Skip to main content
SpringerLink
Log in

As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say?

  • Current Opinion
  • Published:
Drugs Aims and scope Submit manuscript

A Correction to this article was published on 29 October 2019

This article has been updated

Abstract

For the last three decades, the guidelines for asthma management have supported a stepwise therapeutic approach, based on the administration of controller medications (especially inhaled corticosteroids) complemented by on-demand use of rescue medication. Classically, the rescue medication recommended comprised short-acting β agonists (SABA). Some years ago, the use of Symbicort Maintenance and Reliever Therapy (SMART) demonstrated the benefits of a combination of budesonide-formoterol, an inhaled corticosteroid, and a long-acting β agonist (ICS-LABA) as rescue medication in moderate and severe asthma. The results were enthusiastically received, and this therapeutic option was adopted in the guidelines for moderate to severe asthma patients. Recently, four trials (two randomised placebo control trials under the auspices of the SYGMA project and two real-life studies, Novel START, and the PRACTICAL trial) have explored the potential benefits of substituting SABA with budesonide-formoterol as rescue medication in mild asthma patients. The SYGMA 1 and 2 studies showed that the combination with formoterol-budesonide as rescue medication provides better asthma control than short-acting β-agonists alone in GINA step 2 patients, although the superiority was slight. Compared to budesonide maintenance therapy, the fixed combination of ICS-LABA on demand provides poorer asthma control. Regarding exacerbations, the fixed dose ICS-LABA combination on demand showed the same benefits for the prevention of exacerbations as chronic ICS treatment in mild asthma patients. The Novel START study, which assessed a population with milder symptoms, concluded that the fixed dose ICS-LABA combination used as needed was superior to SABA (albuterol) as needed for the prevention of asthma exacerbations. These results in fact show that, in undertreated GINA step 2 with only SABA as needed, ICS-LABA is more effective than SABA. The authors of PRACTICAL concluded that the study provided modest evidence that the ICS-LABA combination used as-needed for symptom relief reduces the rate of severe exacerbations compared with maintenance low-dose budesonide plus terbutaline as needed, although the study was not limited to mild asthma since according to the treatment consumed, it was evident that they had recruited some moderate asthma patients. Despite this poor evidence, and ignoring the clinical histological benefits of chronic inhaled corticosteroids (especially when administered promptly), GINA 2019 recently recommended daily low dose ICS or ICS-LABA as needed as a first option for step 2 patients. For step 1, symptom-driven or as-needed treatment with ICS-LABA is recommended rather than SABA alone (the preferred option until the last GINA update). Finally, the SIENA study showed that 73% of patients with mild asthma do not have an eosinophilic phenotype and that these patients have a similar clinical response to ICS (mometasone) and antimuscarinic drugs (tiotropium), results that challenge the indication of a drug combination that incorporates ICS as a first option. Overall, we believe there is insufficient evidence for the systematic recommendation of as-needed ICS-LABA instead of SABA on request for GINA step 1 or as a replacement for chronic ICS in GINA step 2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Change history

  • 29 October 2019

    Abstract, fourth to last sentence, which currently reads:

References

  1. Rello J, Domingo C. Precision medicine and aerosolization in mechanically ventilated adults. J Thorac Dis. 2018;10(suppl 26):S3111–4. https://doi.org/10.21037/jtd.2018.07.64.

    Article  PubMed  PubMed Central  Google Scholar 

  2. The Global Asthma Network. The Global Asthma Report 2014. [Online]. http://www.globalasthmanetwork.org/publications/Global_Asthma_Report_2014.pdf. Accessed 16 May 2018.

  3. Asher I. ISAAC International Study of Asthma and Alleregies in Childhood. Pediatr Pulmonol. 2007;42:100–10.

    PubMed  Google Scholar 

  4. Kankaanranta H, Tuomisto LE, Ilmarinen P. Age-specific incidence of new asthma diagnoses in Finland. J Allergy Clin Immunol Pract. 2017;5(1):189–91.

    PubMed  Google Scholar 

  5. Sood A, Qualls C, Schuyler M, Arynchyn A, Alvarado JH, Smith LJ, et al. Adult-onset asthma becomes the dominant phenotype among women by age 40 years. Ann Am Thorac Soc. 2013;10:188–97.

    PubMed  PubMed Central  Google Scholar 

  6. Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Bethesda (MD): National Heart, Lung, and Blood Institute (US), 2007).

  7. Beasley R, Burgess C, Crane J, et al. Pathology of asthma and its clinical implications. J Allergy Clin Immunol. 1993;92:148–54.

    CAS  PubMed  Google Scholar 

  8. International Consensus Report on diagnosis and treatment of asthma. National Heart, Lung and Blood Institute, National Institutes of Health. Bethesda, Maryland 20892. Publication number 92-3091, March 1992. Eur Respir J. 1992;5:601–641.

  9. Domingo Ch, Pacheco A, Hinojosa M, Bosque M. The relevance of IgE in the pathogenesis of allergy: the effect of an anti-IgE drug in asthma and other diseases. Recent Pat Inflamm Allergy Drug Discov. 2007;1(2):151–64.

