Developments in the pharmacotherapeutic ... -

Developments in the pharmacotherapeutic ... -

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] . 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)

Kam & Lamontapproval in the US in 1998 [94] . However, due to imbalancesof randomization in that study, the atosiban treatmentgroup had been allocated more women at a gestational ageof < 26 weeks who were also significantly more advancedin SPTL (assessed by the modified Bishop score), so thetreatment and placebo groups were unequal at baseline.Following approval in the European Union in 2000, as ofJune 2007, atosiban was approved in 67 countries, excludingthe US and Japan. The calculated cumulative patient responseto atosiban (January 2000 to December 2005) is estimatedat 156,468 treatment cycles, which, with routine monitoringof drug safety, has revealed no important safety issues.Vasopressin is secreted by the fetus exposed to stress, as ahomeostatic response [103] and it was thought that vasopressinantagonism by atosiban may have led to excess deaths in thetreatment group compared to placebo. However, the authorsexplained that it was unlikely that atosiban had contributedto these deaths, as higher doses of atosiban had previouslybeen associated with an improved perinatal outcome andexperimental toxicity studies in animals had not revealedany adverse events. Fetal plasma atosiban levels have beenshown to be negligible or undetectable [104] .4.3 Calcium channel blockers4.3.1 Mechanism of actionCalcium channel blockers such as nifedipine andnicardipine block voltage-dependent calcium channels onthe myometrial cell membrane. This blocks the influx ofextracellular calcium into the smooth muscle cell. Since lessintracellular calcium is available for binding to myosinlight chain kinase and formation of the calcium–calmodulincomplex, phosphorylation of the actin–myosin apparatusis inhibited [105] .4.3.2 EfficacyNo placebo-controlled trials have been performed to assessthe efficacy of nifedipine tocolysis. The first pilot trial,which compared nifedipine to placebo, also comparednifedipine to ritodrine, with 20 women allocated to eachgroup [106] . Nifedipine was found to have a promising effecton postponement of delivery but 90% of women treatedwith nifedipine suffered from flushing of the face, neck andchest and one woman had marked nausea. Subsequently, themajority of randomized trials have compared the tocolyticefficacy of nifedipine with that of ritodrine [107-113] , whileothers have compared nifedipine to other drugs such asmagnesium sulfate [114,115] or terbutaline [116,117] . The trialsthat compared nifedipine with ritodrine found nodifference in the tocolytic effect but a decreased incidenceof maternal side effects such as chest pain, nausea andvomiting in those treated with nifedipine [107-109,111-113] .These studies were of small scale and blinding was notpossible due to the different routes of administration ofthe drugs. None of the nifedipine studies were reported inan intention-to-treat analysis.Atosiban or nifedipine but not β -agonists are currentlyrecommended for the treatment of SPTL on the basis of thepoor side-effect profile associated with ritodrine therapy andthe apparent similarity of efficacy shared by all threedrugs [52] . Nifedipine remains unlicensed in the UK for useas a tocolytic agent. The guidelines advocating nifedipineuse were based on results from two meta-analyses and aCochrane systematic review [118-120] . The findings of thesemeta-analyses are summarized in Table 1 . The quality of thestudies included in the meta-analyses have been criticizedfor being of poor quality and suggestions were made thatsuch reviews should not be used for making guidelinesor recommendations [121] .4.3.3 Safety4.3.3.1 Fetomaternal effectsThe adverse fetomaternal effects of nifedipine haveincluded maternal pulmonary edema [122,123] , myocardialinfarction [124,125] , hypoxia [126] and atrial fibrillation [127] .Nifedipine is licensed for use in hypertension, due to itseffect on vascular smooth muscle, causing vasodilatation [128] .This may lead to severe hypotension in pregnant womenand has led to fetal distress, thereby necessitating emergencydelivery by cesarean section in one case where nifedipinewas used to treat pregnancy-induced hypertension [129] anddeath of a fetus after tocolytic therapy with nifedipine [130] .‘Near misses’ where nifedipine tocolysis has resulted in severematernal hypotension without lasting morbidity or mortalityare probably under-reported [131] . Van Veen’s report [130] offetal death associated with nifedipine tocolysis wasfollowed by anecdotal evidence that cases of maternalhypotension severe enough to cause fetal compromiseoccur at a higher rate than suggested by the number ofpublished case reports [132,133] .It is still uncertain whether nifedipine carries risks ofteratogenicity. Although digital abnormalities have beenobserved in animals receiving high doses of nifedipine [134,135] ,no congenital defects in humans as a direct result of nifedipineexposure have been reported. The only long-term follow-upstudy of children who were exposed in utero to nifedipinetocolysis compared the behavioral–emotional outcomes,quality of life, motor function, parenting distress andchildhood education of children exposed to nifedipine withthose exposed to ritodrine in utero [136] . No significantdifferences in long-term outcome were observed. A long-termcomparison to placebo would have been more meaningfuland no such follow-up study has been performed to date.4.4 Magnesium sulfateThe pharmacological mechanism of magnesium sulfate is notunderstood. It is thought to decrease myometrial contractilityby competing with calcium for entry into the smooth musclecell at voltage-gated calcium channels [137] . Modulation ofcalcium influx and competitive binding of magnesium withcalcium storage sites in the sarcoplasmic reticulum of theExpert Opin. Pharmacother. (2008) 9(7) 1159

