- Email: [email protected]
Can Montelukast Shorten Prednisolone Therapy in Children with Mild to Moderate Acute Asthma? A Randomized Controlled Trial
Can Montelukast Shorten Prednisolone Therapy in Children with Mild to Moderate Acute Asthma? A Randomized Controlled Trial Suzanne Schuh, MD, FRCPC, Andrew R. Willan, PhD, Derek Stephens, MSc, Paul T. Dick, MDCM, FRCPC, and Allan Coates, MD, FRCPC Objective To examine whether outpatient post-stabilization therapy with montelukast produces more treatment failures than prednisolone.
Study design In this randomized, double-blind, double-dummy non-inferiority trial, 130 children 2 to 17 years of age with mild to moderate acute asthma stabilized with prednisolone in the emergency department received 5 daily treatments with either prednisolone or montelukast after discharge. The primary outcome was treatment failure within 8 days (ie, an asthma-related unscheduled visit, hospitalization, or additional systemic corticosteroids). Results The rates of treatment failure were 7.9% in the prednisolone group and 22.4% in the montelukast group (95% CI, 26.5%–2.4%). Treatment was more likely to fail in younger patients (odds ratio, 4.9). In the montelukast group, more patients received additional pharmacotherapy than in patients receiving prednisolone (23.9% versus 9.5%, P = .03). The differences in the daily salbutamol treatments, asymptomatic days, and changes in the Pediatric Respiratory Assessment Measure score were not significant (P = .85, .75, and .26, respectively). Conclusion Montelukast does not represent an adequate alternative to corticosteroids after outpatient stabilization in mild to moderate acute asthma. This population should receive oral corticosteroids after discharge. (J Pediatr 2009;155:795-800). pproximately 5 million children in the United States have acute asthma.1 Most cases are of mild to moderate severity,2 and virtually all cases are treated with oral corticosteroids for 5 to 7 days.3,4 Although corticosteroid-related adverse effects are usually associated with long-term use, there is some concern about the safety of repetitive courses of these agents, particularly in patients with frequent exacerbations,5,6 leading to poor treatment compliance by patients and parents7 and to under-prescribing of oral corticosteroids with suboptimal outcomes.4 Only 40% of children who are discharged from the hospital with acute asthma receive corticosteroids in the emergency department (ED) with a prescription for use at home.8 The course of corticosteroids is also frequently shortened, and inhaled corticosteroids or leukotriene antagonists intended for prevention are continued.9,10 Examination of alternate anti-inflammatory corticosteroid-sparing therapies would therefore be of interest. The levels of cysteinyl-leukotrienes in the airway and urine correlate with acute asthma severity.11-13 Montelukast blocks the pro-inflammatory effects of leukotrienes through a mechanism distinct from corticosteroids,14 with a maximum benefit within 24 hours of therapy.15 This agent is currently recommended for preventive therapy in children with mild persistent asthma.16 Its main advantage over systemic steroids relates to its lack of adverse effects with long-term use.17 Earlier research in adults and children with acute asthma has shown the clinical benefit of adding montelukast to concomitant treatment limited to inhaled ß2 agonists18-20 and reduction in healthcare use when given to children at the first sign of asthma exacerbation in a non-ED setting.21 However, virtually all children treated in the ED for asthma receive oral steroids during stabilization and after discharge. The potential role of montelukast in successfully reducing steroid exposure in children with acute asthma has not been defined. If this were found to be the case, montelukast might offer a useful post-stabilization treatment option in relatively mild pediatric asthma exacerbations. Specifically, the primary objective of this study was From the Divisions of Pediatric Emergency Medicine to examine whether pediatric outpatients with mild to moderate acute asthma (S.S.), Pediatric Medicine (P.D.), Respirology (A.C.), who are discharged from the ED receiving oral montelukast experience treatDepartment of Pediatrics and Research Institute (A.W., D.S.), The Hospital for Sick Children, University of ment failure not significantly greater than pediatric outpatients who are given Toronto, Toronto, Ontario, Canada prednisolone. Funded as an investigator-initiated study by Merck
A
ED PI PRAM
Emergency department Pulmonary Index Pediatric Respiratory Assessment Measure
Frosst Canada Ltd (S.S.). The funding organization had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors declare no conflicts of interest. Registered with www.clinicaltrials.gov (NCT00213252). 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.06.008
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Methods This was a convenience sample, with enrollment when 1 of 4 trained study nurses was on duty. The nurses were notified about children with acute asthma seen between 8:00 a.m. and midnight in our ED from September 2005 to February 2008. Children were eligible when they were at least 2 years old and had mild to moderate exacerbation, defined as a baseline Pediatric Respiratory Assessment Measure (PRAM) score <8 points2 and Pulmonary Index (PI) score <11.22 Excluded were patients without history of wheezing and bronchodilator therapy, patients who had received more than a single dose of oral prednisolone or >250 mcg per day of inhaled fluticasone within 72 hours, and children who had received montelukast within 7 days. We also excluded children with >2 earlier visits to our asthma clinic, patients previously admitted to the intensive care unit for asthma or hospitalized >3 times within the previous year, patients with pulmonary, cardiac, or neuromuscular disease or immunodeficiency, patients in contact with varicella within 21 days, and families with insufficient command of the English language. The study was approved by our research ethics board, and written consent was obtained from each patient/parent. A log of patients who were missed, excluded, or refused participation was kept to assess generalizability. This study was registered with www. clinicaltrials.gov (NCT00213252). We conducted a randomized, double-blind, doubledummy non-inferiority trial in which study nurses gave all eligible children 2 mg/kg (maximum, 60 mg) oral prednisone or 5 mg/dose prednisolone and nebulized albuterol with 250 mcg/dose ipratropium bromide in 2 mL normal saline via Hudson nebulizer at 0, 30, and 