Optimizing asthma management: Role of long-acting muscarinic antagonists

Patients with asthma who are suboptimally responsive to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) are frequently exposed to oral corticosteroids and high-dose ICS, which can lead to significant side effects. Long-acting muscarinic antagonists (LAMAs) have demonstrated efficacy and safety in a subset of these patients. This review summarizes the results of key studies using LAMAs in patients with asthma aged 12 years or older. LAMA as an add-on treatment improved lung function and asthma control in patients with uncontrolled asthma across studies. The efficacy of LAMAs as an add-on to ICS was superior to that of placebo and ICS dose escalation and comparable with that of LABAs. LAMA plus ICS plus LABA provided modest improvements in bronchodilation and increased the time to first severe exacerbation versus ICS plus LABA. Single-inhaler triple therapy was associated with decreased health care resource utilization and improved cost-effectiveness versus multiple inhalers. LAMAs were generally well tolerated; asthma exacerbations, bronchitis, and nasopharyngitis were common adverse events with LAMA in combination with ICS alone or ICS plus LABA. Thus, the overall evidence presented in this review supports the use of add-on LAMA treatment as a reasonable option in patients with asthma uncontrolled with ICS plus LABA or ICS alone. Patients with asthma who are suboptimally responsive to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) are frequently exposed to oral corticosteroids and high-dose ICS, which can lead to significant side effects. Long-acting muscarinic antagonists (LAMAs) have demonstrated efficacy and safety in a subset of these patients. This review summarizes the results of key studies using LAMAs in patients with asthma aged 12 years or older. LAMA as an add-on treatment improved lung function and asthma control in patients with uncontrolled asthma across studies. The efficacy of LAMAs as an add-on to ICS was superior to that of placebo and ICS dose escalation and comparable with that of LABAs. LAMA plus ICS plus LABA provided modest improvements in bronchodilation and increased the time to first severe exacerbation versus ICS plus LABA. Single-inhaler triple therapy was associated with decreased health care resource utilization and improved cost-effectiveness versus multiple inhalers. LAMAs were generally well tolerated; asthma exacerbations, bronchitis, and nasopharyngitis were common adverse events with LAMA in combination with ICS alone or ICS plus LABA. Thus, the overall evidence presented in this review supports the use of add-on LAMA treatment as a reasonable option in patients with asthma uncontrolled with ICS plus LABA or ICS alone. 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The projected economic and health burden of uncontrolled asthma in the United States.Am J Respir Crit Care Med. 2019; 200: 1102-1112Crossref PubMed Scopus (96) Google Scholar In an observational study undertaken in the United States, patients with severe uncontrolled asthma (SUA) experienced significantly more asthma exacerbations (adjusted rate or risk ratio, 2.12; 95% CI, 1.94-2.32) compared with those without SUA.19Zeiger R.S. Schatz M. Dalal A.A. Qian L. Chen W. Ngor E.W. et al.Utilization and costs of severe uncontrolled asthma in a managed-care setting.J Allergy Clin Immunol Pract. 2016; 4: 120-129.e3Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Patients with SUA also used SABA in excess and had higher all-cause and asthma-related costs than those without SUA.19Zeiger R.S. Schatz M. Dalal A.A. Qian L. Chen W. Ngor E.W. et al.Utilization and costs of severe uncontrolled asthma in a managed-care setting.J Allergy Clin Immunol Pract. 2016; 4: 120-129.e3Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar In this review, we discuss the role of LAMAs as an additional therapeutic option to the existing ICS and LABA therapies to improve asthma control.Muscarinic receptors as a target for treatment of asthmaAcetylcholine (ACh) is the predominant parasympathetic neurotransmitter in the airways and is released from airway neurons and nonneuronal cells, such as airway epithelial cells.20Kolahian S. Gosens R. Cholinergic regulation of airway inflammation and remodelling.J Allergy (Cairo). 