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Beta agonists in asthma: Controversy regarding chronic use
Author
Robert F Lemanske, Jr, MD
Section Editor
Bruce S Bochner, MD
Deputy Editor
Helen Hollingsworth, MD
Last literature review version 19.2: mayo 2011 | This topic last updated: marzo 14, 2011
INTRODUCTION — An inhaled sympathomimetic is the bronchodilator of choice for treatment of
an acute asthmatic attack [1,2]. However, it is controversial whether these medications can be
used safely for chronic maintenance therapy (monotherapy) or should be reserved for acute
symptomatic control. Three arguments have been made against chronic use [3,4]:
Mortality may be increased
Control of asthma may worsen
Equal or superior efficacy can be achieved with inhaled glucocorticoids (corticosteroids)
In the discussion that follows, "short-acting" beta agonists (eg, albuterol) are bronchodilators
whose bronchodilator (but not bronchoprotective) effects last four to six hours. Long-acting beta
agonists (salmeterol and formoterol) are bronchodilators whose effects last 10 to 12 hours. "Beta
agonists" refer to short-acting beta agonists if unspecified.
Controversies surrounding the chronic use of beta agonists in patients with asthma will be
reviewed here. The clinical use of beta agonists and an overview of asthma management are
presented separately. (See "Beta agonists in asthma: Acute administration and prophylactic use",
section on 'Use in acute exacerbations of asthma' and "An overview of asthma management".)
MORTALITY
Short-acting beta agonists — An association between mortality in asthmatic patients and chronic
treatment with beta agonists was initially suggested by several studies (all performed by the same
investigative group) that used a cohort of 12,301 patients for whom asthma medications had been
prescribed between 1978 and 1987 [3].
In an initial case-control study, 129 patients who had fatal or near–fatal asthmatic episodes
(PaCO2 >45 mmHg and/or intubation) were matched with 655 controls who had received asthma
medications but had not had fatal or near–fatal events [3]. An increased risk of death or neardeath from asthma was associated with chronic use of inhaled beta agonist bronchodilators (odds
ratio 1.9, 95% CI 1.6-2.4). The case-control design precluded the establishment of causality [5].
Information about asthma severity was subsequently gathered by questionnaire from the same
129 case patients and 655 control patients [6]. Asthma severity was similar in the two groups,
suggesting that the prior results were not confounded by asthma severity.
In two retrospective cohort studies using all 12,301 patients, deaths due to asthma, cardiac
causes, and all-causes were identified [7,8]. The chronic use of inhaled beta agonist
bronchodilators was associated with asthma-related death, but not all-cause mortality. Cardiac
death was associated with oral and nebulized beta agonist use, but not beta agonist use via
inhaler.
A meta-analysis of six case–control studies found a weak association between death from asthma
and nebulizer-delivered beta agonists [9]. However, the association was so weak that its clinical
significance was doubted.
In a more recent and larger case-control study, 532 patients who died of asthma were compared
to 532 control patients with a history of hospitalization for asthma [10]. There was no association
between mortality and chronic beta-agonist use in the 4 to 12 months preceding death. However,
mortality was associated with chronic beta agonist use one to five years prior to death (odds ratio
2.0, 95% CI 1.3-3.3), suggesting that a causal relationship was unlikely.
Taken together, chronic short-acting beta agonist therapy, provided in conjunction with other
asthma therapy, does not appear to have a large effect on mortality.
Long-acting beta agonists — Numerous studies have demonstrated the efficacy of chronic longacting beta agonists (LABA) in improving pulmonary function, increasing symptom-free days, and
decreasing the need for rescue beta agonists. However, there has been a controversy regarding
the possibility of an association of chronic LABA treatment with severe exacerbations and
increased mortality in a small subgroup of patients [11-20]. Although the association may be
diminished or prevented by concomitant use of inhaled glucocorticoids, the data are not definitive
[21].
Meta-analyses — The controversy regarding the potential association of chronic LABA treatment
with severe exacerbations and increased mortality is illustrated by the following studies:
In a randomized trial, more than 25,000 patients with asthma were assigned to receive the longacting beta agonist, salmeterol, or the short-acting beta agonist, albuterol [11]. There was a
nonstatistically significant three-fold increased likelihood of death among patients that received
salmeterol (12 of 16,787) compared to patients that received albuterol (2 of 8393). Interpretation
of the study was limited by bias due to higher withdrawal from the albuterol group and by inability
to evaluate subgroups that did or did not receive inhaled glucocorticoids.