60 minutes and as often as hourly thereafter. Children requiring in-hospital therapy after 8 hours were hospitalized and were not eligible for randomization. Patients discharged from the hospital by hour 8 were randomized to receive either continued 1 mg/kg prednisone/prednisolone or montelukast (4 mg, 5 mg, and 10 mg in children 2-5, 6-14, and 5-17 years of age, respectively) at 24, 48, 72, 96, and 120 hours after randomization. They were also instructed to take 500 mcg of albuterol via metered dose inhaler/valved holding chamber every 4 hours as needed for 5 more days and to start taking 100 mcg fluticasone twice a day via metered dose inhaler on day 7 for 4 weeks. Children who vomited the experimental medications within 30 minutes received another dose; further vomiting necessitated withdrawal from the study. All children were instructed to visit their physician within 48 hours and also if they experienced severe persistent cough, shortness of breath, tight chest, or other concerning symptoms. All decisions about further therapy were made by physicians unaware of treatment assignment. Four trained study nurses phoned the families daily whenever possible to identify return for care, therapies outside the protocol, and continued symptoms. Two additional trained study nurses visited the patients’ homes at 48 hours and on day 8 to assess their respiratory status and confirm the primary outcome. All 796
Vol. 155, No. 6 participating patients were given a letter for their primary care provider outlining the study goals and encouraging physicians to use additional medications only when medically necessary for persistent or worsening asthma symptoms. Before therapy in the ED, 1 of the 4 study nurses documented relevant medical history and obtained demographic information. At this time, the nurse also measured baseline disease severity, including the validated PRAM score,2 and obtained information on symptoms within the past 24 hours.23 A permuted block randomization code stratified by age was prepared by our research pharmacist from a computergenerated list of random numbers. The pharmacist prepared sequential sealed packets containing the study drugs. The randomization code was secured at our pharmacy until enrollment and analysis decisions were terminated. The study nurses and parents were unable to determine which intervention was given. Masking of Treatment Allocation Children allocated to the montelukast group received an ageappropriate dose of montelukast, manufactured by Merck Frosst (Montreal, Quebec, Canada), and a weight- appropriate dose of prednisolone/prednisone placebo-equivalent syrup or capsule manufactured by our pharmacy. Patients assigned to the prednisolone group received an equivalent dose of montelukast placebo supplied by Merck Frosst and active prednisone/prednisolone. The active and placebo experimental drugs were identical in appearance, taste, and smell. Patients, study nurses, and physicians were blinded to treatment assignment; co-interventions were also given without knowledge of the group to which the patients belonged and of the outcome measurements. Outcome Measures The primary outcome measure was a treatment failure occurring between discharge home and day 8, defined as an asthma-related unscheduled visit or hospitalization to any medical facility or treatment with systemic corticosteroids outside the experimental protocol for asthma symptoms. This was determined through standardized telephone interviews carried out by the study nurses and confirmed by them whenever possible through a review of the patient electronic database. We also examined the association between the main treatment effect and the patients’age, baseline PRAM score, and atopy, defined as either personal or family history of such in first-degree relatives. Other secondary outcome measures by day 8 consisted of the number of inhaled albuterol treatments per day after discharge, the total number of days without asthma symptoms, and the PRAM score2 at 48 hours and on day 8. Statistical Analysis A biostatistician who was not otherwise involved in the study performed the data analysis (SAS software version 9.1, SAS Inc., Cary, North Carolina). The sample size for this nonSchuh et al
ORIGINAL ARTICLES
December 2009 inferiority trial is based on the null hypothesis that the proportion of treatment failures in the montelukast group was at least 5 percentage points higher than that in the prednisolone group. A rejection of the null hypothesis would lead to the conclusion that montelukast is not inferior and could be considered as a therapeutic option. If the proportion of treatment failures in the montelukast group was at least 5 percentage points worse than that in the prednisolone group, we limited the probability of rejecting the null hypothesis to 5% to have 95% probability of retaining standard treatment. Total sample sizes of 190 and 130 patients provide 95% and 80% probability, respectively, of rejecting the null hypothesis if montelukast was superior by 15 percentage points.24 Although we had originally aimed at achieving the former scenario, the latter sample size was obtained because of a lack of funds. The primary analysis was performed by determining the lower limit for the 95% CI for the observed difference of the rate of treatment failure in the prednisolone group minus that in the montelukast group. If this lower limit excluded (ie, was to the right of) –0.05, the null hypothesis would be rejected. The intent-to-treat analysis was performed on all randomized patients. Furthermore, we performed a sensitivity analysis on all patients taking medications as per protocol. As part of the secondary analyses, a logistic regression analysis was performed to determine the effect of the age, baseline PRAM score, and atopy on the primary outcome measure. We also used the Student t test to examine both the difference in the mean number of albuterol treatments received per day and the total number of asymptomatic days in the 2 groups; the log rank test was used to compare the differences in the proportions of patients remaining without additional therapy with time. The differences in the changes in the PRAM score from baseline to 48 hours and day 8 were analyzed with repeated measures analysis of variance, as were the changes in the symptoms score with time within 8 days. Two safety interim analyses were performed with the Haybittle-Peto method25 after 30 and 100 randomized patients; results of both were non-significant. Because the interim analyses tested a different null hypothesis from the final analysis, adjustment in the sample size was not necessary.
