PEDIATRICS Vol. 104 No. 2 August 1999, pp. 187-194

Has Asthma Medication Use in Children Become More Frequent, More Appropriate, or Both?

David C. Goodman, MD, MS^*, , Paula Lozano, MD, MPH^§, , Therese A. Stukel, PhD^*, Chiang-hua Chang, MS^*, and Julia Hecht, PhD^§

From the ^* Center for the Evaluative Clinical Sciences, Department of Community and Family Medicine, and the  Department of Pediatrics, Dartmouth Medical School, Hanover, New Hampshire; ^§ Center for Health Studies, Group Health Cooperative of Puget Sound; and the  Department of Pediatrics, University of Washington, Seattle, Washington.

	ABSTRACT

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Objective.  Despite national initiatives to improve asthma medical treatment, the appropriateness of physician prescribing for children with asthma remains unknown. This study measures trends and recent patterns in the pediatric use of medications approved for reversible obstructive airway disease (asthma medications).

Design.  Population-based longitudinal and cross-sectional analyses.

Setting.  A nonprofit staff model health maintenance organization located in the Puget Sound area of Washington state.

Participants.  Children 0 to 17 years of age enrolled continuously during any one of the years from 1984 to 1993 (N = 83 232 in 1993).

Primary Outcome Measures.  Percent of enrollees filling prescriptions for asthma medications and fill rates by medication class and estimated duration of inhaled antiinflammatory medication use.

Results.  Between 1984 and 1993, the frequency of asthma medication use increased: the percent of children filling any asthma medication prescription increased from 4.0% to 8.1%, whereas the percent filling an inhaled antiinflammatory inhaler rose from 0.4% to 2.4%. In contrast, the intensity of inhaled antiinflammatory use decreased among users; 37% of users filled more than two inhalers during the year in 1984, and 29% in 1993. In high -agonist users (filling more than two -agonist inhalers each quarter per year), the estimated duration of inhaled antiinflammatory use increased slightly from a mean of 4.1 months per year in 1984-1986 to 5.0 months in 1991-1993; estimated duration of use in adolescents 10 to 17 years of age was approximately half that of children 5 to 9 years of age.

Conclusions.  The proportion of children using asthma medications increased substantially during the study period, but the use of inhaled antiinflammatory medication per patient remained low even for those using large amounts of inhaled -agonists. These findings suggest that most asthma medications were used by children with mild lower airway symptoms and that inhaled antiinflammatory medication use in children with more severe disease fell short of national guidelines.  Key words:  asthma, therapeutics, trends, guidelines.

Asthma is a common condition in childhood with an estimated prevalence of 6.9%¹ (18 years of age) and one of the most frequent causes of pediatric hospitalization.² Both prevalence and hospitalization rates are increasing nationally^3-6 for reasons that are understood poorly.⁷ Altogether, pediatric asthma is responsible for an estimated 10 million lost school days, 200 000 hospitalizations, and $456 million in direct medical expenses per annum.^8,9

The pharmacologic treatment of childhood asthma has changed as the burden of illness has increased. Previous studies have shown greater use of inhaled -agonist and antiinflammatory medications, whereas theophylline use has declined.^10,11 These utilization patterns are consistent with practice guidelines developed by the National Asthma Education and Prevention Program (NAEPP), although changes in physician prescribing for asthma predate the release of the first edition of the guidelines in 1991.^5,12

The cornerstone of drug therapy emphasized in both the 1991 and the 1997 editions of the guidelines is the introduction of daily inhaled antiinflammatory medication (corticosteroids, cromolyn, or nedocromil) in patients with moderate or severe asthma.^13,14 Inhaled antiinflammatory medications have been shown to improve airway function, reduce symptoms, and prevent exacerbations in diverse patient populations,^15,16 and most importantly, these agents seem to reduce the likelihood of hospitalization.^17,18 In contrast to recommendations published in the 1980s,¹⁹ long-term daily use of -agonists as a sole agent is undesirable, and when needed, is considered an indication for initiation of inhaled antiinflammatory medications.^14,15

