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Interpreting Recent Developments in COPD Treatments.


Primary care providers (PCPs) play a critical role in diagnosing, managing, and treating patients with chronic obstructive pulmonary disease (COPD), which is encountered routinely in everyday clinical practice. (1) Pharmacologic therapy alleviates COPD symptoms, reduces exacerbation severity and frequency, and improves patients' health status and exercise endurance. (2) Various medications, including bronchodilators (3,-agonists and muscarinic antagonists), inhaled corticosteroids (ICSs), methylxanthines, and phosphodiesterase-4 (PDE-4) inhibitors, are available for treating COPD in the United States. The choice of medication should be made based on symptom severity and exacerbation risk, ease of use, availability, cost, and clinical benefit versus risk of adverse events (AEs). (2)

Bronchodilators--which can be short- or long-acting--help reduce airflow obstruction by causing bronchodilation, reducing hyperinflation (and consequently decreasing air-trapping), and improving exercise performance. (1,2) Short-acting [[beta].sub.2]-agonists (SABAs) and short-acting muscarinic antagonists (SAMAs) are used for maintenance treatment in patients with mild disease, minimal symptoms, and infrequent exacerbations. (3) Long-acting [[beta].sub.2]-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are used for maintenance treatment when the disease severity is any greater (table). Long-acting bronchodilators (LABDs) provide better symptom control, improved health status, and greater reduction of exacerbations than short-acting agents. (1) LABAs and LAMAs, which cause bronchodilation in different ways (FIGURE), (1) are used as either monotherapy or in combination (table) to leverage complementary mechanisms of action. LABAs stimulate [[beta].sub.2]-adrenergic receptors in airway smooth muscle, triggering cellular pathways that eventually cause relaxation of bronchial smooth muscle and bronchodilation, whereas LAMAs inhibit muscarinic receptors, thus reducing contraction of airway smooth muscle. (2,4)

ICSs have anti-inflammatory effects mediated by activation of glucocorticoid receptors. (5) In COPD, ICS monotherapy is not recommended; however, ICS/LABA combination improves lung function and health status, and reduces exacerbations. (2) Methylxanthines such as theophylline have modest antiinflammatory and bronchodilator properties (6); several potential mechanisms for these effects have been postulated. (2) However, limited benefits and a narrow therapeutic window preclude common use. (2) PDE-4 inhibitors, which reduce inflammation by increasing intracellular adenosine 3,'5'-cyclic monophosphate levels, modestly improve lung function and reduce exacerbations. (7)

Most pharmacologic agents for COPD are administered using inhalation devices (8) such as nebulizers, single- and multidose dry powder inhalers (DPI), metered-dose inhalers (MDIs), or slow-mist inhalers (SMIs) (table). (2) Each type of inhalation device has a different mechanism for drug dispersal. Nebulizers, used for many years, aerosolize drug solutions. (9) DPIs rely on patients' inspiratory air flow to diffuse the inhalation powder and create an aerosol of drug particles. (8) MDIs deliver drugs via a propellant spray, whereas nebulizers and SMIs produce an aerosol cloud of fine particles and, therefore, may be less dependent on inspiratory air flow rate for drug delivery. (10)

Because pharmacotherapeutic options for maintenance COPD treatment are rapidly evolving, PCPs should familiarize themselves with current treatment options and determine individual patient requirements. For individualized treatment regimens, symptom severity and exacerbation risk are major determinants. Additionally, factors such as dosing frequency, patient preference, inspiratory flow limitation, and physical and cognitive limitations that may affect correct delivery device use should be considered. (1)


In recent years, better understanding of COPD and its natural history has led to improvements in its diagnosis and management. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, updated numerous times since its original release in 2001, provides a well-accepted strategy for diagnosing and managing COPD. (2) In the GOLD 2011 report, (11) a multidimensional approach for assessment and management of COPD was introduced, where factors beyond spirometric measures of lung function (ie, forced expiratory volume in 1 second [[FEV.sub.1]]) were included. Assessment of symptoms (using the COPD Assessment Test or modified Medical Research Council dyspnea scale) and history of exacerbations were included in this approach, enabling assessment of current symptoms, future exacerbation risk, and overall COPD burden. Patients are categorized as belonging to 1 of 4 groups (A, B, C, or D) based on severity of these parameters, where patients in Group D have significant symptoms and a history of frequent or severe exacerbation (see accompanying supplement article, COPD Management in the Primary Care Setting). (2) ABCD grouping informs the preferred and alternative treatment recommendations. (2)

While [FEV.sub.1] is correlated with clinical outcomes such as hospitalization and mortality at a population level, it has poor precision to predict outcomes at an individual patient level. (2) Moreover, since [FEV.sub.1] is poorly correlated with symptoms and exacerbation frequency, (12,13) it cannot be used as the sole determinant of treatment. These drawbacks were addressed in the GOLD 2017 report in which spirometry was separated from the ABCD assessment tool so that symptoms and exacerbations guide individualized treatment. (14) This revision reduced the complexity of patient classification, making it easier to use in primary care settings.


