University of Michigan
Department of Pediatrics
Evidence-Based Pediatrics Web Site

Question

• 9 y/o boy with asthma on Flovent 110mcg 2 puffs BID, now presenting with increasing frequency of exacerbations, requiring more prn Albuterol and courses of oral steroids over the past several months. Treatment options include adding Serevent or increasing his Flovent. Does the addition of a long-acting inhaled beta-2 agonist to inhaled corticosteroid provide more effective control for children with symptomatic asthma than increased doses of inhaled corticosteroid?

Clinical Bottom Lines

1. The addition of salmeterol to low or moderate doses of inhaled corticosteroids improves lung function and decreases exacerbations in patients greater than 12 y/o with symptomatic asthma.¹
2. NNT = 40. Need to treat 40 patients with salmeterol and inhaled corticosteroid instead of increased inhaled corticosteroid alone to prevent one exacerbation of any kind (mild, moderate, severe).¹
3. There are no currently published RCTs evaluating this question in a strictly pediatric population.

Summary of Key Evidence

1. Systematic review of nine randomized, double-blinded trials (3,685 subjects), which compared the addition of salmeterol to inhaled steroid vs. increased dose of inhaled steroid alone.
   

   Selection of articles/Inclusion criteria
   · Electronic database search of Medline and Embase, and Glaxo-Wellcome internal clinical study registers.
   · RCTs.
   · Direct comparison salmeterol plus inhaled steroid vs. increased dose of current inhaled steroid (at least double of patients' current dose).
   · Adolescents and adults currently using inhaled steroids.
   · Currently symptomatic (based on questionnaires given to patients or recent use of rescue medication).
   · Minimum duration of treatment = 12 weeks.
   

2. Outcome measures: Efficacy (mean difference in PEFR and FEV1) and exacerbations (mean percentage difference in symptoms, use of rescue treatment).
   
3. Data extracted from individual studies by two independent reviewers. Discrepancies were resolved by consensus.
   
4. Results: Patients taking salmeterol and inhaled corticosteroid compared to patients taking increased inhaled corticosteroid alone had¹:
   · Better morning PEFR at three months (average 22.4 L/min greater, 95% CI 15.0-30.0 L/min, P < 0.001) and six months (average 27.7 L/min greater, 95% CI 19.0-36.4 L/min, P < 0.001).
   · Better FEV1 at three months (average 0.1 L greater, 95% CI 0.04-0.16 L, P < 0.001) and six months (average 0.08 L greater, 95% CI 0.020-0.14 L, P < 0.001).
   · Fewer days without symptoms at three months (average 12% fewer, 95% CI 9-15%, P < 0.001) and six months (average 15% fewer, 95% CI 12-18%, P < 0.001).
   · Fewer days needing rescue treatment at three months (average 17% fewer, P < 0.001, 95% CI 14-20%) and six months (average 20% fewer, P < 0.001, 95% CI 17-23%).
   · Fewer nights needing rescue treatment at three months (average 9% fever, 95% CI 7-11%, P < 0.001) and six months (average 8% fewer, 95% CI 6-11%, P < 0.001).
   · Fewer exacerbations of any kind (average 2.73% fewer, 95% CI 0.43-5.04%, P = 0.02).
   
5. Validity: Large review of randomized controlled trials with many patients, focused clinical question, clear inclusion criteria for articles, results consistent between studies. However, did not state how they formally assessed the validity or quality of each study, and only limited data from the individual studies is reported.
   

Additional Comments

• Combined therapy with long-acting beta-2 agonists and inhaled corticosteroids has previously been shown to be beneficial in moderate and severe asthma.²
  
• Many treatment guidelines include long-acting beta-2 agonists as adjunct therapy to inhaled corticosteroids in patients with moderate or severe asthma.³
  
• Patients in all studies were greater than 12 y/o. Need RCT which asks same question in children only.
  
• Data for exacerbations reported as percentage decrease as opposed to actual number of days fewer. Thus, although data is statistically significant, difficult to assess whether or not it is clinically meaningful.
  
• Six of the nine studies required patients have a demonstrable response to beta agonist therapy prior to entry.
  
• Potential inconvenience of children having 2 MDIs (but could switch to Advair diskus).
  
• Study funded by manufacturer of salmeterol. Authors employed by or have received funding from manufacturer.
  

Citation

1. Shrewsbury S, Pyke S, Britton M. Meta-analysis of increased dose of inhaled steroid vs. addition of salmeterol in symptomatic asthma (MIASMA). British Medical Journal 2001; 320: 1368-73.
   
2. Fish JE. Treatment of Moderate Persistent Asthma. UpToDate January 2002; 1-7.
   
3. Greening AP, Ind WP, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroids. Lancet 1994; 344: 523-9.
   

CAT Author: Emily Chou, MD

CAT Appraisers: Katherine Layton, MD

Date appraised: March 4, 2002