全文

Abstract

The aim of this study was to determine the cost effectiveness of atosiban compared to betamimetics in the treatment of preterm labour within the Italian setting. A systematic literature review identified randomised controlled trials (RCTs) comparing atosiban with betamimetics. Meta-analysis of nine RCTs determined that atosiban and betamimetics had similar efficacy in delaying preterm birth by at least 48 h (p = 0.910). Use of atosiban was associated with significantly fewer adverse events (p < 0.008). Results demonstrate that atosiban is cost-saving versus ritodrine or isoxuprine. Atosiban cost savings are €657 per patient from the National Health Service payer's perspective; €299 at 18 h of tocolysis to €189 at 48 h from the hospital's perspective. The respective values versus isoxuprine were €303 and €199. From the combined perspective, using atosiban versus ritodrine saved from €425 to €316; and versus isoxuprine from €429 to €326. Owing to its superior safety profile, atosiban is cost-saving versus betamimetics in the treatment of preterm labour in Italy from the payer's, hospital's and combined perspectives. With the approximate 40,000 annual preterm births in Italy the annual savings could be in excess of €13 million for the payer or €3.8–6.2 million for the hospitals.

Keywords: Preterm labour, Tocolytic, Economic evaluation, Atosiban, Betamimetics.

 

1. Introduction
Preterm birth (PTB) complicates 5–12% of all pregnancies [1] and [2], varying from 6.2% in Europe to 11.9% in Africa [3]. Of all preterm births, 40–50% are associated with preterm labour [4] and [5]. In Italy, PTB has been reported in 6.5% (with 0.85% at <32 weeks) [6] or 7.2% of total births and 6.8% of live-births [7] and [8]. Over recent decades, the frequency of preterm birth in most Western countries appears to have been increasing [9] and [10]. The increased incidence is multifaceted and may be related, at least in part, to the lowering of the gestational age at which the neonate can survive (i.e. 22 weeks of gestation), increased use of ultrasonography to establish gestational age [11], and changes in the definitions of fetal loss, stillbirth and early neonatal death [12] and [13].

A large proportion of PTB is preventable. The ultimate goal of delaying preterm birth is to allow gestation to continue until fetal maturity is achieved (i.e. >36 weeks), but an accepted surrogate outcome is to prolong pregnancy (e.g. by at least 48 h) until the mother can be transferred to a tertiary centre equipped for high-risk pregnancies with a dedicated neonatal unit. Delay of preterm labour allows for administration of corticosteroids, which accelerates fetal lung maturation and reduces the risk of neonatal death, respiratory distress syndrome, cerebro-ventricular hemorrhage, infectious morbidity, necrotising enterocolitis, use of respiratory support and admission to the neonatal intensive care unit [14]. Between 22 and 28 week each day of delay improves survival by 3% [15].

The rationale for using tocolytics is that prolonging pregnancy will reduce perinatal morbidity and mortality. All licensed tocolytics are currently considered equally effective [16]. The focus is therefore on differences in maternal and fetal safety, cost of treatment, cost consequences of treatment and quality of life (QoL). There are no studies of tocolytics to date of sufficient sample size to be able to demonstrate a benefit in mortality and/or morbidity [17], [18], and [19]. This only emphasizes the importance of safety outcomes, which have been established with statistical significance, especially nearer term, when neonatal mortality is less likely to be affected by treatment, yet it is when the majority of preterm labour presentations occur.

The main classes of tocolytics are betamimetics, calcium-channel blockers and vasopressin/oxytocin receptor antagonists, with atosiban and nifedipine being the main tocolytic agents currently used in clinical practice [5]. Betamimetics (e.g. ritodrine, isoxuprine) have been widely used for 30 years, but are being gradually phased out since the early 1990s due to maternal and fetal safety concerns [20]. Occurrence of side-effects is associated with the mechanism of action of betamimetics, affecting multiple functions via ubiquitous beta-adrenergic receptors. Both ritodrine and isoxuprine are licensed in Italy, but like all betamimetics, high frequency of unpleasant and sometimes severe side-effects may limit their desirability as a first-line agent [21]. Furthermore, in Italy betamimetics are contraindicated or should be used with caution in hyperthyroidism, cardiovascular diseases, arrhythmias with long QT, hypertension, and diabetes, and are contraindicated in multiple pregnancy due increased risk of pulmonary oedema [22], [23], and [24].

