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* From the Copenhagen University Hospital (Dr. Bisgaard), Rigshospitalet, Copenhagen, Denmark; Global Health Outcomes (Dr. Price), Glaxo Wellcome Research and Development, Middlesex, UK; Respiratory Therapeutic Development (Ms. Maden), Glaxo Wellcome Research and Development, Uxbridge, UK; and Glaxo Wellcome (Mr. Olsen), Brondby, Denmark.
Correspondence to: Hans Bisgaard, MD, Professor of Paediatrics, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark; e-mail: Bisgaard{at}copsac.dk
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: A retrospective economic analysis conducted from the perspective of the Danish health-care system, based on clinical data from a 12-week study.
Setting: Thirty-three outpatient centers in nine countries.
Patients: Two hundred thirty-seven children aged 12 to 47 months with documented history of recurrent wheeze or asthma symptoms.
Interventions: Two dosages of FP, 100 µg/d and 200 µg/d, and placebo administered in two divided doses via a metered-dose inhaler and a Babyhaler (Glaxo Wellcome; Middlesex, UK) spacer device.
Measurements: Effectiveness in terms of asthma exacerbations, control of cough and wheeze symptoms, symptom-free days, overall direct costs of asthma management in Danish kroner at 1999 prices, and mean and incremental cost-effectiveness ratios.
Results: FP, 200 µg/d,
was significantly more effective than placebo treatment in terms of the
proportion of exacerbation-free patients (73.7% vs 59.8%;
p = 0.025) and patients experiencing a 
25% improvement in cough
symptoms (57.9% vs 39.0%; p = 0.018). The costs per
exacerbation-free patient, per patient with a 25% improvement in
cough and wheeze symptoms from baseline, and per symptom-free day were
lower in the FP groups than in the placebo group. The incremental
cost-effectiveness ratios for these end points indicated that the
additional benefits of FP, 200 µg/d, were achieved at a lower overall
cost compared with placebo treatment.
Conclusions: From the perspective of the Danish health-care system, FP, 100 µg bid, administered via the Babyhaler inhalation device was cost-effective relative to standard therapy with bronchodilators alone.
Key Words: asthma • cost effectiveness • fluticasone propionate • preschool children
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A randomized, placebo-controlled trial evaluated the efficacy and tolerability of fluticasone propionate (FP) [Flixotide; Glaxo Wellcome; Middlesex, UK] administered via a metered-dose inhaler using the Babyhaler (Glaxo Wellcome) spacer device in children aged 12 to 47 months.11 FP, 200 µg/d, produced improvements in terms of asthma exacerbations, symptoms, and parental satisfaction with treatment, providing support for the use of inhaled corticosteroid therapy in young children.
When considering whether to prescribe a new treatment, it is important to identify whether it is an efficient use of health-care resources. This is accomplished by evaluating net changes in both costs and outcomes through economic evaluation. This is particularly important in pediatric asthma because the burden of this condition on the patient, caregiver, and health-care system is high. Childhood asthma can have a profound effect not only on the child but also on the parents/caregivers in terms of distressing respiratory symptoms, sleep disturbance, inability to undertake normal play or social activities, and time lost from school or work.14 In addition to negative effects on quality of life, childhood asthma can be associated with substantial economic costs.15 16 Furthermore, Smith et al15 estimated that preschool asthma accounted for 369,000 bed days in the United States annually, and the associated cost to care for these children was $18.5 million (US dollars); the direct costs of medication and hospitalization in this age group were estimated at $48.1 million and $586.2 million, respectively. The costs for medication and hospitalization represented 6.1% and 74.1% of the total direct costs, respectively. This contrasts with the asthma population as a whole, for which hospital costs typically represent a smaller proportion of overall direct costs than medication costs (20 to 25% and 37%, respectively).17
Improving asthma control through effective intervention is desirable from both clinical and economic viewpoints. In Denmark, the rate of hospital admissions for pediatric asthma remained relatively constant between 1978 and 1993, despite a general increase in asthma prevalence.18 Importantly, during this period, the risk of hospital readmission fell by about one half. These data coincided with an improvement in the treatment of pediatric asthma in Denmark, as a result of the increased emphasis on early treatment with anti-inflammatory drugs.
In light of the burden of pediatric asthma, it is important to assess whether treatment interventions can reduce health-care resource utilization and improve clinical outcomes. The purpose of the present analysis was to evaluate whether adding the inhaled corticosteroid FP to the treatment of asthma in preschool children is a cost-effective treatment intervention.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Salbutamol was used throughout the study as relief medication. Children could continue to receive any regular medication, including sodium cromoglycate, ketotifen, and/or antihistamines throughout the trial, provided the dose remained constant. Inhaled or systemic corticosteroids, anticholinergic medications, nedocromil sodium, ß2-agonists (other than salbutamol rescue medication) and methylxanthines were not permitted during the trial, unless used for the management of an asthma exacerbation.