The Salmeterol Multicenter Asthma Research Trial (SMART) was a randomized trial in which
26,355 patients with asthma were assigned to receive salmeterol or placebo for 28 weeks [12].
Salmeterol use was associated with increased respiratory-related death (relative risk 2.2, 95% CI
1.1-4.4), asthma-related death (relative risk 4.4, 95% CI 1.2-15.3), and combined asthma-related
death or life-threatening experience (relative risk 1.7, 95% CI 1.0-2.9). Subgroup analysis suggested
that the risk may be greater in African Americans. Like the trial above, SMART was not designed to
evaluate subgroups that did or did not receive inhaled glucocorticoids.
A systematic review and meta-analysis assessed the impact of LABA (either formoterol or
salmeterol), taken for at least 12 weeks, on asthma-related total morbidity and mortality among
patients concomitantly using inhaled glucocorticoids [15]. The search of MEDLINE, EMBASE,
ACPJC, and Cochrane (Central) databases yielded 62 relevant blinded, randomized trials with over
29,000 participants (15,710 taking LABA and over 8,000 patient-years observed in the LABA
groups). Three asthma-related deaths and two asthma-related, nonfatal intubations (all in LABA
groups; ≤1 event per study) occurred. The OR for total mortality was 1.26 (95% CI 0.58-2.74),
reflecting 14 deaths in LABA groups and eight deaths in control groups, respectively. Differences in
asthma-related hospitalizations (OR, 0.74; 95% CI 0.53-1.03) and asthma-related serious adverse
events (mostly hospitalizations; OR, 0.75; 95% CI 0.54-1.03) failed to reach statistical significance.
There were very few asthma-related deaths and intubations, and events were too infrequent to
establish LABA's relative effect on these outcomes.
A meta-analysis of 66 trials (20,966 participants) comparing the combination of fluticasonesalmeterol with inhaled glucocorticoid alone found that combination therapy was associated with
a decrease in the risk of severe exacerbation, no change in the risk of hospitalization, and no
apparent increase in the risk of intubation or death [14]. The study population differed from that
of the SMART trial described above in that participants were in closely supervised clinical trials.
A meta-analysis of all AstraZeneca randomized trials involving formoterol and lasting more than 12
weeks found only 10 deaths in a combined study population of 68,004 patients with asthma
(23,600 person years of exposure to formoterol) [17]. The adjusted death rate among patients
taking formoterol was not significantly increased (RR 2.68; 95% CI 0.53-13.5), although the
confidence intervals were broad. Formoterol was associated with a significant reduction in
asthma-related nonfatal severe adverse events. No increase in the rate of serious adverse events
was noted with increasing doses of formoterol. Despite the size of the combined study population,
the meta-analysis did not have the power to conclude absolutely that formoterol is not associated
with an increase in mortality risk.
In a systematic review of trials that compared regular treatment with salmeterol plus inhaled
glucocorticoid to salmeterol alone, 11 deaths occurred in the combined study population of
10,873 asthma patients and none were reported to be asthma-related [21]. The number of
patients experiencing adverse events was too small to definitively exclude the possibility of an
increase in risk related to salmeterol, although there was no significant difference in fatal or nonfatal serious adverse events between the two groups.
The interpretation of these and other data is complicated, particularly regarding the impact of
concurrent inhaled glucocorticoids. Many experts believe that inhaled glucocorticoids diminish or
prevent the potential risk of long-acting beta agonists, while others believe the data are
insufficient to warrant this conclusion [22-24]. However, despite these potential risks in small
numbers of patients, salmeterol in combination with inhaled glucocorticoids significantly reduces
exacerbation rates in the majority of adults. Thus, as with all medications, the proper balance
between risk and benefit with combination therapy should be individually evaluated and
prospectively monitored over time.
Formoterol — The alternative long-acting beta agonist, formoterol, has not been as well studied as
salmeterol. After three small phase III studies of formoterol suggested that higher drug doses are
associated with an increased risk of asthma exacerbations [25], a phase IV study was initiated. In
the prospective study, 2085 patients with asthma were randomly assigned to receive high-dose
formoterol (24 mcg), low-dose formoterol (12 mcg), low-dose-plus formoterol (12 mcg plus an
additional 12 mcg as needed), or placebo twice per day for 16 weeks [26]. The incidence of fatal or
near-fatal asthma-related events did not differ among the groups; however, the study duration of
16 weeks may not have been adequate to definitively assess this outcome.
