Trends in Medication use for Asthma Among Children Christine Phillips; Tim McDonald Posted: 07/16/2008; Curr Opin

Allergy Clin Immunol. 2008;8(3):232-237. 2008 Lippincott Williams & Wilkins Abstract and Introduction Abstract Purpose of Review: To review recent studies of changing medication use for asthma among children. Recent Findings: Although many countries monitor mortality and hospitalizations related to asthma, there is less surveillance of medication use for asthma. Since the late 1990s, and in the United States, Australia and the United Kingdom, there has been a change in the medications used to prevent asthma in childhood, with an increase in inhaled corticosteroids, and a decrease in mast cell stabilizers. Prescriptions for montelukast have increased four-fold in the United Kingdom for children since 2000, with similar increases in the United States and in Australia. There has been a trend in some countries to increased use of fixed dose combined long-acting -agonist/inhaled corticosteroid products; in Australia and the United Kingdom, fixed dose combinations now account for the majority of preparations containing inhaled steroids prescribed to children with asthma. Summary: Studies in a number of countries have shown marked secular trends in asthma medications for children since the late 1990s. Research needs to employ serial cross-sectional studies in the same population to capture changing medication use and to be precise about types of medication within a class. The changes in many countries indicate a greater concordance with guidelines. Introduction Asthma is the most common chronic disease of childhood. In developed countries, the prevalence of asthma appears to be highest in the preteen years, probably due to the higher incidence and severity of disease among males in this age group.[1-3] Evidence-based guidelines now exist in many countries to guide practice.[4-7] The present review examines recent studies of trends in medication use among children and clarifies some of the methodological challenges in studying changing patterns of medication use. Surveillance of Medication Use: Methodological Challenges Although many countries undertake surveillance of asthma prevalence, hospitalization rates and mortality, less attention has been paid to asthma medications. Surveillance of trends in medication use by children with asthma is interesting for several reasons. First, it helps us to recognize patterns of overuse and underuse of medication classes and subclasses particularly as new pharmacotherapies become available. Second, trend data enable us to monitor concordance of asthma treatment with evidence-based guidelines. Most studies of asthma medication use by children have a single-year cross-sectional design. As the trend data for at least the last decade have indicated that prescriptions of asthma medications undergo quite significant increases or decreases over a period of years, data from single-year cross-sectional studies should not be generalized. In choosing the type of trend study they will do, researchers often accept a trade-off between good ascertainment of numerator data (medications prescribed, or dispensed) and clear definition of the denominator population (ideally, a population of people with diagnosed asthma).

Using Databases of Dispensing Records Large databases of prescriptions claimed or dispensed are held by health insurance systems or managed care organizations. Recent trend studies[8,9] have drawn on data held by Medicaid in the United States, Medicare in Australia,[10] the National Health Service in the United Kingdom,[11] the Regie de l'assurance maladie du Quebec (RAMQ) database in Canada,[12] the Dutch InterAction Database[13] and the Norwegian Prescription Database.[14] The major shortcoming of using large prescription databases is that the denominator population is often the general population, rather than those with asthma. This may lead to an overestimate of medication use, because medications like oral corticosteroids (OCSs) may be used for other purposes. In Australia, an increasing trend for children without parentreported asthma to use inhaled salbutamol was noted between 2000 and 2005, with nearly one-third of those taking salbutamol in the previous 12 months not having a diagnosis of asthma.[10] In the United States[8,9,15] and the United Kingdom,[16] a number of studies have linked databases kept by pharmacies and by health services to identify the denominator population of children who had attended services for treatment of asthma and ascertained their medication use through pharmacy databases. Using Parent Report of Asthma Diagnosis and/or Medication Use In these studies, the denominator is defined by parental report of the child's asthma. This has the advantage of clearer definition of the denominator and can be useful for studies of marginalized subpopulations.[17] The accuracy of parental report has been critiqued,[18] though a recent reanalysis of the same data, taking into account the episodic nature of asthma, indicated that parental report of diagnosis was accurate.[19] One of the limitations of these types of studies is accuracy of parental recall about medication use. Parental report of medication frequency was found in one study to be accurate.[20] Nevertheless, when parental reports of children's inhaled corticosteroid use and electronic records of metered dose inhaler activations were compared, parents significantly overstated frequency of medication use.[21] For trend data, concerns about parental accuracy of medication recall may be less problematic, because a trend should still emerge, assuming that parental recall is a systematic bias. In Australia, trends emerging in medication use from a study that used parental recall of medications and parental report of asthma for the diagnosis were mirrored in trends identified in Medicare data over the same time period. [10] Pharmacy-dispensing records do not necessarily tell us about the household use of medications. Parental recall can tell us more about the household use, but may not be accurate. A number of studies in the United States[9,22,23] have now combined parental interview and pharmacy records. This study design would be expected to tell us most about trend data, but unfortunately even in the one study[23] that studied medication use in 3-year-long study periods between 1996 and 2000, data on medication use were aggregated across the years, obscuring any time trends. Conflation of Drug Classes. Some cross-sectional and trend studies report the use of medications by function ('relievers' and 'preventers/controllers') rather than drug class.[17,23,24] The preventer/controller category includes inhaled corticosteroids, long-acting -agonists (LABAs), montelukast and cromolyns. Conflating these drugs misses changes within the categories, such as decreases in mast cell stabilizers and increases in LABAs.[10,25] Studies also tend to aggregate medications within classes. This is of particular importance with increases in use of high-potency inhaled corticosteroids like fluticasone and combination-inhaled corticosteroid and LABAs documented in Australia[10] and the United Kingdom.[11] Conflation of Age Groups. Although there are marked differences in age-specific prevalence of asthma in childhood, many studies aggregate data across childhood. Two of the recent trend studies from the United

