|Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone
|Lofdahl C G, Ericsson A, Svensson K, Andreasson E
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 study examined the combination of budesonide and formoterol (B/F) in a single inhaler for the treatment of chronic obstructive pulmonary disease (COPD). The patients received two inhalations of B/F (160/4.5 microg) twice daily.
Economic study type
The study population comprised patients aged at least 40 years who had had COPD symptoms for at least 2 years. COPD was categorised as Stage III or IV according to the GOLD criteria, patients had a forced expiratory volume in 1 second (FEV1) of no greater than 50% of predicted normal, and a history of at least one COPD exacerbation requiring medical intervention (hospitalisation and/or treatment with oral corticosteroids and/or antibacterials) in the last 2 to 12 months.
The setting was secondary care. The economic study was carried out in Sweden.
Dates to which data relate
The effectiveness and resource use data were derived from a study published in 2003. 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 effectiveness study.
There was limited information on the method of sample selection since the clinical trial had been published already. A sample of 1,022 patients was recruited. The mean age of the patients was 64 years and approximately 75% of patients in each group were male. Of those patients, 30 to 39% were current smokers with an average consumption of 39 pack years. All patients had similar lung function at enrolment (FEV1 0.98 - 1.00 L, 36% of predicted normal, reversibility 6% predicted).
This was a large, randomised, double-blind clinical trial that was carried out in Sweden. The length of follow-up was 12 months and 393 patients withdrew before the end of follow-up. During a 2-week run-in period, patients received oral prednisolone (30 mg once daily) and inhaled formoterol (4.5 microg; two inhalations) twice daily.
Analysis of effectiveness
It was unclear whether the analysis was conducted on an intention to treat basis or for treatment completers only. The primary outcome measures were the number of exacerbations requiring medical intervention, FEV1 and quality of life. Quality of life was estimated using the St. George's Respiratory Questionnaire (SGRQ). The study groups were comparable at baseline.
In terms of the number of exacerbations requiring medical intervention, the rate ratio (ratio between rate in B/F group and rate in comparison group) was:
for B/F versus placebo, 0.76 (95% confidence interval, CI: 0.60 - 0.97; p<0.05);
for B/F versus budesonide, 0.86 (95% CI: 0.68 - 1.10); and
for B/F versus formoterol, 0.75 (95% CI: 0.59 - 0.95; p>0.05).
In terms of the FEV1, the mean ratio (ratio between mean FEV1 during treatment period in B/F group and mean FEV1 during treatment period in comparison group) was:
for B/F versus placebo, 114.9 (95% CI: 110.45 - 117.84; p<0.001);
for B/F versus budesonide, 111.34 (95% CI: 107.82 - 114.97; p<0.001); and
for B/F versus formoterol, 105.36 (95% CI: 101.99 - 108.84; p>0.01).
The mean difference in the SGRQ total score (lower score indicates better health-related quality of life) was:
-7.46 (95% CI: -10.11 - -4.81; p<0.001) for B/F versus placebo;
-4.46 (95% CI: -7.11 - -1.80; p<0.01) for B/F versus budesonide; and
-3.33 (95% CI: -5.99 - -0.67; p<0.05) for B/F versus formoterol.
The clinical analysis showed that B/F was associated with significantly fewer exacerbations and better quality of life than monotherapies or placebo.
Measure of benefits used in the economic analysis
The summary benefit measure used was the expected number of exacerbations associated with each treatment. This was derived directly from the effectiveness study.
The analysis of the costs was carried out from the perspective of the Swedish health care provider. It included the costs of hospital stay (including days in the intensive care unit), visits to the emergency room, visits to a general practitioner (GP), visits to specialists, visits to a nurse, house calls by a GP or nurse, phone calls to a GP or nurse, and visits for occupational therapy. The unit costs were presented separately from the quantities of resources used. The resource use data were collected prospectively alongside the clinical trial after 1, 2, 3, 6 and 12 months of treatment. However, the analysis focused on 951 patients who had full reports on resource use. Patients were asked to keep a diary between visits to minimise recall bias. The costs were derived from Swedish unit costs using price lists and payments. Discounting was not relevant as the costs were incurred during a 12-month timeframe. The price year was 2001. The costs estimated in different years were adjusted to 2001 values using the Swedish Consumer Price Index.
Statistical analysis of costs
The costs were compared across treatments by calculating CIs and p-values. Data from patients who did not complete the full 12 months of the study were normalised to 12 months using the patient-year approach.
The indirect costs were not included, which was appropriate as they were not relevant to the perspective adopted in the analysis.
The costs were estimated in Swedish kroner (SEK) and then converted to Euros. The conversion rate in April 2003 was SEK 1 = Euro 0.11.
