INTRODUCTION — Beta adrenergic drugs are the most potent bronchodilators currently approved for clinical use in asthma. An inhaled beta-agonist with rapid onset of action is the bronchodilator of choice for treatment of an acute asthmatic attack [1-3].
"Short-acting" beta agonists (SABAs; eg, albuterol) have bronchodilator (but not bronchoprotective) effects that last four to six hours. "Long-acting" beta agonists (LABAs) approved for use in asthma (eg, formoterol, salmeterol, vilanterol) have bronchodilator effects that last 12 to 24 hours, depending on the agent.
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".)
CONCERNS ABOUT MORTALITY RISK — In the 1990s and early 2000s, concerns were raised that regular use of beta-agonists might increase asthma mortality despite their clear benefit in acute relief of bronchoconstriction [4-11].
Short-acting beta agonists — Inhaled short-acting beta agonists (SABAs; such as albuterol) are one of the recommended options for acute relief of asthma symptoms [1,2]. Guidelines prefer intermittent use of SABAs over chronic use, although chronic short-acting beta agonists, provided in conjunction with other asthma therapy, do not appear to have a substantive effect on mortality. However, updates to the NAEPP guidelines indicate that as needed SABA is the preferred treatment option for intermittent asthma in patients five years of age and older [2]. In children up to four years of age, as needed SABA along with the addition of a short course of daily inhaled corticosteroids at the start of an upper respiratory tract infection is advised [2].
●Data suggesting that SABAs do not increase mortality – In a large case-control study, 532 patients who died of asthma were compared with 532 control patients with a history of hospitalization for asthma [12]. 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.
●Limited data suggesting an association between regular SABA use and mortality – An association between asthma mortality and chronic treatment with SABAs 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 [4,6,13,14]. The chronic use of inhaled beta agonist bronchodilators, largely fenoterol, was associated with asthma-related death, but not all-cause mortality [6,14]. The conclusions are limited by the case control design and the use of fenoterol as the main bronchodilator [15].
Long-acting beta agonists — Long-acting beta agonists (LABAs; salmeterol, formoterol, vilanterol) improve pulmonary function, increase symptom-free days, and decrease the need for rescue beta agonists. Despite these benefits, there were initial concerns regarding a possible association of chronic LABA treatment with severe exacerbations and increased mortality in a small subgroup of patients [7-10,16-21]. However, the association appears to be diminished or prevented by concomitant use of inhaled glucocorticoids (ICS) [22,23]. It is important to emphasize here that LABAs should not be prescribed as monotherapy. (See 'Evidence of safety' below.)
Clinical trials and systematic reviews that examined the safety of LABAs when used with ICS in fixed-combination inhalers have been reassuring and are described below. (See 'Combination LABA-ICS therapy' below.)
●Formoterol or salmeterol - In a meta-analysis performed by the US Food and Drug Administration (FDA; 60,954 patients), an increased risk of serious asthma events (hospitalization, intubation, or death) was associated with LABA therapy (with or without concomitant ICS) 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 [11]. However, this increased risk was not seen in children and adolescents who also received ICS as an assigned study treatment. Conclusions regarding the protective effect of ICS are limited by the small number of patient events in this subgroup.
A separate 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 ICS [18]. 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 8000 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 (SAEs; 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 the relative effect of LABAs on these outcomes.
●Salmeterol – A meta-analysis of 66 trials (20,966 participants) comparing the combination of fluticasone-salmeterol with ICS alone found that combination therapy was associated with a decrease in the risk of severe exacerbations, no change in the risk of hospitalization, and no apparent increase in the risk of intubation or death [17].
●Formoterol – 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) [10]. 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 use was associated with a significant reduction in asthma-related nonfatal severe adverse events. No increase in the rate of SAEs 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 separate meta-analysis of 22 studies (8032 participants), an increase in 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 [24]. 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.
The effect of combination therapy with formoterol PLUS ICS is discussed below. (See 'Evidence of safety' below.)
●Combination inhaled glucocorticoid-LABA inhalers – Large studies support safety of LABAs when used in combination with ICS, despite initial concerns that ICS given in combination with a LABA might not be protective [9,17,25,26]. (See 'Combination LABA-ICS therapy' below.)
FDA advisory statement — In 2017, the US Food and Drug Administration (FDA) reviewed four large clinical safety trials and concluded that LABA-ICS combination inhalers DO NOT significantly increase the risk of serious asthma-related side effects compared with ICS alone [22]. Based on this review, the FDA removed the "boxed warning" on combination LABA-ICS medications. The "boxed warning" had been in place since the 2010 FDA Drug Safety Communication of concerns about an increased risk of severe exacerbation of asthma leading to hospitalization or death [27].
The FDA continues to warn that monotherapy with a LABA (ie, without the concomitant use of an ICS) is contraindicated in the treatment of asthma [22]. In addition, the FDA advises that LABAs should only be used as additional therapy for patients whose asthma is not adequately controlled despite use of a long-term asthma control medication, such as an ICS. Once asthma control is achieved with a combination LABA-ICS inhaler and maintained, step-down therapy with discontinuation of the LABA is advised, if that is possible without loss of asthma control. However, a systematic review regarding the wisdom of discontinuing LABAs in patients on combination therapy found that stopping LABA slightly reduced asthma control and quality of life [28].
National and international guidelines — The Global Initiative for Asthma (GINA) guidelines and National Asthma Education and Prevention Program support the use of combination LABA-ICS inhalers depending on the severity and frequency of asthma symptoms [1-3]. The British Thoracic Society and Scottish Intercollegiate Guidelines Network recommend the use of combination inhalers when a LABA is added to an ICS [29]. All of these guidelines advise against monotherapy with a LABA in the treatment of asthma, in concert with the FDA guidance noted above. (See 'FDA advisory statement' above.)
A more detailed discussion of asthma management is provided separately. (See "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'.)
CONCERNS ABOUT ASTHMA CONTROL
Regular versus as-needed administration — The current recommendation of national and international guidelines is to prescribe short-acting beta agonists (SABAs) as needed for symptom control rather than on a regular schedule [1-3,29]. This recommendation is made despite the observation of most rigorously designed trials that beta agonists administered on a regular schedule compared with 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 (forced expiratory volume in one second [FEV1] ≥70 percent of the predicted value, concentration of methacholine that provoked a 20 percent decrease in FEV1 (PC20) <16 mg/mL, infrequent use of inhaled beta agonists, and no glucocorticoid use within six 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 [30]. 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 with those randomized to receive placebo [31].
Beta agonists protect against bronchoconstriction induced by chemical stimuli (eg, methacholine), exercise, or allergen exposure [32-37]. This protective effect is diminished by regular use of beta agonists, although this diminution in bronchoprotection does not appear to be clinically important for asthma control [38]. (See "Beta-2 adrenergic receptor dysfunction and polymorphism in asthma".)
Long–acting beta-agonists — The long-acting beta agonists (LABAs; salmeterol, formoterol) achieve prolonged bronchodilation (figure 1) and protection from bronchoprovocation with methacholine in patients with asthma [39,40]. In addition, formoterol has an onset of action similar to albuterol (5 to 20 minutes). Current guidelines support use of combination glucocorticoid-formoterol inhalers for quick relief of asthma symptoms in addition to use as maintenance therapy [2,3].
Some studies suggest that chronic use of LABAs can result in tolerance (tachyphylaxis) to bronchodilation, although the clinical significance of tolerance remains speculative [41-44]. (See 'Long-acting beta agonists' above.)
●Salmeterol and tolerance – Some studies of long-term LABA administration demonstrate development of tolerance to the beta-agonist bronchodilation [45,46], but not all [47]. In a randomized trial, 234 patients were assigned to receive regularly scheduled LABA (salmeterol), short-acting beta agonist (SABA; eg, albuterol), or placebo (figure 1) [47]. Salmeterol was more effective at increasing the morning peak expiratory flow rate than albuterol or placebo (+24, -6, +1 L/min, respectively, p<0.001). The mean overall symptom score was improved most by salmeterol treatment (p<0.05), 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.
●Formoterol and tolerance – 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 [48]. 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.
●Reduced protection to bronchoconstrictor stimuli – Reduced 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 [49].
●Improved asthma control with combination therapy – The combination of a LABA with an inhaled glucocorticoid (ICS) improves asthma control compared with ICS alone, as described below.