Results Between September 2005 and February 2008, 2216 children $2 years of age were seen in our ED with a diagnosis of acute asthma. Of these, 799 were not examined because they presented at times when the research nurses were not available, and 1417 patients were reviewed for eligibility. A total of 395 children had no distress and did not require corticosteroids, 670 children met the exclusion criteria, 66 children were hospitalized before randomization, 127 children refused participation, and 25 patients had been enrolled earlier. Therefore, 134 children were randomized: 69 to the montelukast group and 65 to the prednisolone group. In each group, 1 patient subsequently withdrew consent, and 1 patient could not be contacted despite multiple attempts. Therefore 130 patients were included in the primary analysis, with 67 allocated at random to the mon-
Table I. Baseline characteristics of the study groups Characteristic Age (years)* Male sex (%) History of atopy (%) Family history of atopy (%) Hospitalizations for asthma in last year (%) Duration of respiratory distress (hours)* Prior prednisolone (1 dose; %) Baseline PRAM score* Baseline respiratory rate* Baseline oxygen saturation (%)
Montelukast group Prednisolone group (n = 67) (n = 63) 5.7 3.4 43 (64.2) 27 (40.3) 50 (74.6) 0.2 0.7
5.00 2.9 43 (68.3) 32 (50.8) 44 (69.8) 0.3 0.7
27.6 26.8
25.3 18.0
3 (4.5) 3.5 1.7 39.3 18.1 95.8 2.4
2 (3.2) 4.1 1.6 39.2 11.8 95.4 2.5
*Mean SD.
telukast group and 63 to the prednisolone group. The patients enrolled were comparable with children who were not enrolled in age and sex. The 2 study groups were comparable in their demographic and clinical characteristics (Table I). Deviations from the protocol were uncommon (7 patients, 5.4%). Five patients stopped taking the experimental therapy prematurely (3 in the prednisolone group, 2 in the montelukast group), 1 patient vomited the experimental syrup (prednisolone group), and 1 boy ate all his montelukast tablets on day 2 without any ill effects. A total of 119 families agreed to home visits at 48 hours (montelukast group, 58; prednisolone group, 61), and 114 were visited on day 8 (montelukast group, 55; prednisolone group, 59). Treatment failure occurred in 5 of 63 patients in the prednisolone group (7.9%) and 15 of 67 in the montelukast group (22.4%). The difference between groups was –14.5% (95% CI, –26.5%-–2.4%). The results of the sensitivity analysis performed on the patients taking medications as per protocol is not reported because it yielded similar results. All children experiencing treatment failure underwent asthma-related unscheduled medical visits; none were hospitalized. In the montelukast group, 9 patients received oral corticosteroids outside the protocol, versus 3 patients in the prednisolone group. Other Outcomes Regression-based adjustment of the primary outcome for age, atopy, and baseline PRAM score showed a significant independent association of the treatment effect and young age (Table II). Patients between 2 and 3 years of age were approximately 5 times as likely to return for care as their older counterparts. Twenty-two patients received pharmacotherapy outside the protocol within the 8-day period (additional bronchodilators,
Table II. Adjusted odds ratios for a return for care Variable
Odds ratio
95% CI
Overall treatment effect Age #3 years Atopy history (personal or family) Baseline PRAM score $4
3.95 4.89 0.39 1.64
1.27-14.42 1.66-15.22 0.12-1.35 0.55-5.08
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Figure. Proportion of patients remaining without any additional therapy with time.
steroids, antibiotics, and cough syrup), 16 of 67 patients in the montelukast group (23.9%) and 6 of 63 patients in the prednisolone group (9.5%; P = .03). The proportion of patients remaining without additional therapy with time is illustrated in the Figure (P value for the difference, .009). The mean number of inhaled albuterol treatments given per day during the 8-day observational period was 2.7 1.3 in the montelukast group and 2.8 1.1 in the prednisolone group (P = .85). The mean total number of days without asthma symptoms in the montelukast- versus prednisolonetreated patients was 1.4 1.3 and 1.3 1.4, respectively (P = .75). The differences in improvement in the mean PRAM score from baseline with time were also comparable in the 2 groups, and they are summarized in Table III (P value for the overall difference, .26). Adverse Effects In the montelukast group, adverse effects developed in 3 patients. One patient experienced facial swelling of unknown etiology at 96 hours, another patient had vomiting and diar-
Table III. Changes in the PRAM score with time in the 2 study groups Montelukast group
Prednisolone group
Time
n
PRAM*
n
PRAM*
Baseline 48 hours Day 8
67 61 59
3.5 1.7 2.1 1.9 0.3 0.8
63 58 55
4.1 1.6 2.2 2.0 0.4 0.9
Overall P value for the difference is .26. *Mean SD.
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rhea at 72 hours, and the third patient complained of abdominal and leg pains on day 4. None of these patients required treatment for these events, and the relationship between montelukast and the ‘‘event’’ is questionable. No adverse effects developed in the children given prednisolone after discharge.
