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Fixed-Dose Combinations of Long-Acting Bronchodilators for the Management of COPD: Global and Asian Perspectives

Abstract

Maintenance bronchodilator therapy with long-acting β-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is the cornerstone treatment for patients with stable chronic obstructive pulmonary disease (COPD). Fixed-dose combinations (FDCs) of LABA/LAMA are recommended for the majority of symptomatic COPD patients by global guidelines; regional guidelines such as the Japanese and Korean guidelines also provide similar recommendations for the use of LABA/LAMA FDCs. This review comprehensively describes the latest clinical evidence from key studies on the efficacy and safety of four approved LABA/LAMA fixed-dose combinations: indacaterol/glycopyrronium, vilanterol/umeclidinium, formoterol/aclidinium, and olodaterol/tiotropium. Additionally, in this review we describe the rationale behind the use of LABA/LAMA FDC therapy, key findings from the preclinical and clinical trial evaluation of respective LABA and LAMA monocomponents, and the efficacy and safety of LABA/LAMA FDCs. Special emphasis is placed on the clinical evidence for the monocomponents and LABA/LAMA FDCs from the Asian population. This detailed overview of the efficacy and safety of LABA/LAMA FDCs in global and Asian COPD patients is envisaged to provide a better understanding of the benefits of these therapies and to inform healthcare providers and patients on their appropriate use.

Funding: Novartis Pharma K.K.

Introduction

Burden of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways characterized by persistent symptoms, progressive breathlessness, and poorly reversible airflow obstruction, which ultimately lead to impaired quality of life in these patients [1, 2]. Moreover, COPD exacerbations (acute worsening of the usual symptoms beyond normal day-to-day variation) impose a significant burden on patients due to increased morbidity and associated healthcare costs [3, 4]. COPD is currently the fourth leading cause of death worldwide; the global burden of COPD is indicated by a prevalence of 251 million cases of this disease [5]. In Asia, the estimated COPD prevalence was 6.2%, with 19.1% of patients having severe COPD [6]. The prevalence of COPD in Japan was reported to be 8.6% in a large epidemiological study [7]. In Korea, the prevalence of COPD was found to be 13.4% in a survey population aged 40 years or more [8]. Differences in COPD prevalence and clinical management exist between Asian and global populations: smoke from biomass fuels and industrial toxins are major risk factors, apart from tobacco smoke; rates of COPD-associated mortality and morbidity are higher in Asia; differences in overall healthcare management structure and cultural differences [6, 9].

Management of Stable COPD

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy provides recommendations for COPD maintenance therapy based on COPD severity, symptoms assessment, and exacerbation history [1]. Long-acting bronchodilators (with a duration of action up to 24 h), such as long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs), are the cornerstone of maintenance therapy for patients with moderate-to-very-severe COPD [1, 10]. Addition of an inhaled corticosteroid (ICS) to long-acting bronchodilators is considered for patients with frequent exacerbations and high blood eosinophil levels [1]. Several devices with distinct characteristics are available to deliver inhaled treatments to COPD patients: pressurized metered dose inhalers (pMDIs), dry powder inhalers (DPIs), soft mist inhalers (SMIs), and nebulizers [11].

Place of Bronchodilators in Guideline-Recommended Pharmacological Treatment of COPD

Based on strong clinical evidence, the GOLD 2019 strategy recommends treatment with a LABA/LAMA combination for patients with stable COPD considering its superiority versus monotherapy or LABA/ICS, and its lower risk of pneumonia versus ICS-containing therapy [1]. Moreover, combination inhaler therapy is recommended as the first-line therapy for symptomatic patients with at least two COPD exacerbations or one exacerbation requiring hospitalization in the past year (GOLD group D) [1]. Patients without a significant exacerbation history but with persistent symptoms on monotherapy (LAMA or LABA alone) are also eligible for LABA/LAMA combination therapy (GOLD group B). Therefore, patients in groups B and D have potential for receiving LABA/LAMA combination therapy.

It is noteworthy that the global treatment guidelines for COPD do not recommend region-specific treatment options; thus, regional guidelines such as those in Japan and Korea draw substantially from the global guidelines for treatment recommendations [12, 13]. This review article provides an objective overview of the available inhaled LABA/LAMA fixed-dose combinations (FDCs) for the treatment of COPD with emphasis on the efficacy and safety of their monocomponents, particularly in the context of management of COPD patients from the Asian region. We envisage providing a foundation for informed decision-making by respiratory physicians that would allow appropriate selection of the optimal bronchodilation therapy with LABA/LAMA FDCs for COPD patients.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Fixed-Dose Combinations of Long-Acting Bronchodilators for COPD

Rationale for Use of LABA/LAMA FDC

LAMAs inhibit the action of acetylcholine at muscarinic receptors, while LABAs enhance cyclic adenosine monophosphate (cAMP) signaling through stimulation of β2-adrenergic receptors [14]. Even though a LAMA or a LABA may have an excellent therapeutic profile, monotherapy is not always satisfactory for patients with more severe COPD [15]. Combination therapy has the potential for enhancing and prolonging the effects of monocomponents. Combining LABAs and LAMAs with different mechanisms may increase the degree of bronchodilation with little increase in the risk of side effects compared to increasing the dose of a single bronchodilator [1]. These drugs improve symptoms and quality of life by improving airflow and hence gaseous exchange, and by reversing air trapping and dynamic lung hyperinflation through dilatation of both medium and small airways [16]. Furthermore, FDCs might improve adherence by decreasing the number of medications and/or the number of daily doses required with monotherapy, as well as by offering the opportunity to use a single inhaler [17]. Notably, because of the differences in mechanism of action, administering two bronchodilators may overcome patient-specific differences in treatment responses [1]. The combination of a LABA and a LAMA may compensate for differences in the sympathetic and parasympathetic activity throughout the day [18]. LABA/LAMA FDC may also provide enhanced bronchodilation over monocomponents by allowing for the differences in receptor distribution in the lungs; the M3 receptors are distributed primarily in the bronchus and are not present in the lung parenchyma, while the β2-receptors are predominantly in the sub-segmental bronchus and lung parenchyma [19]. Moreover, safety of LABA/LAMA FDC and monotherapies is comparable [20]. LABA/LAMA FDCs currently approved as maintenance bronchodilator treatment of patients with COPD in Asia are listed in Table 1.

Table 1 Approved fixed-dose combinations of LABAs and LAMAs for COPD treatment

Contribution of Individual Components of LABA/LAMA FDCs to Treatment Efficacy

LABAs

Inhaled LABAs stimulate the β-adrenergic receptors in the airway smooth muscle cells to elicit bronchodilation; the method of inhaled delivery reduces side effects when compared to oral or intravenous treatment with β-agonists [21]. LABAs, like LAMAs, are recommended as first-line maintenance bronchodilator therapy in patients without history of exacerbation but with significant symptoms (GOLD group B) [1]. In general, LABAs have an acceptable safety profile, although there is still a debate on their cardiovascular safety [22, 23]. Key LABAs used for the treatment of COPD include formoterol, indacaterol, and olodaterol (Fig. 1). Pivotal global clinical studies on these LABAs and their key outcomes are listed in Table S1 (see supplementary material).

Fig. 1
figure 1

Major inhaled LABAs and LAMAs used in FDCs. FDC fixed-dose combination, LABAs long-acting β2-agonists, LAMAs long-acting muscarinic antagonists

Formoterol

Formoterol is a twice-daily LABA that produces a bronchodilator effect for up to 12 h with an onset of action of approximately 7 min upon inhalation. Formoterol exhibits a rapid onset of bronchodilation similar to that observed with salbutamol, yet its long bronchodilation duration is comparable to salmeterol. The approved dose range is between 12 and 24 µg twice daily [24, 25]. Pharmacological characterization of formoterol demonstrated that clear effects were maintained for 12 h after inhalation; formoterol showed higher intrinsic activity than salmeterol, which meant that it was a full β2-agonist [26]. Formoterol has been shown to better reduce dynamic hyperinflation, which is responsible for exercise intolerance and dyspnea in COPD patients, compared with other bronchodilators, e.g., salmeterol and ipratropium [25]. Formoterol reduced exacerbations, increased days free of rescue medication use, and improved patients’ quality of life and disease symptoms [25, 27]. Formoterol is generally considered to be well tolerated, and a low incidence of adverse events has been reported versus placebo across clinical studies [25].