Ultra-long-acting beta-agonists — Once daily LABAs (24 hour duration of action), such as indacaterol, olodaterol, and vilanterol [50-54], have been approved by the US Food and Drug Administration (FDA) for use in patients with chronic obstructive pulmonary disease (COPD), but only vilanterol is approved for use in patients with asthma.
Clinically important tolerance seems unlikely during combined treatment with vilanterol and ICS, based on a randomized trial that compared fluticasone furoate-vilanterol (varying doses) with placebo once daily in 613 patients with asthma [51]. After 28 days, no significant diminution was noted in the mean FEV1 after salmeterol (albuterol) in the fluticasone furoate-vilanterol groups relative to placebo.
Impact of race — The possibility that race-ethnicity might affect the safety of LABAs has been examined in a few studies with conflicting results, as evidenced by the following:
●In a post hoc analysis of clinical trials published by the NHLBI-funded Asthma Clinical Research Network, African American patients taking LABAs were more likely to experience treatment failure than White patients taking LABAs (OR 2.1, 95% CI 1.3–3.6) [55]. Treatment failure was defined as an increase in systemic or ICS use, hospitalizations, emergency visits, albuterol use, or a prolonged decrease in peak expiratory flow, although most of the treatment failures were due to increased albuterol use. At baseline, African American patients reported fewer asthma symptoms and less rescue beta-agonist use.
●A randomized trial assigned 742 patients with moderate-to-severe asthma who were of African American descent to budesonide-formoterol (320 microg-9microg twice daily) or budesonide (320 microg twice daily) for 52 weeks [56]. Asthma exacerbations were lower in the budesonide-formoterol group compared with budesonide alone (7.7 versus 14 percent, p=0.006). Morning peak expiratory flow, FEV1, and rescue medication-free days were higher in the combination group.
●In multicenter, randomized trial, 1070 self-identified African American adults with moderate to severe asthma were assigned to ICS plus a LABA (salmeterol or formoterol) or ICS plus tiotropium [57]. Time to first exacerbation did not differ between groups, nor was there a significant difference in exacerbations per person-year.
Beta receptor polymorphisms — A number of polymorphic forms of the beta-2 adrenergic receptor were described in 1993 [58]. 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".)
EVIDENCE AGAINST LABA MONOTHERAPY — While long-acting beta agonists (LABAs) reduce asthma symptoms and reduce airflow limitation in the short term, LABAs SHOULD NOT be prescribed as monotherapy for asthma. (See 'FDA advisory statement' above.)
Several systematic reviews have concluded that LABA monotherapy increases the risk of serious adverse events (SAEs) compared with placebo [24,59,60]. In a systematic review and meta-analysis (72,092 subjects), LABA monotherapy was associated with an increased risk of asthma-related death (RR 3.83, 95% CI 1.21-12.14), particularly in children, subjects receiving salmeterol, and when the duration of treatment was >12 weeks (RR 0.73, 95% CI 0.67-0.79) [59]. However, LABA monotherapy reduced exacerbations requiring oral glucocorticoids. In a systematic review (22 studies, 8032 participants), formoterol was associated with an increase in SAEs compared with placebo, particularly in children (OR 1.57; 95% CI 1.06-2.31); the difference in deaths was not significant [24].
A separate line of evidence against LABA monotherapy comes from studies in which inhaled glucocorticoid (ICS) monotherapy was changed to LABA monotherapy in adult patients and resulted in loss of asthma control, as illustrated by the following studies:
●In a randomized trial, 164 patients with mild asthma received ICS (triamcinolone acetonide) for six weeks, and then were randomly assigned to receive LABA (salmeterol), inhaled triamcinolone acetonide, or placebo for 16 weeks [61]. 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, p = 0.004) and asthma exacerbations (20 versus 7 percent, p = 0.04) than the triamcinolone group.
●In another randomized trial, 175 patients with persistent asthma that was suboptimally controlled during a six-week period of treatment with ICS (triamcinolone acetonide) were randomly assigned to have placebo or long-acting beta agonist (salmeterol) added [62]. In the group receiving salmeterol, a dose reduction of ICS by 50 percent was not associated with any significant increase in treatment failure. However, complete elimination of the ICS led to a significant increase in treatment failure rates (46 versus 14 percent).