Discussion Because montelukast therapy did not yield a comparable treatment outcome and actually proved to have a significantly higher rate of treatment failures compared with prednisolone, our results show that children with mild to moderate acute asthma should take oral corticosteroids after discharge from the ED. Anti-leukotriene agents do not represent an adequate anti-inflammatory alternative to corticosteroids after the initial outpatient stabilization. Earlier studies also suggest that treatment of this population with a single dose of long-acting oral dexamethasone appears comparable with a 5-day course of oral prednisolone and constitutes a reasonable option.26 The most likely explanation for these results centers on the lower potency of montelukast compared with glucocorticosteroids.27 The main hypothesis behind the effect of montelukast lies in its synergism with ß2 agonists28 and ability to regulate ß2 receptors and reduce airway edema.29 However, when added to oral corticosteroids, montelukast did not produce additional improvement in the FEV1 in the ED management of moderate pediatric acute asthma,30 likely because of the high efficacy of corticosteroids.30 Although montelukast counteracts the inflammatory effect of leukotrienes, prednisolone exhibits a broader impact on T cells, eosinophils, and other inflammatory cells.31 Schuh et al
ORIGINAL ARTICLES
December 2009 Patients vary in their response to leukotriene modifiers because of their pharmacogenetic profile.32 The financial limitations and logistic restrictions of the acute care setting did not allow us to obtain this information in our patients. The doses of montelukast used in our study were derived from patients with stable chronic asthma.33 However, the receptor becomes fully saturated at these doses, and higher amounts do not lead to further bronchodilation. Our results also show an independent association of the treatment effect with young age. The effects of even mild airway inflammation will have more consequence in young children because they have smaller airway diameter than their older counterparts and a similar amount of airway edema will cause a much greater increase in airway resistance. Earlier research on montelukast in pediatric acute asthma is limited by patient population and outcome selection. The positive results in the study by Harmanci et al focusing on children with mild exacerbations seen outside the ED and not requiring corticosteroids are unlikely to be generalizable to the acute care setting.20 The authors used a clinical score to measure severity within 4 hours of treatment, which may not translate into extended health care outcomes. In contrast, we chose a return for care or treatment with extra corticosteroids to illustrate the difference in the use of health care resources or significant interventions in the 2 groups seen in the ED, which enhances the generalizability of the study results. This was a single center study with its potential issue of external generalizability. However, the indications for return visits and co-interventions were clearly delineated and consistent with those used elsewhere, and our results should therefore be generalizable to other pediatric EDs. Some may also wonder why the substantial differences in this outcome were not reflected in the PRAM score changes or number of asymptomatic days. The PRAM score was designed to measure respiratory distress in the ED and may not reflect the reasons for unscheduled visits in mild disease. The telephone symptom review is not sensitive enough to reflect actual return for care, and the accuracy of parental recall of symptoms may also be suboptimal. Even relatively mild asthma symptoms may cause anxiety in parents, particularly those caring for young children, who may require reassurance. In conclusion, the treatment failure in children with mild to moderate acute asthma stabilized in the ED and discharged receiving montelukast failed to reach criteria for non-inferiority and proved to be significantly higher compared with that in children given prednisolone. This population should take oral corticosteroids after discharge. n The authors thank Richard Raptopoulos, RN, Audrey Bell-Peters, RN, and Cynthia Bailey, RN, for their assistance. Submitted for publication Jan 8, 2009; last revision received Mar 23, 2009; accepted Jun 5, 2009. Reprint requests: Dr Suzanne Schuh, Division of Paediatric Emergency Medicine, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. E-mail: [email protected].
Refernces 1. Kozak LJ, Owings MF, Hall MJ. National Hospital Discharge Survey: 2002 annual summary with detailed diagnosis and procedure data. Vital Health Stat 2005;13:1-199. 2. Ducharme FM, Chalut D, Plotnick L, Savdie C, Kudirka D, Zhang X, et al. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr 2008;152:476-80. 3. Schuh S, Reisman J, Alshehri M, Dupuis A, Corey M, Arseneault R, et al. A comparison of inhaled fluticasone and oral prednisone for children with severe acute asthma. N Engl J Med 2000;343:689-94. 4. National Asthma Education and Prevention Program. Expert Panel Report 2: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung and Blood Institute; 1997. p. 4051. 5. Dolan LM, Keserwala HH, Holroyde JC, Fischer TJ. Short-term, highdose, systemic steroids in children with asthma: the effect on the hypothalamic-pituitary-adrenal axis. J Allergy Clin Immunol 1987;80:81-7. 6. Wolthers OD, Pedersen S. Short term linear growth in asthmatic children during treatment with prednisolone. BMJ 1990;301:145-8. 7. Crain EF, Weiss KB, Fagan MJ. Pediatric asthma care in US emergency departments. Current practice in the context of the National Institutes of Health guidelines. Arch Pediatr Adolesc Med 1995;149:893-901. 8. Knapp JF, Simon SD, Sharma V. Quality of care for common pediatric respiratory illnesses in United States emergency departments: analysis of 2005 National Hospital Ambulatory Medical Care Survey Data. Pediatrics 2008;122:1165-70. 9. Spector S. Noncompliance with asthma therapy—are there solutions? J Asthma 2000;37:381-8. 10. Butler K, Cooper WO. Adherence of pediatric asthma patients with oral corticosteroid prescriptions following pediatric emergency department visit or hospitalization. Pediatr Emerg Care 2004;20:730-5. 11. Wardlaw AJ, Hay H, Cromwell O, Collins JV, Kay AB. Leukotrienes, LTC4 and LTB4, in bronchoalveolar lavage in bronchial asthma and other respiratory diseases. J Allergy Clin Immunol 1989;84:19-26. 12. Drazen JM, O’Brien J, Sparrow D, Weiss ST, Martins MA, Israel E, et al. Recovery of leukotriene E4 from the urine of patients with airway obstruction. Am Rev Respir Dis 1992;146:104-8. 13. Green SA, Malice MP, Tanaka W, Tozzi CA, Reiss TF. Increase in urinary leukotriene LTE4 levels in acute asthma: correlation with airflow limitation. Thorax 2004;59:100-4. 14. Bisgaard H. Leukotriene modifiers in pediatric asthma management. Pediatrics 2001;107:381-90. 15. Knorr B, Nguyen HH, Kearns GL, Villaran C, Boza ML, Reiss TF, et al. Montelukast dose selection in children ages 2 to 5 years: comparison of population pharmacokinetics between children and adults. J Clin Pharmacol 2001;41:612-9. 16. Global Initiative for Asthma. Global strategy for asthma management and prevention 2003. Bethesda, MD: National Institute of Health; 2003. Publication No. 02-3659. 17. Knorr B, Franchi LM, Bisgaard H, Vermeulen JH, LeSouef P, Santanello N, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001;108:E48. 18. Camargo CA Jr., Smithline HA, Malice MP, Green SA, Reiss TF. A randomized controlled trial of intravenous montelukast in acute asthma. Am J Respir Crit Care Med 2003;167:528-33. 19. Silverman RA, Nowak RM, Korenblat PE, Skobeloff E, Chen Y, Bonuccelli CM, et al. Zafirlukast treatment for acute asthma: evaluation in a randomized, double-blind, multicenter trial. Chest 2004;126:1480-9. 20. Harmanci K, Bakirtas A, Turktas I, Degim T. Oral montelukast treatment of preschool-aged children with acute asthma. Ann Allergy Asthma Immunol 2006;96:731-5. 21. Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007;175:323-9.