Indacaterol

Indacaterol is a once-daily LABA that has a fast onset of action (approximately 5 min) due to its rapid absorption. It was approved by the European Medicines Agency (EMA) in 2009 and by the US Food and Drug Administration (FDA) in 2011 for maintenance treatment of patients with COPD. Indacaterol is approved at once-daily doses of 150 and 300 µg in Europe and in Korea, at 75 µg once daily in the USA, and at 150 µg once daily in Japan [28, 29]. In vitro and in vivo assessments showed that indacaterol had a superior duration of action compatible with once-daily dosing in humans, together with a fast onset of action and an improved cardiovascular safety profile over other LABAs [30]. In phase III studies, indacaterol showed sustained 24-h bronchodilation and significantly greater efficacy in terms of lung function, symptom control, and quality of life compared with placebo, and comparable or superior efficacy compared with twice-daily LABAs and/or tiotropium with good safety profile [31,32,33,34,35]. In a network meta-analysis, indacaterol 300 μg, followed by 150 and 75 μg, was the most effective LABA monotherapy for moderate-to-severe COPD [36].

Vilanterol

Vilanterol is not available as a single agent and is approved for use in COPD only in an FDC with umeclidinium.

Olodaterol

Olodaterol is a LABA with bronchodilator effect up to 24 h. The approved dose is 5 µg once daily (EU and USA; not approved in Korea and Japan) [37]. In vitro pharmacological characterization showed that olodaterol had a potent, nearly full agonistic response for β2-receptors; in vivo, olodaterol provided bronchoprotection over 24 h; further, olodaterol showed a rapid onset of action comparable with that of formoterol [38]. In similar randomized clinical trial conditions, olodaterol and indacaterol have been shown to have similar efficacy in COPD patients [39]. Long-term safety data in patients with moderate-to-severe COPD showed that olodaterol had a good safety profile, comparable with formoterol [40].

LAMAs

LAMAs cause relaxation of airway smooth muscles by blocking acetylcholine activity at the receptor in the large and small airways, glandular and epithelial cells, as well as various other cells of the lung [16, 41]. LAMAs are recommended as first-line maintenance bronchodilator therapy in patients with stable COPD without significant symptoms but who have a high risk of exacerbations (GOLD group C) and those without a history of exacerbation but with significant symptoms (GOLD group B) [1]. Four LAMAs are approved for use in the treatment of COPD: tiotropium bromide, aclidinium bromide, glycopyrronium bromide, and umeclidinium bromide (Fig. 1). Pivotal clinical studies on these LAMAs and their key outcomes are listed in Table S2 (see supplementary material).

Tiotropium

Tiotropium was the first once-daily LAMA approved for COPD [42]. Preclinical evaluation of tiotropium compared with other LAMAs showed that tiotropium had high affinity and potency toward the human muscarinic M3 receptor, comparable with glycopyrronium and aclidinium, but a significantly longer dissociation half-life [43]. Tiotropium inhibited remodeling of the airways as well as pulmonary inflammation in a guinea pig model of COPD [44]. Also in a guinea pig model, treatment with inhaled tiotropium considerably inhibited the increase in airway smooth muscle mass, myosin expression, and contractility [45]. Tiotropium was significantly more effective than short-acting muscarinic antagonist ipratropium 40 μg four-times daily in improving FEV1, and generally improved lung function to a significantly greater extent than salmeterol in patients with COPD [46, 47]. The long-term efficacy (improvements in lung function, quality of life, and exacerbations) and safety of tiotropium have been demonstrated in the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study and a subsequent subgroup analysis of this study [48,49,50]. The 1-year Prevention of Exacerbations with Tiotropium in COPD (POET-COPD) study showed that tiotropium was more effective than salmeterol in preventing exacerbations in patients with moderate-to-very-severe COPD [51]. In the indacaterol: providing opportunity to re-engage patients with life (INVIGORATE) study in exacerbating patients with severe COPD, indacaterol and tiotropium provided clinically relevant improvements in lung function with comparable safety profiles, while tiotropium afforded greater protection from exacerbations compared to indacaterol [52]. In the TIOtropium Safety and Performance In Respimat® (TIOSPIR) study, assessment of tiotropium delivered via two different devices (HandiHaler® and Respimat®) showed that tiotropium Respimat® 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to that of tiotropium HandiHaler® 18 μg in patients with COPD [53]. In comparing the relative clinical effects of tiotropium alone versus LABAs (salmeterol, formoterol, and indacaterol) alone, in randomized studies, it was shown that fewer patients with COPD experienced one or more exacerbations with tiotropium than with LABAs, with no statistical difference in mortality observed between the treatment groups. There was no statistically significant difference in FEV1 or symptom score between tiotropium and LABAs, but there was a lower rate of nonfatal serious adverse events recorded with tiotropium compared with LABAs and a lower rate of study withdrawals [54].

Aclidinium

Aclidinium bromide is a twice-daily LAMA approved for use in the treatment of COPD in Europe, the USA, and Japan, at 400 μg twice daily [55]. A pharmacological assessment of the onset of action of aclidinium versus tiotropium in patients with COPD and human isolated bronchi showed that bronchodilation induced by aclidinium was faster than that induced by tiotropium [56]; other in vivo and in vitro analyses showed that aclidinium and glycopyrronium were both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2 [57]. Four phase III clinical trials demonstrated benefits of aclidinium on the overall lung function and health status of patients with COPD, with a tolerability profile comparable with placebo [58]. Aclidinium showed similar effect on reducing exacerbations compared with tiotropium [59].

Glycopyrronium

Glycopyrronium bromide has a rapid onset (5 min) and 24-h duration of action. The recommended dose is 50 μg once daily; in the USA, the approved dose is 12.5 μg twice daily [60]. Pharmacological characterization of glycopyrronium showed that it had a more rapid onset of action (3–4.8 times) versus tiotropium; glycopyrronium also had greater equilibrium binding and kinetic selectivity for M3 versus M2 receptors [61]. In assessment of lung muscarinic receptor binding, the effect of glycopyrronium lasted for 24 h, with little influence on the muscarinic receptors in the bladder and submaxillary gland [62]. The Symptoms and Pulmonary function in the moRnING (SPRING) study, which assessed the rapid onset bronchodilator profiles of LAMAs, demonstrated superiority of glycopyrronium versus tiotropium in terms of superior bronchodilation in the first 4 h after administration [63]. The FAST study characterized the earlier onset of action associated with glycopyrronium; it was superior to tiotropium in terms of early bronchodilation. Both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters; glycopyrronium reduced specific airway resistance faster than tiotropium [64]. In clinical studies of 6–12 months’ duration in patients with moderate-to-severe COPD, glycopyrronium improved lung function, reduced breathlessness, improved symptoms, and reduced moderate-to-severe exacerbations to a similar extent as tiotropium [65]. Glycopyrronium also produced immediate and significant improvement in exercise tolerance and had a similar safety profile to tiotropium [66]. Pooled data from clinical studies in over 4000 patients with COPD showed that the overall safety profile of glycopyrronium was similar to placebo and tiotropium [67].

Umeclidinium

Umeclidinium bromide is delivered once daily; the FDA and EMA approved dose is 62.5 μg [68]. Pharmacological assessment of umeclidinium showed competitive antagonism of muscarinic cholinergic receptors. Umeclidinium dose-dependently blocked acetylcholine-induced bronchoconstriction with a long duration of action, and was comparable to tiotropium; umeclidinium 2.5 μg offered 50% bronchoprotection for more than 24 h. This pharmacological profile translated into 24-h duration of bronchodilation in vivo [69]. There is a clinically meaningful increase in FEV1 at the current approved dose of umeclidinium. Results generated by pivotal trials indicate comparable effectiveness between umeclidinium and tiotropium [70, 71]. Umeclidinium 62.5 μg demonstrated superior efficacy to tiotropium 18 μg for improvement in trough FEV1 after 12 weeks with a similar safety profile [72]. A pooled meta-analysis of phase III studies showed that umeclidinium had safety similar to placebo; there were no significant differences between umeclidinium and tiotropium [73].