Early diagnosis of COPD and timely treatment with maintenance medication can reduce symptoms and exacerbations, thereby potentially preserving exercise tolerance, reducing hospitalizations, and consequently reducing associated costs. (15) However, only 45% of patients were receiving maintenance medication for COPD in a retrospective analysis of US health care claims data. (16) Moreover, fewer patients under the care of PCPs (40%) than pulmonologists (64%) were treated with maintenance medications. Results of another retrospective claims data analysis indicated that, despite GOLD recommendations emphasizing use of inhaled bronchodilators, ICS, usually as ICS/LABA combination, was one of the most commonly prescribed maintenance medications in the United States. (17) Overall, these results suggest suboptimal use of appropriate maintenance medications. (16,17) Unfortunately, many PCPs are unaware of guideline recommendations (18) or have chosen not to incorporate them in their practices because of perceptions that they are too lengthy or irrelevant or are not consistent with their clinical experience. (19)


In GOLD 2018, an escalation (step-up)/de-escalation (stepdown) strategy according to assessment of patients' symptoms and exacerbation risk, as well as response to treatment, is recommended. (2) For details on the GOLD treatment algorithm and the use of spirometry in diagnosis, please refer to the accompanying supplement article, COPD Management in the Primary Care Setting. For group A patients, short-or long-acting bronchodilators are recommended, which can be continued if symptoms improve. An LABD is recommended for group B patients as initial therapy. However, in patients with severe or persistent breathlessness despite LABD monotherapy, dual LABD therapy is recommended. Step-down to a single LABD is recommended if symptoms do not improve despite adding a second LABD, and in such cases, comorbidities (eg, congestive heart failure) that could account for persistent symptoms should be thoroughly investigated. For group C patients, an LABD is recommended as initial therapy, with LAMAs preferable to LABAs because of better exacerbation benefit. (20,21) For patients with persistent exacerbations, LABA/LAMA or ICS/LABA combination is recommended, with a preference for the former. (2) For group D patients, initial therapy with LABA/LAMA and escalation to LABA/LAMA/ICS or switching to ICS/LABA is recommended, with subsequent addition of roflumilast or a macrolide if frequent exacerbations persist. (2) While GOLD 2018 suggests that LABA/LAMA is preferred over LABA/LAMA/ICS for this patient population, (2,22-25) results of the IMPACT trial showed that triple therapy significantly reduced the annual rate of on-treatment moderate/severe exacerbations compared with either LABA/LAMA (25% reduction) or ICS/LABA (15% reduction). (26) Significant improvements in trough [FEV.sub.1], St. George's Respiratory Questionnaire (SGRQ) score, and time to first on-treatment moderate/severe COPD exacerbation were also observed. These findings and additional studies in progress comparing triple therapy to dual therapies will likely impact future recommendations.

