Role of Long-Acting Muscarinic Antagonist/Long-Acting β 2 -Agonist Therapy in Chronic Obstructive Pulmonary Disease

705149AOPXXX10.1177/1060028017705149Annals of PharmacotherapyPetite review-article2017 Review Article Role of Long-Acting Muscarinic Antagonist/Long-Acting β 2 -Agonist Therapy in Chronic Obstructive Pulmonary Disease Annals of Pharmacotherapy 1 10 The Author(s) 2017 Reprints and permissions: sagepub.com/journalspermissions.nav https://doi.org/10.1177/1060028017705149 DOI: journals.sagepub.com/home/aop Sarah E. Petite, PharmD, BCPS 1 Abstract Objective: To compare the available literature regarding the use of long-acting muscarinic antagonist (LAMA)/longacting β 2 agonists (LABA) and inhaled corticosteroid (ICS)/LABA combination inhaler therapy in chronic obstructive pulmonary disease (COPD) maintenance therapy management. Data Sources: A MEDLINE literature search from database inception to February 2017 was conducted using the search terms chronic obstructive pulmonary disease, adrenergic beta-agonist, muscarinic antagonist, and inhaled corticosteroid. References from extracted sources were further searched for any relevant, missed data sources. Study Selection and Data Extraction: All English-language randomizedcontrolled trials comparing LAMA/LABA and ICS/LABA combination inhaler therapy were evaluated. Data Synthesis: A total of 10 randomized controlled trials have reviewed the use of LAMA/LABA compared with ICS/LABA therapy for COPD maintenance therapy. Results of clinical trials that evaluated LAMA/LABA and ICS/LABA maintenance therapy demonstrated superior improvements in pulmonary function tests via spirometry and improved clinical outcomes with LAMA/LABA therapy, specifically reduction in COPD exacerbation rates. The safety of LAMA/LABA combination therapy also is favorable compared with ICS/LABA combination therapy because of the increased infection risk with ICS therapy. Conclusions: COPD is a disease state with significant morbidity and mortality in the United States and is the third leading cause of death. Long-acting inhalers are recommended for the majority of COPD severities, and combination therapy is typically utilized. LAMA/LABA combination therapy has demonstrated superior improvements in pulmonary function and reduction in COPD exacerbation rates compared with ICS/LABA. LAMA/LABA combination therapy will have a larger future role in COPD maintenance management. Keywords chronic obstructive pulmonary disease, β 2 -adrenergic agonists, inhalers, corticosteroids, inhaled, bronchodilators Introduction Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States. 1 The disease state is characterized by a chronic airflow limitation and inflammation; therefore, inhaled bronchodilators and corticosteroids are frequently utilized medication therapies. 2 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines provide recommendations for COPD maintenance therapy based on COPD severity. 2 Measurement of forced expiratory volume over 1 s (FEV 1 ) is recommended via spirometry to grade the severity of airflow limitation. However, treatment options are chosen primarily based on exacerbation history and symptom assessment (Table 1). Combination inhaler therapy is recommended first line for patients with the presence of symptoms and at least 2 COPD exacerbations or 1 exacerbation requiring hospitalization in the past year (GOLD group D). Patients without significant symptoms but with the above exacerbation history are recommended to receive combination therapy if they have further exacerbations (GOLD group C). Patients without a significant exacerbation history but with persistent symptoms on monotherapy are also eligible for combination therapy (Gold group B). In all groups, the preferred combination therapy is a longacting muscarinic antagonist (LAMA)/long-acting β 2 agonist (LABA). 1 University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH, USA Corresponding Author: Sarah E. Petite, Department of Pharmacy Practice, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43614, USA. Email: sarah.petite@utoledo.edu

