Debate about the potential risks associated with the use of sympathomimetic drugs in asthma has been ongoing for over 80 years. The role of two specific β agonists in epidemics of asthma mortality have dominated this debate. In the 1960s, sudden epidemics of asthma mortality occurred in at least six countries, primarily due to the use of the high dose, poorly selective β agonist isoprenaline metered dose inhaler [1–5]. Patients who died used their metered dose inhaler repeatedly during a severe asthma attack, leading to both delay in seeking medical help due to the temporary relief of symptoms and a risk of cardiotoxicity in the presence of hypoxia. The epidemic resolved following the restriction of isoprenaline forte from the market. In the 1970s and 1980s, history repeated itself when a second epidemic occurred in New Zealand, primarily due to the use of the high-dose preparation of fenoterol, which is less β2 selective and has greater intrinsic activity than the more commonly used β agonist salbutamol [1,6–8]. In addition to the potential for cardiotoxicity and delay with overuse of fenoterol in severe exacerbations, there was also evidence that regular use of fenoterol may lead to an increase in asthma severity . Similar to the experience with isoprenaline forte, the New Zealand epidemic resolved once regulatory restrictions of fenoterol were implemented .
It was against this historical legacy that the long-acting β agonists (LABA) salmeterol and formoterol were introduced in the early 1990s. Initial investigations demonstrated that both agents resulted in a prolonged bronchodilator response and that improvements in lung function and symptom control were achieved with their regular use [11,12]. However, there were also studies reporting that their regular use may reduce bronchodilator sensitivity to β agonists [13,14] and induce tolerance to their bronchoprotective effects [15,16]. It was also recognized that their use had the potential to change patterns of behaviour, including reduced compliance with inhaled corticosteroid (ICS) therapy, due to the good symptomatic control that was achieved. Subsequently there was evidence from two large randomized controlled trials (RCTs) that the LABA salmeterol may increase the risk of mortality, particularly when used as monotherapy in patients with unstable asthma who were not treated with ICS therapy and not under regular medical review [17,18]. In response, the pharmaceutical industry developed combination ICS/LABA inhaler products, which ensured that concurrent ICS therapy was also self-administered by asthma patients taking LABA therapy. The use of ICS and LABA therapy as combination inhaler products rather than separate inhalers is now the preferred therapeutic approach, with the most recent UK asthma guidelines recommending that LABAs should only be prescribed in this way .
In February 2010, the US Food and Drug Administration (FDA), exercising new authority under the FDA Amendment Act of 2007, implemented updated recommendations for the use of LABA therapy and mandated professional drug label changes on all United States-manufactured LABAs [20▪▪].
Specific label changes for LABAs are as follows [20▪▪]:
1. Contraindicate the use of LABAs for asthma in patients of ages without concomitant use of an asthma-controller medication such as an ICS.
2. Stop use of the LABA, if possible, once asthma control is achieved and maintain the use of an asthma-controller medication, such as an ICS.
3. Recommend against LABA-use in patients whose asthma is adequately controlled with a low-dose or medium-dose ICS.
4. Recommend that a fixed-dose combination product containing a LABA and an ICS be used to ensure compliance with concomitant therapy in pediatric and adolescent patients who require the addition of a LABA to an ICS.
The FDA acknowledged that some of their recommendations were limited by the lack of definitive evidence, and due to varied interpretation of available data, differed from consensus guidelines. In recognition of these uncertainties, the FDA recommendations are reviewed.
Label change 1: contraindicate the use of long-acting β agonists for asthma in patients of all ages without concomitant use of an asthma-controller medication such as an inhaled corticosteroid
There is substantive evidence to support this recommendation, as LABA monotherapy has been shown to increase the risk of severe asthma exacerbations and mortality [21▪]. In contrast, the use of LABAs in adults who are symptomatic with low-to-high doses of ICS monotherapy reduces the risk of exacerbations requiring oral steroids and improves lung function and symptoms .
The role of concomitant ICS in ameliorating the risk of life-threatening attacks and asthma mortality with LABA therapy is demonstrated in the independent meta-analysis of all GlaxoSmithKline (GSK) RCTs of salmeterol . This meta-analysis included all 215 RCTs in the GSK database that compared salmeterol with a non-LABA comparator treatment in asthma. In 54 RCTs in which participants received salmeterol or placebo as monotherapy, with no ICS as randomized or baseline prescribed therapy, the risk of death and hospital admission was 7.3 [95% confidence interval (CI) 1.8–29.4] and 1.4 (95% CI 1.0–2.0), respectively. In the 127 studies in which patients were prescribed ICS as randomized or baseline prescribed therapy, the risk of death and hospital admission was 2.1 (95% CI 0.6–7.9) and 1.3 (95% CI 1.1–1.5), respectively. Whereas this analysis indicates a reduction in risk with concomitant ICS therapy, LABA monotherapy may still occur during periods of ICS nonadherence in patients prescribed ICS and LABAs as separate inhalers. For this reason a further analysis was undertaken, restricted to the 63 studies in which the combination salmeterol/fluticasone propionate product was used. This analysis identified no asthma deaths or intubations among over 22 000 individuals, and no increase in risk of hospital admission for asthma (odds ratio 1.0, 95% 0.6–1.7). Together these analyses show that salmeterol monotherapy in asthma increases the risk of mortality, that this risk is reduced with concomitant ICS therapy, and that there is no evidence that combination salmeterol/fluticasone propionate therapy is associated with an increased risk of mortality or severe exacerbations, although this interpretation is limited to some extent by the low statistical power of available studies.
In terms of formoterol, the evidence is somewhat more complex, with an overall nonsignificant 2.5-fold risk (95% CI 0.45–26.0) of asthma mortality with formoterol and a nonsignificant 3.7-fold risk (95% CI 0.4–174.0) of asthma mortality when the analysis was restricted to patients prescribed ICS . However, the same issue applies for patients prescribed separate inhalers being exposed to LABA monotherapy, as with salmeterol, and this may be particularly important in the case of formoterol, which was prescribed as reliever therapy in the major study contributing to this analysis. Reassuringly, studies of the combination formoterol/budesonide product used according to the Single inhaler Maintenance And Reliever Therapy (SMART) regime have demonstrated a reduced risk of severe exacerbations , although there has been insufficient power to determine any potential effect on asthma mortality .
In summary, this FDA recommendation contraindicating the use of LABAs without concomitant use of an asthma-controller medication such as ICS is supported by evidence; however, it comes with two caveats. The first is that the evidence for concomitant use of an asthma-controller medication applies only to ICS therapy, and not other asthma controller medications [such as leukotriene receptor antagonist therapy (LTRA), theophyllines or chromones]. The second caveat is that the use of concomitant ICS and LABA therapy must be in the form of a combination ICS/LABA product, rather than through separate inhalers.
Label change 2: stop use of the long-acting β agonist, if possible, once asthma control is achieved and maintain the use of asthma-controller medication such as an inhaled corticosteroid
The rationale provided by the FDA for this recommendation is that ICS provide clear benefits in patients and are not associated with serious adverse outcomes, and long-term use of LABAs should be limited to patients who truly need them. However, it has been argued that asthma control encompasses both the domains of impairment (e.g. the current level of symptoms, activity limitations, and lung function) as well as risk (of further events, especially severe exacerbations) [27▪▪]. Reduction in risk of subsequent poor control and severe exacerbations may require continued treatment, well beyond the time symptomatic control has been achieved. The importance of this future risk is illustrated by the evidence that stopping LABAs once asthma control is achieved results in a deterioration in subsequent asthma control and lung function .
An alternative approach in which LABA therapy is continued with a reduced dose of ICS is supported by ICS-dose downtitration studies, which have shown that many patients prescribed high-dose ICS and LABA therapy are overtreated [28,29]. Furthermore, asthma control may be achieved with a lower dose of ICS when concomitant LABA therapy is used . Also the inference that asthma-controller medication, other than ICS, might be alternative to LABAs is not supported by evidence that LABAs are superior to LTRAs, when added to ICS .
In summary, downtitration of therapy should be considered in patients with asthma who are well controlled on ICS and LABA therapy, including the options of stopping LABA therapy or reducing the ICS dose. However, maintaining the current ICS/LABA therapeutic regime may be required if patients are at high future risk of unstable asthma or severe exacerbations.
Label Change 3: recommend against long-acting β agonist use in patients whose asthma is adequately controlled with a low-dose or medium-dose inhaled corticosteroid
It had been established that most of the maximum achievable clinical benefit obtained with ICS can be achieved with low-to-medium daily doses of ICS of around 200 μg fluticasone propionate and 400–500 μg beclomethasone dipropionate or budesonide [32–35]. This benefit applies to all major clinical outcomes including the reduction of symptoms, increase in lung function and reduction in severe exacerbations. It has been shown that in corticosteroid naive individuals with mild-to-moderate asthma, the combination of ICS and LABA does not significantly reduce the risks of exacerbations over that achieved with a similar dose of ICS alone, but does result in greater improvements in symptoms and lung function . It has also been shown that starting an ICS within this dose range gives similar efficacy to initiating ICS at higher doses and then stepping down . As a result, if a patient is well controlled on a low-to-medium dose of ICS therapy, then additional treatment with a LABA is unlikely to be necessary.
In summary, the recommendation against LABA use in patients whose asthma is adequately controlled with a low or medium dose of ICS is supported by the available evidence.
Label change 4: recommend that a fixed-dose combination product containing a long-acting β agonist and an inhaled corticosteroid be used to ensure compliance with concomitant therapy in paediatric and adolescent patients who require the addition of a long-acting β agonist to an inhaled corticosteroid
This recommendation recognizes that in standard clinical practice, patients are often poorly adherent to ICS and that they may stop taking their ICS for variable periods. This can result in LABA monotherapy, if the ICS and LABA treatments are prescribed as separate inhalers and the LABA inhaler is used for symptomatic relief during periods of ICS nonadherence . Such periods of monotherapy can only be avoided by prescribing a combination inhaler. Poor adherence to ICS therapy applies to adult patients with asthma [39,40], not just the paediatric and adolescent patients, as suggested by the FDA guidelines. As a result, a recommendation can be made that fixed-dose combination products containing a LABA and an ICS should be the only form in which LABAs are prescribed in asthma .
Combination therapy also has the advantage of improving adherence with ICS therapy as patients prescribed combination therapy take more ICS than when prescribed ICS as a separate inhaler [41,42]. It is also possible that a greater overall use of ICS has resulted from the strong preference by doctors and patients for combination therapy over separate inhalers .
The special consideration of LABA therapy in children relates to the evidence that in comparison with adults, there is reduced efficacy and greater risks [44,45]. This adverse risk/benefit profile also relates to the use of ICS/LABA combination therapy, with the probable exception of the SMART regime , leading to recommendations that this class of drugs should be used with caution in children.
In summary, fixed-dose combination products containing an ICS and LABA should be the only form in which LABAs are prescribed in asthma [47▪▪].
In conclusion, the current β agonist debate focuses on the optimal management approach for the use of LABA therapy to both minimize risk and maximize clinical efficacy. One important regulatory step to achieve this goal would be the withdrawal of LABAs as separate inhaler therapy in asthma and restrict their use to combination ICS/LABA preparations.
The MRINZ has received funding for its LABA research programme from MedSafe, New Zealand Ministry of Health.
Conflicts of interest
The MRINZ has received research grants from Astra Zeneca, Chiesi, Glaxo Smith Kline and Novartis. R.B. has received fees for consulting and/or speaking and/or reimbursement for attending symposia from Astra Zeneca, Boehringer Ingelheim, Glaxo Smith Kline and Novartis.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 121–122).
1. Beasley R, Pearce N, Crane J, et al. Asthma mortality and inhaled beta agonist therapy. Aust N Z J Med 1991; 21:753–763.
2. Inman WH, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 1969; 2:279–285.
3. Speizer FE, Doll R, Heaf P. Observations on recent increase in mortality from asthma. Br Med J 1968; 1:335–339.
4. Stolley PD. Asthma mortality. Why the United States was spared an epidemic of deaths due to asthma. Am Rev Respir Dis 1972; 105:883–890.
5. Stolley PD, Schinnar R. Association between asthma mortality and isoproterenol aerosols: a review. Prev Med 1978; 7:519–538.
6. Beasley R, Pearce N, Crane J. International trends in asthma mortality. Ciba Found Symp 1997; 206:140–150.
7. Crane J, Burgess C, Beasley R. Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline. Thorax 1989; 44:136–140.
8. Crane J, Pearce N, Flatt A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981–83: case–control study. Lancet 1989; 1:917–922.
9. Sears MR, Taylor DR, Print CG, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet 1990; 336:1391–1396.
10. Pearce N, Beasley R, Crane J, et al. End of the New Zealand asthma mortality epidemic. Lancet 1995; 345:41–44.
11. Brogden RN, Faulds D. Salmeterol xinafoate: a review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs 1991; 42:895–912.
12. Faulds D, Hollingshead LM, Goa KL. Formoterol. A review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease. Drugs 1991; 42:115–137.
13. Grove A, Lipworth BJ. Bronchodilator subsensitivity to salbutamol after twice daily salmeterol in asthmatic patients. Lancet 1995; 346:201–206.
14. Newnham DM, Grove A, McDevitt DG, Lipworth BJ. Subsensitivity of bronchodilator and systemic beta 2 adrenoceptor responses after regular twice daily treatment with eformoterol dry powder in asthmatic patients. Thorax 1995; 50:497–504.
15. Bhagat R, Kalra S, Swystun VA, Cockcroft DW. Rapid onset of tolerance to the bronchoprotective effect of salmeterol. Chest 1995; 108:1235–1239.
16. Jones SL, Cowan JO, Flannery EM, et al. Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol. Eur Respir J 2001; 17:368–373.
17. 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; 306:1034–1037.
18. 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; 129:15–26.
19. SIGN/BTS. British Guideline on the Management of Asthma. Thorax 2008; 63(Suppl 4):iv1-121. Revised January 2012. http://www.brit-thoracic.org.uk/
. [Accessed 20 August 2012]
20▪▪. 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; 362:1169–1171.