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22. Becker AB, Nelson NA, Simons FE. The pulmonary index. Assessment of a clinical score for asthma. Am J Dis Child 1984;138:574-6. 23. Santanello NC, Davies G, Galant SP, Pedinoff A, Sveum R, Seltzer J, et al. Validation of an asthma symptom diary for interventional studies. Arch Dis Child 1999;80:414-20. 24. Willan AR. Power function arguments in support of an alternative approach for analyzing management trials. Control Clin Trials 1994; 15:211-9. 25. Geller NL, Pocock SJ. Interim analyses in randomized clinical trials: ramifications and guidelines for practitioners. Biometrics 1987;43:213-23. 26. Altamimi S, Robertson G, Jastaniah W, Davey A, Dehghani N, Chen R, et al. Single-dose oral dexamethasone in the emergency management of children with exacerbations of mild to moderate asthma. Pediatr Emerg Care 2006;22:786-93. 27. Peters SP. Leukotriene receptor antagonists in asthma therapy. J Allergy Clin Immunol 2003;111(1 Suppl):S62-70.
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Vol. 155, No. 6 28. Hui KP, Barnes NC. Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist. Lancet 1991;337:1062-3. 29. Kuitert LM, Barnes NC. Leukotriene receptor antagonists: useful in acute asthma? Thorax 2000;55:255-6. 30. Nelson KA, Smith SR, Trinkaus K, Jaffe DM. Pilot study of oral montelukast added to standard therapy for acute asthma exacerbations in children aged 6 to 14 years. Pediatr Emerg Care 2008;24:21-7. 31. Malavige GN. Why glucocorticoids are better than leukotriene receptor antagonists. BMJ 2003;326:621. 32. Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H, et al. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med 2006;173:379-85. 33. Bronsky EA, Kemp JP, Zhang J, Guerreiro D, Reiss TF. Dose-related protection of exercise bronchoconstriction by montelukast, a cysteinyl leukotriene-receptor antagonist, at the end of a once-daily dosing interval. Clin Pharmacol Ther 1997;62:556-61.
Schuh et al
Study design In this randomized, double-blind, double-dummy non-inferiority trial, 130 children 2 to 17 years of age with mild to moderate acute asthma stabilized with prednisolone in the emergency department received 5 daily treatments with either prednisolone or montelukast after discharge. The primary outcome was treatment failure within 8 days (ie, an asthma-related unscheduled visit, hospitalization, or additional systemic corticosteroids). Results The rates of treatment failure were 7.9% in the prednisolone group and 22.4% in the montelukast group (95% CI, 26.5%–2.4%). Treatment was more likely to fail in younger patients (odds ratio, 4.9). In the montelukast group, more patients received additional pharmacotherapy than in patients receiving prednisolone (23.9% versus 9.5%, P = .03). The differences in the daily salbutamol treatments, asymptomatic days, and changes in the Pediatric Respiratory Assessment Measure score were not significant (P = .85, .75, and .26, respectively). Conclusion Montelukast does not represent an adequate alternative to corticosteroids after outpatient stabilization in mild to moderate acute asthma. This population should receive oral corticosteroids after discharge. (J Pediatr 2009;155:795-800). pproximately 5 million children in the United States have acute asthma.1 Most cases are of mild to moderate severity,2 and virtually all cases are treated with oral corticosteroids for 5 to 7 days.3,4 Although corticosteroid-related adverse effects are usually associated with long-term use, there is some concern about the safety of repetitive courses of these agents, particularly in patients with frequent exacerbations,5,6 leading to poor treatment compliance by patients and parents7 and to under-prescribing of oral corticosteroids with suboptimal outcomes.4 Only 40% of children who are discharged from the hospital with acute asthma receive corticosteroids in the emergency department (ED) with a prescription for use at home.8 The course of corticosteroids is also frequently shortened, and inhaled corticosteroids or leukotriene antagonists intended for prevention are continued.9,10 Examination of alternate anti-inflammatory corticosteroid-sparing therapies would therefore be of interest. The levels of cysteinyl-leukotrienes in the airway and urine correlate with acute asthma severity.11-13 Montelukast blocks the pro-inflammatory effects of leukotrienes through a mechanism distinct from corticosteroids,14 with a maximum benefit within 24 hours of therapy.15 This agent is currently recommended for preventive therapy in children with mild persistent asthma.16 Its main advantage over systemic steroids relates to its lack of adverse effects with long-term use.17 Earlier research in adults and children with acute asthma has shown the clinical benefit of adding montelukast to concomitant treatment limited to inhaled ß2 agonists18-20 and reduction in healthcare use when given to children at the first sign of asthma exacerbation in a non-ED setting.21 However, virtually all children treated in the ED for asthma receive oral steroids during stabilization and after discharge. The potential role of montelukast in successfully reducing steroid exposure in children with acute asthma has not been defined. If this were found to be the case, montelukast might offer a useful post-stabilization treatment option in relatively mild pediatric asthma exacerbations. Specifically, the primary objective of this study was From the Divisions of Pediatric Emergency Medicine to examine whether pediatric outpatients with mild to moderate acute asthma (S.S.), Pediatric Medicine (P.D.), Respirology (A.C.), who are discharged from the ED receiving oral montelukast experience treatDepartment of Pediatrics and Research Institute (A.W., D.S.), The Hospital for Sick Children, University of ment failure not significantly greater than pediatric outpatients who are given Toronto, Toronto, Ontario, Canada prednisolone. Funded as an investigator-initiated study by Merck
A
ED PI PRAM
Emergency department Pulmonary Index Pediatric Respiratory Assessment Measure