2 Annals of Pharmacotherapy 00(0) Table 1. COPD Severity Classifications. GOLD Group Exacerbation History Symptom Assessment Group A 1 Not requiring hospitalization mmrc 1; CAT < 10 Group B 1 Not requiring hospitalization mmrc 2; CAT 10 Group C 2, Or 1 requiring hospitalization mmrc 1; CAT < 10 Group D 2, Or 1 requiring hospitalization mmrc 2; CAT 10 Abbreviations: COPD, Chronic Obstructive Pulmonary Disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; mmrc, Modified Medical Research Council; CAT, COPD Assessment Test. In addition to LAMA and LABA agents, other available maintenance inhaled medication therapy options for COPD include inhaled corticosteroids (ICS). 2 Adherence to inhaler therapy is generally suboptimal, with less than 50% of patients estimated to be adherent to prescribed therapy. 3,4 One method to improve adherence is the use of combination inhalers, an approach that has reduced the risk of hospitalization and emergency department visits with short-acting bronchodilators. 5 The combination of ICS/LABA has been available in the United States for more than a decade; however, the combination of LAMA/LABA was not first available until December 2013, with the Food and Drug Administration approval of umeclidinium/vilanterol. 6 There are limited data available in the United States on prescribing rates of these maintenance medications. A cross-sectional study found that prescribing rates for maintenance medications are increasing in the United States. 7 In 2010, the prescription rates were approximately 28%, 31%, and 17% for LABA, ICS, and LAMA therapy, respectively. In clinical practice, LAMA/LABA combination therapy is infrequently used compared with ICS/LABA therapy. 8 These data suggest that overall prescribing rates of LAMA maintenance therapy are lower than those of other COPD medication options. The focus of this review is an evaluation of combination bronchodilator therapy with a LAMA and LABA compared with combination therapy with an ICS and LABA and to explore the future role of this combination therapy in COPD maintenance treatment. Pharmacologic Rationale for Maintenance Inhaler Therapy in COPD Because of the inflammatory state associated with COPD, an ICS is often used in maintenance therapy regimens. 9 In asthma, the evidence for ICS therapy is more well-established because of a greater understanding of the predominant inflammatory mediator involved eosinophils. 10 Elevated eosinophil count at baseline may predict response to ICS therapy in COPD, with better treatment response associated with higher eosinophil counts. 11 These patients may also be at a greater exacerbation risk. 12 With the exception of very severe COPD where eosinophils have a larger role, macrophages are the major inflammatory mediator involved with COPD, and ICS therapy is less effective against these cells. 10 There are several proposed mechanisms supporting the use of dual bronchodilator therapy in COPD. Because of the differences in mechanism of action, administering 2 bronchodilators may overcome patient-specific differences in treatment responses. 13 There may also be differences in sympathetic and parasympathetic activity throughout the day, leading to increased LABA effectiveness during times of sympathetic activity and similar findings with a LAMA during increased parasympathetic activity. 14 Additionally, there are differences in receptor distribution in the lungs. 15 The muscarinic subtype 3 receptor is distributed primarily in the bronchus and is not present in the lung parenchyma. The β 2 receptors are predominantly in the subsegmental bronchus and lung parenchyma. The differences in receptor distribution throughout the lungs contribute to an enhanced bronchodilation with combination therapy compared with monotherapy with either agent. 