With similar efficacy, the clinical advantage of atosiban results from its superior safety profile, with a significantly lower rate of fetal and maternal side-effects and a significantly lower rate of treatment discontinuation [25]. In a recent study from the Netherlands and Belgium, use of betamimetics was associated with higher incidence of mild and severe side-effects compared with atosiban (R.R = 24.5 [3, 197.5]) [26]. Also nifedipine had an inferior safety profile (R.R = 13.5 [1.7, 102.8]) and safety concerns for the use of calcium channel blockers in pregnancy have been raised [27]. In addition, the incidence of side-effects increased when combined courses of tocolytic agents were used. The study concluded that betamimetics should no longer be used, combined courses of tocolytic agents should not be administered and use of atosiban should be considered especially in cases of multiple gestation, diabetes and maternal cardiovascular problems [26]. Additionally, the quality of nifedipine studies has been brought into question [28]. Taking into account safety of tocolytic treatment, the UK's Royal College of Obstetricians and Gynaecologists (RCOG) recommends that oxytocin receptor antagonists (e.g. atosiban) be used as one of the first lines of treatment [29].

In Italy, atosiban is considered for acute tocolysis as the first-line agent for its efficacy and safety, though cost of treatment is indicated as its “principal side-effect” [21]. Also nifedipine is a consideration for tocolysis [30], but in Italy it is not registered for this indication.

PTB incurs considerable inpatient cost, and use of tocolytics is central in delaying birth. Resource utilisation associated with PTB, including maternal hospital admission, in utero transfer and neonatal care, is a burden on parents and society as a whole [31]. In addition to the economic burden on health services and enormous negative psychosocial and emotional effect on the family, the morbidity and mortality associated with PTB impose an immense burden on the education system and social services [17]. Accounting for costs of healthcare, education and social services, the incremental cost per preterm child surviving to 18 years compared with a term survivor was estimated in the UK at £22,885. The corresponding estimates for a very and extremely preterm child were substantially higher at £61,781 and £94,740, respectively [32].

The economic implications of extremely preterm birth (<28 weeks) are well known, and early PTB (28–32 weeks) is also associated with high perinatal mortality and morbidity with economic implications. A study in the UK revealed that of the £2946 billion annual economic burden of PTB to the public sector, £1956 billion (66.4%) is attributable to moderate disability PTB [32]. The overall cost burden remains high for mildly preterm birth (32–36 weeks) and then doubles for late preterm at 37–38 weeks. The greatest risk of mortality and morbidity is for those infants born at the earliest gestational ages. However, infants born nearer to term represent the greatest number among all infants born preterm and at the same time experience more complications than infants born at term [33]. The aggregate annual cost of treating PTB at <33 weeks in England and Wales was estimated to amount to £1 billion; whereas for those born at 33–36 weeks the cost was nearly double at £1.9 billion [32]. For this reason, prevention of PTB with tocolytics is just as important, if not more important, than prevention of early PTB associated with higher cost per case.

Choice of the tocolytic has considerable economic implications. It has recently been established that atosiban, despite its greater per vial cost, is actually cost-saving when compared to betamimetics in Germany [34] and Austria [35]; cost-savings resulted from the superior safety profile of atosiban. In the UK, evidence on side-effects associated with the use of nifedipine in tocolysis was incorporated in an economic evaluation [31]. The authors found that the protocol combining atosiban with fetal fibronectin diagnostic testing is highly cost-saving when compared to nifedipine alone. An economic evaluation of specific interventions that aim to prevent PTB would allow resources to be allocated in both a clinically and cost-effective manner [17]. The aim of this study was to assess the economic implications of the choice of tocolytics in the Italian setting.

2. Materials and methods
MEDLINE, EMBASE, the Centre for Reviews and Dissemination (CRD) and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched to identify randomized clinical trials comparing atosiban versus betamimetics in women experiencing preterm labour. No search restrictions were applied and all abstracts identified using the keywords “atosiban”, “Tractocile”, “antocin”, and/or “RWJ 22164″ were considered. For the meta-analysis of efficacy and rates of adverse events, we included trials that provided outcomes during 48 h of hospitalisation. Three types of outcomes data were extracted from the selected studies: efficacy in delaying preterm birth by at least 48 h, frequency of maternal and fetal adverse events, and resource utilisation for the economic analysis. Three double-blinded studies were identified. In addition, six non-double-blinded (low-quality) studies were identified and included in a separate meta-analysis. The inclusion and exclusion criteria in the remaining six studies differed from the above in minor details. In one low-quality study usual care, rather than a betamimetic, was used as a comparator of atosiban [36], but since it was a large study with most patients (64.5%) receiving betamimetics, it was included in the meta-analysis of combined high and low-quality studies. In this study the remaining patients in the usual care arm received either a calcium channel blocker (14.8%) or a betamimetic with magnesium (10%), more likely leading to under-estimation, rather than over-estimation of side-effects of betamimetics. The quality characteristics of all identified trials are presented in Table 1 and Table 2. Using the Mantel–Haenszel method (random-effects model), we performed evidence synthesis using a dedicated statistical package [37].