Efficacy and Safety of LABA/LAMA FDC Bronchodilators in COPD

Once-daily LABA/LAMA combinations (indacaterol plus glycopyrronium, vilanterol plus umeclidinium bromide, and olodaterol plus tiotropium bromide) and a twice-daily combination (aclidinium plus formoterol) have been developed or are in clinical development. A systematic review of the efficacy and safety of LABA/LAMA FDCs identified randomized placebo-controlled studies of at least 3 months; all LABA/LAMA combinations improved lung function, transition dyspnea index (TDI), and St. George’s Respiratory Questionnaire (SGRQ) scores compared with monocomponents [74]. Indirect comparisons found no significant differences between LABA/LAMA combinations in terms of greater efficacy for trough FEV1, TDI, and SGRQ scores versus a LAMA or LABA/ICS [74]. The major clinical studies on the LABA/LAMA FDCs are listed in Table 2.

Table 2 Key studies on major LABA/LAMA fixed-dose combinations in patients with COPD

Indacaterol/Glycopyrronium

Indacaterol/glycopyrronium contains indacaterol 110 μg and glycopyrronium 50 μg taken once daily via a DPI device, Breezhaler® or twice-daily (27.5/15.6 µg) via the Neohaler® (USA) [75]. The efficacy of indacaterol/glycopyrronium has been reported in a series of phase III clinical trials under the large IGNITE (indacaterol and glycopyrronium bromide clinical studies) program [76]. Once-daily indacaterol/glycopyrronium demonstrated superior and clinically meaningful efficacy outcomes versus placebo and superiority versus treatment with a single bronchodilator (indacaterol, glycopyrronium, or open-label tiotropium), with a safety and tolerability profile similar to placebo [77]. Indacaterol/glycopyrronium was superior in preventing moderate-to-severe COPD exacerbations compared with glycopyrronium [78]. Indacaterol/glycopyrronium provided superior improvements in patient-reported dyspnea and lung function versus placebo and tiotropium [79]. In patients with moderate-to-severe COPD, indacaterol/glycopyrronium improved exercise endurance time versus placebo but did not show numerical and statistically significant difference versus blinded tiotropium, while indacaterol/glycopyrronium significantly improved lung hyperinflation versus both placebo and tiotropium [80]. The EXPEDITION program showed that indacaterol/glycopyrronium 27.5/12.5 µg twice daily elicited a significant improvement in lung function and patient-reported outcomes, COPD exacerbations, and quality of life when compared with monocomponents and placebo [81]. Once-daily indacaterol/glycopyrronium provided significant, sustained, and clinically meaningful improvements in lung function and dyspnea versus twice-daily salmeterol/fluticasone on non-exacerbating COPD patients [82]. The landmark effect of indacaterol glycopyrronium vs. fluticasone salmeterol on COPD exacerbations (FLAME) study demonstrated the superiority of once-daily indacaterol/glycopyrronium 110/50 μg over twice-daily salmeterol/fluticasone 50/500 μg (a LABA/ICS) in reducing the rate of COPD exacerbations with reduced risk of pneumonia in exacerbating patients with moderate-to-very-severe COPD [83]. In a prospective analysis of the FLAME study, indacaterol/glycopyrronium provided superior or similar benefits over salmeterol/fluticasone independent of blood eosinophil levels [84]. It should be noted that FLAME excluded patients with a high blood eosinophil count (greater than 600 cells/µL) and any history of asthma [83]. A systematic review reported that indacaterol/glycopyrronium had clinically significant effects on symptoms, including dyspnea and health status, lung function, and rate of moderate or severe exacerbations compared to monotherapies in patients with moderate-to-very-severe COPD [85]. Indacaterol/glycopyrronium has been shown to be well tolerated generally, with most adverse events being of mild-to-moderate severity [86].

Vilanterol/Umeclidinium

Vilanterol/umeclidinium was the first fixed LABA/LAMA combination to get approval by the FDA. It is approved in Europe at 22/55 μg once daily, in the USA and Japan at 25/62.5 μg once daily, administered via the DPI Ellipta® [87]. When compared with monocomponents, vilanterol/umeclidinium 25/62.5 μg provided greater improvements in FEV1 and FVC but improvements in dyspnea and quality of life were similar in all active treatment groups [88]. Treatment with vilanterol/umeclidinium resulted in a lower risk of COPD exacerbations versus placebo [89]. A systematic review, which included studies of 12- to 52-week duration, compared vilanterol/umeclidinium with monocomponents or salmeterol/fluticasone in patients with moderate-to-severe COPD. Statistically significant differences were found in trough FEV1 compared with the comparators. Compared with umeclidinium or vilanterol, there were a greater likelihood of patients experiencing a minimal clinically important difference (MCID) in TDI and statistically significant reductions in the risk of COPD exacerbations [90]. Vilanterol/umeclidinium generally showed favorable effects on lung function, quality of life, dyspnea, rescue medication use, and exercise capacity, with no clinically meaningful treatment-related changes in vital signs or clinical laboratory parameters when compared with either placebo or monocomponents [91]. In a 12-week study, vilanterol/umeclidinium 25/62.5 µg showed significantly greater improvements in lung function versus salmeterol/fluticasone 50/500 µg. Both treatments produced clinically meaningful improvements in TDI and SGRQ scores, but there was no statistical difference between the two treatment arms [92].

Formoterol/Aclidinium

This twice-daily FDC is administered using Genuair®, a multiple-dose DPI [93]. Most published data on formoterol/aclidinium is from two 24-week randomized, placebo-controlled studies, AUGMENT and ACLIFORM. Formoterol/aclidinium at doses of 12/400 μg and 6/400 μg was compared with its monocomponents and placebo [94, 95]. The 1-h post-dose FEV1, but not trough FEV1, was significantly higher with both FDC doses compared with aclidinium in both studies. In AUGMENT, the higher FDC dose significantly improved trough FEV1 compared with formoterol but there was no significant difference for the lower dose. A greater effect for the higher FDC on trough FEV1 was also observed in ACLIFORM, indicating that the higher FDC is superior to the monocomponents and the lower FDC dose [94, 95]. The above studies showed a decrease in symptoms and exacerbations versus placebo in the groups treated with formoterol/aclidinium and its good safety profile [96]. In a 24-week study in patients with moderate-to-severe COPD, formoterol/aclidinium produced statistically significant increases in peak FEV1 compared with salmeterol/fluticasone and similar changes in symptom control and risk of exacerbations; however, there were no significant differences in trough FEV1 between the formoterol/aclidinium and salmeterol/fluticasone [97].

Olodaterol/Tiotropium

Olodaterol/tiotropium is the most recently approved LABA/LAMA. It is delivered once daily via the Respimat® SMI [98]. In a combined analysis of two 52-week replicate studies (TONADO 1 and 2), two doses of olodaterol/tiotropium (5/5 µg or 5/2.5 μg) were compared with its monocomponents in patients with moderate-to-very-severe COPD. Both doses significantly improved lung function, dyspnea, reduced the risk of moderate-to-severe exacerbations, and improved quality of life over monocomponents [99]. A Cochrane review of olodaterol/tiotropium compared with monotherapy found that the FDC resulted in a small improvement in SGRQ score compared with tiotropium monotherapy. Statistically significant effects were also seen on FEV1 but not on hospital admissions or mortality [100]. In two replicate 6-week, incomplete-crossover studies in patients with moderate-to-severe COPD (MORACTO 1 and 2), olodaterol/tiotropium improved dyspnea and exercise tolerance versus placebo but not consistently versus monotherapies [101]. Olodaterol/tiotropium has been shown to have similar safety compared to monocomponents [102]. In the recently completed DYNAGITO study, a reduction in rate of moderate to severe exacerbations was observed with olodaterol/tiotropium 5/5 μg versus tiotropium, but this did not meet the targeted level of statistical significance [103].

Efficacy of LABAs, LAMAs, and LABA/LAMA FDCs in Asian Patients with COPD

Several de novo clinical studies as well as post hoc and subgroup analyses of key clinical studies have explored the efficacy of long-acting bronchodilators in Asian populations (Table 3).

