Combination corticosteroid/b-agonist inhaler as relievertherapy: A solution for intermittent and mild asthma?

Richard Beasley, DSc,a Mark Weatherall, FRACP,b Philippa Shirtcliffe, FRACP,a Robert Hancox, MD,c and

Helen K. Reddel, PhDd Wellington and Dunedin, New Zealand, and Sydney, Australia

Abbreviations used

ICS: Inhaled corticosteroid

LABA: Long-acting b-agonist

RCT: Randomized controlled trial

SABA: Short-acting b-agonist

SMART: Single combination budesonide-formoterol inhaler mainte-

nance and reliever therapy

The recommended treatment of mild asthma is regularmaintenance inhaled corticosteroids (ICSs) with a short-actingb-agonist as a separate inhaler used when needed for symptomrelief. However, the benefits of regular ICS use in actual clinicalpractice are limited by poor adherence and low prescriptionrates. An alternative strategy would be the symptom-driven(as-required or ‘‘prn’’) use of a combination ICS/short-actingb-agonist or ICS/long-acting b-agonist inhaler as a relieverrather than regular maintenance use. The rationale for thisapproach is to titrate both the ICS and b-agonist doseaccording to need and enhance ICS use in otherwise poorlyadherent patients who overrely on their reliever b-agonistinhaler. This strategy will only work if the b-agonistcomponent has a rapid onset of action for symptom relief.There is evidence to suggest that this regimen has advantagesover regular ICS therapy and might represent an effective,safe, and novel therapy for the treatment of intermittent andmild asthma. In this commentary we review this evidence andpropose that randomized controlled trials investigatingdifferent combination ICS/b-agonist inhaler productsprescribed according to this regimen in intermittent and mildasthma are an important priority. (J Allergy Clin Immunol2014;133:39-41.)

Key words: Asthma, combination therapy, inhaled steroid,b-agonist

Clinical research and management initiatives primarily focuson severe asthma, yet most adults with asthma have intermittent

From athe Medical Research Institute of New Zealand, Wellington; bthe Department of

Medicine, University of Otago Wellington; cthe Department of Preventive and Social

Medicine, Dunedin School of Medicine, University of Otago, Dunedin; and dthe Clin-

ical Medical Group, Woolcock Institute of Medical Research, Sydney.

Disclosure of potential conflict of interest: R. Beasley is a board member for the Health

Research Council of New Zealand and GlaxoSmithKline; has received consultancy

fees from Cytos Biotechnology and Pharmaxis; has received research support from

AstraZeneca, Chiesi, Cephalon, GlaxoSmithKline, Genentech, Novartis, and the

Health Research Council of New Zealand; has received lecture fees from Glaxo-

SmithKline, Novartis, and Otsuka; and has received travel support from Boehringer

Ingelheim, Nycomed, and Novartis. R. Hancox has received lecture fees from Glaxo-

SmithKline and has received travel support from Boehringer Ingelheim. H. K. Reddel

is a board member for AstraZeneca, GlaxoSmithKline, Merck, and Novartis; has

received consultancy fees from AstraZeneca, Mundipharma, and Novartis; has

received research support from GlaxoSmithKline and AstraZeneca; and has received

payment for manuscript preparation from AstraZeneca, GlaxoSmithKline, and Novar-

tis. The rest of the authors declare that they have no relevant conflicts of interest.

Received for publication July 24, 2013; revised October 25, 2013; accepted for publica-

tion October 30, 2013.

Corresponding author: Professor Richard Beasley, DSc, Medical Research Institute of

New Zealand, Private Bag 7902, Wellington 6242, New Zealand. E-mail: Richard.

Beasley@mrinz.ac.nz.

0091-6749/$36.00

� 2013 American Academy of Allergy, Asthma & Immunology

http://dx.doi.org/10.1016/j.jaci.2013.10.053

or mild disease, and there is a poorly recognized but importantburden of disease in this group.1 The evidence base for the long-term management of intermittent or mild asthma is limited. Inparticular, this is the case with regard to the recommendation ofkey guidelines to initiate treatment with inhaled corticosteroids(ICSs) if a patient requires a short-acting b-agonist (SABA)more than twice a week.2,3 Although airways inflammation is pre-sent even in patients withmild intermittent asthma4 and ICSs havebeen shown to reduce the risk of severe exacerbations in patientswith intermittent symptoms,5 there has been little investigation ofthe cut point at which ICSs should be commenced. Surveys showthat ICSs are not generally prescribed until a consistently worselevel of asthma control is present.6

Prescribers recognize that patients with intermittent or milddisease are often poorly adherent to ICS treatment, and this mightcontribute to their reluctance to prescribe ICSs for such patients.This poor adherence is understandable because patients are askedto take daily treatment regardless of whether they have anysymptoms at all. Prescription database studies show that mostpatients take ICS therapy infrequently, only using 2 to 4 canistersper year.7,8 Even in patients admitted to the hospital with severeexacerbations of asthma, ICS adherence decreases to 50% ofthe prescribed dose within 1 week of discharge.9 Poor adherenceis associated with significant asthma-related morbidity.10

The major gap between management recommendations andcurrent prescribing practice persists despite asthma guidelinesand other educational initiatives.6 Recognition of this disparityhas led to the investigation of a number of strategies to improveICS adherence and clinical outcomes in both adults and childrenwith asthma. One of the most effective strategies is regular main-tenance treatment with combination ICS/long-acting b-agonist(LABA) therapy, which markedly increases ICS use.7

A related therapeutic approach is use of a single combinationICS/LABA inhaler for both maintenance and reliever therapy(referred to as the single combination budesonide-formoterolinhaler maintenance and reliever therapy [SMART] regimen).This prescribing strategy reduces the risk of severe exacerbationsin adults11-13 and children age 4 to 11 years.14 We used covertelectronic inhaler monitoring to show that this strategy reducesthe number of days of nonadherence with ICS therapy comparedwith standard twice-daily ICS/LABA use.12 It is likely that

39

J ALLERGY CLIN IMMUNOL

JANUARY 2014

40 BEASLEY ET AL

improved ICS adherence contributed to the reduced risk of severeexacerbations observed in this study together with the self-titratedescalation of ICS/LABA in response to worsening asthma.12

Importantly, although patients with asthma prescribed ICSs/LABAs according to the SMART regimen received a greatermean daily ICS dose, the reduction in severe exacerbations inthe SMART regimen group resulted in a lower dose of oral corti-costeroid, leading to a similar overall systemic corticosteroidburden between the 2 regimens.12

Another proposed strategy is the symptom-driven (‘‘prn’’) useof a combination ICS/SABA or ICS/LABA inhaler for relieverrather than regular maintenance use.15,16 The rationale for thisapproach is to both titrate the ICS dose according to need andenhance ICS use in otherwise poorly adherent patients who over-rely on their reliever b-agonist inhaler. In this way patients auto-matically receive an ICS dosewhen they use their reliever inhaler,resulting in increased ICS use as soon as asthma worsens. Thisstrategy requires the b-agonist component of the combinationinhaler to have a rapid onset of bronchodilator action for symptomrelief.A proof-of-concept study reports that in adults with mild

asthma, the symptom-driven use of ICSs and SABAs in a singleinhaler results in efficacy similar to that seen with regular ICStherapy.17 However, there were fewer severe exacerbations with aICS/SABA combination when used as reliever therapy comparedwith sole SABA reliever therapy, illustrating the benefits of theICS component of ICS/SABA reliever therapy. This medicationis not generally available worldwide.Another proof-of-concept study reports a related prescribing

strategy whereby patients adjust their ICS use according to theirSABA requirement but use separate inhalers.18 This symptom-driven strategy, in which patients are instructed to use their ICSinhaler when they use their SABA inhaler, results in a similarrisk of treatment failure as intense physician monitoring with 6-week adjustments of the maintenance ICS dose taken togetherwith a SABA for relief. Likewise, in children age 5 to 18 years,there was similar efficacy with as-required symptom-driven useof ICSs and SABAs administered from separate inhalerscompared with regular ICS and SABA use for symptom relief.19

In both of these studies, the use of separate inhalers might haveunderestimated the benefits of a symptom-driven regimenbecause it might have missed the major potential benefit of a sin-gle combination inhaler to ensure that the ICS is delivered whenthe SABA is self-administered for relief. A study of preschoolchildren with frequent wheeze observed that reliever therapywith a nebulized ICS/SABA mixture for symptom relief hadsimilar efficacy as use of a regular daily nebulized ICS withSABA reliever therapy for the primary outcome of symptom-free days but was not as effective for time to first exacerbation.20

Additional evidence supports strategies that start or increasethe dose of ICS during asthma exacerbations.21-25 Quadruplingthe dose of the ICS after asthmaworsens reduces the risk of severeexacerbations,24 and multiple doses of ICSs administered overseveral hours results in faster clinical improvement than systemiccorticosteroids in patients with severe asthma.25 The use of anICS/LABA combination as reliever therapy has greater efficacythan use of an LABA alone as a reliever, showing that as-required use of ICSs provides additional clinical benefits to as-required LABA use.11