This is a key reference to the FDA position on LABA use. This article describes the FDA recommendations and rationale for the LABA label changes.
21▪. Rodrigo GJ, Castro-Rodriguez JA. Safety of long-acting beta agonists for the treatment of asthma: clearing the air. Thorax 2012; 67:342–349.
This review provides a current critical appraisal of the safety of LABA therapy.
22. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled corticosteroids versus same dose inhaled corticosteroids for chronic asthma in adults and children. Cochrane Database Syst Rev 2010: CD005535.
23. Weatherall M, Wijesinghe M, Perrin K, et al. Meta-analysis of the risk of mortality with salmeterol and the effect of concomitant inhaled corticosteroid therapy. Thorax 2010; 65:39–43.
24. Beasley R, Martinez FD, Hackshaw A, et al. Safety of long-acting β-agonists: urgent need to clear the air remains. Eur Respir J 2009; 33:3–5.
25. Edwards SJ, von Maltzahn R, Naya IP, Harrison T. Budesonide/formoterol for maintenance and reliever therapy of asthma: a meta analysis of randomised controlled trials. Int J Clin Pract 2010; 64:619–627.
26. Sears MR, Radner F. Safety of budesonide/formoterol maintenance and reliever therapy in asthma trials. Respir Med 2009; 103:1960–1968.
27▪▪. 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; 126:449–452.
This is an important editorial regarding the FDA's label changes. It discusses the current controversy and suggests that not all of the FDA recommendations are evidence based.
28. 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; 102:1124–1131.
29. 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; 104:1110–1120.
30. 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; 164:1392–1397.
31. Ducharme FM, Lasserson TJ, Cates CJ. Addition to inhaled corticosteroids of long-acting beta2-agonists versus antileukotrienes for chronic asthma. Cochrane Database Syst Rev 2011: CD003137.
32. Adams NP, Jones PW. The dose-response characteristics of inhaled corticosteroids when used to treat asthma: an overview of Cochrane systematic reviews. Respir Med 2006; 100:1297–1306.
33. Holt S, Suder A, Weatherall M, et al. Dose-response relation of inhaled fluticasone propionate in adolescents and adults with asthma: meta-analysis. BMJ 2001; 323:253–256.
34. Masoli M, Holt S, Weatherall M, Beasley R. Dose-response relationship of inhaled budesonide in adult asthma: a meta-analysis. Eur Respir J 2004; 23:552–558.
35. Masoli M, Weatherall M, Holt S, Beasley R. Clinical dose-response relationship of fluticasone propionate in adults with asthma. Thorax 2004; 59:16–20.
36. Ni Chroinin M, Greenstone I, Lasserson TJ, Ducharme FM. Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults and children. Cochrane Database Syst Rev 2009: CD005307.
37. Powell H, Gibson PG. High dose versus low dose inhaled corticosteroid as initial starting dose for asthma in adults and children. Cochrane Database Syst Rev 2004: CD004109.
38. Murphy AC, Proeschal A, Brightling CE, et al. The relationship between clinical outcomes and medication adherence in difficult-to-control asthma. Thorax 2012; 67:751–753.
39. Krishnan JA, Riekert KA, McCoy JV, et al. Corticosteroid use after hospital discharge among high-risk adults with asthma. Am J Respir Crit Care Med 2004; 170:1281–1285.
40. Williams LK, Pladevall M, Xi H, et al. Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma. J Allergy Clin Immunol 2004; 114:1288–1293.
41. Stempel DA, Stoloff SW, Carranza Rosenzweig JR, et al. Adherence to asthma controller medication regimens. Respir Med 2005; 99:1263–1267.
42. Stoloff SW, Stempel DA, Meyer J, et al. Improved refill persistence with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies. J Allergy Clin Immunol 2004; 113:245–251.
43. Wijesinghe M, Perrin K, Harwood M, et al. The risk of asthma mortality with inhaled long acting beta-agonists. Postgrad Med J 2008; 84:467–472.
44. Ducharme FM, Ni Chroinin M, Greenstone I, Lasserson TJ. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database Syst Rev 2010: CD005533.
45. Ni Chroinin M, Lasserson TJ, Greenstone I, Ducharme FM. Addition of long-acting beta-agonists to inhaled corticosteroids for chronic asthma in children. Cochrane Database Syst Rev 2009: CD007949.
46. Bisgaard H, Le Roux P, Bjamer D, et al. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest 2006; 130:1733–1743.
47▪▪. Beasley R, Perrin K, Weatherall M, Wijesinghe M. Call for withdrawal of LABA single-therapy inhaler in asthma. Lancet 2010; 376:750–751.
This provides a perspective regarding the use of combination ICS/LABA products for asthma.