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Inhaled steroids in childhood asthma


Bandolier is frequently asked to "do more on asthma". There is no "quick fix" because asthma is a complicated subject, but there are some good trials being done and at least one systematic review.

Inhaled steroids in childhood asthma

A systematic review from Toronto [1] picked up 24 randomised, double-blind, placebo-controlled studies published in English on inhaled steroids in children. All involved prophylactic inhaled steroids, and included trials with clinical outcomes like symptoms and concomitant drug use, or laboratory outcomes like lung function tests. The 24 studies involved 1087 children, and five studies examined only children dependent on oral steroids. Trial duration was from 4 to 88 weeks, but only eight of the studies were 12 weeks or longer.

Outcome reporting

Because of different outcome data in the original trials, the authors of the review tried to standardise treatment effect for clinical outcomes by using a relative improvement in mean (RIM) measure. This was calculated as:

RIM = (mean outcome placebo - mean outcome steroid) / mean outcome placebo

This works for clinical scoring because higher scores are worse. They did the same for surrogate markers like use of ß2 agonists and oral steroid use. Peak expiratory flow rate (PEFR) was as absolute mean increase in L/min.

Results

The main results are shown in the Figure, where results for each study are given together with the weighted mean value. There were improvements across the board, with only an occasional study failing to find benefit from inhaled steroids. As well as improvements in symptoms, there was also a reduction in concomitant ß-agonist use, and 10 of 12 studies showed a reduction in the use of oral steroids by a weighted mean of 68%.

Twenty-three studies reported adverse effects, and six of these said that no adverse effects were found. Those reported were minor with no child stopping treatment because of them. No evidence of adrenal suppression was found in 12 studies that studied it. Nor was there any evidence of reduction in height velocity in eight studies, nor of cataracts in four studies.

Adding theophylline to inhaled steroid

A randomised, placebo-controlled and double-blind trial examined the effectiveness of 400 µg of inhaled budesonide together with 250 mg or 375 mg oral sustained release theophylline, or 800 µg inhaled budesonide [2]. All doses were twice daily for three months. The entry criterion for the 62 adult patients in the study was that they continued to have cough, wheeze or breathlessness despite inhaled steroid at a daily dose equivalent to 800 µg or 1000 µg budesonide.

Results

Treatment with the lower dose of budesonide plus theophylline resulted in greater improvements in lung function, but with no difference in daily symptom scores or use of ß-agonists. A steroid-sparing effect was thought to be useful.

Long-acting inhaled ß-agonists

A large randomised and double-blind trial in 852 adult patients examined the effects of the long acting inhaled ß-agonist formoterol over one year [3]. The entry requirement was stable asthma assessed over a four week period. So 1114 patients were initially recruited, 852 randomised, and 694 completed a full one year of treatment.

There were four treatments, with each dose given twice daily and inhaled by means of a multidose turbohaler:

  • 100 µg budesonide
  • 100 µg budesonide plus 12 µg formoterol
  • 400 µg budesonide
  • 400 µg budesonide plus 12 µg formoterol
The main outcome measure was the number of severe and mild exacerbations of asthma per patient per year. Severe exacerbation was defined as one needing treatment with oral glucocorticoid, or a decrease in PEFR to more than 30% below baseline for two consecutive days. Mild exacerbations were defined as PEFR more than 20% below baseline, use of more than three additional uses of inhaled therapy a day, or waking at night because of asthma.

Results

There were fewer exacerbations, mild or severe, with higher doses of steroids and with the addition of formoterol (Table).

Clinical outcomes with budesonide and formoterol
Daily dose 200 µg budesonide + placebo 200 µg budesonide + 24 µg formoterol 800 µg budesonide + placebo 800 µg budesonide + 24 µg formoterol
 
Number of patients 213 210 214 215
Withdrawn because of severe exacerbations 10 7 4 0
Event
Severe exacerbations* 0.91 0.67 0.46 0.34
Mild exacerbations* 35 21 22 13
Patients without severe exacerbations (%) 61 70 72 81
Episode free days (%) 42 51 46 55
* Severe and mild exacerbations are number per patient per year
The effects of higher steroid and formoterol appeared to be additive. The proportion of patients with episode free days (no symptoms, no use of medications, and a PEFR of more than 80% of baseline) were higher with higher doses of steroid and with addition of formoterol.

For patients without severe exacerbations a similar trend was seen. But because absolute numbers could be calculated from the data, numbers needed to treat can be derived. Thus increasing the dose of budesonide from 200 µg to 800 µg a day gave an NNT of 9.5 (95% CI 6 to 22) for a patient to be free of severe exacerbation of asthma for one year. Adding formoterol 24 µg per day to budesonide at whatever dose used gave an NNT of 11 (6.6 to 34) for a patient to be free of severe exacerbation of asthma for one year. Adverse effects seemed to be mild and evenly distributed throughout the groups.

Comment

There are a number of national and international guidelines on asthma management and prevention, and those are the obvious places for prescribers to go for advice. A recent MeReC bulletin gives information on the updated British Thoracic Society's guidelines [4].

The systematic review on inhaled steroids in children underpins some of the recommendations. The other two trials contain information which may form part of future guidelines, and both typify some of the high-quality clinical research that is ongoing.

References:

  1. C Calpin, C Macarthur, D Stephens, W Feldman, PC Parkin. Effectiveness of prophylactic inhaled steroids in childhood asthma: a systematic review of the literature. Journal of Allergy and Clinical Immunology 1997 100; 452-7.
  2. DJ Evans, BA Taylor, O Zetterstrom et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide more moderate asthma. New England Journal of Medicine 1997 337; 1412-8.
  3. RA Pauwels, C-G Löfdahl, DS Postma et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. New England Journal of Medicine 1997 337; 1405-11.
  4. New guidelines for the treatment of asthma. MeReC Bulletin 1997 8: number 4.



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