the worldwide randomized comparativetrial [95] and clinical use, no substantiated significantsafety concerns for the fetus have emerged. Atosibantherapy was associated with an increased incidence ofperinatal death when compared to placebo in one studyand this was largely responsible for the FDA denying1158 Expert Opin. Pharmacother. (2008) 9(7)

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