Table 3 Key clinical studies on major LABAs, LAMAs, and LABA/LAMA fixed-dose combinations in Asian patients with COPD

LABAs

Formoterol 4.5 μg and 9 μg twice daily were effective and well tolerated in patients with COPD; both formoterol doses similarly improved lung function in Japanese and European COPD patients [104]. In Japanese patients with COPD, twice-daily formoterol 4.5 μg, 9 μg, and 18 μg showed significantly superior effects to placebo on FEV1 [105]. Indacaterol provided 24-h bronchodilation with a fast onset of action and similar pharmacokinetic and safety profiles in Caucasian and Japanese COPD patients [106]; similar findings were observed in another study in exclusively Japanese patients [107]. In a predominantly Chinese population, indacaterol provided significant improvements in breathlessness and health status [108]; additionally, indacaterol provided clinically significant bronchodilation and improvements in dyspnea and health status in Asian COPD patients, including Japanese patients [109]. In a large real-life observational study in South Korea, indacaterol was shown to be well tolerated in COPD patients [110]. In a phase III study, indacaterol provided significantly superior bronchodilation, significant improvement in breathlessness, and improved health status versus placebo in Korean COPD patients with destroyed lung by tuberculosis [111]. Indacaterol demonstrated clinically relevant improvements versus placebo in lung function, dyspnea, and health status in Asian COPD patients irrespective of disease severity [112]. Once-daily olodaterol showed statistically significant increase in trough FEV1 compared to placebo, demonstrated 24-h bronchodilator efficacy, and was well tolerated in Japanese patients with COPD [113].

LAMAs

In the subgroup analysis of COPD patients from Asia included in the UPLIFT study, tiotropium improved lung function, improved health-related quality of life, and reduced exacerbations over 4 years of treatment [114]. In Japanese patients with COPD, tiotropium Respimat® 5 µg and tiotropium HandiHaler® 18 µg showed a similar profile of efficacy, safety, and pharmacokinetics [115]. In the analysis of an Asian cohort from the TIOSPIR study, both doses of tiotropium showed similar safety and exacerbation efficacy profiles [116]. In Chinese patients with COPD, tiotropium significantly improved lung function and quality of life, and reduced the number of exacerbations [117]. Tiotropium also improved FEV1 more than placebo at 24 months and ameliorated the annual decrease in FEV1 after bronchodilator use in COPD patients of GOLD stages 1 or 2 from China [118]. Aclidinium 400 µg was shown to be safe and efficacious in Korean patients with moderate-to-severe COPD [119]. Additionally, significant improvement in trough FEV1 was shown with aclidinium compared with the placebo in Korean patients with COPD [119]. In the recently conducted phase II study enrolling Japanese patients with moderate-to-severe COPD, twice-daily glycopyrronium 14.4 μg by the new co-suspension delivery technology was found to be the most appropriate dose for use in phase III studies [121], while the currently available glycopyrronium for COPD in Japan is the DPI form of 50 μg once daily. In the glycopyrronium bromide in COPD airways7 (GLOW7) study in which the majority of enrolled patients were Chinese, glycopyrronium 50 μg significantly improved lung function, dyspnea, and health status versus placebo [122]. In a 52-week study, umeclidinium 125 μg was well tolerated in Japanese patients with COPD [123].

LABA/LAMA FDCs

In the LANTERN study and in its Chinese cohort, once-daily indacaterol/glycopyrronium 110/50 μg was superior to twice-daily salmeterol/fluticasone 50/500 μg in improving lung function and in reducing the rate of moderate or severe exacerbations in COPD patients with a history of at most one exacerbation in the previous year [124, 125]. In Japanese patients from the SHINE study, indacaterol/glycopyrronium demonstrated superior improvements in trough FEV1 and FEV1 AUC5min–4h compared to its monocomponents, open-label tiotropium and placebo, and comparable safety [126]. In a pooled analysis of the SHINE and ARISE studies, compared to tiotropium, indacaterol/glycopyrronium provided significant improvements in lung function, health status, and rescue medication use, while having a good safety profile, in Japanese patients with moderate-to-severe COPD [127]. Japanese Respiratory Society guidelines acknowledge that indacaterol/glycopyrronium is a combination of two first-line bronchodilators [128]. In Korea, indacaterol/glycopyrronium was approved in 2015 and it is being further evaluated in symptomatic patients with mild-to-moderate COPD prescribed tiotropium monotherapy [129]. In exacerbating Asian COPD patients from the FLAME study, indacaterol/glycopyrronium was more effective than salmeterol/fluticasone, with significantly less incidence of pneumonia than salmeterol/fluticasone [130]. In Asian patients with COPD, once-daily vilanterol/umeclidinium 25/62.5 μg and 25/125 μg resulted in clinically meaningful and statistically significant improvements in lung function versus placebo. Symptoms and quality of life measures were also improved [131]. In Japanese patients with COPD, no safety concerns for long-term treatment with olodaterol/tiotropium were identified. Numerical improvement in lung function was observed with olodaterol/tiotropium compared with olodaterol in Japanese patients with moderate-to-very severe COPD [132]. Olodaterol/tiotropium 5/5 μg was superior to each monotherapy for lung function and SGRQ in the Japanese subpopulation of patients with COPD from the TONADO study [133]. A phase III study in an East Asian population showed slightly greater trough FEV1 treatment differences between olodaterol/tiotropium 5/5 μg and tiotropium compared to the overall population [134]. The VESUTO® study investigated efficacy of olodaterol/tiotropium compared with tiotropium alone on inspiratory capacity, exercise capacity, and daily physical activity in Japanese patients with COPD. Olodaterol/tiotropium significantly increased inspiratory capacity compared with tiotropium after 6 weeks of treatment (primary endpoint). Although there was no statistical difference between the two arms in 6-min walk distance in the overall population, olodaterol/tiotropium significantly increased 6-min walk distance compared to tiotropium alone in the subgroup of GOLD stages III and IV [135]. In the recently reported Japanese subpopulation analysis of the DYNAGITO study, olodaterol/tiotropium 5/5 μg resulted in a 29% lower rate of moderate-to-severe exacerbations compared with tiotropium [136].

LABA/LAMA/ICS Triple Therapy Versus LABA/LAMA

Very recently, some studies have been conducted on LABA/LAMA versus LABA/LAMA/ICS to assess the contribution of ICS in the efficacy of triple therapy in COPD patients. The IMPACT study compared the efficacy of vilanterol/umeclidinium/fluticasone on the rate of moderate and severe exacerbations versus vilanterol/umeclidinium and vilanterol/fluticasone over 52 weeks in symptomatic exacerbating COPD patients with moderate-to-very severe airflow limitation; these patients could have a history of asthma. Vilanterol/umeclidinium/fluticasone significantly reduced the rate of moderate-to-severe exacerbations by 15% compared to vilanterol/fluticasone and by 25% compared to vilanterol/umeclidinium [137]. The 52-week TRIBUTE study compared formoterol/glycopyrronium/beclomethasone versus indacaterol/glycopyrronium in terms of the rate of moderate-to-severe COPD exacerbations in exacerbating patients with severe-to-very-severe COPD; triple therapy significantly reduced the annual rate of exacerbations compared with dual bronchodilation therapy [138]. Nevertheless, it should be noted that the effects of triple therapy on COPD exacerbations were evident in patients with chronic bronchitis or elevated circulating eosinophils but not in those with emphysema or low circulating eosinophils; thus these results cannot be generalized to the whole COPD population [139].The 26-week SUNSET study has assessed the effects of ICS withdrawal from long-term (at least 6 months) triple therapy to indacaterol/glycopyrronium or continuation of triple therapy [tiotropium (18 μg) once daily plus combination of salmeterol (50 μg) and fluticasone propionate (500 μg) twice daily] in non-frequently exacerbating patients (up to one exacerbation in the past year) with moderate-to-severe COPD [140]. Inhaled corticosteroids withdrawal led to a reduction in trough FEV1 of − 26 mL confidence interval limits exceeding the non-inferiority margin of − 50 mL; the annualized rate of moderate or severe COPD exacerbations did not differ between treatments. However, patients with  at least 300 blood eosinophils/μL at baseline showed statistically greater loss of lung function and higher exacerbation risk in LABA/LAMA compared to triple therapy, implying that COPD patients with higher blood eosinophils benefit from triple therapy [140]. The currently ongoing ETHOS study is assessing the efficacy and safety of formoterol/glycopyrronium/budesonide versus formoterol/glycopyrronium and formoterol/budesonide on COPD exacerbations over 52 weeks [141].

