Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta2 agonists for the treatment of chronic asthma in children under the age of 12 years.

OBJECTIVES: To assess the clinical and cost-effectiveness of inhaled corticosteroids (ICS) alone and ICS used in combination with a long-acting beta2 agonist (LABA) in the treatment of chronic asthma in children aged under 12 years.

DATA SOURCES: Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006).

REVIEW METHODS: A systematic review of clinical and cost-effectiveness studies and economic analyses were carried out. A flexible framework was used to allow different types of economic analyses as appropriate, with either a cost comparison or cost-consequence comparison conducted.

RESULTS: Of 5175 records identified through systematic literature searching, 34 records describing 25 studies were included (16 were fully published randomised controlled trials, six were systematic reviews, and three were post-2004 conference abstracts). The most frequently reported relevant outcomes in the 16 RCTs were peak expiratory flow rate (13 trials), FEV1 (13 trials), symptoms (13 trials), adverse events or exacerbations (13 trials), use of rescue medication (12 trials), markers of adrenal function (e.g. blood or urine cortisol concentrations) (13 trials), height and/or growth rate (seven trials) and markers of bone metabolism (two trials). In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, no consistent significant differences or patterns in differential treatment effect among the outcomes were evident. Where differences were statistically significant at high doses, such as for lung function and growth, they favoured formoterol fumarate (FF), but this was generally in studies that did not compare the ICS at the accepted clinically equivalent doses. Differences between the drugs in impact on adrenal suppression were only significant in two studies. At doses of 200, 400 and 800 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. In the trials comparing ICS at a higher dose with ICS and LABA in combination, most outcomes favoured the combined inhaler. Only the combination inhaler, Seretide Evohaler, is slightly cheaper than the weighted mean cost of all types of ICS at increased dose except BDP 400 microg/day (including CFC-propelled products). Both the combination inhalers, Seretide Accuhaler and Symbicort Turbohaler, are more expensive than the weighted mean cost for all types of ICS at a two-fold increased dose. Compared with the lowest cost preparation for each ICS drug, all the combination inhalers are always more expensive than the ICS products at increased dose.

CONCLUSIONS: The limited evidence available indicates that there are no consistent significant differences in effectiveness between the three ICS licensed for use in children at either low or high dose. BDP CFC-propelled products are often the cheapest ICS currently available at both low and high dose, and may remain so even when CFC-propelled products are excluded. Exclusion of CFC-propelled products increases the mean annual cost of all budesonide (BUD) and BDP, while the overall cost differences between the comparators diminish. There is very limited evidence available for the efficacy and safety of ICS and LABAs in children. From this limited evidence, there appear to be no significant clinical differences in effects between the use of a combination inhaler versus the same drugs in separate inhalers. There is a lack of evidence comparing ICS at a higher dose with ICS and LABA in combination and comparing the combination products with each other. In the absence of any evidence concerning the effectiveness of ICS at higher dose with ICS and LABA, a cost-consequence analysis gives mixed results. There are potential cost savings with the use of combination inhalers compared to separate inhalers. At present prices, the BUD/FF combination is more expensive than those containing FP/SAL, but it is not known whether there are clinically significant differences between them. A scoping review is required to assess the requirements for additional primary research on the clinical effectiveness of treatment for asthma in children under 5 years old. Such a review could also usefully include all treatment options, pharmacological and non-pharmacological, for asthma. A direct head-to-head trial that compares the two combination therapies of FP/SAL and BUD/FF is warranted, and it is important to assess whether the addition of a LABA to a lower dose of ICS could potentially be as effective as an increased dose of ICS alone, but also be steroid sparing. There is also a need for the long-term adverse events associated with ICS use to be assessed systematically. Future trials of treatment for chronic asthma in children should aim to standardise further the way in which outcome measures are defined. There should be a greater focus on patient-centred outcomes to provide a more meaningful estimation of the impact of treatment on asthma control. Methods of reporting also require standardisation.