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      Clinical benefit of fixed-dose dual bronchodilation with glycopyrronium and indacaterol once daily in patients with chronic obstructive pulmonary disease: a systematic review

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          Abstract

          Background and aim

          Long-acting bronchodilators are the preferred option for maintenance therapy of patients with chronic obstructive pulmonary disease (COPD). The aim of this review is to provide an overview of the clinical studies evaluating the clinical efficacy of the once-daily fixed-dose dual bronchodilator combination of indacaterol and glycopyrronium bromide in patients suffering from COPD.

          Methods

          This study comprised a systematic review of randomized controlled trials identified through systematic searches of different databases of published trials.

          Results

          Nine trials (6,166 participants) were included. Fixed-dose once-daily indacaterol/glycopyrronium seems to be safe and well tolerated in patients with COPD. Compared with single therapy with other long-acting bronchodilators (indacaterol, glycopyrronium, and tiotropium) and fixed-combination long-acting β 2-agonist/inhaled corticosteroid (salmeterol/fluticasone twice daily), once-daily fixed-dose indacaterol/glycopyrronium has clinically important effects on symptoms, including dyspnea score, health status, level of lung function, and rate of moderate or severe exacerbations in patients with moderate-to-very severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] spirometric criteria). Furthermore, a very recent study has shown that fixed-dose indacaterol/glycopyrronium improves exercise endurance time compared with placebo, although no significant difference was observed between fixed-dose indacaterol/glycopyrronium and tiotropium.

          Conclusion

          Fixed-dose indacaterol/glycopyrronium has clinically relevant effects on important COPD outcome measures and is, in general, superior to therapy with a single long-acting bronchodilator (with or without inhaled corticosteroid) indicating long-acting dual bronchodilation as a potential important maintenance therapeutic option for patients with symptomatic COPD, possibly also for the treatment of naïve patients.

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          Most cited references 25

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          Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.

           W MacNee,  ,  B Celli (2004)
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            Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study