States, for example, report medication use for children aged 2-18 years[26] or 0-17 years[15] with no subclass analysis. Given that recommendations for treatment may differ according to age group,[4] trend and cross-sectional data should be disaggregated into preschool and school-age years. Interpreting Trends in Medication Use for Children The methodological discussion sets out the rationale for the following caveats about interpreting trend studies. Many of the medication trend studies are not directly comparable, as they have different denominators (general population vs. children with diagnosed asthma), and present their data in different ways. In Figs 1-3, trend data are presented for one study in the United States, for children under 18 years, [15] one for school-entry children in Australia, drawing on Medicare data,[10] and one for Australian children aged 2-14, drawing on the Health Communication Network (HCN) database. Of all the published studies of medication, only the former two use similar methods and denominators allowing them to be mapped together in similar fashion.

Figure 1. Changes in prescription claims for asthma medications for children on Medicaid in Maryland, aged 0-17 years.

Figure 2. Changes in prescription claims for asthma medications for children in the Australian Capital Territory, aged 5 years.

Figure 3. Changes in prescriptions for preventer medications for asthma for children in Australia, aged 214 years. Despite the methodological concerns that exist about ascertainment of medications and denominator populations, some clear trends are now emerging internationally about changing trends in medication use among children. Increases in Inhaled Corticosteroids for Children Inhaled corticosteroids have been recognized as the key class of medication for the control of persistent asthma.[26] It seems clear that there has been an increase in inhaled corticosteroid use for children, and this is confirmed by trend data in the United States,[15] United Kingdom[11] and Australia.[10] In the Australian Capital Territory (ACT), prescription database studies suggest that the rapid increase in the proportion of asthma medications for inhaled corticosteroids, is partly due to increases in combination products containing fluticasone and salmeterol, which were taken by 20% of children in 2005.[10] A policy decision in 2002 to limit prescribing of fluticasone to lower dose formulations may also have led to an increase in dispensing of fluticasone, as the product containing higher dose formulations fluticasone might have lasted longer. Fluticasone has replaced budesonide and beclomethasone as the most used inhaled corticosteroid for asthma in childhood in Australia, with a four-fold increase in this medication in the ACT between 2002 and 2005.[10] Prescribing data in the United Kingdom have indicated that beclomethasone remains the

medication most frequently prescribed to children.[11] In Australia, one-third of scripts for fluticasone are for treatment of children with asthma, with an upward trend in this over the last few years (Fig. 4). Fluticasone is a highly potent corticosteroid; the introduction of this medication to New Zealand led to a near doubling of the equipotent dose of inhaled corticosteroid in children aged 0-5 years because of its potency.[27] In the United Kingdom, 78% of children under 5 years and 83% of children of 5-11 years who were on doses of corticosteroids above the recommended daily dose of 800 g equivalent were taking fluticasone.[16]