Patients were assessed for adverse events, asthma exacerbations, and treatment compliance every 3 weeks during the 12-week treatment period. Parents kept daily diary records of their child’s symptoms, recording daytime and nighttime scores for wheeze, cough, and shortness of breath on a scale of 0 to 3. Parents were also asked to record daytime and nighttime use of rescue salbutamol and the number of occasions they were awoken at night because of their child’s asthma symptoms. Patients were withdrawn from the study if more than one exacerbation occurred that required additional treatment with oral or inhaled corticosteroids, or if symptoms became unacceptable or poorly controlled despite backup medication (short course of oral or inhaled corticosteroids).
The study was conducted in accordance with good clinical practice and the Declaration of Helsinki, and was approved by the local ethics committee at each center. Written informed consent to participate in the study was obtained from the parent/guardian of each patient.
Clinical Effectiveness
A number of outcome measures were used to determine treatment
effectiveness for the purpose of the economic analysis. These included
the proportion of patients remaining free of asthma exacerbations
throughout the study, improvement in cough and wheeze symptoms, and
symptom-free days.
An asthma exacerbation was defined as a worsening of the child’s asthma symptoms that required either a change in medication (other than relief salbutamol) and/or required the parents to contact their general practitioner or the investigator. The proportions of patients who either experienced an exacerbation, or remained free of exacerbations throughout the trial were calculated for each treatment arm. Patients who withdrew prematurely from the study for reasons other than an asthma exacerbation, and who had not previously experienced an asthma exacerbation, were excluded from the analysis. This was because it was impossible to predict whether or not the patient would have had an exacerbation if they had remained in the trial.
The proportion of patients achieving a 25% improvement in the
median frequency of cough-free and wheeze-free days compared to
baseline was determined. For patients who withdrew early from the
study, the percentage of cough-free and wheeze-free days was calculated
from the number of days they were in the study. A symptom-free day was
defined as a 24-h period during which the patient reported no daytime
or nighttime symptoms (score of 0 for cough, wheeze, and shortness of
breath during the day and night).
Patients withdrawn from the study were assumed to have experienced no symptom-free days from the time of withdrawal until the end of the study if withdrawn due to asthma-related adverse events or lack of efficacy. Patients withdrawn for other reasons (eg, unavailable for follow-up or unrelated adverse events) were assumed to have symptom-free days at the mean rate equivalent to the treatment arm as a whole.
Evaluation of Costs of Asthma Management
The economic analysis was conducted from the perspective of the
Danish health-care system. Calculation of the direct costs of asthma
management were based on resources consumed by patients in the
intent-to-treat population during the 12-week treatment phase of the
study. Information on asthma-related direct health-care resource use
was collected during the study using serious adverse event forms,
concurrent medications forms, exacerbation data, and daily diary card
data.
The following resource use data were collected and included in the cost analysis: hospital contacts (emergency department visits, inpatient hospital days), general practitioner contacts, the cost of the Babyhaler device (included in the FP treatment arms only and not the placebo arm) and medications (study drugs, rescue medications, concurrent prescription drugs related to the treatment of asthma, asthma exacerbations, or treatment of adverse effects). All visits included in the cost analysis were "unscheduled." Therefore, health-care contacts related to the study protocol and routine clinic visits associated with regular asthma management were excluded from the cost analysis.
Unit costs of health-care services were derived from published sources and quoted at 1999 prices in Danish kroner (DK).19 20 21 Daily costs of medications were calculated using the cost to the pharmacist. Mean direct asthma treatment costs were calculated for all patients in each treatment arm. When patients were withdrawn from the study, they were assigned a constant mean daily cost following withdrawal (ie, the mean daily cost for the treatment arm during the study period). For ease of interpretation, key cost data have been converted into approximate dollar and pound values as of November 1999 exchange rates.
Economic Analysis
The mean cost-effectiveness ratio provides an indication of the
average cost of achieving a given outcome with each treatment. This was
calculated by dividing the mean daily direct cost by the rate of
success for each treatment (eg, exacerbation-free patients,
improvement in wheeze and cough symptoms, and symptom-free days). For
example, for exacerbation-free patients, the mean cost-effectiveness
ratio was calculated by dividing the mean daily direct cost by the
proportion of exacerbation-free patients at the end of treatment.
Incremental cost-effectiveness ratios (ICERs) were calculated by
dividing the difference in the mean daily direct health-care costs
between the treatment groups by the difference in the rate of success
for each treatment. ICERs evaluate the net change in both cost and
effectiveness between treatments and calculate additional expenditure
required to achieve additional health gains with a treatment relative
to the comparator. This produces a better understanding of the true
value of a new treatment, and so ICERs are more meaningful to
health-care decision makers than mean cost-effectiveness ratios as they
more accurately reflect the types of treatment decisions that must be
undertaken in the real world.