    CAS  PubMed  Google Scholar 

  10. Busse WW, Lemanske RF. Asthma. N Engl J Med. 2001;344:350–62.

    CAS  PubMed  Google Scholar 

  11. Global Initiative for Asthma. Global strategy for asthma management and prevention, 2018. http://www.ginasthma.org. Accessed 16 Oct 2018.

  12. Busse W, Chervinsky P, Condemia J, et al. Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J Allergy Clin Immunol. 1998;101:457–63.

    CAS  PubMed  Google Scholar 

  13. Greening AP, Ind PW, Northfield M, Shaw G, Allen & Hanburys, Limited UK Study Group. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet. 1994;344:219–24.

    CAS  PubMed  Google Scholar 

  14. Papi A, Canonica GW, Maestrelli P, Paggiaro P, Olivieri D, Pozzi E, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med. 2007;356(20):2040–52.

    CAS  PubMed  Google Scholar 

  15. Beasley R, Weatherall M, Shirtcliffe P, Hancox R, Reddel HK. Combination corticosteroid/beta-agonist inhaler as reliever therapy: a solution for intermittent and mild asthma? J Allergy Clin Immunol. 2014;133(1):39–41.

    CAS  PubMed  Google Scholar 

  16. Tattersfield AE, Postma DS, Barnes PJ, The FACET International Study Group, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. Am J Respir Crit Care Med. 1999;16:594–9.

    Google Scholar 

  17. Usmani OS, Ito K, Maneechotesuwan K, Ito M, Johnson M, Barnes PJ, Adcock IM. Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy. AJRCCM. 2005;172(6):704–12.

    Google Scholar 

  18. Adcock IM, Maneechotesuwan K, Usmani O. Molecular interactions between glucocorticoids and long-acting β2-agonists. Allergy Clin Immunol. 2002;110(6):S261–8.

    CAS  Google Scholar 

  19. Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008;4:525–33.

    CAS  PubMed  Google Scholar 

  20. Baraniuk JN, Ali M, Brody D, et al. Glucocorticoids induce beta2-adrenergic receptor function in human nasal mucosa. Am J Respir Crit Care Med. 1997;155(2):704–10.

    CAS  PubMed  Google Scholar 

  21. Tan KS, McFarlane LC, Lipworth BJ. Concomitant administration of low-dose prednisolone protects against in vivo beta2-adrenoceptor subsensitivity induced by regular formoterol. Chest. 1998;113(1):34–41.

    CAS  PubMed  Google Scholar 

  22. Kips J, O’Connor BJ, Inman MD, Svensson K, Pauweks RA, O’Byrne PM. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am J Respir Crit Care Med. 2000;161:996–1001.

    CAS  PubMed  Google Scholar 

  23. Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. Lancet. 2006;938(9537):744–53.

    Google Scholar 

  24. O’Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018;378:1865–76.

    PubMed  Google Scholar 

  25. Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018;378:1877–87.

    CAS  PubMed  Google Scholar 

  26. O’Byrne PM, FitzGerald JM, Zhong N, et al. The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given ‘as needed’ in mild asthma: study protocols for two randomised controlled trials. Trials. 2017;18:12.

    PubMed  PubMed Central  Google Scholar 

  27. Beasley R, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, Hancox RJ, et al. Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med. 2019;380:2020–30.

    PubMed  Google Scholar 

  28. Hardy J, Baggott C, Fingleton J et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial. Lancet. 2019. (published online Aug 23).

  29. Lazarus SC, Krishnan JA, King TS, Lang JE, Blake KV, Covar R, et al. Mometasone or tiotropium in mild asthma with a low sputum eosinophil level. N Engl J Med. 2019;380(21):2009–19.

    PubMed  PubMed Central  Google Scholar 

  30. Dusser D, Montani D, Chanez P, et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy. 2007;62:591–604.

    CAS  PubMed  Google Scholar 

  31. Pawels RA, Löfdal CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes PJ, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and corticoids establishing therapy. New Engl J Med. 1997;337:1405–11 (Erratum in New Engl J Med 1998: 338-139).

    Google Scholar 

  32. Palmqvist M, Arvidsson P, Beckman O, Peterson S, Lötvall J. Onset of bronchodilation of budesonide/formoterol vs salmeterol/fluticasone in single inhalers. Pulm Pharmacol Ther. 2001;14(1):29–34.

    CAS  PubMed  Google Scholar 

  33. Balanag VM, Yunus F, Yang PC, Jorup C. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharmacol Ther. 2006;19(2):139–47.

    CAS  PubMed  Google Scholar 

  34. Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martínez-Jimenez NE, Buhl R. Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations. Int J Clin Pract. 2007;61(5):725–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J Med. 1998;339(17):1194–200.

    CAS  PubMed  Google Scholar 

  36. Laitinen LA, Heino M, Laitinen A, Kava T, Haahtela T. Damage of the airway epithelium and bronchial reactivity in patients with asthma. Am Rev Respir Dis. 1985;131(4):599–606.

    CAS  PubMed  Google Scholar 

  37. Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV, Kay AB. Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis. 1989;140(6):1745–53.