Four LAMA/LABA fixed-dose combination (FDC) inhalers are available in the United States (table). Tiotropium/ olodaterol is delivered using an SMI, umeclidinium/vilanterol and indacaterol/glycopyrronium are administered via DPIs, and formoterol/glycopyrronium is delivered using an MDI. (2,23) Use of 2 LABDs (ie, LABA/LAMA) is recommended because complementary mechanisms of action and interactions between pathways maximize bronchodilator response. (27) In numerous studies in patients with moderate-to-severe COPD with or without a history of recent (ie, in the previous year) exacerbation, LABA/LAMA combinations provided significantly better clinical outcomes than the ICS/LABA FDC of fluticasone/salmeterol. For example, various LABAs (olodaterol, salmeterol, and indacaterol) in combination with oncedaily tiotropium (a LAMA) resulted in significantly improved lung function (ENERGITO study), (28) decreased lung hyperinflation and improved expiratory flow (OCTANE study), (29) and improved inspiratory capacity (30) vs ICS/LABA. In at least 3 studies, the once-daily LABA/LAMA FDC of vilanterol/umeclidinium caused significant and sustained improvements in lung function versus fluticasone/salmeterol. (31,32) Bronchodilation was significantly improved with the twice-daily LABA/ LAMA combination of aclidinium/formoterol vs fluticasone/ salmeterol in the AFFIRM study. (33) Further, in the ILLUMINATE (vs fluticasone/salmeterol), (34) SPARK (vs glycopyrronium), (35) LANTERN (vs fluticasone/salmeterol), (36) and FLAME (vs fluticasone/salmeterol) (24,25) studies, the once-daily LABA/LAMA combination of indacaterol/glycopyrronium resulted in significant improvements in lung function, fewer exacerbations, and a longer time to first exacerbation. Overall, AE incidence was similar between treatment groups across studies. (25,31-32,34,36) Authors of a Cochrane review of 11 studies, including some of the aforementioned studies, involving 9839 patients with mostly moderate-to-severe COPD without recent exacerbations concluded that LABA/LAMA treatment resulted in greater improvements in lung function (FEV,) and quality of life (QoL), fewer exacerbations, and a lower risk of pneumonia than ICS/LABA. (22)


Use of ICSs in combination with LABDs is recommended in patients with frequent exacerbations (ie, in group D patients after failure of LAMA/LABA treatment (37)); however, inappropriate use of ICSs in patients with COPD (ie, in groups A-C patients) has been reported. (37,38) Though generally safe, ICSs--alone or in combination with a LABA--in patients with COPD are associated with increased risk of pneumonia. (2,39,40) Most episodes of ICS-associated pneumonia in randomized clinical trials were moderate in severity, though some serious events leading to hospitalizations were also reported. (39,40) Pneumonia risk was confirmed in observational studies, where the association between ICSs and pneumonia-related hospitalization and mortality was reported. (39,40) Results of a health insurance database study showed that discontinuation of ICSs was associated with a 37% decrease in the rate of serious pneumonia. (41) Therefore, the concept of ICS withdrawal in patients with COPD where ICSs were not indicated or after extended periods of clinical stability has been tested and is now recommended. (2) Recent findings indicate ICSs can be withdrawn in low- or high-risk patients with COPD, provided maintenance treatment with LABDs is continued. In the INSTEAD (42) and OPTIMO (43) studies, no difference in lung function, breathlessness, health status, rescue medication use, or COPD exacerbations was observed among low-risk patients who switched to a LABA (indacaterol) from an ICS/ LABA (fluticasone/salmeterol) combination or those who withdrew ICS from their ICS/LABA maintenance treatment. In the WISDOM study, high-risk patients were randomly assigned to continued triple therapy (tiotropium/salmeterol/ fluticasone) or withdrawal of fluticasone. (44) ICS withdrawal met the prespecified noninferiority criterion with respect to the first moderate or severe COPD exacerbation. (44) However, in 2 post hoc analyses of WISDOM, ICS withdrawal resulted in higher exacerbation in patients with a raised eosinophil count ([greater than or equal to] 300 cells/[micro]L) and a history of frequent exacerbations ([greater than or equal to] 2/year). (45,46) Therefore, the decision to withdraw ICS needs to be individualized and carefully monitored, because withdrawing ICS to reduce unneeded therapy and pneumonia risk might ultimately increase exacerbation risk in some patients, namely in those with persistent symptoms, frequent exacerbations, and high eosinophil counts.


Initial treatment with ICS/LABA is recommended in some patients who have clinical features suggestive of asthma-COPD overlap (ACO). (2) For further details on ACO, please refer to the accompanying supplement article, Asthma-Chronic Obstructive Pulmonary Disease Overlap: Diagnostic and Management Challenges. Patients with ACO have clinical features of both asthma and COPD, and patients with more asthma than COPD features may therefore benefit from ICS therapy. (47) Patients with blood eosinophil counts in the higher range of normal or that are abnormally elevated have increased exacerbation risk. (48) In a post hoc analysis of 3 studies, fluticasone/salmeterol was associated with a significant reduction in exacerbation rates versus tiotropium or placebo in patients with blood eosinophils [greater than or equal to]2%, suggesting baseline blood eosinophil counts may serve as a marker for the efficacy of ICSs in reducing exacerbations in patients with COPD and a history of moderate or severe exacerbations. (49) The accuracy of blood eosinophil counts in predicting ICS benefits improves in a somewhat linear fashion. Therefore, defining a threshold of eosinophil count that best indicates potential benefit with ICS use in COPD is going to be difficult and will always need to be considered in the context of other clinical information. Based on thresholds used in clinical trials, the absolute counts of 150-300 cells/mL or a relative percentage of 2%-4% are plausible; however, more data are needed. (2,49,50)


