title: 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 adults and children aged 12 years and over.
abstract: OBJECTIVE
  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 adults and children aged over 12 years.
  
  
  METHODS
  Major electronic bibliographic databases, e.g. MEDLINE and EMBASE, were searched up to February/March 2006 (and updated again in October 2006).
  
  
  METHODS
  A systematic review of clinical and cost-effectiveness studies was conducted. Cost comparison and cost-consequence analyses were performed where appropriate.
  
  
  RESULTS
  The assessment of clinical effectiveness was based on the 67 randomised controlled trials selected from the 5175 reports identified through the systematic literature search. The most frequently reported relevant outcomes were lung function, symptoms, use of rescue medication and adverse events. The trials varied considerably. In the trials that compared low-dose ICS versus ICS and high-dose ICS versus ICS, there were few significant differences in clinical effectiveness, although a few of the trials had assessed non-inferiority between the comparators rather than superiority. At doses of 400, 800 and 'high-level' doses of 1500 or 1600 microg/day, beclometasone dipropionate (BDP) appears to be the current cheapest ICS product both with the inclusion and exclusion of chlorofluorocarbon (CFC)-propelled products. A significant treatment benefit for combination ICS/LABA therapy across a range of outcomes compared with ICS alone was identified [when the ICS was double the accepted clinically equivalent dose of the ICS in the combination inhaler, and dry powder inhalers (DPIS) were used to deliver the drugs]. When a formoterol fumarate (FF)/salmeterol (SAL) combination inhaler and a budesonide (BUD)/FF combination inhaler were each compared with their constituent drugs delivered in separate inhalers, there were very few statistically significant differences between the treatments across the various efficacy outcomes and the rate of adverse events. Combination inhalers were more often cheaper than doubling the dose of ICS alone. However, the costs were highly variable and dependent on both the dose required and the preparation used in the trials. The estimated mean annual cost of FP/SAL combination varied from being 94 pounds cheaper to 109 pounds more expensive than the alternative of BUD at a higher dose. The BUD/FF combination varied from being 163 pounds cheaper to 66 pounds more expensive than the higher dose of either BUD or FP. When the combination inhalers were compared to each other, the results were mixed, with the FP/SAL combination significantly superior on some outcomes and the BUD/FF combination superior on others; however, meta-analysis showed that there were no significant differences between the two treatments in the rate of adverse events. Taking an ICS with a LABA as either of the two currently available combination products, FP/SAL and BUD/FF, is usually cheaper than taking the relevant constituent drugs in separate inhalers. At very high doses of BUD (1600 microg/day), however, the BUD/FF combination inhaler can be up to 156 pounds more expensive than having the same drugs in separate inhalers. In terms of the relative costs associated with taking one of the combination inhalers, at low dose (400 microg BUD or 200 microg FP/day) the cheapest combination inhaler is FP/SAL as a pressurised metered dose inhaler (pMDI) (Seretide Evohaler). However, this is only slightly cheaper than using BUD/FF as a DPI (Symbicort Turbohaler). At higher dose levels (800 microg BUD or 500 microg FP/day) FP/SAL as either pMDI aerosol (Seretide Evohaler) or a DPI (Seretide Accuhaler) is the cheapest combination product available, but again only slightly cheaper than the DPI BUD/FF combination (Symbicort Turbohaler). It should be highlighted, however, that the three head-to-head trials that compared the effects of FP/SAL with BUD/FF used the FP/SAL DPI combination inhaler, Seretide Accuhaler.
  
  
  CONCLUSIONS
  The evidence indicates that there are few consistent significant differences in effects between the five ICS licensed for use in adults and adolescents over the age of 12 years, at either low or high dose. On average, BDP products currently tend to be the cheapest ICS available and tend to remain so as the daily ICS dose required increases. There is evidence that the addition of a LABA to an ICS is potentially more clinically effective than doubling the dose of ICS alone, although consistent significant differences between the two treatment strategies are not observed for all outcome measures. The cost differences between combination therapy compared with ICS monotherapy are highly variable and dependent on the dose required and the particular preparations used. For the combination therapies of ICS/LABA there are potential cost savings with the use of combination inhalers compared with separate inhalers, with few differences between the two treatment strategies in terms of effects. The only exception to this cost saving is with BUD/FF at doses higher than 1200 microg/day, where separate inhaler devices can become equivalent to or cheaper than combination inhalers. Neither of the two combination inhalers (FP/SAL or BUD/FF) is consistently superior in terms of treatment effect. A comparison of the costs associated with each combination therapy indicates that at low dose FP/SAL delivered via a pMDI is currently the cheapest combination inhaler but only marginally cheaper than BUD/FF delivered as a DPI. At higher doses, both the FP/SAL combination inhalers (PMDI and DPI) are marginally cheaper than BUD/FF (DPI). Future trials of treatment for chronic asthma should standardise the way in which outcome measures are defined and measured, with a greater focus on patient-centred outcomes. For informing future cost-utility and cost-effectiveness analyses from a UK NHS perspective, there is a need for longitudinal studies that comprehensively track the care pathways followed when people experience asthma exacerbations of different severity. Further research synthesis, quantifying the adverse effects of the different ICS, is required for treatment choices by patients and clinicians to be fully informed.
authors.affiliation: Southampton Health Technology Assessments Centre, Wessex Institute for Health Research and Development , University of Southampton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Shepherd
authors.forename: G
authors.initials: G
authors.lastname: Rogers
authors.forename: R
authors.initials: R
authors.lastname: Anderson
authors.forename: C
authors.initials: C
authors.lastname: Main
authors.forename: J
authors.initials: J
authors.lastname: Thompson-Coon
authors.forename: D
authors.initials: D
authors.lastname: Hartwell
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: E
authors.initials: E
authors.lastname: Loveman
authors.forename: C
authors.initials: C
authors.lastname: Green
authors.forename: M
authors.initials: M
authors.lastname: Pitt
authors.forename: K
authors.initials: K
authors.lastname: Stein
authors.forename: P
authors.initials: P
authors.lastname: Harris
authors.forename: G K
authors.initials: GK
authors.lastname: Frampton
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Takeda
authors.forename: A
authors.initials: A
authors.lastname: Price
authors.forename: K
authors.initials: K
authors.lastname: Welch
authors.forename: M
authors.initials: M
authors.lastname: Somerville
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D000328:Adult; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000191:economics / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D002908:Chronic Disease; D003362:Cost-Benefit Analysis; D004359:Drug Therapy, Combination; D006801:Humans; D009330:Nebulizers and Vaporizers; D016032:Randomized Controlled Trials as Topic
chemical_list: D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents