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)
CHANGES IN COPD GUIDELINES
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.
CURRENT STATUS OF COPD TREATMENT
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)
APPLYING GOLD RECOMMENDATIONS IN PRIMARY CARE
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)
WITHDRAWAL OF ICS
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.
APPROPRIATE USE OF ICS/LABA
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)
APPROPRIATE USE OF TRIPLE THERAPY (LABA/LAMA/ICS)
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.
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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 in COPD Drug(s) Brand examples (meg) LABA Arformoterol Brovana (15 mcg/2 mL) Formoterol Perforomist (20 mcg/2 mL) Formoterol Foradil Indacaterol Arcapta (75) Olodaterol Striverdi (2.5) Salmeterol Serevent (50) LAMA 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 vilanterol Drug(s) Inhaler Duration of action (hours) LABA Arformoterol Nebulizer 12 Formoterol Nebulizer 12 Formoterol Aerolizer (DPI) 12 Indacaterol Neohaler (DPI) 24 Olodaterol Respimat (SMI) 24 Salmeterol Diskus (MDI) 12 LAMA 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) vilanterol 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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|Title Annotation:||chronic obstructive pulmonary disease|
|Author:||Sethi, Sanjay; Dransfield, Mark T.|
|Publication:||Journal of Family Practice|
|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.|