16 Literature Review A literature search of the MEDLINE database was conducted from database inception to February 28, 2017, to include studies evaluating LAMA/LABA and ICS/LABA combination therapy in COPD. Utilized search terms included chronic obstructive pulmonary disease, adrenergic beta-agonist, muscarinic antagonist, and inhaled corticosteroid. Results were limited to articles available in English. References from extracted sources were further searched for any relevant, missed data sources. All observational and randomized clinical trial data comparing LAMA/LABA and ICS/LABA combination therapy in COPD patients were eligible for inclusion in this review. A total of 192 studies were identified; 183 studies were excluded after further review (Figure 1). A total of 10 randomized controlled trials from 9 articles were included in this review. A summary of study design and pertinent outcomes is provided in Table 2. Clinical Trials Four distinct LAMA medication therapies have been evaluated in combination with a LABA agent. The majority of the studies evaluating these combination therapies utilized changes in pulmonary function as the primary end point. Whereas it has been established that a change in trough

Petite 3 Figure 1. Literature search. FEV 1 from baseline of at least 100 ml may lead to clinically significant outcomes, the implication on patient outcomes of other pulmonary function assessments performed in the following studies is unknown. 17,18 Clinically significant changes in quality-of-life assessments have also been established. A difference of 4 units with the St George s Respiratory Questionnaire (SGRQ) is considered clinically significant. 17 A difference of 2 points with the COPD Assessment Test (CAT) is clinically relevant. 19 A review of available evidence and the impact of the study findings on patient outcomes for each of these LAMA agents in combination with a LABA compared with an ICS/LABA is provided in the remainder of this article. Tiotropium A comparison between LAMA/LABA and ICS/LABA therapy was first characterized in 2008 by Rabe et al. 20 A 6-week study evaluating tiotropium/formoterol and fluticasone/ salmeterol was conducted in patients with predominantly moderate COPD. The impact of the studied interventions on pulmonary function tests were the predominant end points evaluated. Significant improvements in pulmonary function were demonstrated with tiotropium/formoterol compared with fluticasone/salmeterol. However, the correlation of the studied primary end point, FEV 1 area under the curve over 0 to 12 hours (AUC 0-12 ), with clinical outcomes has not been established. Another small study was conducted by Hoshino et al 21 comparing tiotropium/indacaterol with fluticasone/salmeterol. The primary study outcome was the study medication s effect on airway dimensions, measured using computed tomography scan. Unlike the previous study, other clinical outcomes were assessed in this analysis, including quality of life with the SGRQ. A total of 43 patients with moderate COPD, without a history of exacerbations, were analyzed. For the primary outcome, lung luminal area and total area of the airway were significantly

Table 2. Included Studies. 20-22,24-29 Study Design and Duration Treatment Arms (n) Key / Criteria Study Outcomes (LAMA/LABA vs ICS/LABA Unless Otherwise Specified) Rabe et al, 2008 20 R, DB; 6 weeks Tiotropium 18 µg daily/ Formoterol 12 µg bid (297) Fluticasone 500 µg/salmeterol 50 µg bid (295) Hoshino et al, 2015 21 R, open label; 16 weeks Tiotropium 18 µg/indacaterol 150 µg once daily (22) Magnussen et al, R, crossover; 16 weeks 2012 22 (8 weeks each) Fluticasone 250 µg/salmeterol 50 µg bid (21) Tiotropium 18 µg daily/ Salmeterol 50 µg bid (160) Fluticasone 500 µg/salmeterol 50 µg bid (157) Singh et al, 2015 25 R, DB, DD; 12 weeks Umeclidinium 62.5 µg/ Vilanterol 25 µg once daily (334) Fluticasone 500 µg/salmeterol 50 µg bid (340) Donohue et al, 2015 24 R, DB, DD; 12 weeks Umeclidinium 62.5 µg/ Vilanterol 25 µg once daily (353) Fluticasone 250 µg/salmeterol 50 µg bid (353) 40 Years 10 Pack-year history FEV 1 /FVC <70% FEV 1 <80% Oral steroids in past 6 weeks Comorbid conditions 40 Years 10 Pack-year history FEV 1 /FVC < 0.7 FEV 1 30%-80% Comorbid conditions AECOPD requiring medication therapy 40-75 Years 10 Pack-year history TGV 120% predicted FEV 1 65% Comorbid conditions 40 Years 10 Pack-year history FEV 1 /FVC 30%-70% mmrc 2 AECOPD in previous 12 months 40 Years mmrc 2 FEV 