Figure 4. Preventer medications prescribed to children aged 2-14 years as a proportion of preventer medications prescribed to total population, Australia 2003-2007. Increases in Long-acting -agonists A signal change in the last decade has been the increasing prescription of LABAs in combination with inhaled corticosteroids. In the United Kingdom, 29.5% of children under 5 years on high dose inhaled corticosteroids (ICS) (more than 400 g/day) were prescribed this in a fixed dose combination with a LABA, a process not in accordance with guidelines.[16] The total number of prescriptions for LABAs prescribed to children under 15 years doubled between 2000 and 2006, whereas prescriptions for combination ICS/LABA, mainly fluticasone/salmeterol products, increased by a factor of six.[11] In the ACT, the proportion of 5-year-olds with asthma taking combination LABA/ICS products, mainly fluticasone/salmeterol, increased between 2002 and 2005 from 8 to 20%.[10] Concerns have been raised about the risk of sudden unexplained death in people taking LABAs,[28] leading to the recommendation that it should not be given without an inhaled ICS. It has been proposed that a sudden death on LABAs may have a genetic association. A recent study[29] of the relationship between 2-adrenergic receptor gene (ADRB2) polymorphism and asthma exacerbation or other untoward symptoms found that there was no association between the two. Increases in Montelukast Usage In Australia, in 2005 only 8% of children with asthma were reported to have taken montelukast in the previous year. The Medicare prescription database indicated, however, that montelukast accounted for 20% of all asthma medications (excluding OCSs) (Fig. 2). In the United Kingdom, there has been a steady increase in leukotriene receptor antagonists (LTRAs), with prescriptions for children under 15 increasing from 42 000 to 197 000 between 2000 and 2006.[11] In the United States, among AfricanAmerican children on Medicaid, LTRAs were used by 37% of children in 2002, approximately the same proportion of children as those on inhaled corticosteroids.[8] The authors noted that this was a population with high levels of stress that may interfere with their capacity to dispense and adjust inhaled corticosteroids; montelukast, by contrast, is a simpler medication to administer. Decreases in Bronchodilator Syrups in Some Countries In most countries, children now receive their bronchodilators through inhalational delivery devices. In the ACT, the number of dispensed scripts for salbutamol syrup was negligible.[10] In the United Kingdom, scripts for bronchodilator syrup fell by 60% between 2000 and 2006.[11] Although we do not have trend data for changes in syrup use in the United States, cross-sectional data among African-Americans in 2002 found that 11% of the asthmatic population took their reliever medication this way.[8] In a crosssectional study in Taiwan in 1998, 79% of boys and 77% of girls under the age of six received bronchodilator syrup; overall 69% of the population under 18 years had oral bronchodilator syrup

dispensed, whereas only 10.7% had inhaled bronchodilators.[30] There are no more recent data to document whether there have been subsequent changes to this finding. In Australia, there has been a steady trend down in reported nebulizer use for bronchodilators and a reciprocal increase in use of metered dose inhalers (MDIs) with spacer devices.[10] Comparative data are not available for other countries. Drivers for Change Change in medication use is driven by a number of factors, discussed in recent studies: health policy, health systems and entrenched dispensing practices, and pharmaceutical marketing. The improvement in inhaled corticosteroid use for children appears to point to the effectiveness of dissemination of evidence, as does the decline in outdated therapies such as theophylline. In the United States, the low rates of preventive treatment for homeless children who had very high prevalence of asthma became the trigger for a class action lawsuit, leading to higher rates of prescription and use of preventers.[16] The impact of health systems has been poorly studied. There is some evidence of intercountry practice variation; the provision of oral -agonists in Taiwan[30] occurred at a time when in the United States inhaled -agonists were more commonly used. A small study of neighboring regions in Holland and Germany found marked differences in prescribing practices, though this may be indicative of local, rather than systematic, factors.[31] In the United States, variation was reported between managed care organizations, largely attributable to local prescribing practices.[32,33] Despite being aware of the recommendation that children with persistent asthma should be on inhaled corticosteroids, few emergency physicians in a US study prescribed them to children who presented with exacerbations of asthma. The main reason was because they felt community physicians were more appropriate managers of asthma, even though many of the children did not attend community physicians. Internalized notions of the 'appropriate' division of medical work between emergency departments and community physicians appear to have impacted on the prescribing practice of the physicians in this study.[34] The impact of pharmaceutical company marketing is infrequently addressed in the literature on trends in medication. In 2002 in Australia, the campaign for fluticasone/salmeterol (Seretide) won an award from the Australian Marketing Institute. After 1 year a high level of brand recognition had been achieved by the product, and 80% of competitor products had been shifted to fluticasone or fluticasone/salmeterol. [35] It is likely that this highly successful campaign had a significant impact on the recognition and uptake of this product by parents and doctors in Australia. Finally, changes in medication use are also influenced by decisions made by parents about medication administration. In England, a longitudinal study of medications used by a cohort of children from birth to 7.5 years found that the number of medications given by parents to children peaked at 4.5 years. The most common ongoing medication prescribed by a doctor was an asthma medication.[36] Focus group studies have identified subgroups of parents who are not optimally following the prescribed medical regimen, sometimes unintentionally, and sometimes due to a conception of their child's illness, which is at odds with that presented by their physician.[37,38] Conclusion Measuring trends in asthma management among children is methodologically complex. Although there are many recent studies into medication use, most of these are cross-sectional. The trend studies that we