Escalation to triple therapy (LABA/LAMA/ICS), which requires using 1 or 2 separate inhalers, is recommended when patients have exacerbations despite maximized treatment with LABA/LAMA or ICS/LABA. (2) Clinical trial evidence in patients with COPD and moderate-to-severe exacerbations is accumulating. Single-inhaler triple therapies are generally preferable to 2 different inhalers because the latter is associated with increased risk of inhalation errors and decreased adherence. (51) In GLISTEN, glycopyrronium plus fluticasone/salmeterol (separate inhalers) improved lung function and QoL, and reduced rescue medication use compared with placebo plus fluticasone/salmeterol. (52) In TRILOGY and TRINITY, beclomethasone/formoterol/ glycopyrronium (single inhaler), improved lung function and reduced exacerbations compared with beclomethasone/formoterol. (53,54) Furthermore, triple therapy was noninferior to beclomethasone/formoterol plus tiotropium in TRINITY. (54) Results of randomized trials showed that once-daily fluticasone/umeclidinium/vilanterol (1 or 2 inhalers) significantly improved lung function and QoL compared with placebo plus fluticasone/vilanterol. (55,56) In addition, once-daily fluticasone/umeclidinium/vilanterol (single inhaler) significantly improved lung function and patient-reported outcomes, and reduced the moderate or severe exacerbation rates compared with twice-daily budesonide/formoterol in FULFIL. (57) AE incidence was similar across treatment groups. Recently, results of IMPACT further showed that single-inhaler triple therapy comprising fluticasone/umeclidinium/vilanterol significantly reduced the annual rate of moderate or severe exacerbations compared with fluticasone/vilanterol or umeclidinium/vilanterol. (26) As mentioned, these findings will likely influence future treatment recommendations. Despite triple therapy, many patients continue to have exacerbations. (54,58) These patients may benefit from other options such as PDE-4 inhibitors, macrolides,2 or targeted biologies.


Roflumilast is indicated in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. (2,59,60) In clinical trials, roflumilast reduced exacerbations and modestly improved lung function in patients with moderate-to-severe COPD treated with LABDs (61) and reduced exacerbation risk and hospital admissions in patients with severe COPD who were not controlled with an ICS/LABA (REACT study). (59) Furthermore, results from post hoc analyses of RE (2) SPOND (62) and REACT (63) showed that roflumilast was more beneficial in patients with a prior history of hospitalization for a COPD exacerbation. Roflumilast initiation is often associated with troublesome gastrointestinal AEs and requires monitoring for other AEs (2); therefore, escalation to roflumilast is best managed by specialists.


Chronic use of oral macrolides, such as azithromycin, reduces exacerbation risk and improves QoL in patients with persistent COPD exacerbations who are refractory to standard care. (64-66) However, azithromycin was less beneficial in active smokers than nonsmokers and was associated with an increased risk of bacterial resistance. (64,65) Because oral macrolides increase the risk of antimicrobial resistance and need to be closely monitored, they are best managed by specialists.



Different COPD phenotypes may respond differently to treatment. (4,67) Approximately 20% to 40% of patients with COPD have an eosinophilic phenotype; in these patients, biologies such as mepolizumab or benralizumab--monoclonal antibodies against interleukin-5 (IL-5)--may be useful. (56,67) Results of 2 studies using different doses of mepolizumab (100 mg in METREX, 100/300 mg in METREO) in patients with COPD and an eosinophilic phenotype showed that 100 mg mepolizumab significantly reduced the annual rate of moderate-to-severe exacerbation compared with placebo. (58) Two phase III studies of the efficacy and safety of benralizumab in patients with moderate-to-very severe COPD (GALATHEA and TERRANOVA) are ongoing. (68,69) Further studies are needed to understand the role of different biologies in patients with COPD.