1 /FVC 30%-70% AECOPD in previous 12 months FEV 1 AUC 0-12h 1.64 ± 0.02 L vs 1.56 ± 0.02 L (P = 0.0006) Peak FEV 1 1.78 ± 0.02 L vs 1.67 ± 0.02 L (P < 0.0001) Effect on CT-measured airway dimensions: lung luminal area and total airway area significantly improved with tiotropium/indacaterol (P < 0.01) FEV 1 improvement from baseline 214.2 ± 12.3 ml vs 198.4 ± 16.5 ml (P = 0.362) Total SGRQ scores (P = 0.044) Postdose TGV improvement with tiotropium/salmeterol 182 ± 44 ml at 4 weeks (P < 0.0001); 87 ± 44 ml at 8 weeks (P < 0.05) Trough FEV 1 mean treatment difference at 8 weeks 36 ± 14 ml (P = 0.0115) EET improvements with tiotropium/salmeterol 20 ± 15 s at 4 weeks and 15 ± 13 s at 8 weeks (P = NS) Mean FEV 1 over 0 to 24 hours change from baseline LSM 0.166 L (SE = 0.0122) vs LSM 0.087 L (SE = 0.0121), P < 0.001 Trough FEV 1 on day 85 change from baseline LSM 0.151 L (SE = 0.0126) vs LSM 0.062 L (SE = 0.0125), P < 0.001 SGRQ total change from baseline LSM 5.1 (SE = 0.626) vs LSM 5.64 (SE = 0.619), P = 0.545 Rescue SABA use (mean number of uses/day) LSM 1.3 (SE = 0.08) vs LSM 1.4 (SE = 0.08), P = 0.559 Weighted mean FEV 1 over 0 to 24 hours at day 84 treatment difference 74 ml (95% CI = 38-100), P < 0.001 Trough FEV 1 change from baseline LSM 0.154 L (SE = 0.0133) vs LSM 0.072 L (SE = 0.0134); treatment difference 0.082 (95% CI = 0.045-0.119), P < 0.001 SGRQ total score, change from baseline LSM 6.33 (SE = 0.658) vs LSM 6.79 (SE = 0.655); treatment difference 0.47 (95% CI = 1.36 to 2.29), P = 0.616 Rescue medication use, change from baseline LSM 1.4 (SE = 0.08) vs LSM 1.3 (SE = 0.08); treatment difference 0 (95% CI = 0.3 to 0.2), P = 0.689 (continued) 4

Table 2. (continued) Study Design and Duration Treatment Arms (n) Key / Criteria Study Outcomes (LAMA/LABA vs ICS/LABA Unless Otherwise Specified) Donohue et al, 2015 24 R, DB, DD; 12 weeks Umeclidinium 62.5 µg/ Vilanterol 25 µg once daily (349) Fluticasone 250 µg/salmeterol 50 µg bid (348) Vogelmeier et al, R, DB, DD; 24 weeks Aclidinium 400 µg/formoterol 2016 26 12 µg bid (467) Fluticasone 500 µg/salmeterol 50 µg bid (466) Vogelmeier et al, R, DB, DD; 26 weeks Glycopyrronium 50 µg/ 2013 27 Indacaterol 110 µg daily (259) Fluticasone 500 µg/salmeterol 50 µg bid (264) Zhong et al, 2015 29 R, DB, DD; 26 weeks Glycopyrronium 50 µg/ Indacaterol 110 µg daily (372) Fluticasone 500 µg/salmeterol 50 µg bid (369) Wedzicha et al, R, DB, DD; 52 weeks Glycopyrronium 50 µg/ 2016 28 Indacaterol 110 µg once daily (1680) Fluticasone 500 µg/salmeterol 50 µg bid (1682) 40 Years mmrc 2 FEV 1 /FVC 30%-70% AECOPD in previous 12 months 40 Years 10 Pack-year history CAT 10 FEV 1 /FVC <0.7 FEV 1 <80% AECOPD in previous 6 months 40 Years 10 Pack-year history FEV 1 40%-80% FEV 1 /FVC <0.7 AECOPD in previous year 40 Years 10 Pack-year history FEV 1 30%-80% FEV 1 /FVC <0.7 mmrc 2 >1 AECOPD in previous year 40 Years mmrc 2 FEV 1 25%-60% FEV 1 /FVC <0.7 AECOPD within past year Weighted mean FEV 1 over 0 to 24 hours at day 84 treatment difference 101 ml (95% CI = 63-139), P < 0.001 Trough FEV 1 change from baseline LSM 0.185 L (SE = 0.0138) vs LSM 0.087 L (SE = 0.014); treatment difference 0.098 (95% CI = 0.059-0.137), P < 0.001 SGRQ total score, change from baseline LSM 7.23 (SE = 0.742) vs LSM 5.67 (SE = 0.752); treatment difference 1.55 (95% CI = 3.63 to 0.53), P = 0.143 Rescue medication use, change from baseline LSM 1.6 (SE = 0.08) vs LSM 1.3 (SE = 0.08); treatment difference 0.3 (95% CI 0.6 to 0.1), P = 0.006 Peak FEV 1 improvement 93 ml greater with aclidinium/formoterol (P < 0.0001) CAT improved 2 units in both groups (P = NS) Trough FEV 1 1.405 L vs 1.419 L (P = 0.3635) AECOPD 15.8% vs 16.6% (P = NS) FEV 1 AUC 0-12h LSM 1.695 L (SE = 0.027) vs LSM 1.557 L (SE = 0.026), P < 0.0001 Trough FEV 1 LSM 1.6 L (SE = 0.023) vs LSM 1.498 L (SE = 0.025), P < 0.001 Change from baseline rescue medication use LSM 0.39 (95% CI = 0.71 to 0.06), P = 0.019 SGRQ difference LSM 1.24 (95% CI = 3.33 to 0.85), P = 0.25 Trough FEV 1 LSM 1.26 L (SE = 0.017) vs LSM 1.18 L (SE = 0.017), P < 0.001 Annual AECOPD rate 0.3 vs 0.46 (P < 0.05) SGRQ change from baseline LSM 