 

A cost-minimisation analysis, rather than a cost-effectiveness analysis, was conducted due to the similar efficacy of the analysed tocolytic treatments. A review of resource utilisation and expert opinion revealed that costs related to drug administration were not different and could not be captured in the Italian payment system. Diagnostic costs attributable in cases when the patient was ineligible for betamimetics (e.g. high cardiovascular risk, diabetes, thyrotoxicosis) were not considered, as in such cases alternative tocolytic treatment is typically preferred in clinical practice instead of diagnostic testing. Finally, regardless of the tocolytic agent, it was assumed that the costs of monitoring of tocolysis, as well as all other costs related to management of preterm labour and preterm birth, would be the same in all women experiencing preterm labour. Drug costs were evaluated at 18 and 48 h from the time of hospital admission. For increased accuracy, extended hospitalisation for treatment of emergency adverse events occurring within the 48 h period was also factored into the analysis.

The dosing regimen used for the calculation of costs of drugs was based on the protocols used in the included clinical trials [38], [39], and [40]. Atosiban was administered intravenously in a single bolus dose (6.75 mg in 0.9 mL normal saline), with subsequent infusion of 300 mcg/min atosiban in 5% dextrose for the first 3 h, followed by 100 mcg/min atosiban in 5% dextrose for up to 48-h. The drug regimen for betamimetics was concordant with current practice guidelines for the management of preterm labour.

Ritodrine: 2 vials (50 mg) of miolene in 500cc saline; the initial dose 50–100 mcg/min increasing by 50 mcg/min every 10–30 min in the absence of contraindications (thyroid disease or diabetes mellitus) and side-effects (maternal: hyperglycemia, hyperinsulinemia, hypokalemia, fetal tachycardia, intraventricular hemorrhage); the maximum dose reached 350 mcg [41]. Isoxsuprine: 8 vials (10 mg) of vasosuprina in 500 mL saline; the initial dose 30 drops/min and increasing till uterine contractile activity decreases (not exceeding 60 drops/min). Continued at full dosage until the regression of the contractile activity and then reduced to the lowest effective dose [15]. The following unit costs of tocolytics, current as of January 2010, were used in the evaluation: tractocile (atosiban) (6.75 mg): €24.18; tractocile (atosiban) (37.5 mg): €75.42; miolene (ritodrine) (50 mg): €0.52; vasosuprina (isoxsuprine) (10 mg): €0.24.

In Italy, ritodrine and isoxuprine are the only betamimetic agents indicated for preterm labour, but an analysis of adverse events reported in trials of three different betamimetics demonstrated their comparable safety profile [19]. DRG tariffs were obtained with DRG Grouper v.19 using national schedule applicable to most regions. From the National Health Service payer's perspective, all costs associated with treatment of preterm labour were encompassed by the flat DRG rates per patient diagnosed. For the payer, only extended length of stay and occurrence of chest pain or dyspnoea had cost consequences resulting from DRG recoding. From the hospital's perspective, every extension of length of stay had cost implications for the hospital, even if no DRG recoding was possible, and hence no additional payments were due from the payer. The costs from the combined perspective were also calculated, as they can provide additional, whole-system insight for decision making.

The cost-minimisation analyses were conducted using an economic model developed by the authors in a Microsoft Excel spreadsheet; the model accounted for the payer–provider split characteristic of the Italian system. The modelled cohort of 1000 patients was followed up for up to 48-h of hospitalisation. Tocolytic treatments were assigned based on the all-patients treated population from the combined clinical trials. Discontinuation of drug administration due to adverse events, progression of labour, preterm delivery and other causes was accounted for. Weibull survival curves were fitted to the data on discontinuation at 48 h, preterm delivery at 48 h, and at 7 days. Drug switching was assumed to occur with equal probability during the 48 h hospitalisation period. Hospitalisation length was defined based on expert opinion using beta distribution with the mean of 2.2 days, minimum of 1 day and maximum of 10 days. Occurrence of adverse events was associated with risk of extension of the hospitalisation length. It was assumed that on average only 50% of the patients experiencing any of the adverse events would require hospitalisation extended by one or more days. Occurrence of multiple adverse events was assumed to have the same consequences as occurrence of any single event. Effectively, we conservatively assumed no consequences of occurrence of adverse events in 50% of the patients. Similarly, diagnosis of chest pain or dyspnoea could lead to recoding in 50% of the patients.

