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Beta agonists in asthma: Controversy regarding chronic use

Official reprint from UpToDate www.uptodate.com 2012 UpToDate

Beta agonists in asthma: Controversy regarding chronic use Author Robert F Lemanske, Jr, MD Disclosures All topics are updated as new evidence becomes available and our peer 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 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 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 allcauses 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 nebulizerdelivered beta agonists [9]. However, the association was so weak that its clinical significance was doubted.
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Section Editor Bruce S Bochner, MD

Deputy Editor Helen Hollingsworth, MD

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Beta agonists in asthma: Controversy regarding chronic use

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 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 [21,22]. 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 LABA therapy 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 (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 fluticasone-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 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.
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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 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 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 longacting 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 when regular use of formoterol was compared with placebo (OR 1.57, 95% CI 1.06 to 2.31), but not when compared with regular use of albuterol or terbutaline [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, or indacaterol 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 <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 [35]. 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 [36]. In contrast, diminution of the "bronchoprotective effect" is an important adverse outcome found when patients use beta agonists on a regular schedule [37]. The bronchoprotective effect is described as the ability to protect against bronchoconstriction in response to chemical stimuli (eg, methacholine), exercise, or allergen exposure [38-43]. Although the clinical significance of this diminution has been debated [44], 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 [45]. 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
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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 shortterm 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 of albuterol [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 of albuterol. 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 of albuterol, 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 longacting 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 Research Network, 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, AfricanAmerican 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 longacting 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 6week 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 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 [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 daily long-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 longacting 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 lowdose 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 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 openlabel 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 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 [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 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 (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 inhaler techniques 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 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 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 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 1. 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 Institute, 2007. (NIH publication no. 08-4051) www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on January 05, 2012). 2. Global Initiative for Asthma http://www.ginasthma.com (Accessed on September 03, 2007). 3. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonists and the risk of death and near death from asthma. N Engl J Med 1992; 326:501. 4. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336:1391.
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5. O'Byrne PM, Kerstjens HA. Inhaled beta 2-agonists in the treatment of asthma. N Engl J Med 1996; 335:886. 6. Ernst P, Habbick B, Suissa S, et al. Is the association between inhaled beta-agonist use and life-threatening asthma because of confounding by severity? Am Rev Respir Dis 1993; 148:75. 7. Suissa S, Ernst P, Boivin JF, et al. A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists. Am J Respir Crit Care Med 1994; 149:604. 8. Suissa S, Hemmelgarn B, Blais L, Ernst P. Bronchodilators and acute cardiac death. Am J Respir Crit Care Med 1996; 154:1598. 9. Mullen M, Mullen B, Carey M. The association between beta-agonist use and death from asthma. A metaanalytic integration of case-control studies. JAMA 1993; 270:1842. 10. Anderson HR, Ayres JG, Sturdy PM, et al. Bronchodilator treatment and deaths from asthma: case-control study. BMJ 2005; 330:117. 11. Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment. BMJ 1993; 306:1034. 12. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest 2006; 129:15. 13. Walters EH, Gibson PG, Lasserson TJ, Walters JA. Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid. Cochrane Database Syst Rev 2007; :CD001385. 14. Bateman E, Nelson H, Bousquet J, et al. Meta-analysis: effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events. Ann Intern Med 2008; 149:33. 15. Jaeschke R, O'Byrne PM, Mejza F, et al. The safety of long-acting beta-agonists among patients with asthma using inhaled corticosteroids: systematic review and metaanalysis. Am J Respir Crit Care Med 2008; 178:1009. 16. Martinez FD. Safety of long-acting beta-agonists--an urgent need to clear the air. N Engl J Med 2005; 353:2637. 17. Sears MR, Ottosson A, Radner F, Suissa S. Long-acting beta-agonists: a review of formoterol safety data from asthma clinical trials. Eur Respir J 2009; 33:21. 18. Wijesinghe M, Weatherall M, Perrin K, et al. Risk of mortality associated with formoterol: a systematic review and meta-analysis. Eur Respir J 2009; 34:803. 19. Nelson H, Bonuccelli C, Radner F, et al. Safety of formoterol in patients with asthma: combined analysis of data from double-blind, randomized controlled trials. J Allergy Clin Immunol 2010; 125:390. 20. de Vries F, Setakis E, Zhang B, van Staa TP. Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD. Eur Respir J 2010; 36:494. 21. Cates CJ, Lasserson TJ, Jaeschke R. Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2009; :CD006922. 22. Malone R, LaForce C, Nimmagadda S, et al. The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma. Ann Allergy Asthma Immunol 2005; 95:66. 23. McMahon AW, Levenson MS, McEvoy BW, et al. Age and risks of FDA-approved long-acting -adrenergic receptor agonists. Pediatrics 2011; 128:e1147. 24. O'Byrne PM, Adelroth E. Beta2 dj vu. Chest 2006; 129:3. 25. Nelson HS. Is there a problem with inhaled long-acting beta-adrenergic agonists? J Allergy Clin Immunol 2006; 117:3. 26. Ernst P, McIvor A, Ducharme FM, et al. Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids. Ann Intern Med 2006; 145:692. 27. Cates CJ, Cates MJ. Regular treatment with formoterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2012; 4:CD006923. 28. Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial. JAMA 2001;