31.74 (SE = 1.136) vs LSM 32.43 (SE = 1.130), LSM 0.69 (95% CI = 2.38 to 1) CAT total score LSM 11.1 (SE = 0.46) vs LSM 11.2 (SE = 0.46), LSM 0.2 (95% CI = 0.9 to 0.6) AECOPD rate 3.59 vs 4.03 (rate ratio = 0.89 [95% CI = 0.83-0.96]; P = 0.003) Time to first exacerbation 71 days vs 51 days (HR = 0.84 [95% CI = 0.78-0.91]; P < 0.001) SGRQ decrease 4 points 49.2% vs 43.7% (P < 0.001) Trough FEV 1 difference 62 ml (P < 0.001) Abbreviations: AECOPD, acute exacerbation of chronic obstructive pulmonary disease; AUC, area under the curve; CAT, chronic obstructive pulmonary disease assessment test; CT, computed tomography; DB, doubleblind; DD, double-dummy; EET, exercise endurance time; FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, hazard ratio; ICS, inhaled corticosteroid; LABA, long-acting β 2 -agonist; LAMA, long-acting muscarinic-antagonist; LSM, least-squares mean; mmrc, Modified Medical Research Council; R, randomized; SABA, short-acting β 2 -agonist; SE, standard error; SGRQ, St George s Respiratory Questionnaire; TGV, thoracic gas volume. 5

6 Annals of Pharmacotherapy 00(0) improved in the tiotropium/indacaterol group compared with the fluticasone/salmeterol group (P < 0.01). SGRQ scores were also significantly improved in the tiotropium/ indacaterol group in the impact (P = 0.025) and total (P = 0.044) categories of the score; however, actual score results were not reported. The investigators concluded that tiotropium/indacaterol had a significant morphological and physiological benefit compared with fluticasone/salmeterol in a small patient cohort. Similar to the previous tiotropium study, there is no guidance on the clinical significance of this study s primary outcome; therefore, the clinical significance is unknown. A randomized, crossover study was conducted in 309 patients with severe COPD to evaluate fluticasone/salmeterol and tiotropium/salmeterol and the primary end point of improvement in thoracic gas volume. 22 This is defined as the absolute volume of gas in the thorax at any point of time with any alveolar pressure and is often altered in patients with lung disease, specifically hyperinflated. 23 Assessment of pulmonary function was the predominant end point assessed in this study. 22 Lung hyperinflation had a significantly greater reduction for patients when receiving tiotropium/salmeterol of 182 ± 44 ml at 4 weeks (P < 0.0001) and 87 ± 44 ml at 8 weeks (P < 0.05). There were no significant differences in exercise endurance time at 8 weeks when receiving tiotropium/salmeterol compared with fluticasone/salmeterol. Trough FEV 1 was also assessed, but a clinically significant difference between treatment groups was not observed. This study demonstrated that tiotropium/ salmeterol had a significant impact on the reduction of lung hyperinflation compared with fluticasone/salmeterol. Overall, the 3 studies evaluating tiotropium in combination with a LABA all utilized primary end points without evidence correlating the findings to patient outcomes. Umeclidinium Umeclidinium, in combination with vilanterol, has been compared with an ICS/LABA therapy in 3 clinical trials. 24,25 Umeclidinium/vilanterol and fluticasone/salmeterol were compared in a 12 week clinical trial by Singh et al. 25 The eligible patient population for study inclusion was at a lower risk of COPD complications because of the exclusion criteria of documented COPD exacerbation. However, included patients had a modified Medical Research Council (mmrc) Dyspnea Scale score 2, indicating symptomatic COPD. The primary end point was change from baseline in weighted mean FEV 1 over 0 to 24 hours on day 84 of treatment. Other pulmonary tests were assessed, including trough FEV 1 and quality of life with the SGRQ. GOLD group B was the most prevalent in each group: 54% umeclidinium/vilanterol- versus 56% fluticasone/salmeteroltreated patients. The primary study end point of weighted mean FEV 1 change was significantly improved in the umeclidinium/vilanterol treatment group. Day 85 trough FEV 1 was also significantly improved in the umeclidinium/ vilanterol group compared with the fluticasone/salmeterol group and approached a difference of nearly 100 ml, a potential clinically significant outcome. An improvement of 4 units was observed with the SGRQ in both treatment groups, but no significant differences were noted between medications. The authors concluded that umeclidinium/ vilanterol significantly improved pulmonary function compared with fluticasone/salmeterol over a 12-week period in patients with moderate COPD. Two multicenter, double-blind, double-dummy studies evaluated umeclidinium/vilanterol versus fluticasone/salmeterol. 