On demand use of â 2 agonists led to better asthma control than regular use in moderate to severe asthma
Richter B, Bender R, Berger M. Effects of on-demand â 2 -agonist inhalation in moderate-to-severe asthma. A randomized
controlled trial. J Intern Med 2000 Jun;247:657-66
QUESTION: In patients with moderate to severe asthma, is on demand use of
b2 agonists as effective and safe as regular use?
Design
Randomised (allocation concealed), blinded (outcome
assessors and statistician), crossover trial with 24 weeks
follow up for each treatment condition.
Setting
Outpatient clinic at Düsseldorf University Medical
Centre in Germany.
Patients
80 patients (mean age 48 years, 74% women) with moderate to severe asthma on regularly scheduled â 2 agonist
(minimum daily intake of six puffs) and inhaled corticosteroids (ICS) for >2 years. Exclusion criteria were non-respiratory illnesses or pregnancy. 73 patients (91%)
completed the study.
Intervention
Two 24 week periods in which patients were allocated to
on demand inhalation (salbutamol or fenoterol) or
regular use of â 2 agonist (two inhalations four times
daily plus salbutamol or fenoterol on demand) and
crossed over to the other regimen after completion of
the first period. All patients used constant doses of
inhaled corticosteroids.
Main outcome measures
The primary outcome measure was asthmatic episodes
defined as an asthma attack that could only be treated by
â 2 agonist inhalation. Secondary outcome measures
were safety and consequences of reducing â 2 agonist.
Main results
The treatment groups did not differ for asthmatic
episodes and exacerbations (66% of symptom free days
in on demand treated patients v 62% in regularly treated
patients). However, daytime use of â 2 agonist was lower
in on demand treated patients than in regularly treated
patients (3.3 v 7.9 puffs/day, P < 0.001). Patients in the on
demand group also had fewer days of prednisone use for
asthma exacerbations than did those in the regular use
group (mean of 44 v 52 days, P = 0.001). FEV1 , FVC, and
midexpiratory flow rate at 25% to 75% of FVC were all
higher in patients in the on demand group than in those
in the regular use group (2.53 v 2.42 l, P = 0.008; 3.66 v
3.54 l, P = 0.003; 1.85 v 1.74 ls
.1, P = 0.02, respectively).
The groups did not differ for immunoglobulin E,
peripheral blood eosinophils, or other blood chemistry
values or for changes in unwanted effects in concomitant
medications.
Conclusion
In patients with moderate to severe asthma, on demand
â 2 agonist inhalation led to better asthma control than
regular â 2 agonist inhalation.
COMMENTARY
The â agonist controversy revolves around the question of
whether sustained and regular use of inhaled â adrenergic
agents results in decreased bronchodilator responsiveness
over time and has been addressed in epidemiological and
controlled prospective trials. 1,2 Most recently, the Asthma
Clinical Research Network study found no difference
between patients with mild asthma who were randomly
allocated to regularly scheduled or as needed albuterol over
a 16 week period.3 Richter et al compared the effects of
short acting inhaled bronchodilators over 24 weeks in a
more symptomatic patient population.
Several design and methodological issues deserve
comment. Firstly, although patients were required to have
used ICS for a minimum of two years before enrolment, no
protocol was provided for titrating to a minimum effective
dose of ICS before randomisation. This would have
increased the potential for patients to destabilise during the
study and thereby show a difference between treatment
groups. Secondly, medication compliance was not directly
assessed but was extrapolated from adherence to scheduled
clinic visits and completeness of diary cards. Thirdly, the
crossover design did not include a washout period between
treatments, which is inappropriate if the hypothesis being
tested is that extended exposure to â agonists results in
down regulation of the receptor. Finally, patients in this
study were not blinded. For such a disease as asthma with
subjective and effort dependent end points, this is clearly
suboptimal.
What should the practitioner take from this study? At the
least, this study and others show that regular use of short
acting inhaled â agonists do not confer added benefit over
those used on an as needed basis. The addition or optimisation of ICS treatment with subsequent addition of other
treatments as required is a preferable management
strategy.4
Peter K Honig, Food and Drug Administration, Rockville, Maryland,USA
- Sears MR, Taylor DR. The beta 2.agonist controversy.
Observations, explanations and relationship to asthma
epidemiology. Drug Saf 1994;11:259.83.
- Lipworth B, Tan S, Devlin M, et al. Effects of treatment with
formoterol on bronchoprotection against methacholine.
Am J Med 1998;104:431.8.
- Drazen JM, Israel E, Boushey HA, et al. Comparison of regu.
larly scheduled with as.needed use of albuterol in mild
asthma. Asthma clinical research network. N Engl J Med
1996;19:841.7.
- National Heart, Lung, and Blood Institute. National asthma
education and prevention program expert panel report 2:
guidelines for the diagnosis and management of asthma. US
Department of Health and Human Services. Bethesda, MD:
National Institutes of Health; 1997; DHHS publication No 97.4051.
Dr B Richter, Heinrich-Heine-Universität Düsseldorf, Klinik für Stoffwech. selkrankheiten und Ernährung, Moorenstrasse 5, Postfach 101007, D.40001 Düsseldorf, Germany
Email: richterb@uni.duesseldorf.de
studentBMJ 2001;09:85-128 April ISSN 0966-6494
