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Review  |   September 2006
A Safety Review of Long-Acting β2-Agonists in Patients With Asthma
Author Notes
  • From the Allergy, Asthma, and Immunology Section in the Departments of Medicine and Pediatrics, Penn State University Milton S. Hershey Medical Center, Hershey. 
  • Address correspondence to Timothy J. Craig, DO, Allergy, Asthma, and Immunology Section, Penn State University Milton S. Hershey Medical Center, 500 University Dr, Hershey, PA 17033-2360. E-mail: tcraig@psu.edu 
Article Information
Pulmonary Disorders
Review   |   September 2006
A Safety Review of Long-Acting β2-Agonists in Patients With Asthma
The Journal of the American Osteopathic Association, September 2006, Vol. 106, 562-567. doi:10.7556/jaoa.2006.106.9.562
The Journal of the American Osteopathic Association, September 2006, Vol. 106, 562-567. doi:10.7556/jaoa.2006.106.9.562
Abstract

Inhaled corticosteroids are the mainstay of asthma therapy; however, inhaled long-acting β2-agonists (LABAs) are frequently used in the treatment of patients with asthma. LABAs are combined with high-dose inhaled corticosteroids (ICSs) for patients with severe persistent asthma, and they are combined with low-dose ICSs for patients older than 5 years with moderate persistent asthma. Recent safety concerns raised by data from the Salmeterol Multi-Center Research Trial (SMART) have indicated that use of LABAs in some populations may contribute to increased mortality. These concerns are warranted when LABAs are used as monotherapy in the treatment of patients with asthma in whom they may cause increased exacerbations, blunting of rescue-medication effect, and worsening symptoms. However, when used in combination with an ICS, they decrease both rescue-medication use and symptoms, increase lung function, and act as steroid-sparing agents.

Inhaled long-acting β2-agonists (LABAs) have been used in the routine treatment of patients with asthma since the 1990s. Currently, a LABA combined with a high-dose inhaled corticosteroid (ICSs) is the standard of care for all patients with severe persistent asthma; also, LABAs are combined with low-dose ICSs for patients older than 5 years with moderate persistent asthma.1 These medications (salmeterol xinafoate and formeterol fumarate inhalation powder) bind to airway β2-adrenergic receptors and result in relaxation of airway smooth muscle. In contrast to short-acting rescue β2-agonists such as albuterol, LABAs are indicated for long-term maintenance. 
Safety concerns regarding β2-agonists began in the late 1970s, when short-acting β2-agonists (SABAs) were used as routine maintenance therapy. In the late 1970s and early 1980s, increased mortality was noted with short-acting albuterol, while overuse of the SABA fenoterol produced high death rates in New Zealand.24 In hindsight, the mortality increase associated with albuterol was thought to be due to overuse of bronchodilators and underuse of ICSs.5 Currently, SABAs are approved only as rescue medications, a use for which they are generally safe; however, more recent attention has been focused on the safety of the LABAs (Table 1).6 
Table 1
Comparison of Different β2-Agonists 6


Feature
β2-Agonist
Onset of Action, min
Peak Effect
Duration, H
Route of Administration
Albuterol
□ Nebulizer/MDI1010 min3-4Nebulized/MDI
□ Oral4-610 min4-6Oral
Levalbuterol101.5 h5-8Nebulized
Salmeterol xinafoate102-4 h12MDI Dry powder inhaler
Formoterol315 min12Dry powder inhaler
 MDI indicates metered-dose inhaler
Table 1
Comparison of Different β2-Agonists 6


