|Cost effectiveness of fluticasone propionate plus salmeterol versus fluticasone propionate plus montelukast in the treatment of persistent asthma
|O'Connor R D, Nelson H, Borker R, Emmett A, Jhingran P, Rickard K, Dorinsky P
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
Two combination treatments for patients with persistent asthma were examined. One was fluticasone propionate (FP) 100 microg and salmeterol (SAL) 50 microg administered via a single Diskus inhaler device twice daily. The other was an alternative strategy consisting of FP 100 microg twice daily via a Diskus inhaler plus oral montelukast (MON) 10 mg once daily.
Economic study type
The study population comprised patients aged more than 15 years who had had asthma for at least 6 months and had been taking low-to-moderate doses of an ICS for at least 30 days before screening. At the time of screening, patients were required to have a forced expiratory volume in 1 second (FEV1) of between 50 and 80% of the predicted normal value, and an increase in FEV1 of at least 12% within 30 minutes of the administration of two inhalations of salbutamol (albuterol) 180 microg.
The setting was secondary care. The economic study was carried out in the USA.
Dates to which data relate
The effectiveness and resource use data were gathered in 1999 and 2000. The price year was 2001.
Source of effectiveness data
The effectiveness evidence was derived from a single study.
Link between effectiveness and cost data
The costing was carried out prospectively on the same sample of patients as that used in the clinical study.
The clinical study had been published already, thus limited information on the study design and method of sample selection was reported. Eligible patients entered a 3-week run-in period, during which their prior ICS was switched to FP inhalation powder. Only those patients who remained symptomatic during the run-in period were eligible to continue. Overall, 447 patients were identified. There were 222 patients (39% men) in the FP-SAL group and 225 patients (40% men) in the FP-MON group. The mean age of the patients was 40.2 (+/- 14.4) years in the FP-SAL group and 43 (+/- 13.7) years in the FP-MON group. The mean predicted FEV1 at baseline were 70% (FP-SAL group) and 70.8% (FP-MON group), respectively, while the percentage of baseline symptom-free days was 10.1 in both groups. It was not stated whether any power calculations were performed.
This was a prospective, randomised, double-blind, double-dummy, multi-centre study. Limited information on the number of participating centres and the method of randomisation was provided. The length of follow-up was 12 weeks. Patients visited the clinic after 1, 4, 8 and 12 weeks. No details on the loss to follow-up were given.
Analysis of effectiveness
It was not stated whether the analysis of the clinical study was conducted on an intention to treat basis. The primary outcome measures used were the proportion of patients achieving at least a 12% increase in FEV1 from baseline and the proportion of symptom-free days (SFDs) over the trial period. The proportion of patients experiencing exacerbations was also reported. At study entry, the study groups were comparable in terms of clinical and demographic factors.
The proportion of patients achieving at least a 12% increase in FEV1 from baseline (success rate) was 0.54 (95% confidence interval, CI: 0.47 - 0.61) with FP-SAL and 0.32 (95% CI: 0.26 - 0.38) with FP-MON. The difference of 0.22 (95% CI: 0.13 - 0.31) favoured the FP-SAL group.
The proportion of SFDs was 0.31 (95% CI: 0.26 - 0.35) with FP-SAL and 0.27 (95% CI: 0.23 - 0.32) with FP-MON. The difference between the groups was not statistically significant.
The proportion of patients experiencing exacerbations was 2% with FP-SAL and 6% with FP-MON, (p=0.031).
The effectiveness analysis showed that FP-SAL was more effective than FP-MON in terms of success rate (increase in FEV1). However, the two interventions were comparable in terms of SFDs.
Measure of benefits used in the economic analysis
The summary benefit measures used were the proportion of patients achieving at least a 12% increase in FEV1 from baseline and the proportion of SFDs. Both measures were derived directly from the clinical study.
Discounting was not relevant since the costs were incurred during a short timeframe. The unit costs were presented separately from the quantities of resources used. The health services included in the economic evaluation were study drugs, emergency department visits, physician office visits, rescue medication (salbutamol), adverse drug reaction (treatment of oral candidiasis) and nystatin oral suspension. All scheduled costs driven by the study protocol were not considered. Similarly, the costs of other study drugs were also not considered because the proportion of patients taking concomitant medications was comparable between the groups. The perspective of the third-party payer was adopted. Resource use was estimated on the basis of patient-level data obtained from the sample of individuals enrolled in the clinical study, using an intention to treat approach. The drug costs came from average wholesale prices, emergency department visits came from a published study, and physician visits were estimated for Current Procedural Terminology. All the costs were inflated to 2001 prices using the medical care component of the Consumer Price Index.
Statistical analysis of costs
A bootstrapping approach was used to deal with the non-normal distribution of the costs.
The indirect costs were not considered in the economic evaluation.
The bootstrap approach was used for both costs and benefits to generate CIs. Univariate sensitivity analyses were also performed to examine the impact on the cost-effectiveness ratios of changes in the definition of clinical success (varied from 10 to 15% increase in FEV1) or definition of SFDs. Two scenarios were considered for the latter: all patients who prematurely withdrew were symptom-free; all patients who prematurely withdrew were symptomatic.
Estimated benefits used in the economic analysis
See the 'Effectiveness Results' section.
The mean per patient daily cost was $3.64 (95% CI: 3.60 - 3.68) with SP-SAL and $4.64 (95% CI: 4.56 - 4.73) with FP-MON. The difference in costs reached statistical significance.