Several studies demonstrate improved control of asthma symptoms, decreased rescue short-acting beta agonist (SABA) use, fewer exacerbations, and improved peak expiratory flow (PEF) measurements with ICS compared with LABA monotherapy [63,64], although a few studies found no difference when ICS were compared with LABA [65],
COMBINATION LABA-ICS THERAPY — Combining long-acting beta agonists (LABAs) with inhaled glucocorticoids (ICS) is an attractive therapeutic option for patients whose asthma is not well-controlled with ICS. In theory, the ICS should suppress the underlying inflammatory response while the chronic beta agonist provides enough symptom control to permit lower doses of the ICS to be used, thus reducing glucocorticoid-related adverse effects. Herein, "combination therapy" refers to ICS plus LABA. We follow national and international guidelines regarding the specific indications for adding a LABA for the treatment of asthma [1-3,66]. 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'.)
Evidence of safety — In the past, studies and meta-analyses regarding the safety of LABA administration found inconsistent results, some of which were concerning for an increased risk of asthma-related intubation or death [10,19,67-72] (see 'Long-acting beta agonists' above). However, clinical trials and systematic reviews have been increasingly reassuring with respect to the safety of LABAs when used with ICS in fixed-combination inhalers in terms of mitigating the risks of serious asthma-related adverse events and death that have been associated with LABA monotherapy [20,67,68,73-79]. The more recent data from sufficiently powered clinical trials have enabled the FDA to make a firm statement regarding the safety of LABAs when used in combination with ICS.
●For adults, an analysis of the four FDA-mandated trials [75,78,80,81] comparing combination ICS plus LABA with ICS alone (36,010 participants) found that serious asthma-related adverse events (composite of hospitalization, intubation, or death) occurred in 119 of 18,004 participants (0.66 percent) taking the combination inhaler and in 108 of 18,006 participants (0.60 percent) taking ICS, for a relative risk (RR) of 1.09 (95% CI 0.83 to 1.43) [79]. Thus, combination therapy did not result in a significantly increased risk of serious adverse asthma events compared with ICS alone. A lower risk of asthma exacerbation was noted in the combination inhaler group, compared with ICS alone (RR 0.83, 95% CI 0.78 to 0.89).
●For children, a multicenter trial (VESTRI) randomly assigned 6208 children 4 to 11 years of age who had an asthma exacerbation in the previous year to a combination inhaler with fluticasone propionate (100 mcg or 250 mcg/inhalation) plus salmeterol or to monotherapy with fluticasone propionate (100 mcg or 250 mcg/inhalation), one inhalation twice daily for 26 weeks [77]. Serious adverse events (hospitalization due to asthma exacerbation) occurred in 27 of 3107 patients in the fluticasone-salmeterol group and in 23 of the 3101 patients in the fluticasone group, hazard ratio 1.28 (95% CI 0.73-2.27). No deaths or endotracheal intubations were reported. This hazard ratio suggests that the risk of serious asthma-related events was similar between the two groups.
These studies support the step-wise approach to asthma outlined in national and international guidelines [1-3,29]. (See "An overview of asthma management" and 'National and international guidelines' above.)
Glucocorticoid-sparing effect — A glucocorticoid-sparing effect refers to the ability of a pharmacologic agent to permit ICS dose reduction following its addition to a pre-existing ICS regimen. The efficacy of chronic LABAs as glucocorticoid-sparing agents was examined in a meta-analysis of 10 randomized trials comparing high-dose ICS versus combined low-dose ICS plus chronic LABA [82]. Addition of a chronic LABA permitted 37 to 60 percent reduction of the ICS dose without deterioration of asthma control.
Other studies have confirmed the efficacy of LABAs as glucocorticoid-sparing agents [83,84]. Tapering of the ICS 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 [85]. 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 ICS 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 "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies", section on 'Inhaled glucocorticoid plus LABA' and "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies", section on 'Step-up therapy for mild-to-moderate asthma'.)
Step-down therapy following establishment of control on combination therapy — In the US Food and Drug Administration (FDA) advisory statement that led to the "boxed warning" on drugs containing LABAs [86], 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 [87-90].
