As-needed ICS-LABA in Mild Asthma: What Does the Evidence Say?
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.
Compliance with Ethical Standards
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.
- 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.
- 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).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.Google Scholar
- 11.Global Initiative for Asthma. Global strategy for asthma management and prevention, 2018. http://www.ginasthma.org. Accessed 16 Oct 2018.
- 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
- 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).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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle Scholar
- 49.Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. http://www.ginasthma.org/documents. Accessed 16 Aug 2019.