The primary question we sought to address in this study is whether the trend toward greater per child utilization of asthma medications has been accompanied by an increase in the appropriateness of use. To avoid bias from temporal changes in clinicians' diagnosis of asthma,²⁰ the analyses are not restricted to children with physician-diagnosed asthma. Instead, we analyzed the use of medications approved for reversible obstructive airway disease, which we call asthma medications. Group Health Cooperative of Puget Sound (GHC) was chosen as the study setting because of its unique computerized datasets that allow for accurate measurement of medication use.²¹ In addition, GHC is a nonprofit health maintenance organization (HMO) known for medical care organized to uphold the principles of quality and consumer involvement.²² GHC is a reasonable representation of other not-for-profit, high quality health care organizations.

	METHODS

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Setting

GHC is the largest and oldest consumer-owned HMO in the country with an enrolled population of 380 000 and a medical staff employing 650 physicians in 1993. GHC is organized as a staff-model, closed-panel HMO with enrollees residing in the metropolitan areas of Seattle and Tacoma Washington. The racial and ethnic composition of enrollees at GHC approximates the general Puget Sound population, although the enrollees tend to be slightly more educated and affluent.²¹ Enrollees at GHC identify a primary care physician and receive most of their care at 1 of 28 primary care clinics. More specialized treatment is available at GHC specialty clinics, including allergy and pulmonary care, and at GHC-owned or -leased hospitals.

GHC has maintained an automated data system with comprehensive utilization data including prescription fills for >20 years. These data files have been used extensively in previous epidemiologic studies.²¹ Prescription databases include the date of prescription fill, the medication, and the quantity dispensed. During the study period, most prescription medications were provided for a $5 co-payment when enrollees used GHC pharmacies; as a result, >95% of enrollee prescriptions were captured by the GHC pharmacy database. Other GHC databases provide the enrollees date-of-birth and sex, and for those hospitalized, the date of hospital discharge and discharge diagnosis.

Study Population

We studied patients 0 to 17 years of age who were enrolled continuously during any one of the years from 1984 to 1993 (816 816 enrollee-years). Restriction to those with continuous enrollment eliminated patients newly entering GHC, who may have had transiently higher utilization rates. Continuous enrollment included enrollees with a <90-day interruption, because these enrollment breaks usually occurred for administrative reasons and are not associated with different utilization patterns.

Medication Utilization Data

Medication use was estimated from pharmacy fills. This method will tend to overestimate actual use, because not all medication will be used, and other medication will be lost. A prescription fill was defined as the medication dispensed at a single pharmacy visit regardless of quantity. Medications were grouped into five categories: inhaled -agonist (eg, metaproterenol and albuterol including those delivered by metered-dose inhalers and nebulizer); oral -agonist; inhaled antiinflammatory medication (eg, corticosteroids and cromolyn); oral theophylline; and oral fixed-dose combination drugs (eg, Tedral). Together, these are called asthma medications, although their use is not restricted to asthma and also may include illness with diagnostic overlap, such as bronchitis, chronic cough, bronchiolitis, or upper respiratory infections with wheezing.^23,24 Oral steroid fills also were measured but not grouped as an asthma medication.

Enrollee Subgroups

Three subgroups of enrollees within the 5- to 17-year age group also were studied. Younger enrollees were excluded because of the difficulty in calculating standardized utilization of -agonists, when oral preparations of varying quantity are prescribed. The first subgroup is referred to as high -agonist users and consists of patients filling at least two -agonist inhalers (200 doses per quarter at two puffs per dose) for each quarter during the year. Even assuming that 1 dose a day was used for prevention of exercise-induced asthma, these patients would have used a second dose for control of symptoms. These patients are likely to have persistent asthma and should benefit from inhaled antiinflammatory medication on a daily basis for symptom control.¹⁴ The second subgroup, referred to as the hospitalized group, consisted of those patients hospitalized with asthma (ICD-9-CM 493.xx as the principal diagnosis). The third subgroup, referred to as the oral steroid/-agonist group, included those filling two prescriptions for oral corticosteroids and two for inhaled -agonist agents during 1 year. We expected that most, but not all, patients in the hospitalized and oral steroid/-agonist groups would have benefited from at least several months of an inhaled antiinflammatory agent.