Mucolytics, such as carbocysteine and N-acetylcysteine, reduce exacerbations and improve QoL in COPD patients not treated with ICSs. (2,70,71) However, the target population and correct dose and duration to achieve this benefit are not clear. (2) Clinical experience suggests patients who have concomitant chronic bronchitis and have difficulty clearing secretions are the potential target population. In such patients, an alternative approach is devices that enhance mucus clearance, such as a lung flute or Flutter valve. (72)


Several new therapeutic options for COPD have become available in recent years. Moreover, the GOLD report has been updated, emphasizing patient-reported symptoms and exacerbations to allow clinicians to develop treatment plans using the new ABCD tool. Awareness among PCPs of the full spectrum of therapeutic options and respective places in therapy is important for appropriate treatment of patients with COPD and avoiding undertreatment or overprescribing. Most emerging treatments target patients who do not respond to standard care. However, further studies are warranted to understand the role of individualized treatment of patients with COPD.


Dr. Sethi reports grants and personal fees from AstraZeneca and GlaxoSmithKline; and personal fees from Boehringer Ingelheim, Gilead, Aradigm, Bayer, Pulmonx, Cempra, Sunovion, Circassia, CSL Behring, Novavax, and Theravance Biopharma outside the submitted work.

Dr. Dransfield reports grants from the Department of Defense and National Institute of Health; personal fees from AstraZeneca, Genentech, GlaxoSmithKline, and PneumRx/BTG; and contracted clinical trials from AstraZeneca, Boehringer Ingelheim, Boston Scientific, GlaxoSmithKline, Novartis, PneumRx/BTG, Pulmonx, and Yungjin Pharm outside the submitted work.


The authors meet the criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and formatting assistance were provided by Suchita Nath-Sain, PhD, and Maribeth Bogush, MCI, PhD, of Cactus Communications, which was contracted and compensated by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI) for these services. BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.


(1.) Carlin BW, Schuldheisz SK, Noth I, Criner GJ. Individualizing the selection of long-acting bronchodilator therapy for patients with COPD: considerations in primary care. Postgrad Med. 2017;129(7):725-733.

(2.) Global strategy for the diagnosis, management, and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. wp-content/upIoads/2017/ll/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Accessed January 29, 2018.

(3.) Jones R, Ostrem A. Optimising pharmacological maintenance treatment for COPD in primary care. Prim Care Respir J. 2011;20(1):33-45.

(4.) Montuschi P, Malerba M, Santini G, Miravitlles M. Pharmacological treatment of chronic obstructive pulmonary disease: from evidence-based medicine to phenotyping. DrugDiscov Today. 2014;19(12):1928-1935.

(5.) Ejiofor S, Turner AM. Pharmacotherapies for COPD. Clin Med Insights Circ Respir Pulm Med. 2013;7:17-34.

(6.) Barnes PJ. Theophylline. Am J Respir Crit Care Med. 2013;188(8):901-906.

(7.) Vignola AM. PDE4 inhibitors in COPD--a more selective approach to treatment. Respir Med. 2004;98(6):495-503.

(8.) Riley J, Krtiger P. Optimising inhaler technique in chronic obstructive pulmonary disease: a complex issue. Br J Nurs. 2017;26(7):391-397.

(9.) Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II: the role of inhalant delivery devices and drug formulations in therapeutic effectiveness of aerosolized medications. Br I Clin Pharmacol. 2003;56(6):600-612.

(10.) Anderson P. Use of Respimat' Soft Mist[TM] inhaler in COPD patients. Int J Chron Ohstruct Pulmon Dis. 2006;1(3):251-259.

(11.) Vestbo J, Vogelmeier C, Small M, HigginsV Understanding the GOLD 2011 strategy as applied to a real-world COPD population. Respir Med. 2014;108(5):729-736.

(12.) Hoogendoorn M, Feenstra TL, Hoogenveen RT, Al M, Molken MR. Association between lung function and exacerbation frequency in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2010;5:435-444.

(13.) Jones PW. Health status and the spiral of decline. COPD. 2009;6(1):59-63.

(14.) Global strategy for the diagnosis, management and prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. Accessed December 12, 2017.

(15.) Blanchette CM, Gross NJ, Altman P. Rising costs of COPD and the potential for maintenance therapy to slow the trend. Am Health Drug Benefits. 2014;7(2):98-106.

(16.) Diette GB, Dalai AA, D'Souza AO, Lunacsek OE, Nagar SP. Treatment patterns of chronic obstructive pulmonary disease in employed adults in the United States. Int J Chron Obstruct Pulmon Dis. 2015;10:415-422.

(17.) Fitch K, Iwasaki K, Pyenson B, Plauschinat C, Zhang J. Variation in adherence with Global Initiative for Chronic Obstructive Lung Disease (GOLD) drug therapy guidelines: a retrospective actuarial claims data analysis. Curr Med Res Opin. 2011;27(7):1425-1429.