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285:2583. 29. Lemanske RF Jr, Sorkness CA, Mauger EA, et al. Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial. JAMA 2001; 285:2594. 30. Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev 2008; :CD006363. 31. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med 2006; 144:904. 32. Drazen JM, O'Byrne PM. Risks of long-acting beta-agonists in achieving asthma control. N Engl J Med 2009; 360:1671. 33. Sears MR. Safety of long-acting beta-agonists: are new data really required? Chest 2009; 136:604. 34. Lemanske RF Jr, Busse WW. The US Food and Drug Administration and long-acting beta2-agonists: the importance of striking the right balance between risks and benefits of therapy? J Allergy Clin Immunol 2010; 126:449. 35. Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med 1996; 335:841. 36. Dennis SM, Sharp SJ, Vickers MR, et al. Regular inhaled salbutamol and asthma control: the TRUST randomised trial. Therapy Working Group of the National Asthma Task Force and the MRC General Practice Research Framework. Lancet 2000; 355:1675. 37. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med 2004; 140:802. 38. Cockcroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342:833. 39. Gibson GJ, Greenacre JK, Knig P, et al. Use of exercise challenge to investigate possible tolerance to betaadrenoceptor stimulation in asthma. Br J Dis Chest 1978; 72:199. 40. Bhagat R, Kalra S, Swystun VA, Cockcroft DW. Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 1995; 108:1235. 41. Cockcroft DW, Swystun VA, Bhagat R. Interaction of inhaled beta 2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine. Am J Respir Crit Care Med 1995; 152:1485. 42. Bhagat R, Swystun VA, Cockcroft DW. Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: dose response. J Allergy Clin Immunol 1996; 97:47. 43. Simons FE, Gerstner TV, Cheang MS. Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment. Pediatrics 1997; 99:655. 44. McFadden ER Jr. Perspectives in beta 2-agonist therapy: vox clamantis in deserto vel lux in tenebris? J Allergy Clin Immunol 1995; 95:641. 45. Gauvreau GM, Jordana M, Watson RM, et al. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Respir Crit Care Med 1997; 156:1738. 46. Penn RB, Panettieri RA Jr, Benovic JL. Mechanisms of acute desensitization of the beta2AR-adenylyl cyclase pathway in human airway smooth muscle. Am J Respir Cell Mol Biol 1998; 19:338. 47. Sorkness CA. Beta-adrenergic Agonists. In: Middleton's Allergy: Principles and Practice, 7th ed, Adkinson NF, Bochner BS, Busse WW, et al (Eds), Mosby, Philadelphia 2009. p.1485-503. 48. Taylor DR, Sears MR, Herbison GP, et al. Regular inhaled beta agonist in asthma: effects on exacerbations and lung function. Thorax 1993; 48:134. 49. Hancox RJ, Sears MR, Taylor DR. Polymorphism of the beta2-adrenoceptor and the response to long-term beta2-agonist therapy in asthma. Eur Respir J 1998; 11:589. 50. Chapman KR, Kesten S, Szalai JP. Regular vs as-needed inhaled salbutamol in asthma control. Lancet 1994; 343:1379. 51. Heino M. Regularly inhaled beta-agonists with steroids are not harmful in stable asthma. J Allergy Clin Immunol 1994; 93:80.
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52. Pearlman DS, Chervinsky P, LaForce C, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med 1992; 327:1420. 53. Haahtela T, Jrvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. N Engl J Med 1991; 325:388. 54. Apter AJ, Reisine ST, Willard A, et al. The effect of inhaled albuterol in moderate to severe asthma. J Allergy Clin Immunol 1996; 98:295. 55. Becker AB, Simons FE. Formoterol, a new long-acting selective beta 2-adrenergic receptor agonist: doubleblind comparison with salbutamol and placebo in children with asthma. J Allergy Clin Immunol 1989; 84:891. 56. Simons FE, Soni NR, Watson WT, Becker AB. Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma. J Allergy Clin Immunol 1992; 90:840. 57. Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995; 346:201. 58. Aziz I, Hall IP, McFarlane LC, Lipworth BJ. Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol 1998; 101:337. 59. Haney S, Hancox RJ. Rapid onset of tolerance to beta-agonist bronchodilation. Respir Med 2005; 99:566. 60. Cheung D, Timmers MC, Zwinderman AH, et al. Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma. N Engl J Med 1992; 327:1198. 61. O'Connor BJ, Aikman SL, Barnes PJ. Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma. N Engl J Med 1992; 327:1204. 62. Tattersfield AE. Effect of beta-agonists and anticholinergic drugs on bronchial reactivity. Am Rev Respir Dis 1987; 136:S64. 63. Twentyman OP, Higenbottam TW. Controversies in respiratory medicine: regular inhaled beta-agonists--clear clinical benefit or a hazard to health? (1). Beta-agonists can be used safely and beneficially in asthma. Respir Med 1992; 86:471. 64. Boulet LP, Cartier A, Milot J, et al. Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids. Eur Respir J 1998; 11:1091. 65. Wechsler ME, Castro M, Lehman E, et al. Impact of race on asthma treatment failures in the asthma clinical research network. Am J Respir Crit Care Med 2011; 184:1247. 66. Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8:334. 67. Gardiner PV, Ward C, Booth H, et al. Effect of eight weeks of treatment with salmeterol on bronchoalveolar lavage inflammatory indices in asthmatics. Am J Respir Crit Care Med 1994; 150:1006. 68. Li X, Ward C, Thien F, et al. An antiinflammatory effect of salmeterol, a long-acting beta(2) agonist, assessed in airway biopsies and bronchoalveolar lavage in asthma. Am J Respir Crit Care Med 1999; 160:1493. 69. Roberts JA, Bradding P, Britten KM, et al. The long-acting beta2-agonist salmeterol xinafoate: effects on airway inflammation in asthma. Eur Respir J 1999; 14:275. 70. Nathan RA, Pinnas JL, Schwartz HJ, et al. A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma. Ann Allergy Asthma Immunol 1999; 82:521. 71. Simons FE. A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group. N Engl J Med 1997; 337:1659. 72. O'Byrne PM, Barnes PJ, Rodriguez-Roisin R, et al. Low dose inhaled budesonide and formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J Respir Crit Care Med 2001; 164:1392. 73. Sorkness CA, Lemanske RF Jr, Mauger DT, et al. Long-term comparison of 3 controller regimens for mildmoderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol 2007; 119:64. 74. Greenstone IR, Ni Chroinin MN, Masse V, et al. Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma.
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Cochrane Database Syst Rev 2005; :CD005533. 75. Ni Chroinin M, Greenstone IR, Danish A, et al. Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev 2005; :CD005535. 76. Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994; 344:219. 77. Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153:1481. 78. van der Molen T, Postma DS, Turner MO, et al. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. Thorax 1997; 52:535. 79. Pauwels RA, Lfdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med 1997; 337:1405. 80. Wilding P, Clark M, Thompson Coon J, et al. Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study. BMJ 1997; 314:1441. 81. Langley SJ, Masterson CM, Batty EP, Woodcock A. Bronchodilator response to salbutamol after chronic dosing with salmeterol or placebo. Eur Respir J 1998; 11:1081. 82. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170:836. 83. O'Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 2005; 171:129. 84. Gibson PG, Powell H, Ducharme F. Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children. Cochrane Database Syst Rev 2005; :CD005076. 85. Mcivor RA, Pizzichini E, Turner MO, et al. Potential masking effects of salmeterol on airway inflammation in asthma. Am J Respir Crit Care Med 1998; 158:924. 86. Lemanske RF Jr, Mauger DT, Sorkness CA, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010; 362:975. 87. Chowdhury BA, Dal Pan G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 2010; 362:1169. 88. Bateman ED, Jacques L, Goldfrad C, et al. Asthma control can be maintained when fluticasone propionate/salmeterol in a single inhaler is stepped down. J Allergy Clin Immunol 2006; 117:563. 89. Godard P, Greillier P, Pigearias B, et al. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study. Respir Med 2008; 102:1124. 90. Koenig SM, Ostrom N, Pearlman D, et al. Deterioration in asthma control when subjects receiving fluticasone propionate/salmeterol 100/50 mcg Diskus are "stepped-down". J Asthma 2008; 45:681. 91. Reddel HK, Gibson PG, Peters MJ, et al. Down-titration from high-dose combination therapy in asthma: Removal of long-acting beta(2)-agonist. Respir Med 2010; 104:1110. 92. Salpeter SR, Wall AJ, Buckley NS. Long-acting beta-agonists with and without inhaled corticosteroids and catastrophic asthma events. Am J Med 2010; 123:322. 93. Cates CJ, Lasserson TJ, Jaeschke R. Regular treatment with formoterol and inhaled steroids for chronic 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 over time in patients treated with as needed or regular (continuous) beta agonist therapy. The likelihood of exacerbation was greater 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 first and last days of treatment in patients with asthma. Therapy consisted of salmeterol (40 g BID), albuterol (180 g QID), or placebo. Both beta agonists increased the FEV1, but the effect of a single dose lasted longer with salmeterol. The beneficial effect of both agents persisted at 12 weeks. Redrawn
from 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 equal to 12 years of age and adults

