J Shepherd,^1* G Rogers,² R Anderson,² C Main,² J Thompson-Coon,² D Hartwell,¹ Z Liu,² E Loveman,¹ C Green,² M Pitt,² K Stein,² P Harris,¹ GK Frampton,¹ M Smith,¹ A Takeda,¹ A Price,¹ K Welch¹ and M Somerville²

¹ Southampton Health Technology Assessments Centre (SHTAC), Wessex Institute for Health Research and Development (WIHRD), University of Southampton, UK
² Peninsula Technology Assessment Group (PenTAG), Peninsula Medical School, Universities of Exeter and Plymouth, Exeter, UK

* Corresponding author

Current asthma management

Various strategies are used in the prevention and management of asthma. Pharmacological management includes, among other drugs, inhaled corticosteroids (ICS) and short- and long-acting beta₂ agonists (SABAs/LABAs). Both ICS and LABAs are inhaled controller medications that need to be taken on a long-term daily basis for maximum symptom control. Medication delivery can be via a number of different types of inhaler device; these differ in the efficiency with which they deliver the drug to the lower respiratory tract.

There are currently five ICS available as licensed preparations for the treatment of asthma: beclometasone dipropionate (BDP), budesonide (BUD), fluticasone propionate (FP), mometasone furoate (MF) and ciclesonide (CIC). Two of the ICS are available as licensed preparations in combination with LABA: FP used in combination with salmeterol (FP/SAL), and BUD used in combination with formoterol fumarate (BUD/FF).

Objectives

The objectives of this health technology assessment are:

• to identify, appraise and synthesise, where appropriate, the current evidence base on the clinical effectiveness and cost-effectiveness of ICS alone and ICS used in combination with a LABA in the treatment of chronic asthma in adults and children aged over 12 years
• to identify the costs associated with the different treatments
• to provide estimates of cost-effectiveness, where possible, of the different treatment options.

An accompanying health technology assessment has been conducted in children aged under 12 years.

Methods

The assessment was conducted within the context of the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN) Guideline on the management of asthma.

A literature search was conducted on a number of electronic bibliographic databases (e.g. MEDLINE, Cochrane CENTRAL and EMBASE) up to February/March 2006 (and updated again in October 2006).

Only trials testing different drugs using the same inhaler device/propellant were included. Therefore trials testing, for example, BDP via a pressurised metered dose inhaler (pMDI) versus BUD via a dry powder inhaler (DPI) were excluded, as were trials testing, for example, BDP via hydrofluoroalkane (HFA)-propelled pMDI versus BUD via chlorofluorocarbon (CFC)-propelled pMDI. The scope of the review was to consider the effectiveness of the inhaled steroids, as opposed to their delivery devices. Some clinical trials were specifically designed to evaluate device effects using clinically inequivalent doses. These were therefore excluded to reduce the likelihood of confounding.

A flexible framework was used to allow different types of economic analyses and a cost comparison or a cost–consequence comparison was conducted.

Results

Clinical effectiveness review

Of 5175 reports identified through systematic literature searching, 113 reports describing 84 studies were included. Of these, 67 were fully published RCTs, seven were systematic reviews, and 10 were post-2004 conference abstracts.

The 67 trials varied considerably. While there is a comparatively large evidence base for the more established ICS (BDP, BUD, FP) compared with the newer ICS (MF and CIC), it was not possible to perform pair-wise comparisons for all the five comparators due to a lack of direct head-to-head RCTs. In many cases quantitative meta-analysis was not appropriate or feasible.

The most frequently reported relevant outcomes were lung function, symptoms, use of rescue medication and adverse events. Exacerbations and health-related quality of life were reported less frequently, and differences in the ways in which these were defined between the individual trials meant that few comparisons could be made.

Low-dose ICS versus ICS

Twenty-two RCTs were identified that compared the five ICS at low doses (400–800 μg BDP/day or equivalent). In general, all the ICS were associated with favourable changes from baseline to end-point across efficacy outcomes. Overall, there is little evidence to reject the hypothesis that there is no significant difference in clinical effectiveness between the different ICS, although a few of the trials had assessed non-inferiority between the comparators rather than superiority. A summary of results is given below:

• BDP versus BUD (five RCTs): there were few statistically significant differences between the comparators on a range of outcomes assessed across the five trials. One trial showed a significant difference in terms of morning and evening PEF in favour of BUD, but no difference in measures of forced expiratory volume in 1 second (FEV₁). A further trial showed a significant difference in favour of BDP on a measure of FEV₁. Only one trial reported on adverse events.
• FP versus BDP (six RCTs): five trials reported no statistically significant differences between FP and BDP across the outcomes assessed. One further trial showed a treatment benefit in favour of FP compared with BDP across a number of outcomes.
• FP versus BUD (five RCTs): four trials showed no statistically significant differences between FP and BUD. In a further trial, symptom measures favoured treatment with FP, but no differences on measures on lung function were observed. Meta-analysis of two trials showed BUD to be associated with significantly fewer adverse events than FP.
• CIC versus BUD (one RCT): no significant differences across measures of lung function, symptoms or exacerbation rates were observed between the comparators. Non-inferiority in terms of lung function measures was demonstrated for CIC.
• MF versus BUD (two RCTs): at a nominally equivalent dose ratio of 1:2 (MF, BUD), there was a statistically significant difference in favour of MF for the outcome of FEV₁. No significant differences were shown for the other lung function outcomes or symptoms. At a dose ratio of 1:1 there was a significant treatment benefit in favour of MF on both measures of lung function and symptoms. Adverse event rates were comparable between the two treatment arms.
• CIC versus FP (two RCTs): at nominally equivalent dose ratios of 1:1 there were no statistically significant differences between the comparators on measures of lung function, symptoms, use of rescue medication or number of exacerbations. Non-inferiority was demonstrated for lung function.
• MF versus FP (one RCT): at accepted levels of dose equivalence there were no significant differences between the comparators. At a 1:2 dose ratio (MF, FP) there were statistically significant differences in favour of FP on lung function measures and nocturnal awakenings.

No trials were identified that directly compared either BDP with MF or BDP with CIC.

High-dose ICS versus ICS

Twenty-four trials that compared ICS with ICS at high doses (800–2000 μg BDP/day or equivalent) were included. As with low-dose ICS versus ICS, there were few differences between the ICS where statistical tests had been reported. Again, some of the trials had assessed non-inferiority between the comparators. A summary of results is given below:

• BDP versus BUD (two RCTs): there were no statistically significant differences between the comparators on measures of lung function. The only statistically significant difference was for the number of exacerbations in favour of BUD.
• FP versus BDP (10 RCTs): in seven trials there were no statistically significant differences between the comparators on any of the outcome measures assessed. One trial showed significant differences in favour of FP for lung function measures and the number of exacerbations. No significant differences were observed for symptom measures. Treatment with FP was favoured in one trial for the outcome of HRQoL, whereas symptom scores were significantly lower with BDP treatment in another. There were no further significant differences, however, on any other outcome measure assessed. Across the 10 trials adverse event rates were comparable.
• HFA BDP versus HFA FP (one RCT): no statistically significant differences on measures of lung function and symptoms were shown. Non-inferiority was demonstrated for lung function measures in an intention-to-treat analysis, but not in a per-protocol analysis.
• FP versus BUD (six RCTs): there was a treatment benefit in favour of FP on some measures of lung function in two trials. Four trials showed no statistically significant differences between the comparators across a range of different outcomes. A meta-analysis of three trials showed no significant differences in the number of adverse events.
• MF versus BUD (one RCT): a treatment benefit in favour of MF on a measure of FEV₁ was observed. There were no further significant differences between the comparators.
• CIC versus FP (three RCTs): data are commercial in confidence.
• MF versus FP (one RCT): there were no statistically significant differences on any outcome measure between the two comparators.

No trials were identified that directly compared either BDP with either MF or CIC, BUD with CIC or MF with CIC.

ICS versus ICS/LABA

Ten RCTs evaluated the effectiveness of combination ICS/LABA therapy (FP/SAL or BUD/FF) versus a higher dose of ICS alone. Half of the trials used the FP/SAL combination inhaler and the other half used the BUD/FF combination inhaler. ICS doses, when used in combination with LABAs, varied from 200 to 800 μg/day for BUD and from 200 to 500 μg/day for FP. When used alone the ICS doses varied from 400 to 1600 μg/day for BUD and from 500 to 1000 μg/day for FP. Overall, the ICS dose when used alone was at approximately double the accepted clinically equivalent dose that was used in the combination with the LABA.

The general findings indicated a significant treatment benefit for combination therapy across a range of outcomes compared with ICS alone, when the ICS was double the accepted clinically equivalent dose of the ICS in the combination inhaler. This applied to both of the combination inhalers. However, it should be highlighted that these findings are only applicable to DPIs.

An additional nine trials assessed the effects of adding a LABA to a similar dose of ICS in each of the trial arms. Six evaluated the FP/SAL combination and three the BUD/FF combination. In all the trials a similar ICS dose was used in both arms. The results showed that ICS/LABA combination therapy was statistically superior to ICS alone across most of the outcomes.