Monotherapy — Two studies conducted by the NHLBI-funded Asthma Clinical Research Network
have demonstrated that monotherapy with LABAs increases the risk of asthma exacerbations and
treatment failure in patients previously receiving inhaled glucocorticoid therapy [27,28]. These
data, along with the results observed in the SMART trial described above [12], in which many
patients were receiving salmeterol monotherapy and experienced adverse outcomes, strongly
indicate that LABAs should not be used as monotherapy. (See 'Monotherapy switch' below.)
Combination therapy — It is unclear whether the concomitant administration of inhaled
glucocorticoids attenuates or mitigates the adverse effects attributed to LABA therapy. This
uncertainty is related to results of studies in which the LABA and inhaled glucocorticoid were
administered using separate inhaler devices as opposed to fixed dose combination inhalers that
contain both in one device. Thus, additional research is needed to resolve the questions whether
LABA therapy is associated with an increased risk of severe or fatal asthma exacerbations and
whether associated inhaled glucocorticoid therapy is fully protective [14,16,29,30]. Unfortunately,
the formidable sample size that would be required makes it highly unlikely that such a trial will be
possible [18,31]. (See 'Combination therapy' below.)
FDA advisory statement — The United States Food and Drug Administration (FDA) has mandated
that a "black box" warning label be added to all products containing salmeterol or
formoterol because of "an increased risk of severe exacerbation of asthma symptoms, leading to
hospitalizations, in pediatric and adult patients, as well as death in some patients using LABAs for
the treatment of asthma."
The FDA warning advises that the use of a LABA as monotherapy without the concomitant use of a
long-term asthma control medication, such as an inhaled glucocorticoid, is contraindicated in the
treatment of asthma. In addition, the FDA advises that LABAs should only be used as additional
therapy for patients with asthma who are currently taking a long-term asthma control medication,
such as an inhaled glucocorticoid, but are not adequately controlled. Once asthma control is
achieved and maintained, step-down therapy is advised, with discontinuation of the LABA if
possible without loss of asthma control. For pediatric and adolescent patients who require the
addition of a LABA to an inhaled glucocorticoid, the FDA advises that a combination product
containing both of these medications be used. Additional information is available online:
(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvider
s/ucm213836.htm), or by telephone (888-INFO-FDA).
National Asthma Education and Prevention Program (III) — Based on a thorough review of the
literature regarding safety and efficacy of long acting beta agonists, the National Asthma
Education and Prevention Program (NAEPP) expert panel recommended various options for Step 3
care in both children and adults with asthma whose disease was not well controlled on low doses
of inhaled glucocorticoids (ICS) [1]. One choice consisted of the addition of a LABA, the other
choice an increase in the inhaled glucocorticoid dose to the medium range. Following the release
of the 2010 FDA advisory statement outlined above, members of the NAEPP expert panel did not
feel that any data generated from the time of their report in 2007 to the release of the 2010 FDA
advisory statement would change the 2007 recommendations nor the interpretation of the data
that led to them [32].
ASTHMA CONTROL
Regular versus as-needed administration — The current recommendation of the National Asthma
Education and Prevention Program expert panel report is to prescribe short acting beta agonists as
needed for symptom control rather than on a regular schedule [1]. This recommendation is made
despite most rigorously designed trials suggesting that beta agonists administered on a regular
schedule compared to an "as-needed" schedule do not lead to worsening asthma control or
increased complications. As examples:
In a randomized trial, 255 patients with mild asthma (FEV1 ≥70 percent of the predicted value,
PC20 <16 mg/ml, infrequent use of inhaled beta agonists, and no glucocorticoid use within 6
weeks) were assigned to receive inhaled albuterol on a regular basis plus albuterol as-needed or
placebo inhaled on a regular basis plus albuterol as-needed for 16 weeks [33]. There was no
difference in asthma exacerbations, treatment failures, lung function, asthma symptoms, peak
flow variability, or PC20.
In a similar randomized trial of 983 patients, those assigned to receive regularly scheduled
albuterol for 12 months did not have an increased rate of exacerbations compared to those
randomized to receive placebo [34].
In contrast, diminution of the "bronchoprotective effect" is an important adverse outcome found
when patients use beta agonists on a regular schedule [35]. The bronchoprotective effect is
described as the ability to protect against bronchoconstriction in response to chemical stimuli (eg,
methacholine), exercise, or allergen exposure [36-41].