Commentary and Conclusions

Important demographic differences exist between Asian and Western populations of COPD. For example, the body mass index is lower in Asian COPD patients than Western COPD patients [129, 142]. The cause of COPD is different between populations and there are more patients with biofuel-induced COPD in Asia [143, 144]. Although smoking is still a major risk factor for COPD, genetic, environmental, and developmental factors that exert their effects during an individual’s growing years can diminish the maximally attained FEV1 and accelerate FEV1 decline in adult life, thus increasing the risk of COPD; this aspect has recently garnered attention but remains to be specifically evaluated in Asian populations [145]. Many COPD patients in Asia have a previous history of tuberculosis [146, 147], which can contribute to the development of COPD. Notably, different COPD phenotypes exist among Asian populations. For example, the emphysema phenotype is dominant in Japanese patients with COPD [148] whereas chronic bronchitis is more prevalent than emphysema in the Korean COPD population [149]; this may influence the clinical outcomes of therapies. Air pollution is heavier in Asian countries and this definitely affects COPD outcome [150]. Even though inhaler medication use is steadily increasing in Asia, it is still used less frequently than oral therapies, which reflects the overprescription of oral medications (e.g., theophylline) to COPD patients [6, 151, 152]. Nevertheless, currently available evidence of LABA/LAMA FDC in COPD described above is consistent between Western and Asia, and therefore, global and regional COPD treatment guidelines have supported the use of LABA/LAMA FDCs in clinical practice and their use is growing.

It should be noted that phase III clinical programs on LABA/LAMA combinations in COPD have not fully shown superior efficacy of dual bronchodilators over monotherapy for effects on exercise endurance and physical activity. Moreover, COPD patients with frequent exacerbations and blood eosinophil levels of at least 300 cells/μL may still benefit from ICS therapy. Real-world assessment could further define the place of LABA/LABA FDCs in COPD treatment.

Overall, variable clinical efficacy and safety of individual drugs, differences in population characteristics, phenotypes, patient preferences, and adherence to treatment, and inhaler device use are crucial to the optimal use of LABA/LAMA FDCs in patients with COPD in Asia and globally.

References

  1. The global strategy for the diagnosis, management and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease (GOLD). 2017. http://www.goldcopd.org. Accessed 7 Nov 2018.

  2. Lopez-Campos JL, Tan W, Soriano JB. Global burden of COPD. Respirology. 2016;21:14–23.

    Article  PubMed  Google Scholar 

  3. Anzueto A. Impact of exacerbations on COPD. Eur Respir Rev. 2010;19:113–8.

    Article  CAS  PubMed  Google Scholar 

  4. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet. 2007;370:786–96.

    Article  PubMed  Google Scholar 

  5. World Health Organization. Global burden of chronic respiratory disease. http://www.who.int/respiratory/copd/burden/en/. Accessed 20 Jan 2018.

  6. Lim S, Lam DC, Muttalif AR, et al. Impact of chronic obstructive pulmonary disease (COPD) in the Asia–Pacific region: the EPIC Asia population-based survey. Asia Pac Fam Med. 2015;14:4.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Fukuchi Y, Nishimura M, Ichinose M, et al. COPD in Japan: the Nippon COPD epidemiology study. Respirology. 2004;9(4):458–65.

    Article  PubMed  Google Scholar 

  8. Yoo KH, Kim YS, Sheen SS, et al. Prevalence of chronic obstructive pulmonary disease in Korea: the fourth Korean National Health and Nutrition Examination Survey, 2008. Respirology. 2011;16(4):659–65.

    Article  PubMed  Google Scholar 

  9. Oh Y-M, Bhome AB, Boonsawat W, et al. Characteristics of stable chronic obstructive pulmonary disease patients in the pulmonology clinics of seven Asian cities. Int J Chron Obstruct Pulmon Dis. 2013;8:31–9.

    PubMed  PubMed Central  Google Scholar 

  10. Petite SE. Role of long-acting muscarinic antagonist/long-acting β2-agonist therapy in chronic obstructive pulmonary disease. Ann Pharmacother. 2017;51(8):696–705.

    Article  CAS  PubMed  Google Scholar 

  11. Bonini M, Usmani OS. The importance of inhaler devices in the treatment of COPD. COPD Res Pract. 2015;1:9.

    Article  Google Scholar 

  12. Japanese Respiratory Society. Guidelines for the diagnosis and treatment of COPD. 3rd ed. 2010. http://www.jrs.or.jp/uploads/uploads/files/photos/765.pdf. Accessed 20 Jan 2018.

  13. Yoon HK, Park YB, Rhee CK, Lee JH, Oh YM, Committee of the Korean COPD Guideline 2014. Summary of the chronic obstructive pulmonary disease clinical practice guideline revised in 2014 by the Korean Academy of Tuberculosis and Respiratory Disease. Tuberc Respir Dis (Seoul). 2017;80(3):230–40.

    Article  Google Scholar 

  14. Cohen JS, Miles MC, Donohue JF, Ohar JA. Dual therapy strategies for COPD: the scientific rationale for LAMA + LABA. Int J Chron Obstruct Pulmon Dis. 2016;11:785–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Tashkin DP, Ferguson GT. Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res. 2013;14(1):49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Page C, O’Shaughnessy B, Barnes P. Pathogenesis of COPD and asthma. Handb Exp Pharmacol. 2017;237:1–21.

    CAS  PubMed  Google Scholar 

  17. Cazzola M, Page C. Long-acting bronchodilators in COPD: where are we now and where are we going? Breathe. 2014;10:110–20.

    Article  Google Scholar 

  18. Van Gestel AR, Steier J. Autonomic dysfunction in patients with chronic obstructive pulmonary disease (COPD). J Thorac Dis. 2010;2(4):215–22.

    PubMed  PubMed Central  Google Scholar 

  19. Ikeda T, Anisuzzaman ASM, Yoshiki H, Sasaki M, Koshiji T, Uwada J. Regional quantification of muscarinic acetylcholine receptors and β-adrenoceptors in human airways. Br J Pharmacol. 2012;166(6):1804–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Singh D. New combination bronchodilators for chronic obstructive pulmonary disease: current evidence and future perspectives. Br J Clin Pharmacol. 2015;79(5):695–708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rossi A, Khirani S, Cazzola M. Long-acting β2-agonists (LABA) in chronic obstructive pulmonary disease: efficacy and safety. Int J Chron Obstruct Pulmon Dis. 2008;3(4):521–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aljaafareh A, Valle JR, Lin YL, Kuo YF, Sharma G. Risk of cardiovascular events after initiation of long-acting bronchodilators in patients with chronic obstructive lung disease: a population-based study. SAGE Open Med. 2016. https://doi.org/10.1177/2050312116671337.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Iftikhar IH, Imtiaz M, Brett AS, Amrol DJ. Cardiovascular safety of long acting beta agonist-inhaled corticosteroid combination products in adult patients with asthma: a systematic review. Lung. 2014;192(1):47–54.

    Article  CAS  PubMed  Google Scholar 

  24. Foradil® Aerolizer® prescribing information. US Food and Drug Administration. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020831s028lbl.pdf. Accessed 20 Jan 2018.

  25. Steiropoulos P, Tzouvelekis A, Bouros D. Formoterol in the management of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2008;3(2):205–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lötvall J, Bateman ED, Bleecker ER, et al. 24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroids. Eur Respir J. 2012;40(3):570–9.

    Article  CAS  PubMed  Google Scholar 

  27. Di Marco F, Verga M, Santus P, Morelli N, Cazzola M, Centanni S. Effect of formoterol, tiotropium, and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease: a pilot study. Respir Med. 2006;100(11):1925–32.

    Article  PubMed  Google Scholar 

  28. Murphy L, Rennard S, Donohue J, et al. Turning a molecule into a medicine: the development of indacaterol as a novel once-daily bronchodilator treatment for patients with COPD. Drugs. 2014;74(14):1635–57.

    Article  CAS  PubMed  Google Scholar 

  29. Onbrez Breezhaler summary of product characteristics. European Medicines Agency. 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001114/WC500053732.pdf. Accessed 20 Jan 2018.

  30. Battram C, Charlton SJ, Cuenoud B, et al. In vitro and in vivo pharmacological characterization of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one (indacaterol), a novel inhaled beta(2) adrenoceptor agonist with a 24-h duration of action. J Pharmacol Exp Ther. 2006;317(2):762–70.

    Article  CAS  PubMed  Google Scholar 

  31. Matera MG, Rogliani P, Cazzola M. Indacaterol for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2015;16(1):107–15.

    Article  CAS  PubMed  Google Scholar 

  32. Barnes PJ, Pocock SJ, Magnussen H, et al. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Pulm Pharmacol Ther. 2010;23(3):165–71.

    Article  CAS  PubMed  Google Scholar 

  33. Donohue JF, Fogarty C, Lötvall J, et al. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Am J Respir Crit Care Med. 2010;182(2):155–62.