(18.) Barr RG, Celli BR, Martinez FJ, et al. Physician and patient perceptions in COPD: the COPD resource network needs assessment survey. Am J Med. 2005; 118(12): 1415.

(19.) Casaburi R, Duvall K. Improving early-stage diagnosis and management of COPD in primary care. Postgrad Med. 2014;126(4):141-154.

(20.) Decramer ML, Chapman KR, Dahl R, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Lancet Respir Med. 2013;1(7):524-533.

(21.) Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl] Med. 2011;364(12):1093-1103.

(22.) Horita N, Goto A, Shibata Y, et al. Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017;2:CD012066.

(23.) Tariq SM, Thomas EC. Maintenance therapy in COPD: time to phase out ICS and switch to the new LAMA/LABA inhalers? Int J Chron Obstruct Pulmon Dis. 2017;12:1877-1882.

(24.) Roche N, Chapman KR. Vogelmeier CF, et al. Blood eosinophils and response to maintenance chronic obstructive pulmonary disease treatment Data from the FLAME trial. Am J Respir Crit Care Med. 2017; 195(9):1189-1197.

(25.) Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016;374(23):2222-2234.

(26.) Lipson DA, Barnhart F, Brealey N, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med. 2018. doi: 10.1056/NEJMoal713901.

(27.) Cazzola M, Molimard M. The scientific rationale for combining long-acting [[beta].sub.2]-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther. 2010;23(4): 257-267.

(28.) Beeh KM, Derom E, Echave-Sustaeta J, et al. The lung function profile of once-daily tiotropium and olodaterol via Respimat[R] is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler*1 ENERGITO* study. Int J Chron Obstruct Pulmon Dis. 2016;11:193-205.

(29.) Magnussen H, Paggiaro P, Schmidt H, Kesten S, Metzdorf N, Maltais F. Effect of combination treatment on lung volumes and exercise endurance time in COPD. Respir Med. 2012;106(10):1413-1420.

(30.) Hoshino M, Ohtawa J, Akitsu K. Comparison of airway dimensions with once daily tiotropium plus indacaterol versus twice daily Advair[R] in chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2015;30:128-133.

(31.) Singh D, Worsley S, Zhu CQ, Hardaker L, Church A. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial. BMC Pulm Med. 2015,15:91.

(32.) Donohue JF, Worsley S, Zhu C-Q, Hardaker L, Church A. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. Respir Med. 2015;109(7):870-881.

(33.) Vogelmeier C, Paggiaro PL, Dorca J, et al. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study. Eur Respir J. 2016;48(4):10301039.

(34.) Vogelmeier CF, Bateman ED, Pallante J, et al. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Lancet Respir Med. 2013; 1(1):51-60.

(35.) Wedzicha IA, Decramer M, Ficker JH, et al. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med. 2013;1(3):199-209.

(36.) Zhong N, Wang C, Zhou X, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int] Chron Obstruct Pulmon-Dis. 2015;10:1015-1026.

(37.) Vestbo J, Hurd SS, Agusti AG, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013; 187(4):347-365.

(38.) Price D, Miravitlles M, Pavord I, et al. First maintenance therapy for COPD in the UK between 2009 and 2012: a retrospective database analysis. NPJPrim Care Respir Med. 2016;26:16061.

(39.) Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;10(3):CD010115.

(40.) Lee MC, Lee CH, Chien SC, et al. Inhaled corticosteroids increase the risk of pneumonia in patients with chronic obstructive pulmonary disease: a nationwide cohort study. Medicine (Baltimore). 2015;94(42):el723.

(41.) Suissa S, Coulombe J, Ernst P. Discontinuation of inhaled corticosteroids in COPD and the risk reduction of pneumonia. Chest. 2015;148(5):1177-1183.

(42.) Rossi A, van der Molen T, del Olmo R, et al. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD. Eur Respir J. 2014;44(6): 1548-1556.

(43.) Rossi A, Guerriero M, Corrado A; OPTIMO/AIPO Study Group. Withdrawal of inhaled corticosteroids can be safe in COPD patients at low risk of exacerbation: a real-life study on the appropriateness of treatment in moderate COPD patients (OPTIMO). Respir Res. 2014;15:77.