Although the clinical significance of this diminution has been debated [42], the change in
bronchoprotective effect following allergen challenge is associated with an enhancement of the
late asthmatic response, an increase in the number of sputum eosinophils, and release of
eosinophil mediators [43].
The decreased bronchoprotective effect associated with the chronic use of beta agonists may be
related to a process termed "desensitization" (ie, decreased cellular responsiveness due to
exposure to a continuous stimulus). The mechanisms of desensitization of beta 2-adrenoceptors
(and other G protein-coupled receptors) include rapid (minutes) alterations such as receptor
phosphorylation (by protein kinase A or C and/or G protein-coupled receptor kinases), uncoupling
of the receptor from its attached G protein, and/or sequestration. Slower changes may involve
increased receptor degradation and decreased receptor synthesis [44,45]. (See "Beta-2 adrenergic
receptor dysfunction and polymorphism in asthma".)
Intermediate-acting beta agonists — In a randomized, crossover study, 89 patients with stable
asthma were assigned to receive regularly scheduled intermediate-acting beta agonist (fenoterol)
plus as-needed short-acting beta agonist or regularly scheduled placebo plus as-needed shortacting beta agonist [4]. Of 64 subjects who completed the trial, 17 patients (27 percent) had better
asthma control during regularly scheduled fenoterol treatment, 40 patients (62 percent) had
better asthma control during regularly scheduled placebo treatment, and 7 patients (11 percent)
had equal asthma control regardless of the medication. The median time from the
commencement of each treatment period to the first exacerbation was 33 days with regularly
scheduled therapy versus 66 days with as needed use (figure 1).
In two subsequent reports from the same investigators, using the same cohort of patients:
Regularly scheduled fenoterol was associated with more exacerbations and an increase in airway
responsiveness to methacholine; there was, however, no alteration in bronchodilator
responsiveness [46].
In a subsequent analysis, the deleterious responses noted following chronic beta agonist were not
related to beta-2 receptor polymorphisms [47]. (See "Beta-2 adrenergic receptor dysfunction and
polymorphism in asthma".)
In contrast to these reports, a number of trials have not corroborated the deleterious effects of
intermediate-acting beta agonists in the short-term [48,49] or the long-term [50-52], as measured
by peak expiratory flow rate or symptom control (figure 2).
Long–acting beta-agonists — In studies looking at short-term administration of long-acting beta
agonist monotherapy, the long-acting beta agonists demonstrated prolonged bronchodilation and
protection from bronchoprovocation with methacholine [53,54].
The effects of chronic administration of long-acting beta agonists have also been evaluated. In a
randomized trial, 234 patients were assigned to receive regularly scheduled long-acting betaagonist (salmeterol), short-acting beta agonist (albuterol), or placebo [50]. Salmeterol was more
effective at increasing the morning peak expiratory flow rate than albuterol or placebo (+24, -6, +1
L/min, respectively). The mean overall symptom score was improved most by salmeterol
treatment, with the number of days with symptoms and of nights with awakenings decreasing by
22 percent and 52 percent, respectively. There was no evidence of tolerance to the
bronchodilating effects of salmeterol.
Although salmeterol use in the above study failed to show tolerance to the bronchodilating effects
of salmeterol, other studies demonstrated that salmeterol induced tolerance to the
bronchodilating effect of albuterol [55,56]. The effect was mediated by beta-2 adrenoceptor
downregulation and bronchodilator desensitization to albuterol.
Like salmeterol, formoterol appears to induce tolerance to the bronchodilating effect of albuterol.
In one study, 10 patients with stable asthma were given scheduled formoterol for durations
ranging from a single dose to two weeks [57]. The patients were then exposed to a
bronchoconstrictor stimulus (methacholine) and their bronchodilator response to albuterol was
measured. Bronchodilator tolerance occurred after one dose of formoterol and progressively
increased up to one week. Tolerance resolved three days after discontinuation of the formoterol.
Tolerance to protection against a bronchoconstrictor stimulus has also been studied. As an
example, 24 patients with mild asthma were randomly assigned to receive treatment with inhaled
salmeterol or placebo. The bronchodilatory effects of salmeterol did not change but protection
against a bronchoconstrictor stimulus (inhaled methacholine) declined from a 10-fold increase to a
two-fold increase in the dose of methacholine required to produce a 20 percent fall in FEV1 [58].