Kam & Lamonttreatment failure [159] . Another RCT comparing the tocolyticefficacy of transdermal GTN to that of intravenous ritodrinefound no difference in prolongation of gestation to 37 weeksof gestation or in the proportion of women who deliveredbefore prespecified time limits [160] .The action of nitric oxide on maternal vascular tone maylead to changes in uterine blood flow and fetal side effects.Vasodilatation may also lead to maternal side effects such asflushing, headache, hypotension and tachycardia [158] . TheRCT by Lees et al. [160] found headache to be the commonestmaternal adverse effect, but other side effects such astachycardia, palpitations and nausea and were less commonwith GTN therapy than with ritodrine therapy.5. ConclusionPreterm birth is the major cause of perinatal mortality andmorbidity in the developed world. Not all cases of SPTL aresuitable for tocolytic intervention. The choice and use oftocolytics has evolved over the last 20 – 30 years. The perfecttocolytic, which is uniformly effective and has no fetomaternalside effects, does not exist. Only one tocolytic agent hasbeen developed specifically to treat SPTL (atosiban) and thisis the most utero-specific of all the agents. As a result, atosibanhas placebo-level side effects while all other agents havemulti-organ side effects, particularly cardiovascular adverseeffects. Although more costly than other tocolytics, atosibanhas the most robust evidence base for safety and efficacy ofall available tocolytics and is a useful addition to themanagement of SPTL [95] . Since the remit of this reviewpertains to the pharmacotherapeutic management of SPTL,novel techniques of prediction and prevention are notcovered. However, the reader is recommended to read theexcellent review of the use of genomics, transcriptomics,proteomics and metabolomics for the prediction anddiagnosis of SPTL [161] .6. Expert opinionThe incidence of preterm birth is underestimated [162] and islikely to increase due to increasing risk factors. The associatedmorbidity and mortality results in a huge burden ofhealthcare costs. Despite this there is a disarray and lack ofconsensus on the use of tocolytics [88] , which must be dueto confusion about the evidence supporting the efficacy andsafety of each group of agents. The evidence supportingmagnesium sulfate is poor and this should not be usedas a tocolytic. The evidence supporting nitric oxide donorsis scanty, their use is infrequent and they may causesubstantive cervical changes that predispose to labor andthey should not be used as tocolytics. While PGSIs havetocolytic effects, they have potentially serious fetal adverseeffects and, since better alternatives are available, their useshould be discontinued or extremely limited to third linemanagement. β -agonists are licensed for use but are nomore efficacious than CCBs or VOT receptor antagonistsand have the potential to cause serious maternal adverseeffects, particularly cardiovascular effects. Their use shouldbe limited to second- or third-line choice. The main debateat present is between nifedipine and atosiban.6.1 The case for nifedipine against atosibanThose who favor nifedipine over atosiban will quote thesystematic review [118] of CCBs (effectively nifedipine) versusβ -agonists (effectively ritodrine) to claim that nifedipine ismuch more efficacious and safer than β -agonists. They willalso quote the systematic review [100] of VOT receptorantagonists (effectively atosiban) versus β -agonists to claimthat atosiban lacks safety and efficacy when compared toplacebo or β -agonists. They will claim superiority ofnifedipine over atosiban based on an indirect comparison ofnifedipine versus atosiban [163] and the fact that nifedipinecan be used orally and is inexpensive.6.2 The case for atosiban against nifedipineThose who favor atosiban over nifedipine will argue thatmost of the evidence pertaining to CCBs is contained inmeta-analyses that are retrospective analyses of pooled data,which are only as good as the quality of the studies included.Studies included in the systematic review of CCBs versusβ -agonists [118] have been criticized for being of poor quality,with small sample sizes, having no placebo-controlled trialsor follow-up studies and for lacking robustness with respectto the requirements for regulatory bodies. They would alsodemonstrate that the evidence of randomization, concealmentand attrition bias is such that these studies should not beused to make recommendations or guidelines [121,131] . Thiswould be in contrast to the evidence base for atosiban,which is far more robust. In contrast to nifedipine, atosibanstudies have included well-conducted, placebo-controlled,follow-up, prospective Phase I – IV studies as well as largemultinational studies published on an intention-to-treatbasis with no suggestion of bias. Those who favor atosibanwill also criticize the systematic review of atosiban [100] andprovide evidence for this being biased and flawed [53] .The comparisons between nifedipine and atosiban muchquoted by nifedipine enthusiasts [162] were an indirectcomparison using a mathematical tool that was self-criticalof drawing any meaningful conclusion and two recentstudies directly comparing nifedipine and atosiban thatconcluded that atosiban was as efficacious as nifedipinebut had much fewer cardiovascular side effects [164,165] .In contrast to nifedipine, atosiban is licensed for use andis based upon large, well-conducted studies involvingplacebo-controlled trials and Phase I – IV and follow-upstudies [166] , was developed specifically to treat SPTL [88,102]and is utero-specific with placebo-level side effects.Following the decrease in β -agonist use, as the use ofnifedipine has increased so have the recorded adverseevents [122-127,130] . The cost will be justified based upon theExpert Opin. Pharmacother. (2008) 9(7) 1161