Feature
β2-Agonist
Onset of Action, min
Peak Effect
Duration, H
Route of Administration
Albuterol
□ Nebulizer/MDI1010 min3-4Nebulized/MDI
□ Oral4-610 min4-6Oral
Levalbuterol101.5 h5-8Nebulized
Salmeterol xinafoate102-4 h12MDI Dry powder inhaler
Formoterol315 min12Dry powder inhaler
 MDI indicates metered-dose inhaler
×
The Salmeterol Multicenter Asthma Research Trial (SMART) was a 28-week safety study that compared salmeterol with placebo in the treatment of patients with asthma.7 The study was borne out of a nationwide salmeterol surveillance study and several postmarketing reports that suggested a link between salmeterol and asthma-related deaths. The study compared 13,176 patients using 42 μg of salmeterol xinafoate delivered via a metered-dose inhaler (MDI) twice a day with 13,179 patients using a placebo MDI. Both groups were taking other prescribed asthma medications, and many were not taking optimal ICS doses, as the trial was conducted at a time when salmeterol was approved as monotherapy for the treatment of patients with asthma.5,8 
The primary end point of the SMART was the combined number of respiratory-related deaths or respiratory-related life-threatening events (ie, those requiring endotracheal intubation with mechanical ventilation). Analysis of the data revealed no significant difference for the primary end point for the total population; however, a higher number of asthma-related deaths (37 vs 22) and life-threatening events (13 vs 3) occurred in patients taking aerosolized salmeterol than in patients taking placebo. 
In addition, SMART revealed a statistically significant increase in primary events in African American patients taking salmeterol versus those taking placebo (P<.05). There were no significant differences among Caucasian subjects taking the medication compared with those taking placebo.7,8 These findings were initially reported in January 2003, and resulted in a boxed warning for salmeterol and amendments to the prescribing information for salmeterol xinafoate inhalation powder and the combination fluticisone propionate and salmeterol inhalation powder.8 
In light of the foregoing study results, this review highlights the recent literature supporting the need for an ICS in combination with a LABA in the treatment of patients with asthma. It also discusses further evidence for the danger of using a LABA as monotherapy and present a rationale for the usefulness of LABAs in modern asthma therapy. 
Can Long-Acting β2-Agonists Be Used Safely as Monotherapy?
LABAs are known to improve peak expiratory flow (PEF) and reduce symptoms in patients with asthma.9 In addition, adding a LABA to an ICS is more beneficial than increasing the dose of the ICS,10 thus raising the question of whether a LABA may be used as monotherapy in treating patients with asthma. 
A 28-week multicenter, randomized, blinded, placebo-controlled trial (Salmeterol Or Corticosteriods Study [SOCS])11 addressed this question. Patients aged 12 to 65 years with persistent asthma were given 400 μg of inhaled triamcinolone acetonide twice a day during a 6-week run-in period. The patients were then randomly assigned to continue the triamcinolone treatment or switch to salmeterol (42 μg twice a day) or to take placebo for 16 weeks. All participants were then given placebo for a 6-week run-out period. During the initial 6 weeks, asthma in all patients was well controlled with triamcinolone monotherapy. Control was assessed by morning and evening PEF measurements, asthma symptom scores, need for rescue albuterol, and quality-of-life scoring. Patients receiving triamcinolone and those given salmeterol had improved PEF and forced expiratory volume in 1 second (FEV1) values compared with those receiving placebo; however, the salmeterol-treated group had more treatment failures, more asthma exacerbations, and greater increases in median number of sputum eosinophils and other airway inflammatory markers compared with those taking triamcinolone.11 
Data from SOCS demonstrated that salmeterol was superior to placebo in improving morning PEF and FEV1 values; however, patients receiving triamcinolone had significantly better lung function, used less rescue medication, and had less airway inflammation compared with patients receiving placebo or salmeterol. Both the treatment failure rate and the asthma exacerbation rate were reduced in patients taking triamcinolone. Despite the ability of salmeterol to improve PEF and FEV1 values, inflammatory markers (sputum eosinophils, eosinophil cationic protein, exhaled nitric oxide, and tryptase) increased and correlated with the increase in exacerbation rate. 
In the sister trial to SOCS, the Salmeterol ± Inhaled Corticosteroids (SLIC) trial, 175 patients aged 12 to 65 years whose asthma was suboptimally controlled with a regimen of 400 μg of inhaled triamcinolone acetonide twice a day for 6 weeks were given either add-on therapy with placebo or salmeterol xinafoate 42 μg twice a day with a stable dose of triamcinolone or salmeterol with a tapering dose of triamcinolone for 8 weeks.12 Overall treatment failure in the group receiving triamcinolone acetonide 200 μg twice a day and salmeterol xinafoate 42 μg twice a day was 8.3% for 8 weeks compared with 2.3% in the group receiving triamcinolone acetonide 400 μg plus salmeterol xinafoate 42 μg twice a day, thus demonstrating stable asthma control with reduction of the ICS when a LABA is used with an ICS. Also, patients receiving only 42 μg of salmeterol xinafoate twice a day had a treatment failure rate of 46.3% compared with 13.7% of patients taking 42 μg of salmeterol xinafoate twice a day plus 400 μg of triamcinolone acetonide twice a day for 8 weeks. The results of the SLIC trial demonstrated superior asthma control with the addition of salmeterol to an ICS. The results also showed that the dose of the ICS could be reduced without a loss of control. However, complete elimination of the ICS resulted in a dramatic rise in the treatment failure rate when patients were receiving salmeterol as monotherapy. 
From the SOCS and the SLIC trial, we can conclude that using a LABA as monotherapy is not effective and results in a significant reduction in asthma control. Therefore, a LABA should not be used alone, and maintenance therapy should include a low-, medium-, or high-dose ICS, depending on asthma severity. (Table 2). 
Table 2
Summary of Benefits and Risks of Long-Acting β2-Agonists in Asthma Control