    CAS  PubMed  Google Scholar 

  38. Laitinen LA, Laitinen A, Haahtela T. A comparative study of the effects of an inhaled corticosteroid, budesonide, and a beta 2-agonist, terbutaline, on airway inflammation in newly diagnosed asthma: a randomized, double-blind, parallel-group controlled trial. J Allergy Clin Immunol. 1992;90(1):32–42.

    CAS  PubMed  Google Scholar 

  39. Ulrik CS, Lange P. Decline of lung function in adults with bronchial asthma. Am J Respir Crit Care Med. 1994;150(3):629–34.

    CAS  PubMed  Google Scholar 

  40. Haahtela T, Järvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen K, et al. Effects of reducing or discontinuing inhaled budesonide in patients with mild asthma. N Engl J Med. 1994;331(11):700–5.

    CAS  PubMed  Google Scholar 

  41. Trigg CJ, Manolitsas ND, Wang J, Calderón MA, McAulay A, Jordan SE, et al. Placebo-controlled immunopathologic study of 4 months of inhaled corticosteroids in asthma. Am J Respir Crit Care Med. 1994;150(1):17–22.

    CAS  PubMed  Google Scholar 

  42. Hoshino M, Nakamura Y, Sim JJ, Yamashiro Y, Uchida K, Hosaka K, et al. Inhaled corticosteroid reduced lamina reticularis of the basement membrane by modulation of insulin-like growth factor (IGF)-I expression in bronchial asthma. Clin Exp Allergy. 1998;28(5):568–77.

    CAS  PubMed  Google Scholar 

  43. Olivieri D, Chetta A, Del Donno M, Bertorelli G, Casalini A, Pesci A, et al. Effect of short-term treatment with low-dose inhaled fluticasone propionate on airway inflammation and remodeling in mild asthma: a placebo-controlled study. Am J Respir Crit Care Med. 1997;155(6):1864–71.

    CAS  PubMed  Google Scholar 

  44. Li X, Wilson JW. Increased vascularity of the bronchial mucosa in mild asthma. Am J Respir Crit Care Med. 1997;156(1):229–33.

    CAS  PubMed  Google Scholar 

  45. Orsida BE, Li X, Hickey B, Thien F, Wilson JW, Walters EH. Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax. 1999;54(4):289–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Coumou H, Westerhof GA, de Nijs SB, Zwinderman AH, Bel EH. Predictors of accelerated decline in lung function in adult-onset asthma. Eur Respir J. 2018;51(2):1701785. https://doi.org/10.1183/13993003.01785-2017(Print 2018 Feb).

    Article  CAS  PubMed  Google Scholar 

  47. Tommola M, Ilmarinen P, Tuomisto L, Haanpää J, Kankaanranta T, Niemelä O, et al. Predictors of long-term lung function decline in adult-onset asthma. Eur Resp J. 2016;48:PA566. https://doi.org/10.1183/13993003.congress-2016.pa566.

    Article  Google Scholar 

  48. Domingo C. Ultra-LAMA, ultra-LABA, ultra-inhaled steroids? The future has landed. Arch Bronconeumol. 2013;49(4):131–4.

    PubMed  Google Scholar 

  49. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. http://www.ginasthma.org/documents. Accessed 16 Aug 2019.

  50. Muneswarao J, Hassali MA, Ibrahim B, Saini B, Hyder Ali IA, Verma AK. It is time to change the way we manage mild asthma: an update in GINA 2019. Respir Res. 2019;20:183.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Servei de Pneumologia, Corporació Sanitària Parc Taulí, Parc Taulí s/n, 08208, Sabadell (Barcelona), Spain

    Christian Domingo & Ana Sogo

  2. Departament de Medicina, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain

    Christian Domingo & Ana Sogo

  3. CIBERES, Instituto Salud Carlos III and Vall d’Hebron Institute of Research, Barcelona, Spain

    Jordi Rello

Authors
  1. Christian Domingo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jordi Rello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana Sogo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Domingo.

Ethics declarations

Conflict of interest

Dr. Domingo has received funding to cover travel costs and also lecturer’s fees from Novartis, Sanofi, GSK, TEVA, Boehringer-Ingelheim, Esteve, Almirall, Astra-Zeneca, Chiesi, Menarini, Takeda, Pfizer, Ferrer, Diater, Stallergenes, ALK-Abelló, Allergy therapeutics, Hall Allergy, Inmunotek. With regard to this paper he has no conflicts of interest to declare. Dr. Rello has no conflict of interest to declare with regard to this paper. Dr. Sogo has received funding to cover travel costs and also lecturer’s fees from Novartis, Sanofi, GSK, Boehringer-Ingelheim, Esteve, Almirall, Astra-Zeneca, Chiesi, Menarini, Pfizer, Stallergenes, Diater, ALK-Abelló, Allergy therapeutics, Hall Allergy, Inmunotek. With regard to this paper, she has no conflicts of interest to declare.

Additional information

The original version of this article was revised: Due to Abstract update.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Domingo, C., Rello, J. & Sogo, A. As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say?. Drugs 79, 1729–1737 (2019). https://doi.org/10.1007/s40265-019-01202-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-019-01202-0

Search

Navigation