(44.) Magnussen H, Disse B, Rodriguez-Roisin R, et al. Withdrawal of inhaled glucocorticoids and exacerbations of COPD. NEngl J Med. 2014;371(14):1285-1294.

(45.) Calverley PMA, Tetzlaff K, Vogelmeier C, et al. Eosinophilia, frequent exacerbations, and steroid response in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017;196(9):1219-1221.

(46.) Watz H, Tetzlaff K, Wouters EF, et al. Blood eosinophil count and exacerbations in severe chronic obstructive pulmonary disease after withdrawal of inhaled corticosteroids: a post-hoc analysis of the WISDOM trial. Lancet Respir Med. 2016;4(5):390-398.

(47.) Kaplan AG. Applying the wisdom of stepping down inhaled corticosteroids in patients with COPD: a proposed algorithm for clinical practice. Int J Chron Obstruct Pulmon Dis. 2015;10:2535-2548.

(48.) Vedel-Krogh S, Nielsen SF, Lange P, Vestbo I, Nordestgaard BG. Blood eosinophils and exacerbations in chronic obstructive pulmonary disease. The Copenhagen general population study. Am J Respir Crit Care Med. 2016; 193(9):965-974.

(49.) Pavord ID, Lettis S, Locantore N, et al. Blood eosinophils and inhaled corticosteroid/ long-acting (3-2 agonist efficacy in COPD. Thorax. 2016;71(2):118-125.

(50.) Pascoe S, Locantore N, Dransfield MT, et al. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med. 2015;3(6):435-442.

(51.) Singh D, Corradi M, Spinola M, et al. Triple therapy in COPD: new evidence with the extrafine fixed combination of beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide. Int J Chron Obstruct Pulmon Dis. 2017;12:2917-2928.

(52.) Frith PA, Thompson PJ, Ratnavadivel R, et al. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/ fluticasone in patients with COPD: the GLISTEN study, a randomised controlled trial. Thorax. 2015;70(6):519-527.

(53.) Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting [[beta].sub.2]-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet. 2016;388(10048):963-973.

(54.) Vestbo I, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus longacting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet. 2017;389(10082):1919-1929.

(55.) Siler TM, Kerwin E, Sousa AR, Donald A, Ali R, Church A. Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: results of two randomized studies. Respir Med. 2015; 109(9): 1155-1163.

(56.) Sousa AR, Riley IH, Church A, Zhu CQ, Punekar YS, Fahy WA. The effect of umeclidinium added to inhaled corticosteroid/long-acting [[beta].sub.2]-agonist in patients with symptomatic COPD: a randomised, double-blind, parallel-group study. NPJ Prim Care Respir Med. 2016;26:16031.

(57.) Lipson DA, Barnacle H, Birk R, et al. FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2017; 196(4):438-446.

(58.) Pavord ID, Chanez P, Criner GJ, et al. Mepolizumab for eosinophilic chronic obstructive pulmonary disease. NEngl J Med. 2017;377(17):1613-1629.

(59.) Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015;385(9971):857-866.

(60.) Daliresp (roflumilast). Highlights of prescribing information. https://www. Accessed February 8, 2018.

(61.) Fabbri LM, Calverley PM, Izquierdo-Alonso IL, et al. Roflumilast in moderate-tosevere chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703.

(62.) Martinez FJ, Rabe KF, Sethi S, et al. Effect of roflumilast and inhaled corticosteroid/long-acting [[beta].sub.2]-agonist on chronic obstructive pulmonary disease exacerbations (RE(2)SPOND). A randomized clinical trial. Am J Respir Crit Care Med. 2016; 194(5):559-567.

(63.) Rabe KF, Calverley PMA, Martinez FJ, Fabbri LM. Effect of roflumilast in patients with severe COPD and a history of hospitalisation. Eur Respir J. 2017;50(1):1700158.

(64.) Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. NEngl J Med. 2011;365(8):689-698.

(65.) Han MK, Tayob N, Murray S, et al. Predictors of chronic obstructive pulmonary disease exacerbation reduction in response to daily azithromycin therapy. Am J Respir Crit Care Med. 2014;189(12):1503-1508.

(66.) Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2(5):361-368.

(67.) Bel EH, Ten Brinke A. New anti-eosinophil drugs for asthma and COPD: targeting the trait! Chest. 2017;152(6):1276-1282.

(68.) Benralizumab efficacy in moderate to very severe chronic obstructive pulmonary disease (COPD) with exacerbation history (GALATHEA). ct2/show/nct02138916. Accessed December 21, 2017.