ICS/LABA versus ICS/LABA

FP/SAL combination inhaler and BUD/FF combination inhaler each compared with their constituent drugs delivered in separate inhalers were assessed in three and two RCTs, respectively. An additional trial compared the FP/SAL combination inhaler against BUD + FF in separate inhalers. The ICS doses were similar in both treatment modalities, and ranged from 200 to 1000 μg/day for FP and 800 μg for BUD. There were very few statistically significant differences between the treatments across the various efficacy outcomes and the rate of adverse events. Non-inferiority was demonstrated for some outcomes. Meta-analysis of adverse events showed no statistically significant differences between combination versus separate inhaler therapy.

Three RCTs evaluated the combination inhalers versus each other. Daily ICS doses were 800 μg for BUD and 500 μg for FP. All were delivered via a DPI rather than a pMDI. The results were mixed, with the FP/SAL combination significantly superior on some outcomes and the BUD/FF combination superior on others. Meta-analysis showed that there were no significant differences between the two treatments in the rate of adverse events.

Economic analyses

Low-dose ICS versus ICS

At doses of 400 μg/day, BDP–CFC-propelled devices appear to be the current cheapest ICS, and remain so but at a higher annual cost if CFC-propelled products are excluded from the analysis. Excluding CFC-propelled products at this dose level diminishes the overall cost differences between the five ICS, with CIC products only marginally more expensive than BDP–CFC-free devices. At this dose FP and MF are consistently the two most expensive drugs, at almost two to three times the annual cost of taking BDP.

At the maximum low dose of 800 μg/day, BDP–CFC-propelled products remain the cheapest available. At these doses, if CFC-propelled products are excluded then FP products can be on average the cheapest ICS product available if the mean is weighted by market share. On the whole, when only CFC-free products are considered, the mean annual cost of both BUD and BDP increases. For FP, CIC and MF there are currently no CFC-propelled products available, therefore their costs remain constant. However, the use of weighted averages to represent the cost associated with each ICS tends to conceal the wide variations in costs.

High-dose ICS versus ICS

At a dose level of 1500–1600 μg/day, BDP–CFC-propelled products appear to be the current cheapest ICS available, and remain so if CFC-propelled products are excluded from the analysis. Excluding CFC-propelled products and using current prices cause a substantial increase in the weighted mean annual cost of taking BDP at this dose level. On average, BUD (only available as one preparation at this high dose level) is the most expensive ICS drug, whether CFC-containing products are excluded or not.

ICS versus ICS/LABA

Based on the nine included trials, 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 cheaper to £109 more expensive than the alternative of BUD at a higher dose. The BUD/FF combination varied from being £163 cheaper to £66 more expensive than the higher dose of either BUD or FP.

ICS/LABA versus ICS/LABA

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 μg/day), however, the BUD/FF combination inhaler can be up to £156 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 μg BUD or 200 μg FP/day) the cheapest combination inhaler is FP/SAL as a pMDI (Seretide Evohaler). However, this is only slightly cheaper than using BUD/FF as a DPI (Symbicort Turbohaler). At higher dose levels (800 μg BUD or 500 μg 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. The relative effectiveness of the Seretide Evohaler as a pMDI compared with the Symbicort Turbohaler can therefore not be commented on.

Conclusions

The evidence reviewed 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 at starting doses and to remain so as the daily ICS dose required increases. The exclusion of CFC-propelled products may increase the mean annual cost of both BDP and BUD, but should have no effect on the cost of MF, FP or CIC, as all products for these drugs are CFC-free. The higher cost of BUD and BDP may decrease the overall cost differences between the ICS comparators. However, it should be noted that although the use of weighted averages to calculate these costs can provide a useful way of representing the major differences between the drugs, these often conceal the wide variations in the costs of individual products containing each drug. These costs will also inevitably be sensitive to year-on-year shifts in the market share or price of individual products.

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 and 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 μg/day, where separate inhaler devices can become equivalent to or cheaper than combination inhalers. The evidence regarding the relative effects of the two combination inhalers available is mixed. 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. However, this is 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).

Recommendations for further research

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 such as HRQoL and symptoms. There is also 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.

Publication

Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al. 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. Health Technol Assess 2008;12(19).

NIHR Health Technology Assessment Programme

The Health Technology Assessment (HTA) Programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.

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The research reported in this issue of the journal was commissioned and funded by the HTA Programme on behalf of NICE as project number 04/30/01. The protocol was agreed in April 2006. The assessment report began editorial review in April 2007 and was accepted for publication in July 2007. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

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