Frosst Canada Ltd (S.S.). The funding organization had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. The authors declare no conflicts of interest. Registered with www.clinicaltrials.gov (NCT00213252). 0022-3476/$ - see front matter. Copyright Ó 2009 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.06.008
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Methods This was a convenience sample, with enrollment when 1 of 4 trained study nurses was on duty. The nurses were notified about children with acute asthma seen between 8:00 a.m. and midnight in our ED from September 2005 to February 2008. Children were eligible when they were at least 2 years old and had mild to moderate exacerbation, defined as a baseline Pediatric Respiratory Assessment Measure (PRAM) score <8 points2 and Pulmonary Index (PI) score <11.22 Excluded were patients without history of wheezing and bronchodilator therapy, patients who had received more than a single dose of oral prednisolone or >250 mcg per day of inhaled fluticasone within 72 hours, and children who had received montelukast within 7 days. We also excluded children with >2 earlier visits to our asthma clinic, patients previously admitted to the intensive care unit for asthma or hospitalized >3 times within the previous year, patients with pulmonary, cardiac, or neuromuscular disease or immunodeficiency, patients in contact with varicella within 21 days, and families with insufficient command of the English language. The study was approved by our research ethics board, and written consent was obtained from each patient/parent. A log of patients who were missed, excluded, or refused participation was kept to assess generalizability. This study was registered with www. clinicaltrials.gov (NCT00213252). We conducted a randomized, double-blind, doubledummy non-inferiority trial in which study nurses gave all eligible children 2 mg/kg (maximum, 60 mg) oral prednisone or 5 mg/dose prednisolone and nebulized albuterol with 250 mcg/dose ipratropium bromide in 2 mL normal saline via Hudson nebulizer at 0, 30, and 60 minutes and as often as hourly thereafter. Children requiring in-hospital therapy after 8 hours were hospitalized and were not eligible for randomization. Patients discharged from the hospital by hour 8 were randomized to receive either continued 1 mg/kg prednisone/prednisolone or montelukast (4 mg, 5 mg, and 10 mg in children 2-5, 6-14, and 5-17 years of age, respectively) at 24, 48, 72, 96, and 120 hours after randomization. They were also instructed to take 500 mcg of albuterol via metered dose inhaler/valved holding chamber every 4 hours as needed for 5 more days and to start taking 100 mcg fluticasone twice a day via metered dose inhaler on day 7 for 4 weeks. Children who vomited the experimental medications within 30 minutes received another dose; further vomiting necessitated withdrawal from the study. All children were instructed to visit their physician within 48 hours and also if they experienced severe persistent cough, shortness of breath, tight chest, or other concerning symptoms. All decisions about further therapy were made by physicians unaware of treatment assignment. Four trained study nurses phoned the families daily whenever possible to identify return for care, therapies outside the protocol, and continued symptoms. Two additional trained study nurses visited the patients’ homes at 48 hours and on day 8 to assess their respiratory status and confirm the primary outcome. All 796
Vol. 155, No. 6 participating patients were given a letter for their primary care provider outlining the study goals and encouraging physicians to use additional medications only when medically necessary for persistent or worsening asthma symptoms. Before therapy in the ED, 1 of the 4 study nurses documented relevant medical history and obtained demographic information. At this time, the nurse also measured baseline disease severity, including the validated PRAM score,2 and obtained information on symptoms within the past 24 hours.23 A permuted block randomization code stratified by age was prepared by our research pharmacist from a computergenerated list of random numbers. The pharmacist prepared sequential sealed packets containing the study drugs. The randomization code was secured at our pharmacy until enrollment and analysis decisions were terminated. The study nurses and parents were unable to determine which intervention was given. Masking of Treatment Allocation Children allocated to the montelukast group received an ageappropriate dose of montelukast, manufactured by Merck Frosst (Montreal, Quebec, Canada), and a weight- appropriate dose of prednisolone/prednisone placebo-equivalent syrup or capsule manufactured by our pharmacy. Patients assigned to the prednisolone group received an equivalent dose of montelukast placebo supplied by Merck Frosst and active prednisone/prednisolone. The active and placebo experimental drugs were identical in appearance, taste, and smell. Patients, study nurses, and physicians were blinded to treatment assignment; co-interventions were also given without knowledge of the group to which the patients belonged and of the outcome measurements. Outcome Measures The primary outcome measure was a treatment failure occurring between discharge home and day 8, defined as an asthma-related unscheduled visit or hospitalization to any medical facility or treatment with systemic corticosteroids outside the experimental protocol for asthma symptoms. This was determined through standardized telephone interviews carried out by the study nurses and confirmed by them whenever possible through a review of the patient electronic database. We also examined the association between the main treatment effect and the patients’age, baseline PRAM score, and atopy, defined as either personal or family history of such in first-degree relatives. Other secondary outcome measures by day 8 consisted of the number of inhaled albuterol treatments per day after discharge, the total number of days without asthma symptoms, and the PRAM score2 at 48 hours and on day 8. Statistical Analysis A biostatistician who was not otherwise involved in the study performed the data analysis (SAS software version 9.1, SAS Inc., Cary, North Carolina). The sample size for this nonSchuh et al