The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up. Zileuton is a less desirable alternative due to limited studies as adjunctive therapy and the need to monitor liver function. Theophylline requires monitoring of serum concentration levels. In step 6, before oral systemic corticosteroids are introduced, a trial of high-dose ICS + LABA + either LTRA, theophylline, or zileuton may be considered, although this approach has not been studied 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 for theophylline, and Evidence D for zileuton. Step 4 preferred therapy is based on Evidence B, and alternative therapy is based on Evidence B for LTRA and theophylline and Evidence D for zileuton. Step 5 preferred therapy is based on Evidence B. Step 6 preferred 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, animal danders, 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 in asthma is greater in children than in adults. Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to identify and treat anaphylaxis that may occur. Alphabetical order is used when more than one treatment option is listed within either preferred or alternative therapy. EIB: exercise-induced bronchospasm;
ICS: inhaled corticosteroid; LABA: long-acting inhaled beta 2 -agonist; LTRA: leukotriene receptor antagonist; SABA: inhaled short-acting beta 2 -agonist. 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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Classifying asthma severity and initiating treatment in youths greater than or equal to 12 years of age and adults
Classification of asthma severity (12 years of age)
Intermittent Symptoms Nighttime awakenings Short-acting beta 2 agonist use for symptom control (not prevention of EIB) Interference with normal activity Lung function 2 days/week 2x/month Persistent
Mild Moderate Severe