Statistical Analysis
Data from the intent-to-treat population were used in the
statistical analysis. Between-treatment differences in the
effectiveness parameters were calculated using the van Elteren
extension to the Wilcoxon rank sum test. Statistical tests were two
sided, and all treatment comparisons were pairwise comparisons. For
analyses, p < 0.05 was considered to be significant. Confidence
intervals for the ICERs were calculated using a nonparametric
"bootstrap" method.22
To achieve this, 1,000 bootstrap
resamples of the original cost/effect pairs were generated by taking a
random sample from each treatment arm with replacement from the
original data, and the ICERs were calculated for all the bootstrap
resamples. The 95% confidence intervals (CIs) were calculated by
ranking the bootstrap resamples from least cost-effective to most
cost-effective and selecting the values corresponding to the 26th and
975th points.
Sensitivity Analysis
A range of sensitivity analyses was used to test underlying
assumptions in the economic analysis. For exacerbation-free patients,
the impact of differences in effectiveness between the treatment arms
was assessed using two scenarios for patients withdrawn from the study
(for reasons other than an asthma exacerbation). The first scenario
assumed that these patients had not experienced an exacerbation
(classified as an exacerbation-free patient), and the second scenario
assumed that these patients had experienced an exacerbation. Such an
analysis helps to establish the limits that assumptions regarding
patient withdrawals will have on the final results. Similarly, the
sensitivity analysis for symptom-free days was performed using two
scenarios. The first assumed that all days subsequent to premature
withdrawal from the study were symptom free; the second assumed that
all days subsequent to premature withdrawal were not symptom free. For
improvement in cough and wheeze, a sensitivity analysis was conducted
by redefining the percentage improvement to 50% and 75% (the
base-case analysis was 25%).
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Clinical Effectiveness
The proportion of exacerbation-free patients was significantly
higher in the FP, 200 µg/d, group than in the placebo-treated group
(p = 0.025), as was the proportion of patients with a 25%
improvement in cough symptoms (p = 0.018; Fig 1
). The proportion of patients with a 25% improvement in wheeze
symptoms and the proportion of symptom-free days also favored the FP,
200 µg/d, group, but did not reach statistical significance compared
with placebo treatment. Although there were trends in favor of FP, 100
µg/d, over placebo treatment for three of the effectiveness end
points (exacerbations, cough and wheeze), none of the differences
reached the threshold for statistical significance (Fig 1)
. There were
no significant differences in effectiveness end points between the two
FP groups, although there were trends in favor of the higher dose (200
µg/d).
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1.17 DK), 14.39 DK ($1.80 [US];
1.22 DK), and 20.81 DK ($2.60 [US]; 1.76 DK) in the FP, 100
µg/d; FP, 200 µg/d; and placebo groups, respectively. Although
medication costs were higher in the FP arms than in the placebo-treated
group, these costs were more than offset by lower costs for hospital
contacts and general practitioner visits in the active treatment arms.
Overall costs were slightly higher in the FP, 200 µg/d, group than in
the FP, 100 µg/d, group. This was due to higher study drug costs with
the higher FP dose.