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December 2009 inferiority trial is based on the null hypothesis that the proportion of treatment failures in the montelukast group was at least 5 percentage points higher than that in the prednisolone group. A rejection of the null hypothesis would lead to the conclusion that montelukast is not inferior and could be considered as a therapeutic option. If the proportion of treatment failures in the montelukast group was at least 5 percentage points worse than that in the prednisolone group, we limited the probability of rejecting the null hypothesis to 5% to have 95% probability of retaining standard treatment. Total sample sizes of 190 and 130 patients provide 95% and 80% probability, respectively, of rejecting the null hypothesis if montelukast was superior by 15 percentage points.24 Although we had originally aimed at achieving the former scenario, the latter sample size was obtained because of a lack of funds. The primary analysis was performed by determining the lower limit for the 95% CI for the observed difference of the rate of treatment failure in the prednisolone group minus that in the montelukast group. If this lower limit excluded (ie, was to the right of) –0.05, the null hypothesis would be rejected. The intent-to-treat analysis was performed on all randomized patients. Furthermore, we performed a sensitivity analysis on all patients taking medications as per protocol. As part of the secondary analyses, a logistic regression analysis was performed to determine the effect of the age, baseline PRAM score, and atopy on the primary outcome measure. We also used the Student t test to examine both the difference in the mean number of albuterol treatments received per day and the total number of asymptomatic days in the 2 groups; the log rank test was used to compare the differences in the proportions of patients remaining without additional therapy with time. The differences in the changes in the PRAM score from baseline to 48 hours and day 8 were analyzed with repeated measures analysis of variance, as were the changes in the symptoms score with time within 8 days. Two safety interim analyses were performed with the Haybittle-Peto method25 after 30 and 100 randomized patients; results of both were non-significant. Because the interim analyses tested a different null hypothesis from the final analysis, adjustment in the sample size was not necessary.
Results Between September 2005 and February 2008, 2216 children $2 years of age were seen in our ED with a diagnosis of acute asthma. Of these, 799 were not examined because they presented at times when the research nurses were not available, and 1417 patients were reviewed for eligibility. A total of 395 children had no distress and did not require corticosteroids, 670 children met the exclusion criteria, 66 children were hospitalized before randomization, 127 children refused participation, and 25 patients had been enrolled earlier. Therefore, 134 children were randomized: 69 to the montelukast group and 65 to the prednisolone group. In each group, 1 patient subsequently withdrew consent, and 1 patient could not be contacted despite multiple attempts. Therefore 130 patients were included in the primary analysis, with 67 allocated at random to the mon-
Table I. Baseline characteristics of the study groups Characteristic Age (years)* Male sex (%) History of atopy (%) Family history of atopy (%) Hospitalizations for asthma in last year (%) Duration of respiratory distress (hours)* Prior prednisolone (1 dose; %) Baseline PRAM score* Baseline respiratory rate* Baseline oxygen saturation (%)
Montelukast group Prednisolone group (n = 67) (n = 63) 5.7 3.4 43 (64.2) 27 (40.3) 50 (74.6) 0.2 0.7
5.00 2.9 43 (68.3) 32 (50.8) 44 (69.8) 0.3 0.7
27.6 26.8
25.3 18.0
3 (4.5) 3.5 1.7 39.3 18.1 95.8 2.4
2 (3.2) 4.1 1.6 39.2 11.8 95.4 2.5
*Mean SD.
telukast group and 63 to the prednisolone group. The patients enrolled were comparable with children who were not enrolled in age and sex. The 2 study groups were comparable in their demographic and clinical characteristics (Table I). Deviations from the protocol were uncommon (7 patients, 5.4%). Five patients stopped taking the experimental therapy prematurely (3 in the prednisolone group, 2 in the montelukast group), 1 patient vomited the experimental syrup (prednisolone group), and 1 boy ate all his montelukast tablets on day 2 without any ill effects. A total of 119 families agreed to home visits at 48 hours (montelukast group, 58; prednisolone group, 61), and 114 were visited on day 8 (montelukast group, 55; prednisolone group, 59). Treatment failure occurred in 5 of 63 patients in the prednisolone group (7.9%) and 15 of 67 in the montelukast group (22.4%). The difference between groups was –14.5% (95% CI, –26.5%-–2.4%). The results of the sensitivity analysis performed on the patients taking medications as per protocol is not reported because it yielded similar results. All children experiencing treatment failure underwent asthma-related unscheduled medical visits; none were hospitalized. In the montelukast group, 9 patients received oral corticosteroids outside the protocol, versus 3 patients in the prednisolone group. Other Outcomes Regression-based adjustment of the primary outcome for age, atopy, and baseline PRAM score showed a significant independent association of the treatment effect and young age (Table II). Patients between 2 and 3 years of age were approximately 5 times as likely to return for care as their older counterparts. Twenty-two patients received pharmacotherapy outside the protocol within the 8-day period (additional bronchodilators,
Table II. Adjusted odds ratios for a return for care Variable
Odds ratio
95% CI
Overall treatment effect Age #3 years Atopy history (personal or family) Baseline PRAM score $4
3.95 4.89 0.39 1.64
1.27-14.42 1.66-15.22 0.12-1.35 0.55-5.08
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Figure. Proportion of patients remaining without any additional therapy with time.