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 education: Asthma treatment in adolescents and adults (Beyond the Basics)" and "Patient education: Trigger avoidance in asthma (Beyond the Basics)" and "Patient education: How to use a peak flow meter (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●We agree with current guidelines that advise “as needed” to relieve asthma symptoms rather than scheduled use of short-acting beta agonists (SABAs), even though administering SABAs on a regular schedule compared with an "as needed" schedule does not worsen asthma control or increase complications in most patients. (See 'Regular versus as-needed administration' above.)
●Long-acting beta-agonists (LABAs), such as salmeterol and formoterol, may induce tolerance to the bronchodilating effect of albuterol and reduce the protective effect against a bronchoconstrictor stimulus. However, these effects are not felt to be of clinical significance in the majority of patients. (See 'Long–acting beta-agonists' above.)
●Use of combination glucocorticoid-LABA inhalers for patients with persistent asthma is supported by substantial and consistent safety data. (See 'Combination LABA-ICS therapy' above.)
●LABAs should NOT be prescribed as monotherapy for asthma, based on evidence that LABA monotherapy is associated with worsening asthma control and increased exacerbations compared with inhaled glucocorticoid (ICS) based regimens. (See 'Evidence against LABA monotherapy' above.)
●Combination ICS-LABA therapy has the potential to permit dose reductions in the ICS (ie, they are glucocorticoid-sparing). (See 'Glucocorticoid-sparing effect' above.)
●We follow national and international guidelines regarding the specific indications for adding a LABA for the treatment of asthma. These recommendations are discussed separately. (See 'Combination LABA-ICS 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'.)
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 August 31, 2021).
2 : 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.
3 : 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.
4 : The use of beta-agonists and the risk of death and near death from asthma.
5 : Regular inhaled beta-agonist treatment in bronchial asthma.
6 : A cohort analysis of excess mortality in asthma and the use of inhaled beta-agonists.
7 : The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol.
8 : Long-acting beta2-agonists for chronic asthma in adults and children where background therapy contains varied or no inhaled corticosteroid.
9 : Safety of long-acting beta-agonists--an urgent need to clear the air.
10 : Long-acting beta-agonists: a review of formoterol safety data from asthma clinical trials.
11 : Age and risks of FDA-approved long-actingβ₂-adrenergic receptor agonists.
12 : Bronchodilator treatment and deaths from asthma: case-control study.
13 : Is the association between inhaled beta-agonist use and life-threatening asthma because of confounding by severity?
14 : Bronchodilators and acute cardiac death.
15 : Inhaled beta 2-agonists in the treatment of asthma.
16 : Serevent nationwide surveillance study: comparison of salmeterol with salbutamol in asthmatic patients who require regular bronchodilator treatment.
17 : Meta-analysis: effects of adding salmeterol to inhaled corticosteroids on serious asthma-related events.
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19 : Risk of mortality associated with formoterol: a systematic review and meta-analysis.
20 : Safety of formoterol in patients with asthma: combined analysis of data from double-blind, randomized controlled trials.
21 : Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD.
22 : Long-acting {beta}2-agonists in adult asthma and the pattern of risk of death and severe asthma outcomes: a study using the GPRD.
23 : Combination inhaled glucocorticoid/long-acting beta-agonist safety: The long and winding road.
24 : Regular treatment with formoterol for chronic asthma: serious adverse events.
25 : Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths.
26 : Risks of long-acting beta-agonists in achieving asthma control.
27 : Risks of long-acting beta-agonists in achieving asthma control.
28 : Stopping long-acting beta2-agonists (LABA) for adults with asthma well controlled by LABA and inhaled corticosteroids.
29 : Stopping long-acting beta2-agonists (LABA) for adults with asthma well controlled by LABA and inhaled corticosteroids.
30 : Comparison of regularly scheduled with as-needed use of albuterol in mild asthma. Asthma Clinical Research Network.
31 : 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.
32 : Regular inhaled salbutamol and airway responsiveness to allergen.
33 : Use of exercise challenge to investigate possible tolerance to beta-adrenoceptor stimulation in asthma.
34 : Rapid onset of tolerance to the bronchoprotective effect of salmeterol.
35 : Interaction of inhaled beta 2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine.
36 : Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: dose response.
37 : Tolerance to the bronchoprotective effect of salmeterol in adolescents with exercise-induced asthma using concurrent inhaled glucocorticoid treatment.
38 : Perspectives in beta 2-agonist therapy: vox clamantis in deserto vel lux in tenebris?