    Article  CAS  PubMed  Google Scholar 

  34. Dahl R, Chung KF, Buhl R, et al. Efficacy of a new once-daily long-acting inhaled beta2-agonist indacaterol versus twice-daily formoterol in COPD. Thorax. 2010;65(6):473–9.

    Article  PubMed  Google Scholar 

  35. Kornmann O, Dahl R, Centanni S, et al. Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison. Eur Respir J. 2011;37(2):273–9.

    Article  CAS  PubMed  Google Scholar 

  36. Donohue JF, Betts KA, Du EX, et al. Comparative efficacy of long-acting β2-agonists as monotherapy for chronic obstructive pulmonary disease: a network meta-analysis. Int J Chron Obstruct Pulmon Dis. 2017;12:367–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Striverdi® Respimat® prescribing information. US Food and Drug Administration. 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/203108s000lbl.pdf. Accessed 20 Jan 2018.

  38. Bouyssou T, Casarosa P, Naline E, et al. Pharmacological characterization of olodaterol, a novel inhaled beta2-adrenoceptor agonist exerting a 24-hour-long duration of action in preclinical models. J Pharmacol Exp Ther. 2010;334(1):53–62.

    Article  CAS  PubMed  Google Scholar 

  39. Roskell NS, Anzueto A, Hamilton A, Disse B, Becker K. Once-daily long-acting beta-agonists for chronic obstructive pulmonary disease: an indirect comparison of olodaterol and indacaterol. Int J Chron Obstruct Pulmon Dis. 2014;9:813–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McGarvey L, Niewoehner D, Magder S, et al. One-year safety of olodaterol once daily via Respimat® in patients with GOLD 2-4 chronic obstructive pulmonary disease: results of a pre-specified pooled analysis. COPD. 2015;12(5):484–93.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Alagha K, Palot A, Sofalvi T, et al. Long-acting muscarinic receptor antagonists for the treatment of chronic airway diseases. Ther Adv Chronic Dis. 2014;5(2):85–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Spiriva Respimat prescribing information. US Food and Drug Administration. 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021936s000lbl.pdf. Accessed 20 Jan 2018.

  43. Casarosa P, Bouyssou T, Germeyer S, Schnapp A, Gantner F, Pieper M. Preclinical evaluation of long-acting muscarinic antagonists: comparison of tiotropium and investigational drugs. J Pharmacol Exp Ther. 2009;330(2):660–8.

    Article  CAS  PubMed  Google Scholar 

  44. Pera T, Zuidhof A, Valadas J, et al. Tiotropium inhibits pulmonary inflammation and remodelling in a guinea pig model of COPD. Eur Respir J. 2011;38(4):789–96.

    Article  CAS  PubMed  Google Scholar 

  45. Gosens R, Bos IS, Zaagsma J, Meurs H. Protective effects of tiotropium bromide in the progression of airway smooth muscle remodeling. Am J Respir Crit Care Med. 2005;171(10):1096–102.

    Article  PubMed  Google Scholar 

  46. van Noord JA, Bantje TA, Eland ME, Korducki L, Cornelissen PJ, The Dutch Tiotropium Study Group. A randomized controlled comparison of tiotropium and ipratropium in the treatment of chronic obstructive pulmonary disease. Thorax. 2000;55(4):289–94.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Donohue JF, van Noord JA, Bateman ED, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest. 2002;122(1):47–55.

    Article  CAS  PubMed  Google Scholar 

  48. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543–54.

    Article  CAS  PubMed  Google Scholar 

  49. Celli B, Decramer M, Kesten S, et al. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(10):948–55.

    Article  CAS  PubMed  Google Scholar 

  50. Decramer M, Celli B, Kesten S, et al. Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomized controlled trial. Lancet. 2009;374(9696):1171–8.

    Article  CAS  PubMed  Google Scholar 

  51. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364(12):1093–103.

    Article  CAS  PubMed  Google Scholar 

  52. Decramer ML, Chapman KR, Dahl R, et al. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomized, blinded, parallel-group study. Lancet Respir Med. 2013;1(7):524–33.

    Article  CAS  PubMed  Google Scholar 

  53. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat inhaler and the risk of death in COPD. N Engl J Med. 2013;369(16):1491–501.

    Article  CAS  PubMed  Google Scholar 

  54. Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;9:CD009157.

    Google Scholar 

  55. Tudorza Pressair prescribing information. US Food and Drug Administration. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202450s000lbl.pdf. Accessed 20 Jan 2018.

  56. Rogliani P, Calzetta L, Ora J, et al. Pharmacological assessment of the onset of action of aclidinium and glycopyrronium versus tiotropium in COPD patients and human isolated bronchi. Eur J Pharmacol. 2015;761:383–90.

    Article  CAS  PubMed  Google Scholar 

  57. Gavaldà A, Ramos I, Carcasona C, et al. The in vitro and in vivo profile of aclidinium bromide in comparison with glycopyrronium bromide. Pulm Pharmacol Ther. 2014;28(2):114–21.

    Article  CAS  PubMed  Google Scholar 

  58. Jones P. Aclidinium bromide twice daily for the treatment of chronic obstructive pulmonary disease: a review. Adv Ther. 2013;30(4):354–68.

    Article  CAS  PubMed  Google Scholar 

  59. Ni H, Soe Z, Moe S. Aclidinium bromide for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;(9):CD010509.

  60. Seebri Neohaler prescribing information. US Food and Drug Administration. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207923lbl.pdf. Accessed 20 Jan 2018.

  61. Sykes DA, Dowling MR, Leighton-Davies J, et al. The Influence of receptor kinetics on the onset and duration of action and the therapeutic index of NVA237 and tiotropium. J Pharmacol Exp Ther. 2012;343(2):520–8.

    Article  CAS  PubMed  Google Scholar 

  62. Ogoda M, Niiya R, Koshika T, Yamada S. Comparative characterization of lung muscarinic receptor binding after intratracheal administration of tiotropium, ipratropium, and glycopyrrolate. J Pharmacol Sci. 2011;115(3):374–82.

    Article  CAS  PubMed  Google Scholar 

  63. Marin JM, Beeh KM, Clemens A, et al. Early bronchodilator action of glycopyrronium versus tiotropium in moderate-to-severe COPD patients: a cross-over blinded randomized study (Symptoms and Pulmonary function in the moRnING). Int J Chron Obstruct Pulmon Dis. 2016;11:1425–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Watz H, Mailänder C, May C, Baier M, Kirsten AM. Fast onset of action of glycopyrronium compared with tiotropium in patients with moderate to severe COPD—a randomized, multicentre, crossover trial. Pulm Pharmacol Ther. 2017;42:13–20.

    Article  CAS  PubMed  Google Scholar 

  65. Buhl R, Banerji D. Profile of glycopyrronium for once-daily treatment of moderate-to-severe COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:729–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Compton C, McBryan D, Bucchioni E, Patalano F. The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2013;26(5):562–73.

    Article  CAS  PubMed  Google Scholar 

  67. D’Urzo AD, Kerwin EM, Chapman KR, et al. Safety of inhaled glycopyrronium in patients with COPD: a comprehensive analysis of clinical studies and post-marketing data. Int J Chron Obstruct Pulmon Dis. 2015;10:1599–612.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Incruse Ellipta prescribing information. US Food and Drug Administration. 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/205382s002lbl.pdf. Accessed 20 Jan 2018.

  69. Salmon M, Luttmann MA, Foley JJ, et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. J Pharmacol Exp Ther. 2013;345(2):260–70.

    Article  CAS  PubMed  Google Scholar 

  70. Manickam R, Asija A, Aronow WS. Umeclidinium for treating COPD: an evaluation of pharmacologic properties, safety and clinical use. Expert Opin Drug Saf. 2014;13(11):1555–61.

    Article  CAS  PubMed  Google Scholar 

  71. Segreti A, Calzetta L, Rogliani P, Cazzola M. Umeclidinium for the treatment of chronic obstructive pulmonary disease. Expert Rev Respir Med. 2014;8(6):665–71.

    Article  CAS  PubMed  Google Scholar 

  72. Feldman G, Maltais F, Khindri S, et al. A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg compared with tiotropium 18 μg in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2016;11:719–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Pleasants RA, Wang T, Gao J, Tang H, Donohue JF. Inhaled umeclidinium in COPD patients: a review and meta-analysis. Drugs. 2016;76(3):343–61.

