Beta Agonists in Asthma_ Controversy Regarding Chronic Use

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/06/12 Beta agonists in asthma: Controversy regarding chronic use

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Official reprint from UpToDatewww.uptodate.com

2012 UpToDate

Author

Robert F Lemanske, Jr, MD

Section Editor

Bruce S Bochner, MD

Deputy Editor

Helen Hollingsworth, MD

Beta agonists in asthma: Controversy regarding chronic use

Disclosures

All topics are updated as new evidence becomes available and ourpeer review process is complete.

Literature review current through: May 2012. | This topic last updated: abr 26, 2012.

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 worsenEqual 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 nearfatal asthmatic episodes (PaCO2 >45

mmHg and/or intubation) were matched with 655 controls who had received asthma medications but had not

had fatal or nearfatal events [3]. An increased risk of death or near-death 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 casecontrol 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.


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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 long-acting betaagonists (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 [21,22].

Meta-analysis and clinical trial data The controversy regarding the potential association of chronic LABA

treatment with severe exacerbations and increased mortality is illustrated by the following studies:

In a meta-analysis performed by the United States Food and Drug Administration (60,954 patients), an

increased risk of serious asthma events (hospitalization, intubation, or death) was associated with LABAtherapy versus no LABA (6.3 excess events per 1000 patient years, CI 2.2-10.3), particularly among the

youngest patients aged 4 to 11 years [23]. However, this increased risk was not seen in children and

adolescents who also received inhaled glucocorticoids as an assigned study treatment. Conclusions

regarding the protective effect of inhaled glucocorticoids are limited by the small number of patient events in

this subgroup.

A systematic review and meta-analysis assessed the impact of LABA (eitherformoterol orsalmeterol), 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 offluticasone-salmeterol 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 thatparticipants 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.


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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 non-fatal serious adverse events between the two groups.

In a randomized trial, more than 25,000 patients with asthma were assigned to receive the long-acting 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 topatients 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 might be greater in African

Americans. Like the trial above, SMART was not designed to evaluate subgroups that did or did not receive

inhaled glucocorticoids.

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 [ 23-26]. 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.

In a meta-analysis of 22 studies (8032 participants), an increase in serious adverse events (SAEs) was noted whenregular use of formoterol was compared with placebo (OR 1.57, 95% CI 1.06 to 2.31), but not when compared with

regular use ofalbuterol orterbutaline [27]. Overall, nonfatal SAEs were rare, occurring in 1 percent of patients on

placebo. Too few asthma-related deaths were reported to assess drug-related mortality.

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 [28,29]. 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 [ 30]. 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 [14,16,31,32]. Unfortunately, the formidable

sample size that would be required makes it highly unlikely that such a trial will be possible [18,33]. (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, formoterol, orindacaterol because of "an


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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/PostmarketDrugSafetyInformationforPatientsandProviders/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 or the interpretation of the data that led to them [34].

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


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increased receptor degradation and decreased receptor synthesis [46,47]. (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 short-acting 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 [48].

In a subsequent analysis, the deleterious responses noted following chronic beta agonist were not related to

beta-2 receptor polymorphisms [49]. (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 [50,51] or the long-term [52-54], as measured by peak expiratory flow rate or

symptom control (figure 2).

Longacting beta-agonists The effect of LABA therapy on asthma control has been examined during short-

term and long-term use. 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 [55,56].

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 beta-agonist (salmeterol), short-acting beta

agonist (albuterol), or placebo [52]. 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 ofalbuterol [57,58]. 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 ofalbuterol. In one study, 10

patients with stable asthma were given scheduled formoterol for durations ranging from a single dose to two weeks[59]. 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 [60].

Taken together, the data suggest that chronic long-acting beta agonists improve pulmonary function and asthma


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symptoms. Although salmeterol and formoterol induce tolerance to the bronchodilating effect ofalbuterol, the

clinical significance of the tolerance remains speculative [61-63]. 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 [64].

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.)

Impact of race In a post hoc analysis of clinical trials published by the NHLBI-funded Asthma Clinical ResearchNetwork, African American patients taking LABA were more likely to experience treatment failure than white

patients taking LABA (OR 2.1, 95% CI 1.33.6) [65]. Treatment failure was defined as an increase in systemic or

inhaled glucocorticoid use, hospitalizations, emergency visits, albuterol use, or a prolonged decrease in peak

expiratory flow, although most of the treatment failures were due to increased albuterol use. At baseline, African-

American patients reported fewer asthma symptoms and less rescue beta-agonist use.

Beta receptor polymorphisms A number of polymorphic forms of the beta-2 adrenergic receptor were

described in 1993 [66]. 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 [67,68] while others do not [69]. 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) [70], most studies favored inhaled glucocorticoids over chronic beta agonist therapy

[53,71]. 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) [53]. 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 long-acting beta

agonist (salmeterol), an inhaled glucocorticoid (beclomethasone), or placebo [71]. 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 long-acting 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 [28]. 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


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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 [29]. 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

[1,34]. 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 nave 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 [72,73]. Thus, there is insufficient evidence to recommendcombination 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 [73].

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 [74,75]:

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 dailylong-acting beta agonist reduced the risk of exacerbations requiring systemic glucocorticoids by 19 percent

[75]. 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 short-acting 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 long-acting 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 [ 74]. There was no


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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 [76-81]. 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 [82,83].

The first trial (the GOAL study) evaluated whether aggressive escalation of therapy (until total control or

maximum dose inhaled glucocorticoids) affects asthma control [82]. 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 [ 83]. 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 [83]. 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 [84]. 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 [ 80,85].