Benefits (Combined With an ICS)

Risks (Monotherapy)
Improved FEV1 and PEFIncreased exacerbations
Improved symptom scoresAttenuation of rescue medication effect
Reduction of necessary ICS doseDecreased recognition of symptoms
Synergistic with ICS effectsIncreased inflammation
May be given in conjunction with an ICS
Decreased exacerbations
Decreased use of rescue medication
 FEV1 indicates forced expiratory volume in 1 second; PEF, peak expiratory flow rate; ICS, inhaled corticosteroid.
Table 2
Summary of Benefits and Risks of Long-Acting β2-Agonists in Asthma Control

Benefits (Combined With an ICS)

Risks (Monotherapy)
Improved FEV1 and PEFIncreased exacerbations
Improved symptom scoresAttenuation of rescue medication effect
Reduction of necessary ICS doseDecreased recognition of symptoms
Synergistic with ICS effectsIncreased inflammation
May be given in conjunction with an ICS
Decreased exacerbations
Decreased use of rescue medication
 FEV1 indicates forced expiratory volume in 1 second; PEF, peak expiratory flow rate; ICS, inhaled corticosteroid.
×
Combination Therapy
The combination of a LABA and an ICS has beneficial effects in patients with asthma.13,14 Intuitively, the increased efficacy of the combination of a LABA and an ICS over the individual drugs makes sense given the pathophysiology of asthma (inflammation and bronchoconstriction). Evidence exists to suggest that administration of a LABA and an ICS from the same inhaler is more effective than taking the medications separately.14 Synergy between the two classes of medications was noted when comparing FEV1 measurements of patients receiving 4 weeks of budesonide plus formoterol versus 4 weeks of budesonide alone, and in comparing 4 weeks of fluticasone plus salmeterol versus 4 weeks of fluticasone alone.13 The mean FEV1 was improved in patients receiving the combination therapy versus the ICS monotherapy. Although ICSs are considered to be safe, they are not without adverse effects. Therefore, the National Heart, Lung, and Blood Institute in the National Asthma Education and Prevention Program1 endorses the goal of using the lowest effective dose of an inhaled steroid to control asthma. To that end, LABAs function as steroid-sparing agents and may be used in combination with an ICS to lower the ICS dose needed for optimal asthma control. 
The effectiveness of salmeterol's steroid-sparing effect is noted in a randomized, double-blind, parallel-group study of 458 patients who required moderate doses of an ICS to maintain asthma control. Adding a LABA (salmeterol xinafoate 50 μg twice a day) to the ICS allowed the dose of the ICS to be tapered by 60%.15 Participants whose asthma was controlled with a regimen of 220 μg twice a day (or equivalent) of fluticasone propionate MDI were given either fluticasone propionate/salmeterol xinafoate (100 μg/50 μg) dry powder twice a day or fluticasone propionate (250 μg) dry powder alone twice a day for 24 weeks. Efficacy of the therapy was assessed by FEV1 along with morning and evening PEF measurements, percentage of symptom-free days, daily asthma symptom score, albuterol use per 24-hour period, percentage of rescue-medication–free days, and nighttime awakenings. Overall, the patients taking 100 μg of fluticasone propionate plus 50 μg of salmeterol xinafoate either had improved or equivalent measures of lung function and quality of life compared with those taking 250 μg of fluticasone propionate alone.15 These data indicate that the dose of an ICS can be safely reduced after the addition of a LABA to the therapeutic regimen. 
Reduction of the steroid dose in patients with asthma raises the concern of accompanying subclinical airway inflammation. However, a 50% decrease in the ICS dose and the addition of a LABA result in no worsening of airway inflammation.16 Bronchoalveolar lavage in subjects receiving combination therapy (200 μg of fluticasone propionate with 50 μg twice a day salmeterol) compared with subjects taking an ICS alone (500 μg of fluticasone propionate twice a day) showed no increase in submucosal eosinophils or mast cells. This study also corroborated findings of improved or stable lung function noted elsewhere.1315 Therefore, LABAs function synergistically with ICSs by improving asthma control while reducing the amount of ICS necessary to achieve control. 
There appears to be a point of diminishing returns beyond which further reduction of the ICS dose results in worsening of asthma control. This point was shown in a study of airway inflammation in patients with asthma who were using both an ICS and a LABA. Their sputum eosinophil levels, symptom scores, and FEV1 values were compared with those of patients with asthma who were using the same ICS dose with placebo.17 The subjects on the combination ICS and LABA therapy were symptom free with stable symptom scores and FEV1 values following a stepwise reduction in the ICS dose. However, these patients were found to have significantly higher sputum eosinophil levels prior to exacerbation compared with the patients taking placebo with the same dose of ICS. In this study, the LABA appeared to mask airway inflammation, whereas patients taking the low-dose ICS plus placebo reported asthma symptom scores that correlated with increasing sputum eosinophil levels. Presumably, the patients taking the low-dose ICS plus the LABA were not aware of their worsening asthma while those taking an ICS plus placebo had symptoms coexistent with increasing airway inflammation that would allow them to escalate therapy or seek medical attention. 
