Implementing Antiinflammatory Reliever Strategies in Asthma

Asthma is a major cause of morbidity in adults in the United States. For decades, asthma guidelines have supported the use of separate daily maintenance inhalers and as needed short-acting beta-2-agonist (SABA) inhalers for relief. Recently, a paradigm shift has occurred with the emergence of treatment strategies that incorporate the use of inhaled corticosteroids (ICSs) within relievers for asthma symptoms, called antiinflammatory reliever (AIR) therapies. Use of AIR improves outcomes by providing both an antiinflammatory and bronchodilator for relief, presumably because airway inflammation is acutely worsening when asthma symptoms increase. As more data surrounding the risks and benefits of AIR strategies emerge, clinicians and patients will need to determine how to implement the different AIR strategies that are available to achieve optimal outcomes. AIR strategies differ based on the severity of the asthma. For mild asthma (steps 1 and 2), the Global Initiative for Asthma recommends use of ICS/formoterol as needed,1Global Initiative for Asthma. Global stategies for asthma management and prevention. 2023. Updated July 2023. Global Initiative for Asthma website.https://ginasthma.org/2023-gina-main-report/Date accessed: July 31, 2023Google Scholar whereas the National Asthma Education and Prevention Program recommends use of SABA as needed in step 1 therapy and daily low-dose ICSs and as needed SABA for step 2 (the safety and efficacy of ICS/formoterol was not reviewed for these patients).2Cloutier M.M. Baptist A.P. Blake K.V. et al.Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC)2020 Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.J Allergy Clin Immunol. 2020; 146: 1217-1270Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar Evidence has shown that use of as needed ICS/formoterol reduces severe asthma exacerbations, compared with the use of as needed SABA.3Crossingham I. Turner S. Ramakrishnan S. et al.Combination fixed-dose β agonist and steroid inhaler as required for adults or children with mild asthma: a Cochrane systematic review.BMJ Evid Based Med. 2022; 27: 178-184Crossref Scopus (12) Google Scholar Additionally, as needed ICS/formoterol and combination beclomethasone/salbutamol (not available in the United States) were shown to be as effective as regular use of ICSs and as needed SABA, with less average daily exposure to ICSs.3Crossingham I. Turner S. Ramakrishnan S. et al.Combination fixed-dose β agonist and steroid inhaler as required for adults or children with mild asthma: a Cochrane systematic review.BMJ Evid Based Med. 2022; 27: 178-184Crossref Scopus (12) Google Scholar,4Papi A. Canonica G.W. Maestrelli P. et al.Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma.N Engl J Med. 2007; 356: 2040-2052Crossref PubMed Scopus (307) Google Scholar For moderate asthma, the Global Initiative for Asthma and the National Asthma Education and Prevention Program both incorporate the use of a single combination ICS and a rapid long-acting beta agonist (formoterol) for both maintenance and quick relief.1Global Initiative for Asthma. Global stategies for asthma management and prevention. 2023. Updated July 2023. Global Initiative for Asthma website.https://ginasthma.org/2023-gina-main-report/Date accessed: July 31, 2023Google Scholar,2Cloutier M.M. Baptist A.P. Blake K.V. et al.Expert Panel Working Group of the National Heart, Lung, and Blood Institute (NHLBI) administered and coordinated National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC)2020 Focused updates to the asthma management guidelines: a report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.J Allergy Clin Immunol. 2020; 146: 1217-1270Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar For patients with moderate-to-severe asthma, the evidence supporting maintenance and reliever therapy (MART) has been robust; the use of MART has been shown to reduce asthma exacerbations by approximately one-third.5Sobieraj D.M. Weeda E.R. Nguyen E. et al.Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis.JAMA. 2018; 319: 1485-1496Crossref PubMed Scopus (204) Google Scholar For people aged ≥ 12 years, Reddel et al6Reddel H.K. Bateman E.D. Schatz M. Krishnan J.A. Cloutier M.M. A practical guide to implementing SMART in asthma management.J Allergy Clin Immunol Pract. 2022; 10: S31-S38Abstract Full Text Full Text PDF Scopus (0) Google Scholar propose the use of one to two puffs of budesonide/formoterol 160/4.5 μg twice daily for maintenance and one puff every 4 to 6 hours as a reliever, for a total of up to 12 puffs of budesonide/formoterol per day. Recently, two additional reliever approaches that incorporate ICSs for symptom relief (patient-activated reliever-triggered inhaled glucocorticoid strategy [PARTICS] and single combination albuterol/budesonide) were shown to reduce severe asthma exacerbations in patients with moderate-to-severe asthma.7Israel E. Cardet J.C. Carroll J.K. et al.Reliever-triggered inhaled glucocorticoid in black and Latinx adults with asthma.N Engl J Med. 2022; 386: 1505-1518Crossref PubMed Scopus (37) Google Scholar,8Papi A. Chipps B.E. Beasley R. et al.Albuterol-budesonide fixed-dose combination rescue inhaler for asthma.N Engl J Med. 2022; 386: 2071-2083Crossref PubMed Scopus (40) Google Scholar With PARTICS, patients used one puff of ICS (beclomethasone) for each puff of quick-acting reliever and five puffs of ICS for each quick reliever nebulization received. PARTICS, which was studied in Black and Latinx patients, was also shown to reduce asthma symptoms and days of impairment.7Israel E. Cardet J.C. Carroll J.K. et al.Reliever-triggered inhaled glucocorticoid in black and Latinx adults with asthma.N Engl J Med. 2022; 386: 1505-1518Crossref PubMed Scopus (37) Google Scholar In the setting of reducing severe exacerbations, combination albuterol/budesonide earned US Food and Drug Administration approval as a reliever for patients with moderate-to-severe asthma.8Papi A. Chipps B.E. Beasley R. et al.Albuterol-budesonide fixed-dose combination rescue inhaler for asthma.N Engl J Med. 2022; 386: 2071-2083Crossref PubMed Scopus (40) Google Scholar Albuterol/budesonide was studied with two puffs (total 180 μg of albuterol/160 μg of budesonide) as needed as a reliever for up to six total doses or 12 inhalations.8Papi A. Chipps B.E. Beasley R. et al.Albuterol-budesonide fixed-dose combination rescue inhaler for asthma.N Engl J Med. 2022; 386: 2071-2083Crossref PubMed Scopus (40) Google Scholar Despite the evidence that supports the use of AIR strategies, barriers across multiple levels have made implementation challenging. In the United States, ICS/formoterol has not been approved by the US Food and Drug Administration for the MART indication, and insurance and formulary restrictions make it difficult for patients to obtain an adequate supply of ICS/formoterol for both maintenance and relief. There is a knowledge gap among clinicians regarding the new asthma management guidelines that promote the use of AIR strategies. Physicians frequently prescribe SABA in addition to MART because they perceive that patients are more familiar with SABAs,9Chapman K.R. Hinds D. Piazza P. et al.Physician perspectives on the burden and management of asthma in six countries: the Global Asthma Physician Survey (GAPS).BMC Pulm Med. 2017; 17: 153Crossref PubMed Scopus (46) Google Scholar potentially limiting the efficacy of MART. Clinicians also perceive that patients do not understand how to use MART or are unwilling to transition to MART.10Zaeh S.E. Eakin M. Chupp G.L. Clinical practices and barriers to the use of single maintenance and reliever therapy for asthma.Am J Respir Crit Care Med. 2023; 207: A6006Google Scholar Additionally, patients with moderate-to-severe asthma who are on maintenance inhalers other than ICS/formoterol must be transitioned to ICS/formoterol to use MART. In considering practical guidance for clinicians and patients trying to implement AIR strategies, we suspect different patients may have different preferences based on their current medication regimens, personal preferences, and insurance coverage. For example, patients with moderate-to-severe asthma on ICS/formoterol for maintenance might transition easily to MART, whereas patients on maintenance inhalers that do not contain formoterol might prefer the use of PARTICS or albuterol/budesonide. Use of PARTICs and albuterol/budesonide allow patients to continue using albuterol within their reliever, with PARTICs incorporating use of nebulizers. However, these two approaches require multiple inhalers, making them potentially more cumbersome than MART. Additionally, combination albuterol/budesonide will not be available in the United States until 2024 and may be costly. Within Figure 1, we propose considerations for clinicians when choosing an AIR strategy for moderate-to-severe asthma. Gaps remain in our knowledge of AIR strategies and require further investigation. These gaps include whether alternative AIR approaches to ICS/formoterol are effective or needed in all patients with asthma (ie, step 1 or those who do not have systemic corticosteroids that require exacerbations), how AIR can be used in patients on biologics, safety and efficacy of AIR in young children, and whether ICS/formoterol can be used as a reliever with alternative ICS/long-acting beta agonist controllers (an approach not previously recommended because of safety concerns). As further data are collected, we anticipate that asthma management recommendations will need to be adjusted. In the real-world setting, not all patients will transition their inhaler regimen to ICS/formoterol. Alignment between asthma management guidelines will help to avoid confusion among clinicians and patients. Improving the implementation of AIR goes beyond data and guidelines. First, AIR must be more affordable and available for patients. Prior cost-effectiveness studies have shown MART to be cost-effective11Price D. Wirén A. Kuna P. Cost-effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy.Allergy. 2007; 62: 1189-1198Crossref PubMed Scopus (42) Google Scholar; these studies should be performed for other AIR strategies to provide support for enhanced insurance coverage. There have been calls to make ICS/formoterol available over the counter, given its safety and efficacy and the possibility of decreasing SABA monotherapy for relief. The need for enhanced education regarding the use of AIR among clinicians and patients is obvious. We must develop patient education strategies that are comprehended easily and translated into different languages, which allow patients to self-manage their asthma. In conclusion, although the use of AIR has been shown to improve asthma outcomes and represents a fundamental change in asthma management, questions surrounding AIR strategies in asthma management remain and require further investigation. Implementation of these new reliever strategies will depend on making them patient-centered, more affordable, and more available. M. N. E. has ongoing funding support from two National Institutes of Health grants (R61 HL157845 and R01 HL146785); however, these grants did not specifically fund this research. S. E. Z. has funding support from the American Lung Association Catalyst Award (1053115).