In the high -agonist user and the oral steroid/-agonist groups, the presence of a physician diagnosis of asthma was determined during 1992-1993; 1992 was the first year that GHC included accurate diagnoses in its outpatient datasets. These estimates are limited by the brief time within our study period (18 months) for which ambulatory diagnoses were available. A total of 60% of users of any asthma medication and 80% of users of high -agonist inhalers had an outpatient or inpatient diagnosis of asthma during 1992-1993. In the oral steroid/-agonist group, 96% had a diagnosis of asthma recorded. All the children in the group with asthma hospitalizations had physician-diagnosed asthma.

Medication Use Variables and Statistical Methods

The two population-based outcomes of interest were the percent of enrollees filling a prescription for an asthma medication and the number of prescriptions filled per 1000 enrollees per annum. Because the denominator for these measures were counts of GHC enrollment by groups, the unit of analysis was the age group-sex stratum for each study year from 1984 to 1993. Age was grouped as 0 to 1, 2 to 4, 5 to 9, or 10 to 17 years. For each stratum and year, we computed both the number of enrollees filling at least one asthma prescription and the total number of asthma prescriptions filled, both overall and by type of prescription. Enrollee counts by age group and sex also were computed for each year. We analyzed trends in asthma medication using methods for the analysis of longitudinal clustered binary data (the proportion filling a prescription) or Poisson data (the number of prescriptions filled per 1000 enrollees), controlling for age group and sex and weighting by the number of enrollees.²⁵ Year was included as a continuous variable to assess the linear trend in prescription fill rates over the study period. As a measure of the intensity of medication use, we determined the number of prescriptions filled for each medication category per year for those filling at least one prescription by age group-sex stratum. We analyzed the proportion of enrollees with more than two prescription fills per year using methods for the analysis of longitudinal, clustered binary data, similar to the data above. Point estimates and CIs for the odds ratios (ORs) (binary data) and rate ratios (Poisson data) were obtained by transforming the corresponding regression parameters.

We also estimated the maximum possible duration of inhaled antiinflammatory medication use for the purpose of comparing utilization with the recommendations of NAEPP guidelines. Maximum duration of use was calculated as the number of months per year that the medication could be used continuously if taken at the lowest dose recommended by either the package insert or by the NAEPP guidelines.^14,26 Inhalers were assumed to have been used daily at the minimum dose until gone, and fills of multiple inhalers were assumed to have been taken consecutively. These assumptions tend to overestimate the months of use, because some medication will be unused or will be taken at doses higher than the minimum recommended but for shorter periods. Trends in the number of months per year of use of inhaled antiinflammatory drugs for an individual patient were analyzed using methods for the longitudinal analysis of continuous outcomes, controlling for age group, sex, and period (1984-1986, 1987-1990, and 1991-1993), as above. All tests were performed at the 5% level of significance and were two-sided.

	RESULTS

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Asthma Medication Utilization in Pediatric Enrollees

The percent of children at GHC receiving at least one asthma medication fill during the year doubled from 4.0% to 8.1% (P < .001) during the 1984-1993 period, and exceeded 9% in 1993 for enrollees 0 to 1 year of age (Table 1). Inhaled -agonist agent use increased approximately fourfold from 1.4% to 6.0% (P < .001) and was highest in enrollees 10 to 17 years of age with 7.6% filling at least one prescription by 1993. Oral -agonist use also increased from 1.5% to 2.2% (P < .001) and was highest in 1993 in enrollees 0 to 1 years of age at 8.1%. Inhaled antiinflammatory use rose more than fivefold to 2.4% (P < .001). In 1993, 0.7% of infants, 1.7% of preschoolers, 2.5% of elementary school children, and 2.8% of adolescents filled at least one prescription for cromolyn or a steroid inhaler. Oral fixed-dose combination agents were not filled at all during 1993 (P < .001), and oral theophylline use declined 10-fold to include only 0.25% (P < .001) of the pediatric population in 1993. 