Taken together, the data suggest that chronic long-acting beta agonists improve pulmonary
function and asthma symptoms. Although salmeterol and formoterol induce tolerance to the
bronchodilating effect of albuterol, the clinical significance of the tolerance remains speculative
[59-61]. Indeed, one study demonstrated that, despite the development of a loss of
bronchoprotection, no loss of asthma control occurred as measured by respiratory symptoms,
rescue beta agonist use, and baseline FEV1 [62].
Tolerance induced by chronic use of long-acting beta agonists may contribute to the association of
chronic long-acting beta agonists with serious adverse events and mortality as discussed above.
(See 'Long-acting beta agonists' above.)
Beta receptor polymorphisms — A number of polymorphic forms of the beta-2 adrenergic
receptor were described in 1993 [63]. The potential role of beta-2 adrenergic receptor dysfunction
in the pathogenesis of asthma and in individual responses to beta agonists is discussed separately.
(See "Beta-2 adrenergic receptor dysfunction and polymorphism in asthma".)
BETA AGONISTS VERSUS INHALED GLUCOCORTICOIDS
Direct comparison — Advocates for inhaled glucocorticoids (corticosteroids) argue that chronic
beta agonist therapy may be harmful by providing symptom relief while permitting the underlying
inflammatory process to progress. It is unclear whether this is true as some studies reveal
decreased inflammation associated with chronic beta agonist therapy [64,65] while others do not
[66]. Conversely, advocates for chronic beta agonist therapy describe adverse effects associated
with inhaled glucocorticoid therapy.
Although some studies found no difference when inhaled glucocorticoids were compared to
monotherapy with long-acting beta agonists (LABA) [67], most studies favored inhaled
glucocorticoids over chronic beta agonist therapy [51,68]. This is illustrated by the following
studies:
In a randomized trial, 103 patients with newly detected asthma were assigned to receive inhaled
glucocorticoid (budesonide) or chronic beta agonist (terbutaline) [51]. Budesonide was more
effective at reducing symptoms, decreasing rescue beta agonist administration, and improving
peak expiratory flow rate (PEFR).
In a separate trial, 241 children with asthma were randomly assigned to receive a chronic longacting beta agonist (salmeterol), an inhaled glucocorticoid (beclomethasone), or placebo [68].
Beclomethasone was associated with decreased airway responsiveness to methacholine,
decreased need for rescue beta agonist, and fewer asthma exacerbations compared to salmeterol
or placebo. Both beclomethasone and salmeterol were associated with less variability of PEFR
compared to placebo. Linear growth was impaired in the children receiving beclomethasone, but
not salmeterol or placebo.
Monotherapy switch — Conversion from inhaled glucocorticoid monotherapy to chronic longacting beta agonist monotherapy in adult patients cannot be performed without loss of asthma
control, as illustrated by the following studies:
In a controlled trial, 164 patients with mild asthma received inhaled glucocorticoid (triamcinolone)
for six weeks, and then were randomly assigned to receive long-acting beta agonist (salmeterol),
triamcinolone, or placebo for 16 weeks [27]. No differences were detected between the
salmeterol and triamcinolone groups for peak expiratory flow rate, asthma symptom scores,
rescue beta agonist use, or quality of life scores. Both were superior to placebo. However, the
salmeterol group had more treatment failures (24 versus 6 percent) and asthma exacerbations (20
versus 7 percent) than the triamcinolone group.
In another controlled trial, 175 patients with persistent asthma that was suboptimally controlled
during a 6-week period of treatment with inhaled glucocorticoid (triamcinolone acetonide) were
randomly assigned to have placebo or long-acting beta agonist (salmeterol) added [28]. In the
group receiving salmeterol, a dose reduction of inhaled glucocorticoid by 50 percent was not
associated with any significant increase in treatment failure. However, complete elimination of the
inhaled glucocorticoid led to a significant increase in treatment failure rates (46 versus 14
percent).
Thus, as discussed above, monotherapy with a LABA is not advised. (See 'Monotherapy' above.)
Combination therapy — Combining chronic beta agonists with inhaled glucocorticoids is an
attractive therapeutic option. In theory, the inhaled glucocorticoid should suppress the underlying
inflammatory response while the chronic beta agonist provides enough symptom control to
permit lower doses of the inhaled glucocorticoid to be used, thus reducing glucocorticoid-related
adverse effects. Herein, "combination therapy" refers inhaled glucocorticoids plus long-acting
inhaled beta agonist. We follow the National Asthma Education and Prevention Program expert
panel report III regarding the specific indications for adding a LABA for the treatment of asthma
[1,32]. These recommendations are discussed separately. (See "An overview of asthma
management" and "Treatment of moderate persistent asthma in adolescents and adults", section
on 'Summary and recommendations'.)