A sensitivity analysis was carried out to assess the robustness of cost estimates. The full sample of patients (without excluding patients with less than 15 days in the study) and sub-groups of patients, such as European patients and severely ill patients (GOLD stage IV; FEV1 </=30% of predicted normal) were used. A bootstrap analysis was also performed to estimate CIs for the cost-effectiveness ratios. Cost-effectiveness acceptability curves were then generated. These indicated how much the relevant payer would have to be willing to pay for the additional clinical effect to offset any additional cost with the most effective treatment.
Estimated benefits used in the economic analysis
See the 'Effectiveness Results' section.
The total health care costs were Euro 2,518.21 (95% CI: 1,272.76 - 3,764.06) with B/F, Euro 3,193.93 (95% CI: 1,943.26 - 4,445.01) with budesonide, Euro 3,653.25 (95% CI: 2,381.30 - 4,925.20) with formoterol, and Euro 3,212.8 (95% CI: 1,921.58 - 4,504.43) with placebo. The differences between the groups did not reach statistical significance.
Synthesis of costs and benefits
Cost-effectiveness ratios (i.e. the cost per avoided exacerbations) were calculated, but were reported graphically using cost-effectiveness planes. The bootstrap analysis showed that B/F was cost-effective in comparison with formoterol. B/F was also cost-effective over placebo if the decision-maker was willing to payer about Euro 2.00 per day per avoided exacerbation. No clear results for the comparison between B/F and budesonide were obtained since no statistically significant differences in the number of exacerbations were observed.
The combination of budesonide and formoterol (B/F) in a single inhaler, for the treatment of patients with severe chronic obstructive pulmonary disease (COPD; GOLD Stages III or IV), could be cost-effective from the health-care provider perspective in comparison with either component alone.
CRD COMMENTARY - Selection of comparators
The selection of the comparators was appropriate as widely used treatments for COPD were considered. The choice of the drugs was based on the interventions examined in the clinical trial. Dosages were reported. You should decide whether they are valid comparators in your own setting.
Validity of estimate of measure of effectiveness
The effectiveness data came from a published clinical trial, thus only limited details of the methods and design of the study were reported. In general, the use of a double-blinded, randomised clinical trial ensures a high internal validity. Further, the large sample of patients recruited and the baseline comparability of the study groups enhance the robustness of the clinical estimates.
Validity of estimate of measure of benefit
The summary benefit measure was specific to the disease considered in the study. It is not comparable with the benefits of other health care interventions.
Validity of estimate of costs
The analysis of the costs was consistent with the perspective adopted in the study. The exclusion of the indirect costs should not represent a major limitation of the analysis, as the majority of the patients enrolled in the trial were not employed. Thus, the interventions should have had no substantial impact in terms of productivity losses. Extensive information on the unit costs and quantities of resources used was provided, which means that it should be possible to replicate the analysis in other settings. The costs were estimated from typical Swedish sources. Resource use reflected treatment patterns within the trial setting and might not be generalisable to a real-world setting. However, the cost analysis was replicated in different sub-groups of patients, as well as in the whole sample of patients. Since the base-case results were confirmed, the cost estimates appear to have been robust. The price year was reported, which will facilitate reflation exercises in other time periods. Statistical analyses of the costs were carried out because of the great variance in cost estimates. The authors noted that generic budesonide was not available in Sweden, thus the potential impact of the generic drug was not analysed.
The authors stated that their study was the first economic evaluation of B/F in patients with COPD. Thus, comparisons with other studies were not possible. In terms of the generalisability of the study results to other settings, it was noted that the trial was carried out in several countries and that the Swedish costs used in the economic evaluation might be considered representative of European costs. Thus, the external validity of the study is high. The study referred to patients with COPD and this was reflected in the conclusions of the analysis.
Implications of the study
The study results supported the use of B/F in a single inhaler for the treatment of COPD. The authors stated that the current economic evaluation should be carried out in other European countries in order to corroborate the results of the study.
Source of funding
Supported by a grant from AstraZeneca.
Lofdahl C G, Ericsson A, Svensson K, Andreasson E. Cost effectiveness of budesonide/formoterol in a single inhaler for COPD compared with each monocomponent used alone. PharmacoEconomics 2005; 23(4): 365-375
Other publications of related interest
Calverley P M, Boonsawat W, Cseke Z, et al. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003;22:912-9.
Andersson F, Borg S, Jansson SA, et al. The costs of exacerbations in chronic obstructive pulmonary disease (COPD). Respir Med 2002;96:700-8.
Niederman MS, McCombs JS, Unger AN, et al. Treatment cost of acute exacerbations of chronic bronchitis. Clin Ther 1999;21:576-91.
Subject indexing assigned by NLM
Administration, Inhalation; Adult; Aged; Bronchodilator Agents /administration & Budesonide /administration & Cost-Benefit Analysis; Drug Combinations; Ethanolamines /administration & Female; Formoterol Fumarate; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive /drug therapy /physiopathology; Randomized Controlled Trials as Topic; Respiratory Function Tests; dosage /economics /therapeutic use; dosage /economics /therapeutic use; dosage /economics /therapeutic use
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Date abstract record published