Oral corticosteroid use increased more than threefold to 1.9% (P < .001) during the study period, although it should be noted that there are many nonrespiratory indications for this medication in children. By 1993, 2.5% of infants, 2.6% preschoolers, and 1.7% of elementary school children and adolescents filled at least one such prescription during the year.

Trends in per capita prescription fills paralleled the changes in the proportion of the enrollees using asthma medications. Trends by age are shown in Fig 1. The number of inhaled -agonist fills per enrollee increased by 15% (95% CI: 13,16) per annum during the 10-year study period. Oral -agonist fill rates rose slowly at 4% per annum (95% CI: 2,6). The rate of inhaled antiinflammatory medication fills also increased at 17% per annum (95% CI: 16,19) with the greatest increase in enrollees 0 to 1 years of age who had a 25% per annum (95% CI: 21,29) increase. Overall, oral theophylline fills decreased 16% per annum (95% CI: 14,17) to very low levels in 1993. 

View larger version (37K): [in this window] [in a new window]   Fig. 1.   Asthma medication fills per 1000 enrollees 0 to 17 years of age of GHC.

Ratio of Antiinflammatory to Bronchodilator Fills

The ratio of antiinflammatory to bronchodilator fills has been used in research and quality improvement efforts to measure the appropriateness of asthma medication prescribing.^27-30 We restricted our analysis to the ratio of inhaled antiinflammatory fills to -agonist fills in children 5 years of age, an age in which inhalers are preferred strongly over oral formulations, because they have greater efficacy and fewer side effects. In 1993, the ratio was 0.50. Between 1984 and 1993, the ratio increased from 0.51 to 0.64 (P < .01) in children 5 to 9 years of age and from 0.28 to 0.39 (P < .001) in children 10 to 17 years of age.

Intensity of Asthma Medication Use

Although a greater proportion of children 5 to 17 years of age filled asthma prescriptions by 1993, and fill rates increased accordingly, there was a decline in the annual number of fills among users (Fig 2). The proportion of -agonist users filling only one or two -agonist inhalers during the year was 76% (95% CI: 73,78) in 1984 and 79% (95% CI: 78,80) in 1993 (test for trend: P < .01). This low intensity of -agonist use might be expected, because most children with asthma have mild disease and require only occasional bronchodilators. In contrast, inhaled antiinflammatory medication is recommended for long-term use for moderate or severe asthma.^13,14 In 1984, 37% (95% CI: 32,43) of inhaled antiinflammatory users filled more than two, and 20% (95% CI: 16,25) filled more than four antiinflammatory prescriptions. By 1993, the number of fills per user declined with only 29% (95% CI: 27,32) filling more than two, and 13% (95% CI: 11,14) filling more than four per year (test for trend: P < .001).

View larger version (29K): [in this window] [in a new window]   Fig. 2.   Changes in the use of inhaled asthma medications for enrollees 5 to 17 years of age. During the 1984-1993 period, the number of enrollees using medications increased, although the intensity of use (as measured by the number of prescriptions filled per year) changed little. The number of enrollees increased slightly (11%) during this 10-year period.

Estimated Duration of Inhaled Antiinflammatory Medication Use

We examined the duration of inhaled antiinflammatory medication use in three subgroups of children with likely indications for chronic preventive therapy: 1) high -agonist users; 2) hospitalized asthmatic children; and 3) oral steroid/-agonist users. High -agonist users were those children filling at least two -agonists inhalers (200 doses) each quarter of the year. Enrollees without any use of inhaled -agonist inhalers during a study year were excluded from these analyses. Controlling for age and sex, the mean duration of inhaled antiinflammatory medication in high -agonist users was 4.7 months (95% CI: 4.5,5.0) per year compared with 0.7 months (95% CI: 0.7,0.7) in patients with low -agonist medication use (P < .001). The use of inhaled antiinflammatory medication in high -agonist users increased during the study period from a mean of 4.1 months (95% CI: 3.5,4.6) per year in 1984-1986 to 5.0 months (95% CI: 4.6,5.4) in 1991-1993 (P < .05; Table 2). Controlling for time and sex, patients 10 to 17 years of age used less inhaled antiinflammatory medication per year than did patients 5 to 9 years of age (P < .001).

