|Cost-effectiveness of fluticasone propionate in the treatment of chronic obstructive pulmonary disease: a double-blind randomized, placebo-controlled trial
|Ayres J G, Price M J, Efthimiou J
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.
The use of fluticasone propionate (FP; 2 puffs of 250 microg twice daily), added to regular bronchodilator therapy for the treatment of chronic obstructive pulmonary disease (COPD).
Economic study type
The study population comprised patient with moderate-to-severe COPD. The inclusion criteria were:
current or ex-smokers;
a history of at least one COPD exacerbation each year in the last3 years that required a doctor or visit to the hospital;
high expectation of a COPD exacerbation during the study;
regular productive cough;
predicted forced expiratory volume in 1 second (FEV1) of 35 to 90%;
FEV1 to forced vital capacity ratio of 70% or less; and
FEV1 reversal of less than 15% from baseline after the inhalation of salbutamol (400 or 800 microg).
Patients were excluded if they had an abnormal chest radiograph, or had received oral or depot corticosteroids, inhaled corticosteroids (at least 500 microg/day) or antibiotic therapy. Also excluded were those who had been admitted to hospital in the last 4 weeks, or were currently taking FP. Patients with a history of asthma were also excluded.
The setting was primary care. The economic study was conducted in the UK.
Dates to which data relate
The dates which the effectiveness and resource use data were gathered was not reported. The price year was 1998.
Source of effectiveness data
The effectiveness evidence was derived from a single study, the results of which had been published elsewhere (Paggiaro et al., see Other Publications of Related Interest).
Link between effectiveness and cost data
The costing was conducted prospectively on the same sample of patients as that used in the effectiveness study.
The use of power calculations was not reported. After a 2-week run-in period during which inhaled corticosteroids therapy was stopped, those who were asymptomatic on at least 4 days were considered eligible. Of the 365 patients initially identified, 84 withdrew before group allocation. Thus, 281 patients participated in the study. There were 142 patients in the FP group and 139 in the placebo group. The patients in the FP group had a mean age of 62 year (age range: 49 - 75) and 70% were men. The patients in the placebo group had a mean age of 64 years (age range: 50 - 75) and 78% were men.
This was a prospective, double-blind, randomised, parallel-group, placebo-controlled trial, which was conducted in several international centres. The methods of randomisation and blinding were not described. The length of follow-up was 6 months. The outcomes were assessed at baseline and at weeks 4, 8, 16 and 24. Twenty-seven patients in the placebo group and 19 in the FP group withdrew, mainly due to adverse events.
Analysis of effectiveness
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 an improvement of at least 10% in FEV1 from baseline by the end of treatment (success rate), and the proportion of patients remaining free of exacerbation over the 6 months of treatment. Other measures were symptom scores for median daily cough and sputum volume, and safety profile. The study groups were comparable at baseline in terms of the demographic and clinical characteristics.
There were 76 exacerbations in the FP group and 111 in the placebo group.
Sixty per cent of the FP group and 86% of the placebo group had at least one moderate or severe exacerbation, (p<0.001).
Thirty-two per cent of the FP group and 19% of the placebo group achieved at least a 10% improvement in FEV1 from baseline by the end of treatment, (p<0.02).
Sixty-three per cent of the FP group and 58% of the placebo group remained free of exacerbation over the 6 months of treatment, (p=0.32).
Seventy-five per cent of the FP group and 63% of the placebo group remained free of moderate or severe exacerbation, (p=0.02).
The symptom scores for median daily cough and sputum volume were significantly lower with FP.
Both treatments were well tolerated.
The effectiveness study showed that FP was more effective than placebo in improving lung function and reducing moderate-to-severe exacerbations.
Measure of benefits used in the economic analysis
The summary benefit measures used were the proportion of patients achieving an improvement of at least 10% in FEV1, the proportion of exacerbation-free patients, and the proportion of moderate or severe exacerbation-free patients. All measures were derived from the effectiveness analysis.