24 criteria were similar to the previous umeclidinium/vilanterol study, with included patients having a mmrc Dyspnea Scale score 2 and no history of a COPD exacerbation in the past year requiring medication therapy and/or hospitalization. The primary study end point was 0 to 24 hours weighted mean FEV 1 at day 84 of the study. study end points included trough FEV 1 at day 85 and quality-of-life assessment with the SGRQ and CAT. COPD severity types were split evenly between each treatment arm in each study between moderate or severe COPD. The primary end point of 0 to 24 hours weighted mean FEV 1 at day 84 was significantly improved in the umeclidinium/vilanterol groups in both studies. For the secondary end point, trough FEV 1 was significantly improved for patients receiving umeclidinium/vilanterol in study 1 (82 ml [95% CI = 45-119]; P < 0.001) and study 2 (98 ml [95% CI = 59-137]; P < 0.001). The SGRQ had no significant differences between treatment arms in each study, with the exception of day 28 in study 2, and favored umeclidinium/vilanterol (treatment difference = 1.95; P = 0.026). CAT scores were assessed in this study, but comparisons between treatment groups were not reported. There was a 2-point improvement in each treatment group from baseline. These studies demonstrated that umeclidinium/ vilanterol treatment resulted in significant improvements in lung function via spirometry compared with fluticasone/salmeterol. Neither study demonstrated a potential clinically significant improvement in trough FEV 1. Study 2 approached the suggested 100-mL improvement and may have contributed to a statistically significant improvement in SGRQ scores. Overall, the studies evaluating umeclidinium assessed clinical outcomes, including quality of life, but clinically significant outcomes were not found in pulmonary function tests in the 3 studies. Aclidinium One study has characterized the use of a LAMA/LABA combination of aclidinium/formoterol versus fluticasone/ salmeterol. 26 Vogelmeier et al 26 evaluated patients with moderate to severe COPD with no COPD exacerbation

Petite 7 within the previous 6 months and a CAT score 10 at baseline, demonstrating symptomatic COPD. The primary study end point was peak FEV 1 at week 24. The majority of patients included in the study were GOLD group B with 56.5% and 55.2% of aclidinium/formoterol- and fluticasone/salmeterol-treated patients, respectively. Approximately one-third of included patients experienced a COPD exacerbation in the previous year. Peak FEV 1 was significantly improved in aclidinium/formoterol-treated patients; however, trough FEV 1 was not different between groups. Other clinical outcomes including CAT, COPD exacerbation rates and rescue medication use were not significantly different between groups. This study demonstrated a superior improvement in the primary study end point, but clinical outcomes were similar, regardless of treatment group. Glycopyrronium Three studies have evaluated glycopyrronium in combination with indacaterol compared with ICS/LABA therapy. 