Developments in the pharmacotherapeutic management of spontaneous preterm laborresearch and development required to market a newutero-specific compound with placebo-level side effectsdeveloped specifically to treat SPTL, which meets therequirements to satisfy regulatory bodies, in comparison tothe cost of preterm birth in general and in comparison toother drug budgets. Finally, those in favor of atosiban wouldcounter their argument with respect to oral therapy bypointing out that rapid-onset preparations of nifedipinecompromise safety, leading to the use of long-acting or slowreleasepreparations that compromise efficacy and lead tothe use of additional tocolytics such as magnesium sulfate orβ -agonists, which further compromise safety. The decisionon whether to use nifedipine or atosiban should be basedon the evidence available. There is no doubt that theevidence supporting the use of atosiban is more robust,more plentiful and of much higher quality. This evidenceleads to the conclusion that atosiban is at least as effective asnifedipine and β -agonists with much fewer side effects thanboth, particularly cardiovascular ones and the need todiscontinue therapy because of unacceptable side effectsis decreased. Except for cost pressures, most units wouldprefer to use atosiban because they are convinced by thesupporting evidence and because of the safety and lack ofside effects.For a number of reasons, pharmacotherapy for themanagement of SPTL may not be a high priority for thepharmaceutical industry. Firstly, the market is relativelysmall. Secondly, litigation costs are high. While the sameworries of litigation could be said of diabetics, the hugemarket makes this condition more attractive for pharmaceuticalcompanies. Thirdly, two patients (mother and fetus)are involved in each treated case, which increases andcomplicates the data required to satisfy regulatory bodies.In this way, the cost of carrying out good quality studies tosatisfy regulatory bodies may not be reflected in thereimbursement that governments and other healthcareproviders are prepared to offer. A review by Goodwin [167]elegantly displays the hurdles that have to be overcome tosatisfy the FDA. Two other oxytocin receptor antagonists arecurrently under evaluation and development: barusiban(Ferring, St Prex, Switzerland) and relcovaptan (Sanofi-Synthelabo Recherche, Paris, France). Relcovaptan(SR49059), like atosiban, is a VOT receptor antagonist withantagonistic activity against both the vasopressin V 1a andoxytocin receptors in the uterus. In a randomized, doubleblind,placebo-controlled trial of 18 women (12 of whomreceived relcovaptan and six placebo) in preterm laborbetween 32 and 36 weeks of gestation the frequencyof uterine contractions over a 30-min period wassignificantly lower in the relcovaptan group compared toplacebo-treated women [168] .In contrast to both atosiban and relcovaptan, barusiban(FE200440) has a high affinity for the oxytocin receptor,which is of the order of 300-fold that for the vasopressinV 1a receptor. In animal studies using a model of oxytocininducedpreterm labor in non-human primates, barusibanwas effective in suppressing such contractions with no longtermadverse events [169,170] . Whether such a selectiveoxytocin receptor antagonist would be as effective inspontaneous preterm labor (as opposed to oxytocin-inducedpreterm labor-like contractions) has not been demonstratedin human clinical studies and we await with interest thereports of a Phase II study of barusiban, which we understandis to be reported at the meeting of the Society forGynecological Investigation in San Diego, US, in March 2008.Little is known about the use of combination tocolytictherapy. At a time when the cost and adverse sequelae oftocolytics are hot topics of debate, it seems counterintuitiveto suggest using double or triple tocolytic therapy unlesslower doses of each are used. In addition, if, due to infection,SPTL and preterm birth has ‘survival value’ for the motheror her fetus, three different tocolytics with different mechanismsof action may be powerful enough to combat theprotective response of nature to empty the uterus ratherthan a single tocolytic, thereby causing more harm thangood to the maternal host and the fetus. However, at thelimits of viability combined tocolytic therapy (terbutaline,atosiban and sulindac) together with combined antibiotics(cephalexin and metronidazole) have been employed withsurprisingly good results [171] .Declaration of interestRonald F Lamont has given lectures and advice and chairedsessions at conferences supported by Ferring Pharmaceuticalsand sanofi-synthelabo.1162 Expert Opin. Pharmacother. (2008) 9(7)

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