Discounting was not relevant since the costs were incurred during a 6-month period. The quantities of resources used were reported, but the unit costs were not. A breakdown of the cost items was presented. The health services included in the economic evaluation were medications (FP, rescue medication and COPD-related drugs), hospital resources and general practitioner (GP) contacts at the clinic or at home. The hospital resources covered accident and emergency visits, inpatient stay, outpatient visits and intensive care unit stay. The cost/resource boundary of the study was that of the NHS. Resource use was derived from actual data estimated alongside the clinical trial. The costs were derived from published NHS sources. The price year was 1998.
Statistical analysis of costs
The costs were presented as mean (+/- standard deviation, SD) and median values. Confidence intervals (CIs) for the difference in mean costs were also estimated.
The indirect costs (i.e. productivity losses or absence from usual activities) were included in the analysis as a societal perspective was also adopted. Days of work lost were estimated from the sample of patients involved in the effectiveness trial. The costs were derived from age- and gender-adjusted average wage rates. The unit costs were not reported, but the quantities of resources used were. No discounting was applied and the price year was 1998.
Sensitivity analyses were conducted to assess the robustness of the estimated incremental cost-effectiveness ratios (ICERs) to variations in base-case assumptions. For the end point based on improvement in FEV1, the criterion for success was varied from >/= 5% to >/= 15%. For the proportion of exacerbation-free patients, best-case (patients who prematurely withdrew remained exacerbation-free for the remainder of the study) and worst-case (all patients who prematurely withdrew experienced an exacerbation) scenarios were considered. Bootstrapped 95% CIs were calculated around the ICERs.
Estimated benefits used in the economic analysis
See the 'Effectiveness Results' section.
The mean daily costs from the NHS perspective were 2.72 (SD=9.22; median 0.86; range: 0.86 - 80.25) in the placebo group and 2.75 (SD=4.35; median 2.11; range: 2.11 - 51.16) in the FP group.
The mean difference was 0.03 (range: -1.72 - 1.54).
The mean (SD; median; range) daily costs from the societal perspective were 4.06 (SD=11.75; median 0.86; range: 0.86 - 86.45) in the placebo group and 3.65 (SD=6.24; median 2.11; range: 2.11 - 59.06) in the FP group.
The mean difference was -0.42 (range: -2.7 - 1.62).
Therefore, the extra costs of adding FP to regular bronchodilator therapy were offset by fewer non-drug health care costs.
Synthesis of costs and benefits
ICERs were calculated to combine the costs and the three benefit measures.
>From the NHS perspective:
the incremental cost per additional patient achieving a >/= 10% improvement in FEV1 with FP over placebo was 0.25 (95% bootstrap CI: -18.6 - 12.27);
the incremental cost per additional exacerbation-free patient with FP over placebo was 0.54 (95% bootstrap CI: -87.08 - -12.09); and
the incremental cost per additional moderate or severe exacerbation-free patient with FP over placebo was 0.25 (95% bootstrap CI: -16.52 - 41.15).
>From the societal perspective:
the incremental cost per additional patient achieving a >/= 10% improvement in FEV1 with FP over placebo was -3.39 (95% bootstrap CI: -28.90 - 12.88);
the incremental cost per additional exacerbation-free patient with FP over placebo was -7.19 (95% bootstrap CI: -118.24 - -18.11); and
the incremental cost per additional moderate or severe exacerbation-free patient with FP over placebo was -3.28 (95% bootstrap CI: -26.67 - 45.23).
The cost-effectiveness acceptability curve showed that, if decision-makers were willing to pay an additional 5.00 per day to improve the FEV1 by at least 10%, from an NHS perspective, FP was cost-effective for more than 80% of the time. From a societal perspective, FP was more effective and less costly 68% of the time.
If decision-makers were willing to pay an additional 15.00 per day per additional moderate or severe exacerbation-free patient, from an NHS perspective, FP was cost-effective for more than 90% of the time. From a societal perspective, FP was more effective and less costly more than 60% of the time.