Efficacy — In approaching an evaluation of efficacy, it is important to note that inhaled
glucocorticoid monotherapy versus combination therapy may differentially affect various outcome
measures. As an example, one treatment may be better at improving pulmonary function, while
both may be equally good at controlling exacerbations. Thus, the choice of therapy may depend
on which outcome needs greater control in an individual patient. In addition, the patient's current
medication regimen should be considered (eg, receiving or not receiving controller medications).
In glucocorticoid naïve patients with mild airway obstruction, the initiation of combination therapy
does not reduce the rate of exacerbations compared to initiation of inhaled glucocorticoids alone.
Combination therapy does improve lung function and symptom-free days, but does not reduce use
of short-acting inhaled beta agonists as a rescue medication compared to inhaled glucocorticoids
alone [69,70]. Thus, there is insufficient evidence to recommend combination therapy for patients
with mild persistent asthma who have not previously received inhaled glucocorticoids (figure 3)
[1,2]. Similar findings regarding overall greater clinical efficacy using monotherapy with inhaled
glucocorticoids versus combination therapy with inhaled glucocorticoids and salmeterol have been
reported in school age children and adolescents with mild to moderate persistent asthma [70].
In patients already receiving low to high doses of inhaled glucocorticoids and whose asthma is not
well controlled, two meta-analyses have compared low to high-dose inhaled glucocorticoid
monotherapy versus combination therapy [71,72]:
The first meta-analysis examined 26 randomized, controlled trials that compared the addition of
salmeterol versus placebo to inhaled glucocorticoids. The meta-analysis found that the addition of
a daily long-acting beta agonist reduced the risk of exacerbations requiring systemic
glucocorticoids by 19 percent [72]. Furthermore, the addition of a long-acting beta agonist
improved FEV1, the number of symptom-free days, and the number of days in which rescue shortacting beta agonists were required. A similar number of serious adverse events and withdrawal
rates occurred in both groups.
Another meta-analysis examined 30 randomized, controlled trials (9509 patients) that compared
increasing the dose of inhaled glucocorticoid versus keeping the dose constant and adding a longacting beta agonist. There was improvement in FEV1 (WMD 100 mL, 95% CI 0.77-1.02 L),
symptom-free days (WMD 11.9 percent, 95% CI 7.4-16.4 percent), and use of rescue beta agonist
(WMD -1.0 puffs/day, 95% CI -1.41 to -0.58 puffs/day) in the combination therapy group
compared to the monotherapy group [71]. There was no difference in the incidence of
exacerbations requiring systemic glucocorticoids (relative risk 0.88, 95% CI 0.77-1.02), the overall
adverse events (relative risk 0.93, 95% CI 0.84-1.03), or side effects.
Additional studies similarly found low-dose inhaled glucocorticoid plus chronic long-acting beta
agonist combination therapy to be superior to high-dose inhaled glucocorticoid monotherapy [7378]. It is important to emphasize that the number of patients enrolled in these trials was
insufficient to determine if the results observed in adults similarly apply to pediatric patients. (See
'Step-up therapy in children and adolescents' below.)
Two major studies evaluated combination therapy using novel therapeutic approaches [79,80].
The first trial (the GOAL study) evaluated whether aggressive escalation of therapy (until total
control or maximum dose inhaled glucocorticoids) affects asthma control [79]. In the GOAL study,
3421 patients with asthma were randomly assigned to receive inhaled glucocorticoid (fluticasone)
or inhaled glucocorticoid (fluticasone) plus long-acting beta agonist (salmeterol). More patients
achieved total asthma control with salmeterol/fluticasone than fluticasone monotherapy both
immediately after escalation (31 versus 19 percent) and one year later (41 versus 28 percent). In
addition, control was achieved more rapidly and at a lower glucocorticoid dose with
salmeterol/fluticasone than fluticasone alone.
The second trial (the STAY study) evaluated whether a combination drug (inhaled glucocorticoid
plus long-acting beta agonist) could serve as both maintenance therapy and as a rescue inhaler
[80]. Since formoterol has a rapid onset of action, the investigators hypothesized that patients
receiving maintenance dose budesonide/formoterol would benefit from replacement of their
short-acting beta-2-agonist (SABA) rescue medication with as-needed budesonide/formoterol due
to rapid symptom relief and simultaneous increase in anti-inflammatory therapy.