The risk of serious adverse events also needs to be consideredin any novel regimen incorporating either SABA or LABA

therapy. These concerns relate to the epidemics of asthmamortality that occurred with the high-dose preparations of thepotent and poorly selective b-agonists isoprenaline and feno-terol26,27 and the increased risk of mortality associated with theuse of LABA monotherapy in patients with poorly controlledasthma.28,29 Therefore it is reassuring that no increased risk oflife-threatening attacks leading to intensive care unit admissionor mortality have been observed when LABA therapy is pre-scribed in a combination ICS/LABA inhaler.28,29 This has led tothe recommendation that LABA monotherapy is contraindicatedin the treatment of asthma and must always be prescribed in acombination ICS/LABA inhaler,30 as proposed with this novelregimen.With regard to potential corticosteroid side effects, treat-ment with ICS and SABA reliever therapy is characterized by alower average ICS dose17-19 and in children with greater heightgain19 than treatment with a regular daily ICS.In light of this research, the current recommendation that

regular ICSs should be initiated only when patients use theirSABAs more than twice per week needs to be revisited. Theevidence that this approach works in real-life clinical practice islimited. The potential benefits of this approach are compromisedby both low rates of ICS prescription in patients, even in thesetting of poor control, and poor adherence by patients who areprescribed ICS therapy. Among the therapeutic strategies thatcould improve outcomes in patients with intermittent and mildasthma is use of the combination ICS/SABA or ICS/fast-actingLABA single inhaler as reliever therapy. There is evidence thatthese regimens have advantages over regular ICS therapy andmight represent an effective, safe, and novel therapy for thetreatment of intermittent mild asthma.We propose that randomized controlled trials (RCTs) investi-

gating different combination ICS/SABA (where available) andICS/fast-acting LABA inhaler products prescribed according tothis regimen in patients with intermittent and mild asthma are animportant priority. Such RCTs will need to assess a range ofoutcomevariables, including clinical control, risk of exacerbations,and measures of airways inflammation.31 These RCTs will alsoneed to be designed to investigate serious adverse events, as wellas efficacy, in both children and adults; assess cost-effectiveness;and be undertaken concurrently with, rather than after, the USFood and Drug Administration–mandated RCTs of the safety ofconcomitant use of regular LABAand ICS therapy.32 This researchwill require close collaboration with the academic research com-munity, pharmaceutical industry, and regulatory authorities.

REFERENCES

1. Dusser D, Montani D, Chanez P, de Blic J, Delacourt C, Deschildre A, et al. Mild

asthma; an expert review on epidemiology, clinical characteristics and treatment

recommendations. Allergy 2007;62:591-604.

2. Global Initiative for Asthma. Global strategy for asthma management and preven-

tion (updated 2012). Available at: http://www.ginasthma.org/local/uploads/files/

GINA_Report_March13.pdf. Accessed November 22, 2013.

3. National Heart, Lung and Blood Institute, National Asthma Education and Preven-

tion Program. Expert panel report 3: guidelines for the diagnosis and management

of asthma. Full report 2007. Available at: http://www.nhlbi.nih.gov/guidelines/

asthma/asthgdln.pdf. Accessed November 22, 2013.

4. Beasley R, Roche W, Roberts J, Holgate S. Cellular events in the bronchi in mild

asthma and after bronchial provocation. Am Rev Respir Dis 1989;139:806-17.

5. Pauwels RA, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, et al. Early

intervention with budesonide in mild persistent asthma: a randomised, double-

blind trial. Lancet 2003;361:1071-6.

6. Rabe K, Adachi M, Lai C, Soriano JB, Vermeire PA, Weiss KB, et al. Worldwide

severity and control of asthma in children and adults: the global Asthma Insights

and Reality surveys. J Allergy Clin Immunol 2004;114:40-7.

J ALLERGY CLIN IMMUNOL

VOLUME 133, NUMBER 1

BEASLEY ET AL 41

7. Stempel DA, Stoloff SW, Carranza Rosenzweig JR, Stanford RH, Ryskina KL, Le-

gorreta AP. Adherence to asthma controller medication regimens. Respir Med

2005;99:1263-7.

8. Suissa S, Ernst P, Benayoun S, Baltzan M, Cai B. Low-dose inhaled corticosteroids

and the prevention of death from asthma. N Engl J Med 2000;343:332-6.

9. Krishnan JA, Rickert KA, McCoy JV, Stewart DY, Schmidt S, Chanmugam A,

et al. Corticosteroid use after hospital discharge among high-risk adults with

asthma. Am J Respir Crit Care Med 2004;170:1281-5.

10. Williams LK, Peterson EL, Wells K, Ahmedani BK, Kumar R, Burchard EG, et al.

Quantifying the proportion of severe asthma exacerbations attributable to inhaled

corticosteroid nonadherence. J Allergy Clin Immunol 2011;128:1185-91.e2.

11. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budeso-

nide in combination with formoterol for reliever therapy in asthma exacerbations: a

randomised controlled, double-blind study. Lancet 2006;368:744-53.

12. Patel M, Pilcher J, Pritchard A, Perrin K, Travers J, Shaw D, et al. Efficacy and

safety of maintenance and reliever combination budesonide-formoterol inhaler in

patients with asthma at risk of severe exacerbations: a randomised controlled trial.

Lancet Respir Med 2013;1:32-42.

13. Papi A, Corradi M, Pigeon-Francisco C, Baronio R, Siergiejko Z, Petruzzelli S,

et al. Beclometasone formoterol as maintenance and reliever treatment in patients

with asthma: a double-blind randomised controlled trial. Lancet Respir Med 2013;

1:23-31.

14. Bisgaard H, Le Roux P, Bj�amer D, Dymek A, Vermeulen JH, Hultquist C. Bude-

sonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric

asthma. Chest 2006;130:1733-43.

15. Barnes PJ. Scientific rationale for using a single inhaler for asthma control. Eur

Respir J 2007;29:587-95.

16. Papi A, Caramori G, Adcock IM, Barnes PJ. Rescue treatment in asthma: more

than as-needed bronchodilation. Chest 2009;135:1628-33.

17. Papi A, Canonica G, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, et al. Rescue use

of beclomethasone and albuterol in as a single inhaler for mild asthma. N Engl J

Med 2007;356:2040-52.

18. Calhoun W, Ameredes B, King T, Icitovic N, Bleecker ER, Castro M, et al. Com-

parison of physician-, biomarker-, and symptom-based strategies for adjustment of

inhaled corticosteroid therapy in adults with asthma: the BASALT randomized

controlled trial. JAMA 2012;308:987-97.

19. Martinez FD, Chinchilli VM, Morgan WJ, Boehmer SJ, Lemanske RF Jr, Mauger

DT, et al. Use of beclomethasone dipropionate as rescue treatment for children with

mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled

trial. Lancet 2011;377:650-7.

20. Papi A, Nicolini G, Baraldi E, Boner AL, Cutrera R, Rossi GA, et al. Regular

vs prn nebulized treatment in wheeze preschool children. Allergy 2009;64:

1463-71.

21. Boushey HA, Sorkness CA, King TS, Sullivan SD, Fahy JV, Lazarus SC, et al.

Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med

2005;352:1519-28.

22. Zeiger RS, Mauger D, Bacharier LB, Guilbert TW, Martinez FD, Lemanske RF Jr,

et al. Daily or intermittent budesonide in preschool children with recurrent

wheezing. N Engl J Med 2011;365:1990-2001.

23. Turpeinen M, Nikander K, Pelkonen AS, Syvanen P, Sorva R, Raitio H, et al. Daily

versus as-needed inhaled corticosteroid for mild persistent asthma (the Helsinki

early intervention childhood asthma study). Arch Dis Child 2008;93:654-9.

24. Oborne J, Mortimer K, Hubbard RB, Tattersfield AE, Harrison TW. Quadrupling

the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized,

double-blind, placebo-controlled, parallel-group clinical trial. Am J Respir Crit

Care Med 2009;180:598-602.

25. Rodrigo GJ. Rapid effects of inhaled corticosteroids in acute asthma: an evidence-

based evaluation. Chest 2006;130:1301-11.

26. Beasley R. An historical perspective of the New Zealand asthma mortality epi-

demics. J Allergy Clin Immunol 2006;117:225-8.

27. Beasley R, Pearce N, Crane J. International trends in asthma mortality. Ciba Found

Symp 1997;206:140-50.

28. Rodrigo GJ, Castro-Rodriguez JA. Safety of long-acting beta agonists for the treat-

ment of asthma: clearing the air. Thorax 2012;67:342-9.

29. Weatherall M, Wijesinghe M, Perrin K, Harwood M, Beasley R. Meta-analysis of

the risk of mortality with salmeterol and the effect of concomitant inhaled cortico-

steroid therapy. Thorax 2010;65:39-43.

30. Beasley R, Perrin K, Weatherall M, Wijesinghe M. Call for withdrawal of LABA

single-therapy inhaler in asthma. Lancet 2010;376:750-1.

31. Reddel HK, Taylor DR, Bateman ED, Boulet L-P, Boushey HA, Busse WW, et al.

An official American Thoracic Society/European Respiratory Society Statement:

asthma control and exacerbations: standardizing endpoints for clinical trials and

clinical practice. Am J Respir Crit Care Med 2009;180:59-99.

32. Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety of adding

LABAs to inhaled corticosteroids for treatment asthma. N Engl J Med 2011;364:

2473-5.