            Introduction Bronchodilators are the cornerstone of symptomatic management of chronic obstructive pulmonary disease (COPD) [1]. Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate-to-very-severe COPD [1]. The use of two bronchodilators with different mechanisms of action has been shown to provide additional benefits compared with either given alone, without significantly increasing side-effects [2, 3]. Both indacaterol, a long-acting β2-agonist (LABA), and tiotropium, a long-acting muscarinic antagonist (LAMA), are effective as monotherapies and have acceptable safety profiles [4, 5]. In addition, their concurrent use has been shown to provide superior bronchodilation and improvement in air trapping compared with tiotropium alone [6]. Glycopyrronium (NVA237) is a recently approved once-daily LAMA for the treatment of moderate-to-severe COPD, and has been shown to provide rapid and sustained improvements in lung function, dyspnoea, health status, exercise endurance and exacerbation risk, with improvements similar to tiotropium and a safety profile similar to placebo [7–9]. QVA149 is a novel once-daily dual bronchodilator containing a fixed dose of the LABA indacaterol with the LAMA glycopyrronium. In patients with COPD, QVA149 has demonstrated rapid and sustained bronchodilation, which is significantly superior to that observed with indacaterol alone or placebo, and it is well tolerated, with an adverse event profile similar to placebo [10, 11]. In the current SHINE study, we sought to confirm the “rule of combination” [12] that dual bronchodilation with QVA149 will provide additional therapeutic benefits compared to the monocomponents indacaterol and glycopyrronium, as well as compared to tiotropium, the current gold standard of care, and placebo in patients with moderate-to-severe COPD. Methods Study design The study was a multicentre, randomised, double-blind, parallel-group, placebo- and active-controlled 26-week trial, and comprised a washout, run-in and the 26-week treatment period, with 30 days of follow-up after the last visit (fig. 1). The first patient’s first visit was September 21, 2010, and the last patient’s last visit was February 10, 2012. Patients receiving fixed-dose combinations of LABA/inhaled corticosteroid (ICS) were switched to an equivalent dose of ICS monotherapy. After screening, eligible patients were randomised in a 2:2:2:2:1 ratio (via interactive response technology) to treatment with double-blind QVA149 (indacaterol 110 μg/glycopyrronium 50 μg), indacaterol 150 μg, glycopyrronium 50 μg, open-label tiotropium 18 μg or placebo. All medications were administered once daily in the morning via the Breezhaler® (Novartis Pharma AG, Stein, Switzerland) device except for tiotropium, which was administered via the HandiHaler® (Boehringer Ingelheim, Ingelheim, Germany) device. A salbutamol/albuterol pressurised metered-dose inhaler was provided as rescue medication. Additional details of the study design and randomisation/blinding procedures are included in the online supplementary material. Figure 1– The SHINE study design. Patients Participants were aged ≥40 years, had moderate-to-severe stable COPD (stage II or III according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2008 criteria [13]) and a smoking history of ≥10 pack-years. At screening, they were required to have a post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥30% and 100 mL or >200 mL in trough FEV1 at week 26). Figure 3– Trough forced expiratory volume in 1 s (FEV1) a) at week 26 and b) over the entire 26-week treatment period. a) Data are presented as least squares mean±se. One-sided adjusted p-values are presented for comparisons in the statistical gatekeeping procedure and two-sided p-values are presented for all other comparisons. b) QVA149 was superior to all active treatments and placebo at all timepoints (all p 30 days after the last dose of study drug but before the end of the follow-up visit (indacaterol (n = 1): pneumonia and glycopyrronium (n = 1): colon cancer). None of the deaths were considered by the investigator to be related to the study drug. Discussion Combining two bronchodilators with different mechanisms of action has the potential to enhance efficacy compared with single agents without increasing adverse effects [2, 3]. In the SHINE study, dual bronchodilation with QVA149, administered once-daily, provided superior improvements in lung function compared with its monocomponents indacaterol and glycopyrronium given alone, as well as tiotropium and placebo. Improvement in the primary end-point, trough FEV1 was both statistically and clinically significant (considered to be ≥100 mL in COPD) over placebo, and versus active comparators it approached clinical significance. Furthermore, lung function improvements with QVA149 were superior at their peak and, in a subset of patients monitored over 24 h, throughout the day. Similar trends to the overall population were observed in subgroup analyses. Improvements in lung function versus placebo were greater in patients with moderate versus severe COPD; however, statistically and clinically significant improvements in trough FEV1 were seen for both moderate and severe patient subgroups. Improvements in lung function were not influenced by patient age, sex or concurrent use of ICS. Furthermore, they were maintained throughout the 26-week treatment period, and the onset of action of QVA149 was confirmed to be rapid, similar to that of a short-acting β2-agonist. These beneficial effects of QVA149 on lung function were paralleled by statistically significant improvements in other clinically important end-points: dyspnoea, health status and patient symptoms and reduced rescue medication use. QVA149 was significantly superior to placebo and tiotropium for both the TDI and SGRQ total score at week 26; no other active treatment achieved a significant improvement in SGRQ versus placebo. Furthermore, a significantly higher proportion of patients on QVA149 achieved a clinically meaningful improvement in TDI (≥1 unit) and SGRQ (≥4 units) versus placebo and tiotropium. QVA149 was well tolerated over the 26-week study with an adverse event profile similar to that of placebo. In addition, no actual or potential safety signals were observed with the combination compared with the single bronchodilators. Despite previous concerns that LABAs and LAMAs may present a risk of cardiovascular events [14–17], the CCV safety profile of this LABA/LAMA combination was similar to that of placebo. The results of this study are consistent with those of several published studies that have investigated the efficacy and safety of free combinations of LABAs and LAMAs in patients with COPD [6, 18–20], but this is the first to demonstrate the additive benefit of the two classes of long-acting bronchodilator in a combination device. Previous studies have been limited by different durations of actions of the LAMA and LABA components (i.e. formoterol or salmeterol having to be administered twice daily). Our study confirms that the additive benefit of indacaterol and glycopyrronium persists over 24 h, without tachyphylaxis, providing further support for the use of dual bronchodilators. The present study supports the GOLD 2013 strategy alternative choice recommendation that the addition of a second bronchodilator in patients with moderate-to-severe COPD (groups B–D) may optimise symptom benefit [1]. In “low-risk” patients who remain symptomatic on a single bronchodilator (group B), the combination of indacaterol plus glycopyrronium in a single inhaler may lead to significantly improved outcomes compared with LABA or LAMA monotherapy. In “high-risk” patients with severe or very severe COPD (high symptom level and historical exacerbation frequency; groups C and D in the GOLD management strategy [1]) a LABA plus a LAMA is recommended as an alternative to a LABA/ICS combination (group C) or ICS plus LABA and/or LAMA (group D). In comparing LABA plus LAMA and LABA/ICS combination, improvements in lung function achieved with two bronchodilators are expected to be numerically superior to the single bronchodilator in LABA/ICS combinations. In the TORCH (Towards a Revolution in COPD Health) study, combination therapy achieved 50 mL and 44 mL improvement in FEV1 versus salmeterol and fluticasone propionate alone, respectively; however, the LABA/ICS combination is selected for its demonstrated effect on COPD exacerbations [21]. A real-world analysis has indicated that a high proportion of patients at low risk for exacerbations (groups A or B) may be receiving ICS inappropriately [22]. Some patients currently receiving combined LABA/ICS may do better on a LABA/LAMA combination [23]. This would provide dual bronchodilation without the need for ICS treatment, and therefore without the inherent risks of ICS [24], as recommended by the GOLD 2013 strategy [1]. The 26-week ILLUMINATE study supports the use of QVA149 versus LABA/ICS in this population [25]. QVA149 once daily was associated with significant improvements in lung function and dyspnoea versus twice-daily salmeterol/fluticasone. Furthermore, the current SHINE study provides evidence for the additive benefit and safety of a LABA/LAMA combination, demonstrating that QVA149 is superior for most end-points over tiotropium, which is currently recommended as an alternative to LABA/ICS combination, alone or in combination with a LABA. Features of QVA149 that may help to reduce nonadherence to treatment, which remains high in COPD [26], are the convenience of once-daily dosing [27] which is generally preferred by patients [26, 28, 29] and the need for only a single inhaler. Furthermore, the rapid onset of action may be evident to patients as they wake at the nadir of their daily lung function cycle when symptoms are most prominent [30]. However, these advantages of a LABA/LAMA combination and QVA149 are speculative and need to be tested in further prospective studies. We acknowledge several limitations in our study. Firstly, with regards to the study population, we did not intend to include the full range of COPD severities that might benefit from dual long-acting bronchodilators. Since our main objective was to assess the incremental benefit of two bronchodilators in combination (versus one), we elected to recruit only patients with moderate-to-severe COPD. As in our study, results of studies involving LABA/ICS combinations (e.g. the TORCH study [21]) and tiotropium (e.g. the UPLIFT study [31]), have confirmed that patients with moderate disease showed the greatest improvements in lung function. The apparent high reversibility of FEV1 (20%) is attributable to the fact that both salbutamol and ipratropium were administered during this test, and reversibility of this magnitude is not unusual in moderate COPD. We went to lengths to exclude patients with asthma (inclusion criteria: age of onset of symptoms >40 years, absence of rhinitis and blood eosinophil count of <600 cells·mm−3 (see the online supplementary material)). Finally, unlike most COPD studies, which enrich for patients with exacerbations, in our study we excluded patients with a recent COPD exacerbation (in the previous 6 weeks) to reduce the impact of withdrawal due to exacerbations on the primary spirometric end-point. For this reason, along with the fact that patients had milder disease and the study was relatively short (6 months), the present study does not provide useful information on the effect of QVA149 on COPD exacerbations, which has been examined in studies of appropriate design (SPARK study [32]). A further limitation of our study is the difficulty in evaluating the clinical significance of spirometric and other clinical end-points (TDI and SGRQ) versus active (monocomponent) treatments. Although statistically superior to all monocomponents, QVA149 attained the MCID for only some comparisons (fig. 3 and online supplementary table S3). However, it should be noted that the MCID for a trough FEV1 of 100 mL is generally used for comparisons versus placebo, and that the mean improvements of 70, 80 and 90 mL versus indacaterol, glycopyrronium and tiotropium, respectively, approach this threshold value; comparative data for TDI and SGRQ also support this trend. In conclusion, once-daily QVA149 demonstrated superior efficacy compared with placebo, its monocomponents indacaterol and glycopyrronium, and the current standard of care (tiotropium) in patients with moderate-to-severe COPD. QVA149 was also associated with an adverse event profile that was similar to placebo with no additional safety signal compared with monotherapies. This is the first study to demonstrate the advantage of dual bronchodilation with a fixed-dose LABA/LAMA combination, compared with a single bronchodilator in patients with moderate-to-severe COPD.
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              Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.

              QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease (COPD). It combines indacaterol (a longacting β2-agonist) with glycopyrronium (a longacting muscarinic antagonist) as a dual bronchodilator. We aimed to compare the efficacy, safety, and tolerability of QVA149 versus salmeterol-fluticasone (SFC) over 26 weeks in patients with moderate-to-severe COPD. In this multicentre double-blind, double-dummy, parallel-group study, 523 patients (age 40 years or older, Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages II-III, without exacerbations in the previous year) were randomly assigned (1:1; via automated, interactive response technology and stratified for smoking status) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks. Efficacy was assessed in the full analysis set (randomised patients who received at least one dose of study drug); safety was assessed in all patients who received at least one dose of study drug. The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the standardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second (FEV1 AUC0-12h) after 26 weeks of treatment. This trial was registered at ClinicalTrial.gov, NCT01315249. Between March 25, 2011, and March 12, 2012, 259 patients were randomly assigned to receive QVA149 and 264 to receive SFC. At week 26, FEV1 AUC0-12h was significantly higher with QVA149 than with SFC (treatment difference 0·138 L; 95% CI 0·100-0·176; p<0·0001). Overall incidence of adverse events (including COPD exacerbations) was 55·4% (143 of 258) for the QVA149 group and 60·2% (159 of 264) for the SFC group. Incidence of serious adverse events was similar between treatment groups (QVA149, 13 of 258 [5·0%]; SFC 14 of 264 [5·3%]); COPD worsening was the most frequent serious adverse event (one of 13 [0·4%] and three of 14 [1·1%], respectively). Once-daily QVA149 provides significant, sustained, and clinically meaningful improvements in lung function versus twice-daily SFC, with significant symptomatic benefit. These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients. Novartis Pharma AG. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2014
                01 April 2014
                : 9
                : 331-338
                Affiliations
                Department of Respiratory Medicine, Hvidovre Hospital and University of Copenhagen, Hvidovre, Denmark
                Author notes
                Correspondence: Charlotte Suppli Ulrik, Department of Respiratory Medicine 253, Hvidovre Hospital, DK-2650 Hvidovre, Denmark, Email csulrik@ 123456dadlnet.dk
                Article
                copd-9-331
                10.2147/COPD.S60362
                3979690
                24729699
                © 2014 Ulrik. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Respiratory medicine

                indacaterol, glycopyrronium, long-acting bronchodilators, copd

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