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Expert Review: Associate Professor Jim Reid. Associate Professor of Graduate Education, Dunedin School of Medicine
The current literature regarding the use of LABAs in asthma can only be described as ‘busy’. Central to the debate are
two issues - firstly how safe are LABAs in the treatment of asthma and secondly how should exacerbations be managed in
patients currently using combination LABA/ICS inhalers.
- Long acting beta agonists (LABAs) are not indicated as first-line therapy for any asthmatic patient.
- Adverse reactions to LABAs such as hyper-responsiveness, bronchospasm and respiratory arrest are rare but patients
should be closely monitored for the first 6 - 12 weeks after the initiation of treatment.
- LABAs should only be prescribed for people who are already on inhaled corticosteroids (ICS).
- LABAs may be indicated as add-on therapy if symptoms do not respond to low to moderate doses of ICS (e.g. in adults
400 - 800 micrograms beclomethasone or equivalent).
- Patients on LABAs should be counselled and reminded on the importance of continuing their ICS.
- LABAs should be discontinued after a trial period if no benefit is seen.
- Patients with acutely deteriorating asthma should not be started on a LABA.
- Review the asthma management plans of people on combination LABA/ICS inhalers.
Adding a LABA improves symptom control, lung function and reduces the need for rescue
Randomised controlled trials (RCTs) have found that adding a LABA improves symptom control, lung function and reduces
the need for rescue medication compared with placebo in people with asthma that is poorly controlled by ICS. There was
no significant difference in the exacerbation rates between the two groups in any of the RCTs (Clinical Evidence, 2006).
Furthermore, adding regular doses of LABA improves lung function and symptoms, decreases exacerbation episodes and reduces
the need for rescue medication compared with increasing the dose of ICS (Clinical Evidence, 2006).
Adding a LABA is more effective than doubling the dose of ICS (at a dose of 400 micrograms beclomethasone per day or
equivalent) and should always be considered if a dose of ICS greater than 800 micrograms per day is required (NZGG, 2002).
In this regard LABA can be considered to have two advantages; improved symptom control along with a steroid sparing effect.
Adverse respiratory reactions to LABA possible
There have been occasional reports of deterioration in asthma control, impairment of response to short acting bronchodilators
and even respiratory arrest following commencement of a LABA. Several mechanisms may be implicated including paradoxical
bronchospasm, increased bronchial responsiveness and tolerance, but none of these have been identified in prospective
trials. Prescribers need to be aware of the possibility of these rare adverse reactions and monitor patients closely especially
during the first 6 - 2 weeks after starting a LABA (Taylor, 1999).
Peak flow monitoring should be encouraged and patients should be advised to seek advice if they perceive a lack of benefit
from using their reliever (short acting bronchodilator) medication. When people are put on a LABA symptoms often improve
and compliance with ICS may be reduced.
It is therefore important to remind patients to continue to take their inhaled steroids regularly in addition to the
LABA. The LABA should be withdrawn if asthma control continues to deteriorate in the absence of other explanations (Taylor,
Latest trials question safety of LABA
Two recent trials have raised awareness of the possible safety concerns regarding the use of LABAs, and prompted regulatory
authorities in some countries to reiterate warnings about their appropriate use, especially the need for concurrent use
of an ICS.
Salpeter et al conducted a meta-analysis of 19 RCTs involving almost 34,000 asthmatic patients. The primary objective
was to estimate the risk of serious adverse events associated with LABA use. The use of LABA was associated with increased
asthma exacerbations and asthma related deaths. In addition, statistically significant increases in hospitalisations occurred
in both adults and children with salmeterol or formoterol, compared with placebo (Salpeter, 2006). It was estimated that
LABAs cause an excess of approximately one death per 1000 years of patient use.
The Salmeterol Multicentre Asthma Research Trial (SMART) compared the addition of salmeterol or placebo to existing
asthma treatment in over 26,000 patients aged 12 years and over (mean age 39 years) (Nelson, 2006). All patients had a
current diagnosis of asthma and were receiving asthma medication. Exclusion criteria included the previous use of inhaled
LABA and a history of adverse reactions to sympathomimetic amine drugs. The intervention group received 42 micrograms
of salmeterol twice daily by metered dose inhaler and the control received a matched placebo inhaler. All subjects were
followed for 28 weeks and continued to use their current asthma drugs.
The composite primary end point was respiratory related death or life threatening experience (i.e. intubation and mechanical
ventilation). Secondary endpoints included all cause mortality, asthma related death, respiratory related death, life
threatening experiences and combinations of these.
The trial was stopped early after the interim analysis due to enrolment problems and preliminary findings from a subgroup
analysis which indicated a significant risk of harm in African-Americans. In this group there were more respiratory deaths
(24 vs 11) and asthma related deaths (13 vs 3) in the salmeterol group than the placebo group (Table 1).