Synthesis of costs and benefits
Average and incremental cost-effectiveness ratios were calculated to combine the costs and success rate. Only the average cost-effectiveness ratios were calculated when the second benefit measure (proportion of SFDs) was used. This was despite the authors' statement that a cost-minimisation analysis was performed, owing to the lack of a statistically significant difference in the proportion of SFDs.
The average cost per successfully treated patient was $6.77 (95% CI: 5.99 - 7.66) with FP-SAL and $14.59 (95% CI: 12.12 - 17.77) with FP-MON. The incremental analysis revealed that FP-SAL dominated FP-MON, which was both less effective and more expensive.
The average cost per SFD was $11.96 (95% CI: 10.33 - 13.97) with FP-SAL and $17.10 (95% CI: 14.56 - 20.35) with FP-MON.
The bootstrap analysis showed that all replicates representing the cost per treatment success rate (increase in FEV1) laid in the second quadrant, thus showing the dominance of FP-SAL. All replicates for the incremental cost per SFD laid in the second or third quadrant, thus showing that FP-SAL was less costly than FP-MON. Moreover, FP-SAL resulted also in a greater proportion of SFDs in about 85% of replications.
The one-way sensitivity analysis showed that the base-case results were robust to any variation in the benefit measures and FP-SAL was always dominant or cost-saving.
Patients with poor asthma control who were treated with a combination of fluticasone propionate (FP) plus salmeterol (SAL) had better clinical and economic outcomes than those treated with FP plus montelukast (MON). This conclusion was supported over a range of assumptions tested in the sensitivity analysis.
CRD COMMENTARY - Selection of comparators
The selection of the comparators reflected the interventions examined in the primary clinical trial. The authors stated that both MON and SAL were agents that treated the two main components of asthma, that is, inflammation and bronchoconstriction. The dosages used were clearly reported. You should decide whether they are valid comparators in your own setting.
Validity of estimate of measure of effectiveness
The clinical evidence came from a well-conducted clinical trial, which was appropriate for the study question. The randomised allocation of the intervention and the double-blind nature of the study ensure the high internal validity of the analysis. Further, the study groups were comparable at baseline. The evidence came from several centres, which makes the study sample representative of the patient population. However, limited information on the clinical trial was reported because the study had already been published. Thus, it was not possible to assess all aspects of the design, such as the use of power calculations or the management of patients who could have been lost to follow-up.
Validity of estimate of measure of benefit
The summary benefit measures were specific to the interventions considered in the study and are not comparable with the benefits of other health care interventions. Quality of life issues were not analysed. The use of a more generalisable measure could have been useful.
Validity of estimate of costs
The cost analysis included all items relevant from the perspective adopted in the study. A justification was provided for the exclusion of some categories of costs. Extensive information on the source of the data, as well the unit costs, resource consumption and price year was provided. This enhances the possibility of replicating the analysis and reflating the results of the study in other settings and time periods. Statistical analyses of the costs were carried out, but the cost estimates were specific to the study setting.
The authors stated that their findings were consistent with those from two other published studies, the methodological differences of which were highlighted. It was also noted that much of the data were US-specific, thus caution is required when extrapolating the results of the analysis to other countries. The authors stated that variations in the outcome measures were investigated to make the results of the analysis more similar to a real-world environment rather than a controlled one (which represents a typical limitation of clinical trials). It was stressed that the current analysis represented a short-term economic evaluation of SAL versus MON, and the long-term relative cost-effectiveness of the two treatments was not examined.
Implications of the study
The study results supported the use of FP-SAL for the treatment of patients with persistent asthma. However, the authors noted that caution is required when extrapolating the results of their analysis to other settings.
Source of funding
Sponsored by a grant from GlaxoSmithKline, Research Triangle Park, NC, USA.
O'Connor R D, Nelson H, Borker R, Emmett A, Jhingran P, Rickard K, Dorinsky P. Cost effectiveness of fluticasone propionate plus salmeterol versus fluticasone propionate plus montelukast in the treatment of persistent asthma. PharmacoEconomics 2004; 22(12): 815-825
Other publications of related interest
Nelson H, Busse W, Kerwin E, et al. Fluticasone propionate/ salmeterol combination provides more effective asthma control than low-dose inhaled corticosteroid plus montelukast. Journal of Allergy and Clinical Immunology 2000;106:1088-95.
O'Connor R, O'Donnell J, Pinto L, et al. Two year retrospective economic evaluation of three dual controller therapies used in the treatment of asthma. Chest 2002;121:1028-35.
Stempel D, O'Donnell J, Meyer J. Inhaled corticosteroids plus salmeterol or montelukast: effects on resource utilization and costs. Journal of Allergy and Clinical Immunology 2002;109:433-9.
Subject indexing assigned by NLM
Acetates /administration & Administration, Inhalation; Administration, Oral; Adult; Albuterol /administration & Androstadienes /administration & Anti-Asthmatic Agents /administration & Asthma /drug therapy; Chronic Disease; Cost-Benefit Analysis; Drug Therapy, Combination; Female; Fluticasone; Humans; Male; Nebulizers and Vaporizers; Prospective Studies; Quinolines /administration & Randomized Controlled Trials as Topic; Salmeterol Xinafoate; derivatives /economics /therapeutic use; dosage /analogs & dosage /economics /therapeutic use; dosage /economics /therapeutic use; dosage /economics /therapeutic use; dosage /economics /therapeutic use
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