The use of inhaled antiinflammatory medication also was estimated during the 3 months after an asthma exacerbation in hospitalized children (Table 3). The duration of use increased in a stepwise manner from 0.8 months (95% CI: 0.5,1.2) in 1984-1986 to 1.2 months (95% CI: 0.9,1.4) in 1987-1990 and then to 1.9 months (95% CI: 1.7,2.1) in 1991-1993 (P < .001). In terms of age or sex, no differences were observed in the use of these preventative medications.

A second course of oral corticosteroids during the same year that two -agonist prescriptions were filled, served as an additional indicator of an asthma exacerbation (oral steroid/-agonist group; Table 3). During the 3 months after the second oral steroid use, the mean duration of inhaled antiinflammatory medication utilization was 1.6 months (95% CI: 1.4,1.8) in 1984-1986 and 1.9 months (95% CI: 1.7,2.0) in 1991-1993 (P = .06). In terms of age or sex, no differences were observed.

	DISCUSSION

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During the 1984-1993 period, the proportion of children at GHC filling prescriptions approved by the Food and Drug Administration for reversible obstructive airway disease doubled at the same time that the intensity of inhaled -agonist and antiinflammatory use declined. Most notably, users of corticosteroid and cromolyn inhalers were less likely to have filled three or more inhalers per year in 1993 than in 1984. In children 5 years with more symptomatic asthma, the estimated duration of inhaled antiinflammatory medication use increased, although it still fell short of the amount recommended for long-term control even at the minimal dose that we used in our calculations. The use of inhaled antiinflammatory medications was particularly low for adolescents who were high -agonist users.

Our finding of increased use of asthma medications is consistent with other reports showing recent rises in total US^10,12 and foreign^31-34 sales. Similar increases also have been observed in asthmatic children receiving Medicaid.^12,35 These reports cannot distinguish between a greater number of users or higher fill rates in users. We found that higher medication use was primarily attributable to greater numbers of children with infrequent fills and presumably mild illness.

Many of these children using small amounts of asthma medications may not have physician-diagnosed asthma. This possibility is supported by preliminary analyses of 1992-1993 outpatient diagnoses associated with GHC asthma medication fills: 40% did not have a hospital or outpatient diagnosis of asthma during the 9 months before or after fills. The effectiveness of asthma medications is understood poorly in nonasthma illness, such as infants with bronchiolitis or older children with mild or transient coughing and wheezing. Because pediatric efficacy trials generally have studied asthmatic populations in which the diagnosis of asthma was certain, the majority of prescriptions for asthma medications now may be written for illness in which efficacy and benefit to the patient are unknown.

The utilization patterns observed in GHC may represent a best-case scenario during the time of the study. GHC is a consumer-owned and -governed HMO with a long history of clinical measurement and improvement. Nearly all physicians are board-certified. Independent surveys rate GHC at the top in consumer satisfaction.²² Although at the time of these observations, GHC had not instituted specific measures at an organizational level to improve the management of pediatric asthma, its overall delivery of medical services is far more coordinated and comprehensive than in many other health care organizations. As a result, inhaled antiinflammatory inhaler use is likely to be higher than in independent practice associations or fee-for-service delivery systems. Additional research is needed to understand the medication utilization of asthmatic children receiving care in less structured health care systems.

Although other investigators^27-30 have used the ratio of antiinflammatory to -agonist inhalers as a measure of the appropriateness of medication use, our results demonstrate that these ratios should be interpreted cautiously. The ratio of fills does not control for the numbers of users or the per person intensity of either antiinflammatory or -agonist medication use. Even when the ratio reflects overall high antiinflammatory use, one cannot infer directly that patient use is appropriate. For example, the 1993 GHC ratio was higher than was that observed in many centers participating in the European Community Respiratory Health Survey,³⁰ but use occurred primarily in children filling only one or two antiinflammatory inhalers per year.