27-29 The use of glycopyrronium/indacaterol compared with fluticasone/salmeterol was first evaluated by Vogelmeier et al. 27 Patients with moderate to severe COPD with no history of a COPD exacerbation in the previous year were eligible for inclusion. The primary study end point was FEV 1 AUC 0-12h at week 26. In all, 80% of patients were classified as having moderate COPD based on spirometry assessment. Overall, glycopyrronium/indacaterol demonstrated significant improvements in pulmonary function compared with fluticasone/salmeterol in patients with moderate to severe COPD. The clinical relevance of the primary outcome difference is unknown; however, the difference observed in trough FEV 1, a secondary outcome, was greater than 100 ml and is clinically significant. A statistically, but not clinically, significant difference was found with rescue medication use. The difference in SGRQ total scores was also not significantly different between groups. Zhong et al 29 conducted a study evaluating glycopyrronium/indacaterol in a higher-risk patient population than in the previous study. In the present study, patients could have no greater than 1 COPD exacerbation requiring medical treatment in the past year, but the majority of included patients had no history of a COPD exacerbation requiring medication therapy. GOLD group B was the most common COPD severity in 51.9% and 53.1% of glycopyrronium/indacaterol- and fluticasone/salmeterol-treated patients, respectively. Trough FEV 1 demonstrated noninferiority and superiority favoring glycopyrronium/indacaterol, but a clinically significant difference of 100 ml was not found between treatment groups. The annual rate of COPD exacerbations was lower in the glycopyrronium/ indacaterol group (0.3) when compared with the fluticasone/salmeterol group (0.46); P < 0.05. Changes in quality of life were not significantly different between treatment groups. This study was one of the first to allow patients with a previous history of COPD exacerbations to be included and was the first study to demonstrate a potential decrease in the rate of COPD exacerbations compared with fluticasone/salmeterol. The largest clinical outcome study for glycopyrronium/indacaterol was a randomized, double-blind, double-dummy, noninferiority study conducted by Wedzicha et al. 28 This was the only study to require patients to have a history of at least 1 COPD exacerbation in the past year. Additionally, this was the first study to utilize a clinical end point, COPD exacerbation annual rate, as the primary study outcome. A total of 3362 patients underwent randomization: 1680 in the glycopyrronium/indacaterol group and 1682 in the fluticasone/salmeterol group. The majority of patients in each group were GOLD group D COPD severity (75.3% vs 74.3%). The primary end point of annual rate of all COPD exacerbations demonstrated noninferiority and superiority for glycopyrronium/indacaterol (3.59) versus fluticasone/salmeterol (4.03): rate ratio = 0.89 (95% CI = 0.83-0.96); P = 0.003. Time to first exacerbation was longer in the glycopyrronium/indacaterol patients by 20 days, and the annual rate of moderate to severe COPD exacerbations was lower in the glycopyrronium/indacaterol patients compared with the fluticasone/salmeterol patients (0.98 vs 1.19; rate ratio = 0.83 [95% CI 0.75-0.91]; P < 0.001). Quality-of-life assessment with the SGRQ total scores had a clinically relevant difference of greater than 4 points between treatment groups. The difference in trough FEV 1 was less than 100 ml between treatment groups. This study demonstrated several clinically relevant outcomes with the use of glycopyrronium/indacaterol versus fluticasone/salmeterol in a high-disease-severity patient cohort, without finding a significant difference between lung function tests. The reviewed studies for LAMA/LABA therapy compared with ICS/LABA demonstrated improvements in the primary study end point, which were predominantly pulmonary function tests, with the exception of the study by Wedzicha et al. 28 Important considerations with each of the studies were the included patient population and study durations. With the exception of 2 glycopyrronium/indacaterol studies, patients with a recent history of COPD exacerbation were excluded from study participation. Moderate COPD was the most frequently included COPD severity in the studies, and higher disease severity was frequently excluded, with the exception of the large GOLD group D patient population included in the Wedzicha trial. All available studies are 1 year or less in duration, limiting applicability to prolonged durations of medication therapy.

