CMAJ • September 13, 2005; 173 (6_suppl).
© 2005 CMA Media Inc. or its licensors
All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association.
Pharmacotherapy — add-on therapies
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Literature review
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A literature search was carried out using MEDLINE and Google search engines and the NIH database and the key words "children" (and "pediatric"), "asthma," and 1 of "inhaled corticosteroids," "corticosteroids, add-on," "theophylline," "sodium cromoglycate," "nedocromil" and "omalizumab." Also included were the references from the Canadian Asthma Consensus Report, 1999,1 the update in 2001,2 the Third International Pediatric Consensus Statement on the Management of Childhood Asthma3 and the guidelines of the Global Initiative on Asthma.4 References were also obtained from the scientific departments of AstraZeneca, MerckFrosst and GlaxoWellcome. Publications through to December 2004 were also reviewed, but they contained insufficient data on the young child with asthma to modify our recommendations.
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Current evidence
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ICSs are the agents of first choice for children with asthma. When control is inadequate despite the use of ICSs, the 1999 guidelines1 recommend assessment to confirm the following:
- good delivery technique
- compliance with treatment
- the absence of a complicating illness (i.e., sinus disease, reflux)
- the absence of an alternative disease (cystic fibrosis, immunodeficiency, etc.)
Level V evidence (group opinion) suggests that most children with asthma will have adequate long-term control with ICSs alone and will not require additional therapy. For the minority of children with asthma who require additional therapy, there are several options.
ICSs and long-acting bronchodilators (LABAs)
Studies of patients under 12 years of age can be divided into 2 types: studies in which the addition of LABA (salmeterol or formoterol) was compared with the existing dose of ICS and studies comparing LABA with placebo. In the latter, children continued to take their usual medications, 1 of which might be an inhaled steroid.
Of the 11 studies in this group,5,6,7,8,9,10,11,12,13,14,15 7 were published before the previous update. Nine of the studies involve salmeterol5,6,7,8,9,10,11,12,13 and 2 formoterol.14,15 A total of 2326 children took part in the salmeterol studies and 804 in the formoterol studies.
In 9 studies, the primary outcome measure was pulmonary function (FEV1, PEF, methacholine challenge); in 1 study, the primary outcome measure was quality of life. In contrast to adult studies, none of these used frequency of asthma exacerbation as the primary end point.
In summary, this group of studies provides evidence that LABAs, when added to an ICS, improve pulmonary function, sometimes reduce symptoms and the use of rescue ß- agonist and are safe. Concerns remain about tachyphlaxis to LABA with long-term use. There is no evidence that they reduce exacerbation frequency or can be used to reduce the dose of ICS.
No studies compare salmeterol and formoterol as add-on therapies.
One study16 examined the effectiveness of adding a LABA compared with doubling the dose of inhaled steroid in 177 children on regular ICSs with symptoms of inadequate asthma control (several nocturnal awakenings per week). Study duration was 1 year and the primary outcome measure was FEV1. There were 3 arms: beclomethasone dipropionate, 400 µg/day; beclomethasone dipropionate, 400 µg/day, plus salmeterol, 100 µg/day; and beclomethasone dipropionate, 800 µg/day. All 3 groups showed similar significant improvement in asthma control throughout the study and there were no differences in FEV1 or in any of the secondary outcome measures (daytime and nighttime symptoms, morning PEF, methacholine challenge, exacerbation rates). There was no evidence of tolerance to salmeterol. In the beclomethasone plus salmeterol group, when salmeterol was discontinued, FEV1 decreased significantly (5.6%). On the negative side, growth was significantly slower in the beclomethasone dipropionate (800 mg) group.16 This investigation suggests that there is limited added benefit of LABA or even doubling the dose of ICS in children with mild-to-moderate persistent asthma. A limitation of this study is the fact that the doses used are now recognized as being near the top of the beclomethasone dipropionate dose–response curve.
LTRAs as add-on therapy
Three studies17,18,19 of LTRAs as add-on therapy involved 1304 patients; 2 of the studies were published since the last formal guidelines. No studies compare adding an LTRA with doubling of the ICS dose. The results are based on studies in which subgroups of patients happened to be using ICS. Montelukast is the only LTRA that has been studied in children. Compared with placebo, montelukast led to improvement in pulmonary function (FEV1), better quality of life, a decrease in the use of rescue ß-agonist (by approximately a third) and a decrease in the total number of days the patient experienced an asthma exacerbation. There was no evidence of tolerance to a bronchodilator response nor were there any concerns regarding adverse events.
The response to the use of an LTRA was independent of the use of ICSs. The response to the LTRA was the same regardless of ongoing use of an ICS. Thus, the study investigators concluded that the effect of LTRAs was additive to that of ICSs.
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Implications for research
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- 1. In mild-to-moderate and moderate-to-severe pediatric asthma, comparison of a lower dose of ICS (e.g., beclomethasone 200 mg/day) with beclomethasone plus salmeterol and with a moderate dose of beclomethasone (e.g., 400 mg/d).