In the STAY trial, 2760 patients with asthma were randomly assigned to receive rescue plus
maintenance budesonide/formoterol, rescue terbutaline plus maintenance
budesonide/formoterol, or rescue terbutaline plus maintenance budesonide [80]. The group
receiving budesonide/formoterol for both rescue and maintenance had prolonged time to first
severe exacerbation, lower exacerbation risk, improved symptoms, fewer awakenings, and better
lung function compared to the other groups.
Glucocorticoid-sparing — A glucocorticoid-sparing effect refers to the ability of a pharmacologic
agent to permit inhaled glucocorticoid dose reduction following its addition to a preexisting
inhaled glucocorticoid regimen. The efficacy of chronic LABAs as glucocorticoid-sparing agents has
been studied. This was best illustrated in a meta-analysis of 10 randomized, controlled trials
comparing high-dose inhaled glucocorticoid versus combined low-dose inhaled glucocorticoid plus
chronic long-acting beta agonist [81]. Addition of a chronic long-acting beta agonist permitted 37
to 60 percent reduction of the inhaled glucocorticoid dose without deterioration of asthma
control.
Other studies have confirmed the efficacy of long-acting beta agonists as glucocorticoid-sparing
agents [77,82]. Tapering of the inhaled glucocorticoid was associated with increased sputum
eosinophils in one study, but this was not accompanied by increased symptoms.
Step-up therapy in children and adolescents — The efficacy of three treatment regimens as stepup treatment was evaluated in children and adolescents whose asthma was not well-controlled on
fluticasone 100 mcg twice daily [83]. Adding a LABA was 1.6 times as likely as adding a leukotriene
receptor antagonist (LTRA) and 1.7 times as likely as increasing the inhaled glucocorticoid to result
in improved asthma control. However, some children demonstrated their best response to ICS or
LTRA step-up rather than to the LABA, highlighting the need to regularly monitor and
appropriately adjust each child's asthma therapy. (See "Chronic asthma in children younger than
12 years: Controller medications", section on 'Efficacy'.)
Step-down therapy following establishment of control on combination therapy — In the FDA
advisory statement that led to the new black box warnings on drugs containing LABAs [84], the
FDA recommended that, once asthma control is achieved and maintained, therapy should be
stepped down with discontinuation of the LABA if possible without loss of asthma control.
However, a number of published studies have questioned the rationale of choosing to eliminate
the LABA once control is satisfactorily achieved [85-88].
Potential risk — It remains unclear whether the combination of an inhaled glucocorticoid and a
long-acting beta agonist (LABA) carries an increased risk of catastrophic asthma events or death
compared with an inhaled glucocorticoid alone [19,89].
A meta-analysis examined data from 42 clinical trials that included a total of 23,510 patients
randomly assigned to formoterol plus an inhaled glucocorticoid or an inhaled glucocorticoid alone
[19]. No asthma-related deaths and one asthma-related intubation occurred. Asthma related
hospitalizations were lower in the formoterol plus inhaled glucocorticoid group (RR 0.79; 95% CI,
0.54-1.01). A similar meta-analysis of formoterol safety data from 68,004 patients reported eight
asthma-related deaths among 49,906 formoterol-treated patients and two among 18,098 nonformoterol treated patients [17]. However, this larger study included 10 asthma-related deaths
that occurred in open-label trials, in trials without a non-LABA control arm, after the end of
randomized treatment, or were later adjudicated as non-asthma-related.
A separate meta-analysis examined clinical trial data from 4039 patients treated with a LABA plus
an inhaled glucocorticoid compared with 3214 patients treated with an inhaled glucocorticoid
without a LABA [89]. A statistically significant increase in the risk of an asthma-related intubation
or death was noted in the LABA-treated group. However, methodologic issues limit the
interpretation of this meta-analysis. Only trials that included at least one event were included; the
use of inhaled glucocorticoids was not necessarily controlled; and the dose of inhaled
glucocorticoids varied between the LABA plus inhaled glucocorticoid and the inhaled
glucocorticoid alone groups.
The potential benefits and risks of adding a LABA to an inhaled glucocorticoid in a patient whose
asthma is not well-controlled on inhaled glucocorticoid alone need further study [32]. In the
meantime, we follow the step-wise approach to asthma outlined in National Asthma Education
and Prevention Program [1]. (See "An overview of asthma management".)