3. Results
Based on three high-quality studies [38], [39], and [40], efficacy of atosiban in delaying preterm birth by at least 48-h was found to be identical to that of betamimetics (88.1% vs. 88.7%, respectively, p = 0.910) (OR = 0.94 [0.59, 1.48]) (Fig. 1). Addition of two single-blinded [42] and [43], two open label [1], [44], and [45], and one study with usual care in the control arm [36], resulted in slightly higher success rate for atosiban and lower for betamimetics (90.1% vs. 88.6%), but also with no significant difference (p = 0.61) (OR = 1.14 [0.82, 1.56]) (Fig. 2).

 

Meta-analysis of the three double-blinded clinical trials revealed that use of atosiban was associated with significantly lower frequency of adverse events compared to betamimetics (for individual adverse events p-value varied from <0.001 to 0.008). Compared to betamimetics, use of atosiban was associated with a significantly lower frequency of adverse events for tachycardia (5.5% vs. 75.5%; OR = 0.02 [0.00, 0.05]), fetal tachycardia (3.3% vs. 27.7%; OR = 0.10 [0.05, 0.22]), dyspnoea (0.2% vs. 7.3%; OR = 0.07 [0.02, 0.31]), chest pain (1.1% vs. 4.8%; OR = 0.21 [0.07, 0.63]), palpitation, vomiting, headache, hyperglycaemia, tremor, hypocalemia. Inclusion of all nine studies yielded similar safety advantage of atosiban with the frequency of tachycardia (3.6% vs. 56.4%; OR = 0.02 [0.01, 0.04]); fetal tachycardia (9.3% vs. 26.2%; OR = 0.18 [0.05, 0.56]); dyspnoea (0.6% vs. 8.5%; OR = 0.09 [0.04, 0.22]) and chest pain (1.6% vs. 8.9%; OR = 0.17 [0.08, 0.36]); with p-value <0.001 for each adverse event.

Cost results for the three treatment options based on high-quality trials are presented in Fig. 3. From the payer's perspective, cost-saving from using atosiban versus either beta-mimetic was €657 per patient. From the hospital's perspective, savings from using atosiban versus ritodrine ranged from €299 for 18-h of tocolysis to €189 for 48-h; the respective values for isoxuprine were €303 and €199. From the combined perspective, using atosiban versus ritodrine saved from €425 for 18-h of tocolysis to €316 for 48-h; versus isoxuprine the results were €429 and €326, respectively. When all nine RCTs were considered, cost-saving from the payer's perspective using atosiban versus either betamimetic was €646 per patient. From the hospital's perspective, savings from using atosiban versus ritodrine ranged from €261 for 18-h of tocolysis to €152 for 48-h; the respective values for isoxuprine were €265 and €161. From the combined perspective, using atosiban versus ritodrine saved from €414 for 18-h of tocolysis to €304 for 48-h; versus isoxuprine the results were €418 and €315, respectively. The results were robust in the probabilistic sensitivity analyses (PSA), where cost-savings in all scenarios was achieved in 98.2–100% of cases. Twenty percent variation in DRG tariff to account for regional differences was factored in the PSA.

 

With the approximate 40,000 annual preterm births in Italy and based on the assumption that only half of women who deliver preterm are treated with tocolytics the annual savings could be in excess of €13 million for the payer or €3.8–6.2 million for the hospitals.

Acknowledgements
JW is a director of an independent consultancy, who received an unrestricted research grant from Ferring Pharmaceuticals to study cost-effectiveness of tocolytic treatments. The sponsor was not involved in the study. AS was involved in the study through the consultancy. GC and GCDR were not remunerated for their contribution and declared no competing interests. JW conceived of the analytical approach, contributed to the literature review, designed the economic model and drafted the manuscript. AS contributed to the analysis of data and to the review clinical evidence. GC and GCDR contributed to the analysis and interpretation of data and provided clinical information for costing study. All authors revised the manuscript and have given their final approval for submission.

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