do have demonstrate an increase in inhaled corticosteroids, which began in the 1990s, and a decline in sodium cromoglycate and methylxanthines, which is in accordance with guidelines. The high rates of usage of fixed dose combinations of fluticasone and salmeterol in children in some countries need ongoing monitoring. Sidebar: References Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1.Australian Institute of Health and Welfare 2005. Incidence and prevalence of chronic diseases. http://www.aihw.gov.au/cdarf/data_pages/ incidence_prevalence/index.cfm. [Accessed 10 January 2008]. 2.Schatz M, Camargo CA Jr. The relationship of sex to asthma prevalence, healthcare utilization, and medications in a large managed care organization. Ann Allergy Asthma Immunol 2003; 91:553-558. 3.Moorman JE, Rudd RA, Johnson CA, et al. National Surveillance for Asthma - United States, 19802004. October 19, 2007/56(SS08);1-14;18-54. http://www.cdc.gov/mmwr/preview/ mmwrhtml/ss5608a1.htm#tab2. [Accessed 14 January 2008]. 4.British Thoracic Society/Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma. Revised July 2007. http://www.sign.ac.uk/pdf/sign63.pdf . [Accessed 14 January 2008]. 5.National Asthma Council of Australia Ltd. Asthma Management Guidelines 2006; Melbourne 2006. 6.US Department of Health and Human Services. National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for Diagnosis and Management of Asthma. 28 August 2007. http://www.nhlbi.nih.gov/guidelines/ asthma/asthgdln.htm. [Accessed 14 January 2008]. 7.Canadian Medical Association. Canadian Asthma Consensus Report, 1999. CMAJ 1999; 161 (11 Suppl):S1-S61. 8.Smith MJ, Pawar V. Medical services and prescription use for asthma and factors that predict inhaled corticosteroid use among African-American children covered by Medicaid. J Asthma 2007; 44:357-363. 9.Butz AM, Tsoukleris M, Donitham M, et al. Patterns of inhaled anti-inflammatory medication use in young underserved children with asthma. Pediatrics 2006; 118:2504-2513. 10. Phillips CB, Toyne H, Ciszek K, et al. Trends in asthma medication use among school-entry children in the Australian Capital Territory. Med J Australia 2007; 187:10-13. Serial cross-sectional study of medication use among 5-year-old children with parent-reported asthma during 2000-2005. 11. Cohen S, Taitz J, Jaffe A. Paediatric prescribing of asthma drugs in the UK: are we sticking to the guideline? Arch Dis Child 2007; 92:847-849. Examines trends in asthma medications in children under 18 years 2000-2006 in the United Kingdom. 12.Blais L, Beauchesne M-F, Levesque S. Socioeconomic status and medication prescription patterns in pediatric asthma in Canada. J Adolesc Health 2006; 38:607. 13.de Vries TW, Tobi H, Schirm E, et al. The gap between evidence-based medicine and daily practice in the management of paediatric asthma. A pharmacy-based population study from The Netherlands. Eur J Clin Pharmacol 2006; 62:51-55. 14.Faru K, Skurveit S, Langhammer A, Nafstad P. Use of antiasthmatic medications as a proxy for prevalence of asthma in children and adolescents in Norway: a nationwide prescription database analysis. Eur J Clin Pharmacol 2007; 63:693-698. 15. Bollinger ME, Smith SW, LoCaSale R, Blaisedell C. Transition to managed care impacts healthcare service utilization by children insured by Medicaid. J Asthma 2007; 44:717-722. Trend data on