2012; 2012681258PubMed Google Scholar ACh binds to muscarinic M1, M2, and M3 receptors, which are found on airway epithelial cells, smooth muscle cells, and submucosal glands.21Gosens R. Zaagsma J. Meurs H. Halayko A.J. 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Depending on their duration of action (DOA), the muscarinic antagonists approved by the US Food and Drug Administration and/or the European Commission for the treatment of asthma are classified as short acting (eg, ipratropium; DOA, 4-8 hours) and long acting (eg, tiotropium, glycopyrronium, and umeclidinium; DOA, ≥24 hours).23Papi A. Fabbri L.M. Kerstjens H.A.M. Rogliani P. Watz H. Singh D. Inhaled long-acting muscarinic antagonists in asthma—a narrative review.Eur J Intern Med. 2021; 85: 14-22Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,26Gross N.J. Anticholinergic agents in asthma and COPD.Eur J Pharmacol. 2006; 533: 36-39Crossref PubMed Scopus (124) Google Scholar LAMAs could be used as an alternative add-on for the management of asthma with the convenience of single daily-dose regimen.27Aalbers R. Park H.S. 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Positioning of long-acting muscarinic antagonists in the management of asthma.Allergy Asthma Immunol Res. 2017; 9: 386-393Crossref PubMed Scopus (17) Google Scholar LAMAs, such as tiotropium, are potent because a longer interaction with M1 and M3 receptors causes prolonged bronchodilation.27Aalbers R. Park H.S. Positioning of long-acting muscarinic antagonists in the management of asthma.Allergy Asthma Immunol Res. 2017; 9: 386-393Crossref PubMed Scopus (17) Google Scholar Umeclidinium is a LAMA that exhibits slow functional reversibility at the M3 receptors and has a long DOA.28Salmon M. Luttmann M.A. Foley J.J. Buckley P.T. Schmidt D.B. 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New perspectives on the role of muscarinic antagonists in asthma therapy.Expert Rev Respir Med. 2020; 14: 817-824Crossref PubMed Scopus (2) Google ScholarReview of studies that have examined the use of LAMAs in patients with asthmaWe reviewed the results of studies indexed in PubMed that had examined the use of LAMAs in patients with asthma: (1) LAMA monotherapy; (2) LAMA plus ICS versus ICS monotherapy; (3) add-on LAMA versus ICS (±LABA) dose escalation; (4) LAMA plus ICS versus LABA plus ICS; (5) LAMA plus ICS plus LABA (open triple therapy) versus ICS plus LABA; and (6) single-inhaler triple therapy versus ICS plus LABA plus LAMA. There is extensive literature on the above topics; consequently, not all studies are covered in detail. Therefore, we will highlight and review some of the most relevant studies. 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For a complete summary of studies reviewed in the preparation of this article, please see this article's Online Repository at www.jacionline.org.Table IWeighting of studies comparing LAMA with other treatments in adults or adolescents with asthmaAuthors (trial name, if any)Previous treatmentLAMA-containing intervention arm (n)Comparator(s) (n)Systematic reviewsSobieraj et al,34Sobieraj D.M. Baker W.L. Nguyen E. Weeda E.R. Coleman C.I. White C.M. et al.Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: a systematic review and meta-analysis.JAMA. 2018; 319: 1473-1484Crossref PubMed Scopus (60) Google Scholar 2018ICSICS plus LAMA;15 RCTs in patients with uncontrolled persistent asthma (n = 7122)Pbo∗LAMA/comparator was used as an add-on to previous treatment.Kew et al,35Kew K.M. Evans D.J. Allison D.E. Boyter A.C. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long-acting beta2-agonists (LABA) for adults with asthma.Cochrane Database Syst Rev. 2015; 2015: CD011438Google Scholar 2015ICSICS plus LAMA; 8 studies including 4 double-blind, double-dummy studies (≈n = 2000)LABA∗LAMA/comparator was used as an add-on to previous treatment.Kew and Dahri,36Kew K.M. Dahri K. Long-acting muscarinic antagonists (LAMA) added to combination lo