Components of severity

Impairment Normal FEV1 /FVC: 8-19 yr 85 percent 20-39 yr 80 percent 40-59 yr 75 percent 60-80 yr 70 percent

>2 days/week but not daily 3-4x/month

Daily >1x/week but not nightly Daily

Throughout the day Often 7x/week Several times per day

2 days/week

>2 days/week but not daily, and not more than 1x on any day Minor limitation FEV1 80 percent predicted FEV1 /FVC normal

None

Some limitation FEV1 >60 but <80 percent predicted FEV1 /FVC reduced 5 percent

Extremely limited FEV1 <60 percent predicted FEV1 /FVC reduced >5 percent

Normal FEV1 between exacerbations FEV1 >80 percent predicted FEV1 /FVC normal

Risk

Exacerbations requiring oral systemic corticosteroids

0-1/year (see footnote)

2/year (see footnote)

Consider severity and interval since last exacerbation Frequency and severity may fluctuate over time for patients in any severity category Relative annual risk of exacerbations may be related to FEV1

Recommended step for initiating treatment

Step 1

Step 2

Step 3

Step 4 or 5

And consider short course of oral systemic corticosteroids In 2-6 weeks, evaluate level of asthma control that is achieved and adjust therapy accordingly.

Assessing severity and initiating treatment for patients who are not currently taking long-term control medications. The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual patient needs. Level
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of severity is determined by assessment of both impairment and risk. Assess impairment domain by patient's/caregiver's recall of previous 2-4 weeks and spirometry. Assign severity to the most severe category in which any feature occurs. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. In general, more frequent and intense exacerbations (eg, requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate greater underlying disease severity. For treatment purposes, patients who had 2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma. FEV1 : forced expiratory volume in 1
second; FVC: forced vital capacity; ICU: intensive 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

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