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Official topic from UpToDate®, the clinical information service on the web and mobile devices. To subscribe to UpToDate®, visit us online at http://www.uptodate.com/store. 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 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 the Basics 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" 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. REFERENCES National Asthma Education and Prevention Program: Expert panel report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood 1 Institute, 2007. 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