Effect of LABAs on Performance of Rescue Medication
As already discussed, symptoms and lung function are improved when a LABA is added to an ICS. Why then do patients who take a LABA alone have treatment failures and exacerbations at a similar rate or greater compared with patients taking the placebo? Evidence exists suggesting that patients already taking a LABA may have an attenuated response to rescue medications.18 Patients receiving a LABA-and-ICS combination compared with those taking ICS as monotherapy had diminished albuterol recovery following methacholine challenge.13 However, conflicts on this issue exist and some researchers failed to demonstrate an attenuated response to albuterol despite the regular use of salmeterol.19 From these data, it appears that the physiologic response to short-acting rescue medications may be blunted by the effect of LABAs on airway smooth muscle. 
Other evidence that the LABAs affect performance of rescue medication was seen in a study of 23 patients given salmeterol for 2 weeks and then formoterol for 2 weeks.20 The group was challenged with methacholine following each 2-week medication course. Airway response to the SABA fenoterol was attenuated after methacholine challenge following LABA administration compared with airway response to placebo. Again, it appears that the airway smooth muscle response to rescue medication may be reduced by LABA use. It should be noted, however, that fenoterol has never been approved for use in the United States. 
Adverse Effects of Inhaled Corticosteroids
Although the ICSs are considered as first-line therapy in treating patients with persistent asthma, they are not without side effects. According to the National Asthma Education and Prevention Program guidelines,1 a low-dose ICS may be used as monotherapy for mild persistent asthma. For moderate persistent asthma, a medium-dose ICS may be used as monotherapy or a low- or medium-dose ICS may be combined with a LABA, while high-dose ICSs with add-on therapy are reserved for patients with severe persistent asthma.1 The ICSs are considered to be safe medications with few side effects at low to medium doses, but higher doses have been linked to adverse effects such as adrenal suppression, decreased growth velocity, decreased bone mineral density (BMD), glaucoma, and cataracts.21 Thrush and dysphonia are common; these adverse effects may be seen routinely as a result of ICS use even at low and medium doses. 
Although adrenal suppression leading to crisis is extremely rare in patients using an ICS, sensitive measurements of mild acute adrenal suppression have been used to show a dose-dependent suppression with increasing-dose ICS.22,23 Although mild perturbations of the hypothalamic-pituitary-adrenal axis occur in patients taking ICSs, no long-term cumulative suppression of the axis has been detected in children receiving low to medium doses of ICSs.21 High-dose ICS has been shown to cause adrenal crisis; however, reports of this adverse event are rare.21 Despite the safety of low- to medium-dose ICSs in the treatment of asthma, conservative use is prudent given the small but real effect on adrenal function seen in patients taking an ICS. 
If growth suppression occurred in children taking an ICS, it would be a prime concern. Studies following up prepubertal children who are taking low- to medium-dose ICSs for less than or equal to 1 year reveal an average decrease in growth of approximately 1 cm.24 Long-term prospective studies on the effects of ICSs on growth have not been completed; however, results of the Childhood Asthma Management Program study25 indicate that children taking an ICS for 4 to 6 years do not have continued slowing of their growth velocity beyond the first year of therapy. Extrapolations from this study's data indicate that the patients will achieve their predicted adult height and therefore undergo catch-up growth.25 In addition, in their long-term retrospective study, Agertoft and Pedersen26 found that ultimate height achieved by age 21 years was normal compared with expected height calculated by parental height and ethnicity. 
The effect of systemic glucocorticoids on BMD is an obvious long-term concern. Evaluations of the effect of ICSs on BMD have shown a decrease in the serum concentrations of the bone-forming proteins osteocalcin and procollagen; however, lower serum concentrations of these proteins have not been proven to predict development of osteoporosis.2729 Inhaled corticosteroids do not seem to cause osteoporosis; however, they may add risk to a patient with other predispositions to low BMD. Therefore, it would be prudent to monitor BMD in patients using an ICS who have additional risks of osteoporosis and fracture, such as repeated dosing of oral corticosteroids. 