steroids, antibiotics, and cough syrup), 16 of 67 patients in the montelukast group (23.9%) and 6 of 63 patients in the prednisolone group (9.5%; P = .03). The proportion of patients remaining without additional therapy with time is illustrated in the Figure (P value for the difference, .009). The mean number of inhaled albuterol treatments given per day during the 8-day observational period was 2.7 1.3 in the montelukast group and 2.8 1.1 in the prednisolone group (P = .85). The mean total number of days without asthma symptoms in the montelukast- versus prednisolonetreated patients was 1.4 1.3 and 1.3 1.4, respectively (P = .75). The differences in improvement in the mean PRAM score from baseline with time were also comparable in the 2 groups, and they are summarized in Table III (P value for the overall difference, .26). Adverse Effects In the montelukast group, adverse effects developed in 3 patients. One patient experienced facial swelling of unknown etiology at 96 hours, another patient had vomiting and diar-
Table III. Changes in the PRAM score with time in the 2 study groups Montelukast group
Prednisolone group
Time
n
PRAM*
n
PRAM*
Baseline 48 hours Day 8
67 61 59
3.5 1.7 2.1 1.9 0.3 0.8
63 58 55
4.1 1.6 2.2 2.0 0.4 0.9
Overall P value for the difference is .26. *Mean SD.
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rhea at 72 hours, and the third patient complained of abdominal and leg pains on day 4. None of these patients required treatment for these events, and the relationship between montelukast and the ‘‘event’’ is questionable. No adverse effects developed in the children given prednisolone after discharge.
Discussion Because montelukast therapy did not yield a comparable treatment outcome and actually proved to have a significantly higher rate of treatment failures compared with prednisolone, our results show that children with mild to moderate acute asthma should take oral corticosteroids after discharge from the ED. Anti-leukotriene agents do not represent an adequate anti-inflammatory alternative to corticosteroids after the initial outpatient stabilization. Earlier studies also suggest that treatment of this population with a single dose of long-acting oral dexamethasone appears comparable with a 5-day course of oral prednisolone and constitutes a reasonable option.26 The most likely explanation for these results centers on the lower potency of montelukast compared with glucocorticosteroids.27 The main hypothesis behind the effect of montelukast lies in its synergism with ß2 agonists28 and ability to regulate ß2 receptors and reduce airway edema.29 However, when added to oral corticosteroids, montelukast did not produce additional improvement in the FEV1 in the ED management of moderate pediatric acute asthma,30 likely because of the high efficacy of corticosteroids.30 Although montelukast counteracts the inflammatory effect of leukotrienes, prednisolone exhibits a broader impact on T cells, eosinophils, and other inflammatory cells.31 Schuh et al
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December 2009 Patients vary in their response to leukotriene modifiers because of their pharmacogenetic profile.32 The financial limitations and logistic restrictions of the acute care setting did not allow us to obtain this information in our patients. The doses of montelukast used in our study were derived from patients with stable chronic asthma.33 However, the receptor becomes fully saturated at these doses, and higher amounts do not lead to further bronchodilation. Our results also show an independent association of the treatment effect with young age. The effects of even mild airway inflammation will have more consequence in young children because they have smaller airway diameter than their older counterparts and a similar amount of airway edema will cause a much greater increase in airway resistance. Earlier research on montelukast in pediatric acute asthma is limited by patient population and outcome selection. The positive results in the study by Harmanci et al focusing on children with mild exacerbations seen outside the ED and not requiring corticosteroids are unlikely to be generalizable to the acute care setting.20 The authors used a clinical score to measure severity within 4 hours of treatment, which may not translate into extended health care outcomes. In contrast, we chose a return for care or treatment with extra corticosteroids to illustrate the difference in the use of health care resources or significant interventions in the 2 groups seen in the ED, which enhances the generalizability of the study results. This was a single center study with its potential issue of external generalizability. However, the indications for return visits and co-interventions were clearly delineated and consistent with those used elsewhere, and our results should therefore be generalizable to other pediatric EDs. Some may also wonder why the substantial differences in this outcome were not reflected in the PRAM score changes or number of asymptomatic days. The PRAM score was designed to measure respiratory distress in the ED and may not reflect the reasons for unscheduled visits in mild disease. The telephone symptom review is not sensitive enough to reflect actual return for care, and the accuracy of parental recall of symptoms may also be suboptimal. Even relatively mild asthma symptoms may cause anxiety in parents, particularly those caring for young children, who may require reassurance. In conclusion, the treatment failure in children with mild to moderate acute asthma stabilized in the ED and discharged receiving montelukast failed to reach criteria for non-inferiority and proved to be significantly higher compared with that in children given prednisolone. This population should take oral corticosteroids after discharge. n The authors thank Richard Raptopoulos, RN, Audrey Bell-Peters, RN, and Cynthia Bailey, RN, for their assistance. Submitted for publication Jan 8, 2009; last revision received Mar 23, 2009; accepted Jun 5, 2009. Reprint requests: Dr Suzanne Schuh, Division of Paediatric Emergency Medicine, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8, Canada. E-mail: [email protected].
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