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25%
improvement in cough or wheeze symptoms, and per symptom-free day were
consistently lower for both FP dosages (100 µg/d and 200 µg/d) than
for placebo (Table 3
), indicating that clinical benefits with FP were consistently achieved
at lower mean costs than with placebo (Table 3)
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While there were no statistically significant differences between the FP-treatment groups with respect to exacerbations, improvement in cough/wheeze, and symptom-free days, it is clear that from an economic perspective, FP, 200 µg/d, is more cost-effective than FP, 100 µg/d. Although asthma management costs with FP, 100 µg/d, were lower than with placebo treatment and similar to FP, 200 µg/d, there were no significant differences in treatment effectiveness relative to placebo, and so the net health gains demonstrated with the higher dose were not realized with the lower dose. This result is consistent with the clinical findings.11
Sensitivity Analysis
The data obtained were robust to changes in underlying assumptions
across a range of sensitivity analyses. Effectiveness results for the
proportion of exacerbation-free patients remained similar to the
base-case scenario (patients withdrawn for reasons other than an asthma
exacerbation were excluded from the analysis) when patients who were
prematurely withdrawn were assumed to be exacerbation-free or to have
had an exacerbation (Table 4
). Similarly, effectiveness results remained consistently in favor of
FP, 200 µg/d, vs placebo treatment when the proportion of patients
achieving a 50% improvement in cough symptoms and wheeze symptoms
was calculated. The differences between the three treatment groups
became smaller when the proportions of patients achieving a 75%
improvement in wheeze and cough symptoms were determined, owing to a
diminished number of patients achieving this level of improvement
(Table 4)
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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25% improvement in the
frequency of asthma cough symptoms. There were no significant
improvements in effectiveness in the FP, 100 µg/d (50 µg bid),
group compared with the placebo group, although the overall costs of
treatment were still lower than in the placebo arm. In both FP groups,
health-care resource utilization was lower than that in the placebo
arm, both in terms of primary care and secondary care contacts. In this study, the incremental cost-effectiveness analysis showed that FP, 200 µg/d, resulted in improved asthma control in terms of cough and incidence of exacerbations and was cost-saving relative to placebo treatment (plus treatment with a short-acting ß2-agonist when required). The study did not differentiate explicitly between the two doses, and this was not the primary objective of the economic evaluation. The primary objective was to assess whether adding FP to the treatment of asthma patients aged 12 to 47 months receiving rescue salbutamol and controller medications (regular sodium cromoglycate, ketotifen, and/or antihistamines) is cost-effective. A secondary objective was to evaluate which dose was most cost-effective, although the primary clinical analysis had already demonstrated that FP, 200 µg/d, is more effective than FP, 100 µg/d.11 The economic analysis supports this finding, with FP, 200 µg/d, demonstrating cost reductions and improved effectiveness. The lack of improved effectiveness with FP, 100 µg/d, despite lower costs indicates that this dose is less cost-effective.
Improvements in the diagnosis of asthma in preschool children and a
better understanding of which patients most benefit from inhaled
corticosteroid therapy could produce even greater economic benefits
with FP. One study23
reported that children with frequent
asthma symptoms (symptoms on 3 days per week or 21 days of
symptoms over a 4-week period) and those with a family history of
asthma showed a greater response to treatment with FP, 200 µg/d,
compared with placebo than children with less frequent symptoms or no
family history of asthma, in terms of a greater increase in
symptom-free days and a greater reduction in exacerbations. Future
studies should attempt to characterize those patients who are more
likely to respond to treatment. It is possible that pharmacogenetics
will enable us to predict which patients are most likely to respond to
inhaled corticosteroid therapy.
Because all patients could continue receiving their regular asthma treatment(s), this study demonstrates that adding an inhaled corticosteroid to existing asthma therapy is a cost-effective strategy in preschool children, relative to their usual controller medication alone. This study also illustrates the very high burden of asthma in this age group. During this 12-week study, there were nine hospitalizations, 6 emergency department visits, and 66 unscheduled primary-care visits as a result of the children’s asthma. This emphasizes the importance of focusing on reducing asthma exacerbations in children from a health-care system perspective, as well as taking into account the impact of such events on the quality of life of the patients and their families.
There have been few economic analyses of asthma treatments in preschool children. Connett et al24 concluded that budesonide was cost-effective in terms of improvement in asthma symptom control in children aged 1 to 3 years, although with only 40 subjects, the study was relatively small. Similar findings were also reported in another study in older children (aged 7 to 16 years) in which treatment with an inhaled corticosteroid plus bronchodilator resulted in lower overall costs and better clinical outcomes than treatment with a bronchodilator alone.25 Both of these studies demonstrate that inhaled corticosteroid therapy improves outcomes and reduces asthma management costs in children. These findings are consistent with those from the current study, which represents the first large-scale economic evaluation of inhaled corticosteroids in this age group.
There are a number of limitations to this study that need to be considered. The clinical study on which the economic analysis was based was of short duration, which may underestimate the true long-term economic consequences of poor asthma control. In particular, the cost of hospitalization, a rare but expensive event, may have been underestimated. Furthermore, this was a retrospective analysis and patients were not followed up after premature withdrawal from the study, so it was necessary to make a number of assumptions about resource use and outcomes during these periods. It is possible that these patients could have been the most severe asthmatics, and therefore the true economic benefits of treatment may have been underestimated. However, despite these limitations, this study provides further evidence of the economic value of inhaled corticosteroid therapy in preschool children. Further large-scale, long-term studies would be beneficial to further validate the findings of this and other economic studies in this age group.
In conclusion, the results of this study suggest that in children aged 12 to 47 months with a history of asthma symptoms, FP, 100 µg bid, administered via the Babyhaler spacer device is a well-tolerated, cost-effective management strategy, from the perspective of the Danish health-care system. Thus, there is both clinical and economic rationale for using inhaled corticosteroids for asthma therapy in this age group.
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Acknowledgements |
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Footnotes |
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This study was sponsored by Glaxo Wellcome (protocol reference FLTB3016).
Received for publication November 6, 2000. Accepted for publication July 7, 2001.
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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