The variations conducted in the sensitivity analysis did not substantially change the base-case conclusions.
Fluticasone propionate (FP) added to regular bronchodilator therapy led to improvements in lung function and reductions in the number of severe-to-moderate exacerbations, without increasing health care and societal costs. Therefore, FP should be considered a cost-effective strategy.
CRD COMMENTARY - Selection of comparators
The rationale for the choice of the comparator was clear. Regular bronchodilator therapy represents the standard treatment for patients with COPD. You should decide whether this is a valid comparator in your own setting.
Validity of estimate of measure of effectiveness
The analysis of effectiveness was based on a well-conducted clinical trial, which was appropriate for the study question. Limited information on the methods and design was provided since the main results had been published elsewhere. Randomisation, double-blind nature, intention to treat analysis, multi-centre and international design, and baseline comparability between the study groups, ensured the internal validity of the analysis. The authors noted that a longer follow-up would have been required to better assess the long-term impact of the intervention under evaluation.
Validity of estimate of measure of benefit
The benefit measures were derived directly from the effectiveness analysis and are commonly used measures for COPD patients. However, they were specific to the intervention considered in the study and it would be difficult to compare them with the benefits of other health care interventions. The use of a more transferable measure would have been helpful. Evidence on health status was not available, thus the calculation of quality-adjusted survival was not feasible.
Validity of estimate of costs
Two distinct perspectives were adopted in the analysis. As such, it appears that all the relevant categories of costs have been considered. All results for each perspective were reported. The quantities of resources used were reported, as was the price year. This enhances the possibility of replicating the study and of conducting reflation exercises in other settings. The source of the data was reported, although the unit costs were not presented. A detailed breakdown of the cost items was provided. CIs were estimated to assess cost-differences. However, the cost estimates were specific to the study setting and sensitivity analyses were not conducted to address variability in the data. Wide SDs were observed, reflecting a skewed distribution of the costs. As the authors noted, it was unclear whether the economic study was powered sufficiently to detect statistically significant differences in the cost estimates.
The authors compared their findings with those of a published study, finding that similar conclusions were reached, although a population with more severe disease than the one included in the current study was considered. The issue of the generalisability of the study results to other settings was not explicitly addressed and few sensitivity analyses were conducted. Therefore, caution is required when extrapolating the results of the analysis to other settings. The study involved patients with clearly defined, non-asthmatic COPD and this was reflected in the authors' conclusions. The authors noted some limitations of their analysis, which have been reported already in the relevant fields.
Implications of the study
The study results suggested that there is both a clinical and an economic rationale for using inhaled corticosteroids in COPD patients for at least 6 months. However, the authors pointed out that the clinical benefits of FP could be reduced in less severe patients.
Source of funding
Funded by GlaxoSmithKline Plc.
Ayres J G, Price M J, Efthimiou J. Cost-effectiveness of fluticasone propionate in the treatment of chronic obstructive pulmonary disease: a double-blind randomized, placebo-controlled trial. Respiratory Medicine 2003; 97(3): 212-220
Other publications of related interest
Paggiaro PL, Dahle R, Bakran I, et al. Multicentre randomised placebo-controlled trial of inhaled fluticasone propionate in patients with chronic obstructive pulmonary disease. Lancet 1998;351:773-80.
van den Boom G, Rutten van Molken MP, Molema J, et al. The cost-effectiveness of early treatment with fluticasone propionate 250 microg twice a day in subjects with obstructive airway disease. Results of the DIMCA Program. American Journal of Respiratory and Critical Care Medicine 2001;164:2057-66.
Subject indexing assigned by NLM
Aged; Androstadienes /economics /therapeutic use; Bronchodilator Agents /economics /therapeutic use; Cost-Benefit Analysis; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume /drug effects; Health Care Costs; Health Expenditures; Health Resources /utilization; Humans; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive /drug therapy /economics /physiopathology; Treatment Outcome; Vital Capacity /drug effects
Date bibliographic record published
Date abstract record published