Although the potential side effects of ICSs are of concern, the fact remains that these medications are extremely effective in controlling asthma. However, as with any medication, the risks and benefits to the patient must be considered before prescribing. Given the real and potential side effects of these medications, the lowest effective dose should be used to control asthma. Add-on therapy with a LABA and other medications therefore provides a rational benefit in reducing the ICS dose needed to control asthma in the majority of patients. 
β2-Adrenergic Receptor Polymorphisms in Asthma Therapy
The β2-adrenergic receptor target of both SABAs and LABAs has an associated gene (ADRB2) with several polymorphisms on chromosome 5q31–q33.3032 Specifically, substitutions of the amino acids at position 16 (arginine [Arg] or glycine [Gly]) and at position 27 (glutamic acid [Glu] or glutamine [Gln]) alter the receptor sensitivity to LABA-induced bronchoprotection.33 These receptor polymorphisms have implications on both SABA's and LABA's effects on the receptor in terms of mediated bronchoprotection and receptor regulation. Patients with homozygous and heterozygous genotypes containing the arginine-16 polymorphism (Arg16-Arg16 or Arg16-Gly16) display greater bronchoprotection by LABA than the homozygous Gly-16 genotype (Gly16-Gly16).34 However, studies have shown that the homozygous Arg-16 receptor genotype is associated with poor outcomes of asthma control following regular salmeterol and albuterol use.35,36 In addition, the use of an ICS with salmeterol did not protect the patients with Arg16-Arg16 from an increased risk of asthma instability. 
Although it is too early to base therapeutic recommendations on genotype, we anticipate that the future will include genotyping to determine which therapy is the most appropriate for a given patient. The 20% of African American and 15% of Caucasians with Arg16-Arg16 genotype will be encouraged to avoid regular use of β-agonists. Patients with the Gly16-Gly16 genotype will be prime candidates for combination ICS and LABA therapy. (This theoretic proposal is based on a recent study demonstrating that patients with the Arg16-Arg16 genotype have increased peak flow variability when taking albuterol regularly and have improved peak flow values when using albuterol as needed.36) 
Comments
Adverse effects of LABA monotherapy in patients with asthma are likely due to myriad factors. LABAs may allow for asymptomatic airway inflammation by preventing bronchospasm in asthmatic patients. Suppressing symptoms could hinder recognition of worsening asthma control by patients and make them less likely to seek further treatment. LABAs may also prevent SABAs from working properly at the β2-receptor by altering the function and population of receptors in the airway. 
Finally, LABAs may have different dose responses with the various β2-receptor polymorphisms expressed. Specific receptor polymorphisms may predispose certain patients to diminished pharmacologic effect of the LABAs and may facilitate more severe asthma symptoms and more difficult asthma control. In these individuals, the addition of an ICS does not prevent the detrimental effects of LABAs. 
A recent meta-analysis of the safety of LABAs, including salmeterol and formoterol, concluded that there was a significant increase in hospitalization and mortality secondary to their use.6 This meta-analysis must be reviewed carefully. Most patients in the meta-analysis were from SMART, and most patients in SMART were taking salmeterol as monotherapy. This meta-analysis does not represent the use of a LABA with an ICS, which is the only approved use of LABAs in asthma. 
As described here, LABAs are important in improving lung function and quality of life in most patients with asthma. They are also effective as ICS-sparing agents, thereby reducing the risk of potential adverse effects from ICSs. Despite evidence that LABAs should not be used as monotherapy in the treatment of patients with asthma, these medications are important second-line agents. In an effort to improve quality of life and lung function, LABAs are a useful and safe tool when used in combination with an ICS. Up to 15% of Caucasian and 20% of African American patients will not tolerate LABAs even with an ICS, and in patients who have worsening symptoms after a LABA is added, alternate therapy should be used in place of the LABA. 
 Dr Rider has no conflicts of interest. Dr Craig discloses that he has received research support from Boerhinger Ingelheim; GlaxoSmithKline; Genentech, Inc; Merck & Co, Inc; Novartis; Pfizer, Inc; and Schering-Plough. He has also served on the speakers bureau of all the preceding companies except Boehringer Ingelheim and is a consultant to Sanofi-Aventis.
 