- 2. In children with mild-to-moderate asthma, comparison of ICS plus LABA with ICS plus LTRA.
- 3. In mild persistent asthma, comparison of low-dose and moderate-dose ICS with placebo and comparison of low-dose ICS with montelukast and with placebo.
- 4. Population studies to indicate the prevalence of mild intermittent, and mild, moderate and severe asthma.
- 5. Delivery and safety studies in children under 5 years of age.
- 6. Studies of montelukast as intermittent therapy for intermittent asthma.
- 7. Development of better methods to assess asthma severity, control and airway inflammation and repair in children.
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Implementation strategies
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- 1. Introduce the asthma guidelines as previously recommended.
- 2. Consider a similar strategy to involve the public via an already established and credible organization.
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References
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- Boulet LP, Becker A, Bérubé D, Beveridge R, Ernst P. Canadian asthma consensus report, 1999. CMAJ 1999;161(11 suppl):S1-62.
- Boulet LP, Bai TR, Becker A, Bérubé D, Beveridge R, Bowie DM, et al. What is new since the last (1999) Canadian Asthma Consensus Guidelines? Can Respir J 2001;8(suppl A):5-27A.
- Warner JO, Naspitz CK. Third International Pediatric Consensus statement on the management of childhood asthma. International Pediatric Asthma Consensus Group. Pediatr Pulmonol 1998;25(1):1-17.[CrossRef][Medline]
- Von Mutius E. Presentation of the new GINA guidelines for paediatrics. The Global Initiative on Asthma. Clin Exp Allergy 2000;30(suppl 1):6-10.
- Meijer GG, Postma DS, Mulder PG, van Aalderen WM. Long-term circadian effects of salmeterol in asthmatic children treated with inhaled corticosteroids. Am J Respir Crit Care Med 1995;152(6 pt 1):1887-92.[Abstract]
- Russell G, Williams DA, Weller P, Price JF. Salmeterol xinafoate in children on high dose inhaled steroids. Ann Allergy Asthma Immunol 1995;75(5):423-8.[Medline]
- Lenney W, Pedersen S, Boner AL, Ebbutt A, Jenkins MM. Efficacy and safety of salmeterol in childhood asthma. Eur J Pediatr 1995;154(12):983-90.[CrossRef][Medline]
- von Berg A, de Blic J, la Rosa M, Kaad PH, Moorat A. A comparison of regular salmeterol vs ‘as required’ salbutamol therapy in asthmatic children. Respir Med 1998;92(2):292-9.[Medline]
- Zarkovic J, Gotz MH, Holgate ST, Taak NK. Effect of long-term regular salmeterol treatment in children with moderate asthma. Clin Drug Invest 1998;15(3):169-75.
- Weinstein SF, Pearlman DS, Bronsky EA, Byrne A, Arledge T, Liddle R, et al. Efficacy of salmeterol xinafoate powder in children with chronic persistent asthma. Ann Allergy Asthma Immunol 1998;81(1):51-8.[Medline]
- Mahajan P, Stahl E, Arledge T. Quality of life in pediatric asthma patients treated with salmeterol and impact on the daily activities of their patients. Pediatr Asthma Allergy Immunol 1998;12:21-8.
- Van den Berg NJ, Ossip MS, Hederos CA, Anttila H, Ribeiro BL, Davies PI. Salmeterol/fluticasone proprionate (50/100 microg) in a Diskus inhaler (Seretide) is effective and safe in children with asthma. Pediatr Pulmonol 2000;30(2):97-105.[CrossRef][Medline]
- Byrnes C, Shrewsbury S, Barnes PJ, Bush A. Salmeterol in paediatric asthma. Thorax 2000;55(9):780-4.[Abstract/Free Full Text]
- Bensch G, Berger WE, Blokhin BM, Socolovsky AL, Thomson MH, Till D, et al. One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma. Ann Allergy Asthma Immunol 2002;89(2):180-90.[Medline]
- Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, et al. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids alone in the treatment of asthma. Pediatr Pulmonol 2002;34(5):342-50.[CrossRef][Medline]
- Verberne AA, Frost C, Duiverman EJ, Grol MH, Kerrebijn KF. Addition of salmeterol versus doubling the dose of beclomethasone in children with asthma. Am J Respir Crit Care Med 1998;158(1):213-9.
- Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSpouef P, Santanello N, et al. Montelukast, a leukotriene receptor antagonist, for treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108(3):1-10.[Abstract/Free Full Text]
- Knorr B, Matz J, Bernstein JA, Nguyen H, Seidenberg BC, Reiss TF, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. Pediatric Montelukast Study Group. JAMA 1998;279(15):1181-6.[Abstract/Free Full Text]
- Simons FE, Villa JR, Lee BW, Teper AM, Lyttle B, Aristizabal G, et al. Montelukast added to budesonide in children with persistent asthma: a randomized double-blind crossover study. J Pediatr 2001;138(5):694-8.[CrossRef][Medline]
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Literature review
Current evidence