LEVALBUTEROL — Albuterol is a racemic mixture with a 1:1 ratio of the isomers R-albuterol
(levalbuterol) and S-albuterol. The R-isomer is responsible for the drug's bronchodilating activity,
while the S-isomer has been proposed to contribute to some of the adverse consequences that
have been observed following chronic beta agonist use [90]. Preferential retention of the S-isomer
within the lung has been demonstrated which could lead to its accumulation after long term use of
racemic albuterol [91].
Levalbuterol, the R-isomer of racemic albuterol, was approved for the prevention and treatment
of bronchospasm in patients at least 12 years old. Approval has since been granted for use in
children at least six years old [92]. A metered dose inhaler has been approved for patients ≥4 years
of age [93].
In both adult and pediatric patients, levalbuterol is approximately twice as potent in improving
baseline lung function versus racemic albuterol [94,95]. With regard to toxicity, beta-receptor
mediated side effects are primarily dependent on the levalbuterol dose, whether administered as
the single enantiomer or racemic albuterol [95]. Thus far, aside from increased potency,
levalbuterol appears to have no clinically significant advantage over racemic albuterol [96-100].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The
Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient
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Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a variety
of subjects by searching on “patient info” and the keyword(s) of interest.)
Beyond the Basics topics (see "Patient information: Asthma treatment in adolescents and
adults" and "Patient information: Trigger avoidance in asthma" and "Patient information: How to
use a peak flow meter" and "Patient information: Asthma inhaler techniques in adults")
SUMMARY AND RECOMMENDATIONS
Chronic short-acting beta agonists, provided in conjunction with other asthma therapy, do not
have a large effect on mortality. (See 'Short-acting beta agonists' above.)
Chronic long-acting beta agonists (LABA) are efficacious in improving pulmonary function,
increasing symptom-free days, and decreasing the need for rescue beta agonists. (See 'Direct
comparison' above and 'Long-acting beta agonists' above.)
Beta agonists administered on a regular schedule compared to an "as needed" schedule do not
worsen asthma control or increase complications in most patients. (See 'Regular versus as-needed
administration' above.)
Salmeterol and formoterol may induce tolerance to the bronchodilating effect of albuterol. In
addition, the protective effect of salmeterol against a bronchoconstrictor stimulus is reduced with
chronic use. (See 'Long–acting beta-agonists' above.)
Despite the beneficial effects of LABA, there has been a controversy over whether chronic use of
long-acting beta agonists may be associated with rare severe asthma exacerbations and increased
asthma and cardiac mortality in a small subgroup of patients. (See 'Long-acting beta
agonists' above.)
Long acting beta agonists should NOT be prescribed as monotherapy for asthma. (See
'Monotherapy' above and 'FDA advisory statement' above.)
Conversion from inhaled glucocorticoid monotherapy to chronic long-acting beta agonist
monotherapy can result in loss of asthma control and is NOT advised. (See 'Monotherapy
switch' above.)
In patients naïve to inhaled glucocorticoids (also known as inhaled corticosteroids or ICS) therapy
and requiring a controller medication for mild persistent asthma (eg, Step 2 care based on
guideline recommendations), monotherapy with inhaled glucocorticoids rather than combination
therapy with both ICS and LABA is advised as first line therapy (table 1 and figure 3). (See
'Efficacy' above.)
We follow the National Asthma Education and Prevention Program expert panel report III
guidelines regarding the specific indications for adding a LABA for the treatment of asthma. These
recommendations are discussed separately. (See 'Combination therapy' above and "An overview
of asthma management" and "Treatment of moderate persistent asthma in adolescents and
adults", section on 'Summary and recommendations' and "Treatment of severe asthma in
adolescents and adults", section on 'Summary and recommendations'.)
Chronic long-acting beta agonist therapy has the potential to permit inhaled glucocorticoid dose
reductions (ie, they are glucocorticoid-sparing). (See 'Combination therapy' above.)
Studies are insufficient to conclude whether inhaled glucocorticoids are protective against any
potential increase in mortality related to chronic LABA use. (See 'Long-acting beta
agonists' above.)
Patients receiving long-acting beta agonists should be monitored closely and advised of the
reported increased risk noted in a small number of patients and of the importance of seeking
medical care if their symptoms persist or worsen. (See 'Long-acting beta agonists' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
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