(69.) Efficacy and safety of benralizumab in moderate to very severe chronic obstructive pulmonary disease (COPD) with exacerbation history (TERRANOVA). https:// ronic+obstructive%22&rank=3. Accessed December 21, 2017.

(70.) Cazzola M, Calzetta L, Page C, et al. Influence of N-acetylcysteine on chronic bronchitis or COPD exacerbations: a meta-analysis. Eur Respir Rev. 2015;24(137):451-461.

(71.) Poole P, Chong I, Cates CI. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;(7): CD001287.

(72.) Sethi S, Yin I, Anderson PK. Lung flute improves symptoms and health status in COPD with chronic bronchitis: a 26 week randomized controlled trial. Clin Transl Med. 2014;3(29).

Sanjay Sethi, MD, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University at Buffalo, State University of New York, NY

Mark T. Dransfield, MD, Lung Health Center, University of Alabama at Birmingham and Birmingham VA Medical Center, Birmingham, AL

Caption: FIGURE Mechanism of action of the common pharmacologic agents for COPD
TABLE Examples of commonly used maintenance medications

Drug(s)                        Brand examples (meg)

Arformoterol                   Brovana (15 mcg/2 mL)
Formoterol                     Perforomist (20 mcg/2 mL)
Formoterol                     Foradil
Indacaterol                    Arcapta (75)
Olodaterol                     Striverdi (2.5)
Salmeterol                     Serevent (50)

Aclidinium                     Tudorza (400)
Glycopyrronium                 Seebri (15.6)
Glycopyrronium                 Lonhala (25 mcg/1 mL)
Tiotropium                     Spiriva (18/2.5)

Umeclidinium                   Incruse (62.5)

Combination of LABA and LAMA
Glycopyrronium/formoterol      Bevespi (9/4.8)
Indacaterol/glycopyrronium     Utibron (27.5/15.6)
Tiotropium/olodaterol          Stiolto (2.5/2.5)
Umeclidinium/vilanterol        Anoro (62.5/25)

Combination of LABA and ICS
Budesonide/formoterol          Symbicort (160/4.5)
Fluticasone/salmeterol         Advair (250/50)
Fluticasone/vilanterol         Breo (100/25)

Combination of LABA, LAMA,
and ICS
Fluticasone/umeclidinium/      Trelegy 100/62.5/25

Drug(s)                        Inhaler               Duration of
                                                     action (hours)
Arformoterol                   Nebulizer             12
Formoterol                     Nebulizer             12
Formoterol                     Aerolizer (DPI)       12
Indacaterol                    Neohaler (DPI)        24
Olodaterol                     Respimat (SMI)        24
Salmeterol                     Diskus (MDI)          12

Aclidinium                     Pressair (DPI, MDI)   12
Glycopyrronium                 Neohaler (DPI)        12-24
Glycopyrronium                 Magnair nebulizer     24
Tiotropium                     HandiHaler (DPI);     24
                               Respimat (SMI)
Umeclidinium                   Ellipta (DPI)         24

Combination of LABA and LAMA
Glycopyrronium/formoterol      Aerosphere (pMDI)     12
Indacaterol/glycopyrronium     Neohaler (DPI)        12-24
Tiotropium/olodaterol          Respimat (SMI)        24
Umeclidinium/vilanterol        Ellipta (DPI)         24

Combination of LABA and ICS
Budesonide/formoterol          pMDI                  --
Fluticasone/salmeterol         Diskus (DPI)          --
Fluticasone/vilanterol         Ellipta (DPI)         --

Combination of LABA, LAMA,
and ICS
Fluticasone/umeclidinium/      Ellipta (DPI)

Abbreviations: DPI, dry powder inhaler; ICS, inhaled
corticosteroid; LABA, long-acting fe-agonist; LAMA, long-acting
muscarinic antagonist; MDI, metered-dose inhaler; pMDI, pressurized
metered-dose inhaler; SMI, slow-mist inhaler. Source: GOLD 20182
and prescribing information of the respective drugs.
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Article Details
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Title Annotation:chronic obstructive pulmonary disease
Author:Sethi, Sanjay; Dransfield, Mark T.
Publication:Journal of Family Practice
Article Type:Report
Geographic Code:1USA
Date:Oct 1, 2018
Previous Article:COPD Management in the Primary Care Setting.
Next Article:Optimizing Adherence to Improve Clinical Outcomes in Patients with Chronic Obstructive Pulmonary Disease.

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