8 Annals of Pharmacotherapy 00(0) Dosing and Administration Each of the 4 commercially available LAMA/LABA inhalers in the United States (umeclidinium/vilanterol, glycopyrrolate/formoterol, tiotropium/olodaterol, glycopyrrolate/indacaterol) have 1 fixed-dose regimen available. 6,30-32 Umeclidinium/vilanterol is the only available inhaler that requires 1 inhalation, once daily. 6 All other inhalers require either 2 actuations in order to achieve 1 dose or multiple doses per day. 30-32 This may present an adherence issue for patients, and a pharmacist on dispensing of these medications should perform appropriate counseling. Of note, glycopyrronium was assessed in a series of 3 studies. 27-29 The dosage form utilized in these studies was a once-daily formulation with glycopyrronium/indacaterol. In the United States, the medication is available as glycopyrrolate/indacaterol as a twice-daily formulation. 32 Both components of the inhaler are only available in the United States as a lower dosage than what was studied, in part because of differences in approved strengths of indacaterol. 33 Glycopyrronium/indacaterol is available as the studied dosage form in Europe. Safety Considerations The 4 currently available LAMA/LABA combination products all have precautions for worsening of narrow-angle glaucoma and urinary retention as a result of administration of a muscarinic antagonist. 6,30-32 However, the incidence of these effects are low and not observed in clinical trials evaluating these inhalers. An increased incidence of morbidity and mortality from cardiovascular causes was initially a concern with tiotropium, but the available evidence does not indicate an increased incidence of cardiovascular outcomes in patients without significant cardiac comorbidites. 34 Increased cardiovascular risk is also a precaution with these medications because of the LABA component; however, there are inconsistent data regarding this warning. 35 The safety of LAMA/LABA therapy in patients with significant cardiac comorbidities has not been extensively studied. The product information for the 4 available agents report that the most common adverse events observed in clinical trials are cough (3.6%-4%) and nasopharyngitis (2%- 12.4%). 6,30-32 These findings were also confirmed in the aforementioned studies at similar incidence rates. 20-22,24-29 In contrast, an increased rate of pneumonia was observed with ICS/LABA combination therapy when compared with LAMA/LABA combination therapy. 28 This finding was found to be numerically higher in the Zhong et al 29 study (1.1% vs 0.5%) and statistically significant in the study by Wedzicha et al (3.2% vs 4.8%; P = 0.02). 28,29 Previous studies in COPD patients receiving ICS/LABA therapy consistently found an increased risk of pneumonia associated with ICS therapy. 36 Place in Therapy In the reviewed studies, LAMA/LABA combination therapy demonstrated significant improvements in pulmonary function tests compared to ICS/LABA. The clinical significance of evaluated pulmonary function tests is not well defined for all outcomes. LAMA/LABA combination therapy reduces the rate of COPD exacerbations; however, this has only been demonstrated with glycopyrronium/indacaterol. Many studies evaluating pulmonary function outcomes that compared these combination medication therapies excluded patients with a recent history of COPD exacerbation, limiting the applicability to the entire COPD population. However, the glycopyrronium/indacaterol studies evaluating clinical outcomes permitted recent COPD exacerbations in their inclusion criteria. 28,29 Additionally, nearly all patients assessed in these studies had either moderate to severe COPD, limiting the ability to extrapolate study results to patients with very severe COPD. Although the GOLD guidelines recommend a LAMA/LABA as initial therapy in group D patients, this patient population was frequently excluded from the reviewed studies. Inhaler combinations that have been evaluated in these studies are not uniformly available in the United States. Another consideration is the differences in available doses in the United States for glycopyrrolate and indacaterol. Further research needs to be conducted to determine if the clinically significant reductions in COPD exacerbation rate is maintained at lower doses of these medications than what has previously been studied. There are no studies available comparing the available LAMA/LABA combination products; however, a meta-analysis found similar efficacy and safety with the 4 commercially available products in the United States. 37 All combination long-acting inhalers in COPD have a significant cost associated with them. The LAMA/LABA combination inhaler with clinical outcome data, glycopyrrolate/ indacaterol, is approximately $360 for 1 inhaler. 38 All commercially available LAMA/LABA combination products in the United States have a similar cost. This is also similar to the cost of a fluticasone/salmeterol inhaler ($400). Reduction in exacerbation rate and mortality are outcomes that affect pharmacoeconomic analyses of COPD medications. 39 The potential reduction in rate of COPD exacerbations may provide the evidence needed to recommend a LAMA/LABA combination therapy over an ICS/LABA because of the overall health care cost savings. However, the cost savings associated with LAMA/LABA combination therapy is currently inconclusive in pharmacoeconomic analyses. The role of ICS therapy in COPD should be reserved for more advanced disease (GOLD group D) after use of a LAMA/LABA combination therapy. However, evidence regarding the efficacy of triple combination therapy is conflicting. 40 The GOLD guidelines recommend considering triple combination therapy

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