Table 1: SMART trial results: addition of salmeterol vs placebo to usual pharmacotherapy in patients with
|Outcomes at 28 weeks
||RRI (95% CI)
||NNH (95% CI)
|Combined respiratory related death or life threatening
||0.4% (n = 50)
||0.3% (n = 36)
||40% (-9 – 114)
|Asthma related death
||0.1% (n = 13)
||0.02% (n = 3)
||337% (25 – 1434)
||1239 (705 - 5126)
|Respiratory related death
||0.2% (n = 24)
||0.1% (n = 11)
||116% (6 – 341)
||965 (515 - 7861)
|Combined asthma related death or life threatening experience
||0.3% (n + 37)
||0.2% (n = 22)
||71% (1 – 189)
||810 (415 - 16050)
|RRI = Relative Risk Increase, CI = Confidence Interval, NNH
= Number Needed to Harm (Lipchik, 2006)
As the trial was stopped early there are insufficient data to indicate whether the apparent increased risk in African-Americans
applies to other populations.
Taken together SMART and the meta-analysis indicate that LABAs may be responsible for a small increase in the absolute
risk of asthma related deaths and serious exacerbations. In both trials the number of adverse events was small and it
is not possible to ascertain if inappropriate use of LABAs (e.g. monotherapy, poor adherence to ICS use or continued use
of LABAs despite lack of response) was a contributing factor.
The important messages are to ensure that LABAs are prescribed and used in accordance with current recommendations;
ensure concurrent use of ICS, monitor for adverse reactions (especially early in treatment) and discontinue if there
is a lack of or inadequate response.
Role of combination LABA/ICS inhalers
The combination of a LABA and ICS in one inhaler provides a convenient and effective dose form in a single inhaler and
also ensures the concurrent use of an ICS with the LABA. However they do not allow flexibility in adjusting the doses
of individual components and their use in asthma exacerbations is unclear. They are most suitable for people who are already
established on a moderate dose of ICS and a LABA in separate inhalers.
LABA/ICS combination in asthma exacerbation
Indications for LABA
The addition of a LABA to inhaled corticosteroids can be considered:
- For younger children (under 12 years) where asthma is poorly controlled despite using ICS for at least three months
at total daily doses of 200 micrograms beclomethasone or budesonide or 100 micrograms fluticasone.
- For adults and older children (12 years and over) despite using ICS for at least three months at total daily doses
of 400 micrograms beclomethasone or budesonide or 200 micrograms fluticasone.
Source: Current PHARMAC Schedule. This is consistent with current evidence (Masoli, 2005, Fitzgerald, 2006).
There is currently significant controversy and debate on optimal treatment of early asthma exacerbations in those patients
who are already taking a combination LABA/ICS preparation.
Budesonide and fluticasone share similar anti-inflammatory characteristics but there are differentiating features between
salmeterol and eformoterol which affect how they can be used in worsening asthma. Salmeterol should not be given at doses
greater than the maximum maintenance dose, but the dose of eformoterol can be temporarily increased with the potential
of quadrupling the lowest recommended dose (Fitzgerald, 2006).
In the management of early exacerbations the patient should follow an individual management plan and for those on combined
LABA/ICS options include temporary additional ICS doses provided via a separate inhaler, a short course of oral prednisone
or a temporary increase in the dose of eformoterol/budesonide (Symbicort®).
A LABA should not be started during worsening asthma and the dose of either of the LABAs alone or salmeterol/fluticasone
combination (Seretide®) should not be increased during exacerbation.
- Clinical Evidence (BMJ publishing) 2006. Fitzgerald JM, Gibson PG. Asthma Exacerbations. Thorax 2006;61:992-999.
- Lipchik RJ. Addition of salmeterol to usual asthma pharmacotherapy may increase reparatory related deaths or life
threatening experiences. Evid Based Med 2006;11:139.
- Masoli M, Weatherall M, Holt S, Beasley R. Moderate dose inhaled corticosteroids plus salmeterol versus higher doses
of inhaled corticosteroids in symptomatic asthma. Thorax 2005:60:730-34.
- Nelson HS, Weiss ST, Bleecker ER et al. The Salmeterol Multicenter Asthma Research Trial; a comparison of usual pharmacotherapy
for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129:15-26.
- New Zealand Guidelines Group. Diagnosis and trreatment of adult asthma. 2002 available from;
- Salpeter SR, Buckley NS, Ormiston TM et al. Meta-analysis: effect of long acting beta agonists on severe asthma exacerbations
and asthma related deaths. Ann Intern Med 2006; 144:904-12.
- Taylor D R. .Adverse respiratory reactions to long acting beta agonists. Prescriber Update 1999;18;24-28. Available
Accessed October 2006).