    Article  CAS  PubMed  Google Scholar 

  74. Rodrigo GJ, Price D, Anzueto A, et al. LABA/LAMA combinations versus LAMA monotherapy or LABA/ICS in COPD: a systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2017;12:907–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ultibro Breezhaler summary of product characteristics. European Medicines Agency 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002679/WC500151255.pdf. Accessed 20 Jan 2018.

  76. Matera MG, Rogliani P, Cazzola M. QVA149 (indacaterol/glycopyrronium) for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2015;16(7):1079–90.

    Article  CAS  PubMed  Google Scholar 

  77. Bateman ED, Ferguson GT, Barnes N, et al. Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J. 2013;42(6):1484–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wedzicha JA, 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 randomized, double-blind, parallel-group study. Lancet Respir Med. 2013;1(3):199–209.

    Article  CAS  PubMed  Google Scholar 

  79. Mahler DA, Decramer M, D’Urzo A, et al. Dual bronchodilation with QVA149 reduces patient-reported dyspnea in COPD: the BLAZE study. Eur Respir J. 2014;43(6):1599–609.

    Article  PubMed  Google Scholar 

  80. Beeh KM, Korn S, Beier J, et al. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Respir Med. 2014;108(4):584–92.

    Article  PubMed  Google Scholar 

  81. Mahler DA, Kerwin E, Ayers T, et al. FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) versus its mono-components and placebo in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2015;192(9):1068–79.

    Article  CAS  PubMed  Google Scholar 

  82. 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 randomized, double-blind, parallel group study. Lancet Respir Med. 2013;1(1):51–60.

    Article  CAS  PubMed  Google Scholar 

  83. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016;374(23):2222–34.

    Article  CAS  PubMed  Google Scholar 

  84. 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):1189–97.

    Article  PubMed  Google Scholar 

  85. Ulrik CS. Clinical benefit of fixed-dose dual bronchodilation with glycopyrronium and indacaterol once daily in patients with chronic obstructive pulmonary disease: a systematic review. Int J Chron Obstruct Pulmon Dis. 2014;9:331–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Frampton JE. QVA149 (indacaterol/glycopyrronium fixed-dose combination): a review of its use in patients with chronic obstructive pulmonary disease. Drugs. 2014;74(4):465–88.

    Article  PubMed  Google Scholar 

  87. Anoro Ellipta Prescribing information. US Food and Drug Administration. 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203975s000lbl.pdf. Accessed 20 Jan 2018.

  88. Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med. 2013;107(10):1538–46.

    Article  CAS  PubMed  Google Scholar 

  89. Donohue JF, Niewoehner D, Brooks J, O’Dell D, Church A. Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study. Respir Res. 2014;15:78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rodrigo GJ, Neffen H. A systematic review of the efficacy and safety of a fixed-dose combination of umeclidinium and vilanterol for the treatment of COPD. Chest. 2015;148(2):397–407.

    Article  PubMed  Google Scholar 

  91. Matera MG, Rogliani P, Rinaldi B, Cazzola M. Umeclidinium bromide + vilanterol for the treatment of chronic obstructive pulmonary disease. Expert Rev Clin Pharmacol. 2015;8(1):35–41.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Duaklir Genuair summary of product characteristics. European Medicines Agency. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003745/WC500178413.pdf. Accessed 20 Jan 2018.

  94. Singh D, Jones PW, Bateman ED, et al. Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomized study. BMC Pulm Med. 2014;14:178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. D’Urzo AD, Rennard SI, Kerwin EM, et al. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study. Respir Res. 2014;15:123.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Bateman ED, Chapman KR, Singh D, et al. Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomized studies (ACLIFORM and AUGMENT). Respir Res. 2015;16:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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):1030–9.

    Article  CAS  PubMed  Google Scholar 

  98. Stiolto Respimat prescribing information. US Food and Drug Administration. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206756Orig1s000lbl.pdf. Accessed 20 Jan 2018.

  99. Buhl R, Maltais F, Abrahams R, et al. Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). Eur Respir J. 2015;45(4):969–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Farne HA, Cates CJ. Long-acting beta2-agonist in addition to tiotropium versus either tiotropium or long-acting beta2-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015;(10):CD008989.

  101. O’Donnell DE, Casaburi R, Frith P, et al. Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD. Eur Respir J. 2017;49(4):1601348.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Buhl R, Magder S, Bothner U, et al. Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease. Respir Med. 2017;122:58–66.

    Article  PubMed  Google Scholar 

  103. Calverley PMA, Anzueto AR, Carter K, et al. Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomized, parallel-group, active-controlled trial. Lancet Respir Med. 2018;6(5):337–344.

  104. Bogdan MA, Aizawa H, Fukuchi Y, et al. Efficacy and safety of inhaled formoterol 4.5 and 9 μg twice daily in Japanese and European COPD patients: phase III study results. BMC Pulm Med. 2011;11:51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Minakata Y, Iijima H, Takahashi T, et al. Efficacy and safety of formoterol in Japanese patients with COPD. Intern Med. 2008;47(4):217–23.

    Article  PubMed  Google Scholar 

  106. Hosoe M, Woessner R, Matsushima S, Lawrence D, Kramer B. Efficacy, safety and pharmacokinetics of indacaterol in Caucasian and Japanese patients with chronic obstructive pulmonary disease: a comparison of data from two randomized, placebo-controlled studies. Clin Drug Investig. 2011;31(4):247–55.

    Article  CAS  PubMed  Google Scholar 

  107. Kato M, Makita H, Uemura K, et al. Bronchodilator efficacy of single doses of indacaterol in Japanese patients with COPD: a randomized, double-blind, placebo-controlled trial. Allergol Int. 2010;59(3):285–93.

    Article  CAS  PubMed  Google Scholar 

  108. Yao W, Wang C, Zhong N, et al. Effect of once-daily indacaterol in a predominantly Chinese population with chronic obstructive pulmonary disease: a 26-week Asia–Pacific study. Respirology. 2014;19(2):231–8.

    Article  PubMed  Google Scholar 

  109. Kinoshita M, Lee SH, Hang LW, et al. Efficacy and safety of indacaterol 150 and 300 µg in chronic obstructive pulmonary disease patients from six Asian areas including Japan: a 12-week, placebo-controlled study. Respirology. 2012;17(2):379–89.

    Article  PubMed  Google Scholar 

  110. Yum HK, Kim HR, Chang YS, et al. Safety and effectiveness of indacaterol in chronic obstructive pulmonary disease patients in South Korea. Tuberc Respir Dis (Seoul). 2017;80(1):52–9.

    Article  Google Scholar 

  111. Kim CJ, Yoon HK, Park MJ, et al. Inhaled indacaterol for the treatment of COPD patients with destroyed lung by tuberculosis and moderate-to-severe airflow limitation: results from the randomized INFINITY study. Int J Chron Obstruct Pulmon Dis. 2017;12:1589–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. To Y, Kinoshita M, Lee SH, et al. Assessing efficacy of indacaterol in moderate and severe COPD patients: a 12-week study in an Asian population. Respir Med. 2012;106(12):1715–21.

    Article  PubMed  Google Scholar 

  113. Ichinose M, Takizawa A, Izumoto T, et al. Efficacy and safety of the long-acting β2-agonist olodaterol over 4 weeks in Japanese patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2015;10:1673–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Fukuchi Y, Fernandez L, Kuo HP, et al. Efficacy of tiotropium in COPD patients from Asia: a subgroup analysis from the UPLIFT trial. Respirology. 2011;16(5):825–35.

    Article  PubMed  Google Scholar 

  115. Ichinose M, Fujimoto T, Fukuchi Y. Tiotropium 5microg via Respimat and 18microg via HandiHaler; efficacy and safety in Japanese COPD patients. Respir Med. 2010;104(2):228–36.

    Article  CAS  PubMed  Google Scholar 

  116. Zhong N, Moon HS, Lee KH, et al. TIOtropium safety and performance in Respimat® (TIOSPIRTM): analysis of Asian cohort of COPD patients. Respirology. 2016;21(8):1397–403.

    Article  PubMed  Google Scholar 

  117. Tang Y, Massey D, Zhong NS. Evaluation of the efficacy and safety of tiotropium bromide (5 µg) inhaled via Respimat in Chinese patients with chronic obstructive pulmonary disease. Chin Med J (Engl). 2013;126(19):3603–7.

    CAS  Google Scholar 

  118. Zhou Y, Zhong NS, Li X, et al. Tiotropium in early-stage chronic obstructive pulmonary disease. N Engl J Med. 2017;377(10):923–35.