Less than ideal antiinflammatory inhaler use could be the result of patient or provider behavior. Despite studies showing a minimal risk of adverse effects,¹⁵ physicians may have been reluctant to prescribe inhaled corticosteroids. These concerns would not explain the failure to prescribe an alternative medication such as cromolyn. Clinicians also may differ in their interpretation of the indications for antiinflammatory medications in specific clinical situations. The current NAEPP guidelines clearly recommend the regular use of preventative medication for the high -agonist users whose medication utilization indicates symptoms throughout the year. Initiation of inhaled preventative medications at the time of an exacerbation is not recommended necessarily, even if the child is hospitalized. Physicians also may have prescribed short courses of inhaled antiinflammatory medications to treat exacerbations. This is an unproved strategy, but one that could have resulted in patients' filling only 1 or 2 prescriptions a year.^36,37

Irrespective of clinician recommendations, the behavior of patients and families influence medication use. The initiation of medication usually requires a physician visit and families vary in their threshold of seeking care. Within the high -agonist users, less frequent physician visits could explain the lower inhaled antiinflammatory medication use in adolescents. Recent data from the National Ambulatory Medical Care Survey indicate that adolescent and young adult asthmatics have less than half the number of physician visits per year than do patients <15 years of age.¹¹ These patients may have received -agonist prescriptions with long-term refills or may have requested refills over the phone without their physicians' knowledge of their high frequency of medication use. Interestingly, when adolescents had exacerbations that were likely to have resulted in a face-to-face encounter with a physician, such as hospitalization or the second course of oral corticosteroids, their inhaled antiinflammatory use was similar to that of younger children. Another important factor in low antiinflammatory medication use may be limited adherence to prescribed medications,^38-41 particularly in the more autonomous adolescents.

There are several elements of the study design that may limit our findings. First, we have relied on prescription fills to estimate the use of inhaled antiinflammatory medications without knowing whether the medications actually are taken by the patients. The duration of use that we report for these medications is likely to be an overestimate of the actual duration, because some medication will be unused or used at a higher dose but for shorter periods. Second, we have relied on patterns of asthma medication utilization and hospitalization to identify comparable groups of patients by age, sex, and over time as likely candidates for preventative inhalers. We acknowledge that with additional clinical data, some of these patients may not have been classified as meeting the National Institutes of Health criteria for antiinflammatory medication use. However, utilization data does indicate a generally high level of lower respiratory illness. Finally, we note that physician practices may have changed since 1993, the last year of our study, because of the ongoing national dissemination of asthma guidelines.

These findings provide several lessons relevant to improving the clinical care of children with asthma:  Clinicians are prescribing asthma medications more frequently, but most utilization seems to be for children with mild illness. The efficacy and effectiveness of these medications has been studied primarily in patients with moderate or severe disease. Additional research is needed in the majority of children whose lower respiratory symptoms are mild or transient.
In the most severely ill asthmatic children, the use of antiinflammatory medications fell considerably short of national guidelines during the years when the guidelines were first actively disseminated and promoted. Clinicians need to reexamine their own current practices and provide closer supervision of the patients with more severe asthma to encourage medication adherence. Additional studies examining the relative role of physicians and patient families in these use patterns would assist future asthma care.

	ACKNOWLEDGMENTS

This research was supported by National Heart, Lung, and Blood Institute Grants R29-HL52076-01 (D.C.G. and C.C.), Glaxo Wellcome, Inc (P.L. and J.H.), and the Poncin Foundation (P.L.).

We thank Edward Wagner, MD, MPH, Andy Stergachis, PhD, and John E. Wennberg, MD, MPH, for their suggestions throughout this project. We also appreciate the editorial assistance of Susan Hemphill and the bibliographic research of Andrew Goodman.

	FOOTNOTES

Received for publication Dec 28, 1998; accepted Mar 1, 1999.

This work was presented in part at the Ambulatory Pediatrics Association Annual Meeting; May 2, 1997; Washington, DC.

Reprint requests to (D.C.G.) 211 Strasenburgh Hall, Dartmouth Medical School, Hanover, NH 03755. E-mail: david.goodman{at}dartmouth.edu

	ABBREVIATIONS

NAEPP, National Asthma Education and Prevention Program; GHC, Group Health Cooperative of Puget Sound; HMO, health maintenance organization; ORs, odds ratios.

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