39 : Formoterol, a new long-acting selective beta 2-adrenergic receptor agonist: double-blind comparison with salbutamol and placebo in children with asthma.
40 : Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma.
41 : Tolerance to the nonbronchodilator effects of inhaled beta 2-agonists in asthma.
42 : Effect of beta-agonists and anticholinergic drugs on bronchial reactivity.
43 : 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.
44 : Tolerance to the protective effects of salmeterol on methacholine-induced bronchoconstriction: influence of inhaled corticosteroids.
45 : Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients.
46 : Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma.
47 : A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma.
48 : Rapid onset of tolerance to beta-agonist bronchodilation.
49 : Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.
50 : Olodaterol: a review of its use in chronic obstructive pulmonary disease.
51 : 24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroids.
52 : Efficacy and optimal dosing interval of the long-acting beta₂agonist, vilanterol, in persistent asthma: a randomised trial.
53 : Long-acting inhaled therapy (beta-agonists, anticholinergics and steroids) for COPD: a network meta-analysis.
54 : Indacaterol, a once-daily beta2-agonist, versus twice-daily beta₂-agonists or placebo for chronic obstructive pulmonary disease.
55 : Impact of race on asthma treatment failures in the asthma clinical research network.
56 : Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: a randomized controlled trial.
57 : Anticholinergic vs Long-Actingβ-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma: The BELT Randomized Clinical Trial.
58 : Mutations in the gene encoding for the beta 2-adrenergic receptor in normal and asthmatic subjects.
59 : Safety of regular use of long-acting beta agonists as monotherapy or added to inhaled corticosteroids in asthma. A systematic review.
60 : Regular treatment with salmeterol for chronic asthma: serious adverse events.
61 : Long-acting beta2-agonist monotherapy vs continued therapy with inhaled corticosteroids in patients with persistent asthma: a randomized controlled trial.
62 : Inhaled corticosteroid reduction and elimination in patients with persistent asthma receiving salmeterol: a randomized controlled trial.
63 : Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma.
64 : A comparison of beclomethasone, salmeterol, and placebo in children with asthma. Canadian Beclomethasone Dipropionate-Salmeterol Xinafoate Study Group.
65 : A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma.
66 : The US Food and Drug Administration and long-acting beta2-agonists: the importance of striking the right balance between risks and benefits of therapy?
67 : Regular treatment with salmeterol and inhaled steroids for chronic asthma: serious adverse events.
68 : Long-acting beta-agonists with and without inhaled corticosteroids and catastrophic asthma events.
69 : Once-daily fluticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone.
70 : Efficacy and safety evaluation of once-daily fluticasone furoate/vilanterol in Asian patients with asthma uncontrolled on a low- to mid-strength inhaled corticosteroid or low-dose inhaled corticosteroid/long-acting beta2-agonist.
71 : Vilanterol and fluticasone furoate for asthma.
72 : Inhaled steroids with and without regular salmeterol for asthma: serious adverse events.
73 : Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events.
74 : Safety of regular formoterol or salmeterol in adults with asthma: an overview of Cochrane reviews.
75 : Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone.
76 : The relationship between combination inhaled corticosteroid and long-actingβ-agonist use and severe asthma exacerbations in a diverse population.
77 : Safety of Adding Salmeterol to Fluticasone Propionate in Children with Asthma.
78 : Serious Asthma Events with Budesonide plus Formoterol vs. Budesonide Alone.
79 : Combined Analysis of Asthma Safety Trials of Long-Actingβ2-Agonists.
80 : Serious asthma outcomes with mometasone furoate plus formoterol versus mometasone alone
81 : Serious asthma outcomes with mometasone furoate plus formoterol versus mometasone alone
82 : Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children.
83 : Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study.
84 : Potential masking effects of salmeterol on airway inflammation in asthma.
85 : Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids.
86 : The FDA and safe use of long-acting beta-agonists in the treatment of asthma.
87 : Asthma control can be maintained when fluticasone propionate/salmeterol in a single inhaler is stepped down.
88 : Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study.
89 : Deterioration in asthma control when subjects receiving fluticasone propionate/salmeterol 100/50 mcg Diskus are "stepped-down".
90 : Down-titration from high-dose combination therapy in asthma: Removal of long-acting beta(2)-agonist.