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 step-up

treatment was evaluated in children and adolescents whose asthma was not well-controlled on fluticasone 100 mcg

twice daily [86]. 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 [87], the FDA recommended that,

once asthma control is achieved and maintained, therapy should be stepped down with discontinuation of the LABA


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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 [88-91].

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 [19,92,93].

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 inhaledglucocorticoid 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 non-

formoterol 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 [92]. 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 inhaledglucocorticoids 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 [34]. 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".)

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 might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond theBasics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with

some medical jargon.

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 (Beyond

the Basics)" and "Patient information: Trigger avoidance in asthma (Beyond the Basics)" and "Patient

information: How to use a peak flow meter (Beyond the Basics)" and "Patient information: Asthma inhalertechniques in adults (Beyond the Basics)")

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.)


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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 ofalbuterol. 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-actingbeta 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 nave 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 ICSand 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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asthma: serious adverse events. Cochrane Database Syst Rev 2009; :CD006924.

Topic 557 Version 10.0


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GRAPHICS

Tolerance to chronic beta agonist therapy in asthma

Number of patients without an exacerbation of asthma overtime in patients treated with as needed or regular (continuous)beta agonist therapy. The likelihood of exacerbation wasgreater in the patients treated with continuous beta agonist,suggesting the development of tolerance. Redrawn from Taylor,DR, Sears, MR, Herbison, GP, et al, Thorax 1993; 48:134.


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Persistence of beta agonist efficacy over time

Mean FEV1 as a percentage of the predicted value on the firstand last days of treatment in patients with asthma. Therapyconsisted of salmeterol (40 g BID), albuterol (180 g QID),or placebo. Both beta agonists increased the FEV1, but theeffect of a single dose lasted longer with salmeterol. Thebeneficial effect of both agents persisted at 12 weeks. Redrawnfrom Pearlman, DS, Chervinsky, P, LaForce, C, et al, N Engl J Med 1992;

327:1420.


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Stepwise approach for managing asthma in youths greater than or equalto 12 years of age and adults

The stepwise approach is meant to assist, not replace, the clinical decision-makingrequired to meet individual patient needs. If alternative treatment is used andresponse is inadequate, discontinue it and use the preferred treatment beforestepping up. Zileuton is a less desirable alternative due to limited studies asadjunctive therapy and the need to monitor liver function. Theophylline requires

monitoring of serum concentration levels. In step 6, before oral systemiccorticosteroids are introduced, a trial of high-dose ICS + LABA + either LTRA,theophylline, or zileuton may be considered, although this approach has not beenstudied in clinical trials. Step 1, 2, and 3 preferred therapies are based on Evidence A;step 3 alternative therapy is based on Evidence A for LTRA, Evidence B fortheophylline, and Evidence D for zileuton. Step 4 preferred therapy is based onEvidence B, and alternative therapy is based on Evidence B for LTRA and theophyllineand Evidence D for zileuton. Step 5 preferred therapy is based on Evidence B. Step 6preferred therapy is based on (EPR-2 1997) and Evidence B for omalizumab.Immunotherapy for steps 2-4 is based on Evidence B for house-dust mites, animaldanders, and pollens; evidence is weak or lacking for molds and cockroaches.


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Evidence is strongest for immunotherapy with single allergens. The role of allergy inasthma is greater in children than in adults. Clinicians who administer immunotherapyor omalizumab should be prepared and equipped to identify and treat anaphylaxisthat may occur.Alphabetical order is used when more than one treatment option is listedwithin either preferred or alternative therapy.EIB: exercise-induced bronchospasm;ICS: inhaled corticosteroid; LABA: long-acting inhaled beta2-agonist; LTRA: leukotriene receptor

antagonist; SABA: inhaled short-acting beta2-agonist.Reproduced from: National Heart, Blood,

and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management ofAsthma. NIH Publication no. 08-4051, 2007.


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Classifying asthma severity and initiating treatment in youths greater thanor equal to 12 years of age and adults

Components of severity

Classification of asthma severity (12 yearsof age)

IntermittentPersistent

Mild Moderate Severe

Impairment

NormalFEV1/FVC:

8-19 yr 85percent

20-39 yr80 percent

40-59 yr

75 percent

60-80 yr70 percent

Symptoms 2days/week

>2 days/weekbut not da ily

Daily Throughoutthe day

Nighttimeawakenings

2x/month 3-4x/month >1x/weekbut notnightly

Often7x/week

Short-acting beta2-

agonist use forsymptom control(not prevention ofEIB)

2days/week

>2 days/weekbut not daily,and not morethan 1x onany day

Daily Severaltimes perday

Interference withnormal activity

None Minorlimitation

Somelimitation

Extremelylimited

Lung function Normal FEV1betweenexacerbations

FEV1 >80

percentpredicted

FEV1/FVC

normal

FEV1 80

percentpredicted

FEV1/FVC

normal

FEV1>60 but


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of severity is determined by assessment of both impairment and risk. Assessimpairment domain by patient's/caregiver's recall of previous 2-4 weeks andspirometry. Assign severity to the most severe category in which any feature occurs.At present, there are inadequate data to correspond frequencies of exacerbations withdifferent levels of asthma severity. In general, more frequent and intense exacerbations(eg, requiring urgent, unscheduled care, hospitalization, or ICU admission) indicategreater underlying disease severity. For treatment purposes, patients who had 2exacerbations requiring oral systemic corticosteroids in the past year may beconsidered the same as patients who have persistent asthma, even in the absence ofimpairment levels consistent with persistent asthma. FEV1: forced expiratory volume in 1

second; FVC: forced vital capacity; ICU: intens ive care unit.Reproduced from: National Heart, Blood,and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of

Asthma. NIH Publication no. 08-4051, 2007.


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Beta Agonists in Asthma_ Controversy Regarding Chronic Use