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Table 1
Comparison of Different β2-Agonists 6


Feature
β2-Agonist
Onset of Action, min
Peak Effect
Duration, H
Route of Administration
Albuterol
□ Nebulizer/MDI1010 min3-4Nebulized/MDI
□ Oral4-610 min4-6Oral
Levalbuterol101.5 h5-8Nebulized
Salmeterol xinafoate102-4 h12MDI Dry powder inhaler
Formoterol315 min12Dry powder inhaler
 MDI indicates metered-dose inhaler
Table 1
Comparison of Different β2-Agonists 6


Feature
β2-Agonist
Onset of Action, min
Peak Effect
Duration, H
Route of Administration
Albuterol
□ Nebulizer/MDI1010 min3-4Nebulized/MDI
□ Oral4-610 min4-6Oral
Levalbuterol101.5 h5-8Nebulized
Salmeterol xinafoate102-4 h12MDI Dry powder inhaler
Formoterol315 min12Dry powder inhaler
 MDI indicates metered-dose inhaler
×
Table 2
Summary of Benefits and Risks of Long-Acting β2-Agonists in Asthma Control

Benefits (Combined With an ICS)

Risks (Monotherapy)
Improved FEV1 and PEFIncreased exacerbations
Improved symptom scoresAttenuation of rescue medication effect
Reduction of necessary ICS doseDecreased recognition of symptoms
Synergistic with ICS effectsIncreased inflammation
May be given in conjunction with an ICS
Decreased exacerbations
Decreased use of rescue medication
 FEV1 indicates forced expiratory volume in 1 second; PEF, peak expiratory flow rate; ICS, inhaled corticosteroid.
Table 2
Summary of Benefits and Risks of Long-Acting β2-Agonists in Asthma Control

Benefits (Combined With an ICS)

Risks (Monotherapy)
Improved FEV1 and PEFIncreased exacerbations
Improved symptom scoresAttenuation of rescue medication effect
Reduction of necessary ICS doseDecreased recognition of symptoms
Synergistic with ICS effectsIncreased inflammation
May be given in conjunction with an ICS
Decreased exacerbations
Decreased use of rescue medication
 FEV1 indicates forced expiratory volume in 1 second; PEF, peak expiratory flow rate; ICS, inhaled corticosteroid.
×