    Article  CAS  PubMed  Google Scholar 

  119. Lee SH, Lee J, Yoo KH, et al. Efficacy and safety of aclidinium bromide in patients with COPD: a phase 3 randomized clinical trial in a Korean population. Respirology. 2015;20(8):1222–8.

    Article  PubMed  Google Scholar 

  120. Sekiya M, Kawayama T, Fukuchi Y, et al. Safety and efficacy of NVA237 once daily in Japanese patients: the GLOW4 trial. Eur Respir J. 2012;40:P2103

    Google Scholar 

  121. Fukushima Y, Nakatani Y, Ide Y, et al. Randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of three doses of co-suspension delivery technology glycopyrronium MDI in Japanese patients with moderate-to-severe COPD. Int J Chron Obstruct Pulmon Dis. 2018;13:1187–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wang C, Sun T, Huang Y, et al. Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study. Int J Chron Obstruct Pulmon Dis. 2015;10:57–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Yamagata E, Soutome T, Hashimoto K, Mihara K, Tohda Y. Long-term (52 weeks) safety and tolerability of umeclidinium in Japanese patients with chronic obstructive pulmonary disease. Curr Med Res Opin. 2016;32(5):967–73.

    Article  CAS  PubMed  Google Scholar 

  124. Zhong N, Wang C, Zhou X, et al. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10:1015–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhong N, Wang C, Zhou X, et al. Efficacy and safety of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone in chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the chinese cohort from the LANTERN study. COPD. 2016;13(6):686–92.

    Article  PubMed  Google Scholar 

  126. Hashimoto S, Ikeuchi H, Murata S, et al. Efficacy and safety of indacaterol/glycopyrronium in Japanese patients with COPD: a subgroup analysis from the SHINE study. Int J Chron Obstruct Pulmon Dis. 2016;11:2543–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Asai K, Hirata K, Hashimoto S, et al. Efficacy and safety of indacaterol/glycopyrronium in Japanese patients with COPD: pooled analysis of SHINE and ARISE. Respir Investig. 2016;54(6):428–35.

    Article  PubMed  Google Scholar 

  128. Horita N, Kaneko T. Role of combined indacaterol and glycopyrronium bromide (QVA149) for the treatment of COPD in Japan. Int J Chron Obstruct Pulmon Dis. 2015;10:813–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rhee CK, Park HY, Park JW, et al. Efficacy and safety of indacaterol/glycopyrronium fixed-dose combination in mild-to-moderate COPD patients symptomatic on tiotropium in Korea: study protocol for a randomized controlled trial. Trials. 2017;18(1):80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Wedzicha JA, Zhong N, Ichinose M, et al. Indacaterol/glycopyrronium versus salmeterol/fluticasone in Asian patients with COPD at a high risk of exacerbations: results from the FLAME study. Int J Chron Obstruct Pulmon Dis. 2017;12:339–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zheng J, Zhong N, Newlands A, et al. Efficacy and safety of once-daily inhaled umeclidinium/vilanterol in Asian patients with COPD: results from a randomized, placebo-controlled study. Int J Chron Obstruct Pulmon Dis. 2015;10:1753–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ichinose M, Kato M, Takizawa A, et al. Long-term safety and efficacy of combined tiotropium and olodaterol in Japanese patients with chronic obstructive pulmonary disease. Respir Investig. 2017;55(2):121–9.

    Article  PubMed  Google Scholar 

  133. Ichinose M, Taniguchi H, Takizawa A, et al. The efficacy and safety of combined tiotropium and olodaterol via the Respimat® inhaler in patients with COPD: results from the Japanese sub-population of the Tonado® studies. Int J Chron Obstruct Pulmon Dis. 2016;11:2017–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Bai C, Ichinose M, Lee SH, et al. Lung function and long-term safety of tiotropium/olodaterol in East Asian patients with chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2017;12:3329–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ichinose M, Minakata Y, Motegi T, et al. Efficacy of tiotropium/olodaterol on lung volume, exercise capacity, and physical activity. Int J COPD. 2018;13:1407–19.

    Article  CAS  Google Scholar 

  136. Ichinose M, Nishimura M, Akimoto M, et al. Tiotropium/olodaterol versus tiotropium in Japanese patients with COPD: results from the DYNAGITO study. Int J Chron Obstruct Pulmon Dis. 2018;13:2147–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 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;378(18):1671–80.

    Article  CAS  PubMed  Google Scholar 

  138. Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomized controlled trial. Lancet. 2018;391(10125):1076–84.

    Article  CAS  PubMed  Google Scholar 

  139. Agusti A. Filling the gaps in COPD: the TRIBUTE study. Lancet. 2018;391(10125):1004–6.

    Article  PubMed  Google Scholar 

  140. Chapman KR, Hurst JR, Frent SM, et al. Long-term triple therapy de-escalation to indacaterol/glycopyrronium in COPD patients (SUNSET): a randomized, double-blind, triple-dummy clinical trial. Am J Respir Crit Care Med. 2018;198(3):329–39.

    Article  CAS  PubMed  Google Scholar 

  141. ClinicalTrials.gov number NCT02465567. https://clinicaltrials.gov/ct2/show/NCT02465567. Accessed 20 Jan 2018.

  142. Lim JU, Lee JH, Kim JS, et al. Comparison of World Health Organization and Asia-Pacific body mass index classifications in COPD patients. Int J Chron Obstruct Pulmon Dis. 2017;12:2465–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet. 2009;374(9691):733–43.

    Article  PubMed  Google Scholar 

  144. Rhee CK. High prevalence of chronic obstructive pulmonary disease in Korea. Korean J Intern Med. 2016;31(4):651–2.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Martinez FD. Early-life origins of chronic obstructive pulmonary disease. N Engl J Med. 2016;375(9):871–8.

    Article  PubMed  Google Scholar 

  146. Rhee CK, Yoo KH, Lee JH, et al. Clinical characteristics of patients with tuberculosis-destroyed lung. Int J Tuberc Lung Dis. 2013;17(1):67–75.

    Article  CAS  PubMed  Google Scholar 

  147. Hwang YI, Kim JH, Lee CY, et al. The association between airflow obstruction and radiologic change by tuberculosis. J Thorac Dis. 2014;6(5):471–6.

    PubMed  PubMed Central  Google Scholar 

  148. Tatsumi K, Kasahara Y, Kurosu K, et al. Clinical phenotypes of COPD: results of a Japanese epidemiological survey. Respirology. 2004;9(3):331–6.

    Article  PubMed  Google Scholar 

  149. Lee HY, Kim JW, Lee SH, et al. Lower diffusing capacity with chronic bronchitis predicts higher risk of acute exacerbation in chronic obstructive lung disease. J Thorac Dis. 2016;8(6):1274–82.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Ko FW, Tam W, Wong TW, et al. Temporal relationship between air pollutants and hospital admissions for chronic obstructive pulmonary disease in Hong Kong. Thorax. 2007;62(9):780–5.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Kim C, Yoo KH, Rhee CK, et al. Health care use and economic burden of patients with diagnosed chronic obstructive pulmonary disease in Korea. Int J Tuberc Lung Dis. 2014;18(6):737–43.

    Article  CAS  PubMed  Google Scholar 

  152. Lee J, Lee JH, Kim JA, Rhee CK. Trend of cost and utilization of COPD medication in Korea. Int J Chron Obstruct Pulmon Dis. 2016;12:27–33.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Funding

The preparation of this manuscript and the journal’s article processing charges were funded by Novartis Pharma K.K.

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All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Chin Kook Rhee received consulting and lecture fees from MSD, AstraZeneca, Novartis, GSK, Takeda, Mundipharma, Sandoz, Boehringer Ingelheim and Teva-Handok. Hajime Yoshisue is an employee of Novartis. Rahul Lad is an employee of Novartis.

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This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

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Rhee, C.K., Yoshisue, H. & Lad, R. Fixed-Dose Combinations of Long-Acting Bronchodilators for the Management of COPD: Global and Asian Perspectives. Adv Ther 36, 495–519 (2019). https://doi.org/10.1007/s12325-019-0893-3

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Keywords

  • Asia
  • Chronic obstructive pulmonary disease
  • Fixed-dose combination
  • Formoterol/aclidinium
  • Indacaterol/glycopyrronium
  • Long-acting β-agonists
  • Long-acting muscarinic antagonists
  • Olodaterol/tiotropium
  • Vilanterol/umeclidinium