medications for children under the age of 17 years during 1997-2000. 16.Thomas M, Turner S, Leather D, Price D. High-dose inhaled corticosteroid use in childhood asthma: an observational study of GP prescribing. Br J Gen Pract 2006; 56:788-790. 17. Grant R, Bowen S, McLean DE, et al. Asthma among homeless children in New York City: an update. Am J Public Health 2007; 97:448-450. This study provides some trend data, and discusses the use made of their data to lobby for improved asthma care for homeless children. 18.Roberts EM. Does your child have asthma? Parent reports and medication use for pediatric asthma. Arch Pediatr Adol Med 2003; 156:449-455. 19.Joetsch JM, Kim H, Kieckhefer GM, et al. Does your child have asthma? Filled prescriptions and household report on child asthma. J Pediatr Healthcare 2006; 20:374-383. 20.Wogelius P, Poulsen S, Srensen HT. Validity of parental-reported questionnaire data on Danish children's use of asthma-drugs: a comparison with a population-based prescription database. Eur J Epidemiol 2005; 20:17-22. 21. Bender BG, Bartlett SJ, Rand CS, et al. Impact of interview mode on accuracy of child and parent report of adherence with asthma-controller medication. Pediatrics 2007; 120:e471-e477. A careful study with an excellent gold standard in the electronic monitor of medication dispensed. 22.Mudd K, Bollinger E, Hsu VD, et al. Pharmacy fill patterns in young urban children with persistent asthma. J Asthma 2006; 43:597-600. 23.Wang LY, Zhong Y, Wheeler L. Asthma medication use in school-aged children. J Asthma 2006; 43:495-499. 24.Lozano P, Finkelstein JA, Hecht J, et al. Asthma medication use and disease burden in children in a primary care population. Arc Pediatr Adolesc Med 2003; 157:81-88. 25.David C. Preventive therapy for asthmatic children under Florida Medicaid: changes during the 1990s. J Asthma 2004; 41:655-661. 26.Guevara JP, Ducharme FM, Keren R, et al. Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma. Cochrane Database Syst Rev 2006; (4). (Last update 14 February 2006). 27.Johansson M, Hall J, Reith D, et al. Trends in the use of inhaled corticosteroids for childhood asthma in New Zealand. Eur J Clin Pharmacol 2003; 59:48307. 28.Nelson HS, Weiss SC, Bleecker ER, et al, SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129:15-26 (Erratum, Chest 2006; 129:1393). 29.Bleecker ER, Postma DS, Lawrance RM, et al. Effect of ADRB2 polymorphisms on response to longacting 2-agonist therapy: a pharmacogenetic analysis of two randomised studies. The Lancet 2007; 370:2118-2125. 30.Hen C-Y, Chir H-F, Yeh M-K, et al. The use of antiasthmatic medications among pediatric patients in Taiwan. Pharmacoepidemiol Drug Safety 2003; 12:129-133. 31.Mommers M, Swaen GM, Weishoff-Houben M, et al. Differences in asthma diagnosis and medication use in children living in Germany and the Netherlands. Prim Care Respir J 2005; 14:31-37. 32.Adams RJ, Fuhlbrigge A, Finkelstein JA, et al. Use of inhaled antiinflammmatory medication in children with asthma in managed care settings. Arch Pediatr Adol Med 2001; 153:501-507. 33.Donahue JG, Fuhlbrigge A, Finkelstein JA, et al. Asthma pharmacotherapy and utilization by children in 3 managed care organisations. J Allergy Clin Immunol 2000; 106:1108-1114. 34.Scarfone RJ, Zorc JJ, Angusco CJ. Emergency physician's prescribing of asthma controller medications. Pediatrics 2006; 117:821-827. 35.National Award Winners. Australia's top marketers honoured. Marketing Update November 2002, p. 14. http://www.ami.org.au/library/ ami_awards/2002_winners.pdf. 36. Headley J, Northstone K. Medication administered to children from 0 to 7.5 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). Eur J Clin Pharmacol 2007; 63:189-195.

Detailed longitudinal study of all medications taken by children from birth to 7.5 years. 37.Bokhour BG, Cohn ES, Corts DE, et al. Patterns of concordance and nonconcordance with clinician recommendations and parents' explanatory models in children with asthma. Patient Educ Couns 2008; 70:376-385. 38.Graves MM, Adams CD, Bender JA, et al. Volitional nonadherence in pediatric asthma: parental report of motivating factors. Curr Allergy Asthma Rep 2007; 7:427-432. Acknowledgments We are grateful to Mr Michael Bramble, Merck Sharp and Dohme for summary data on medication use from HCN, Australia, and Ms Maxine Robinson and staff of the Drug Utilisation Sub-Committee of the Pharmaceutical Benefits Advisory Committee, Australian Government Department of Health and Ageing for assistance with accessing Medicare Australia data. Reprint Address Dr Christine Phillips, Senior Lecturer, Academic Unit of General Practice and Community Health, Medical School, Australian National University, Canberra, Australia Tel: +61 2 61257665; E-mail: christine.phillips@anu.edu.au Curr Opin Allergy Clin Immunol. 2008;8(3):232-237. 2008 Lippincott Williams & Wilkins